Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

Lee, Doohyun; Kim, Daehun; Lee, Seungyeon; Kim, Taegeum; Kim, Joobin; Kim, Sohee; Liu, Kwang-Hyeon; Lee, Sangkyu; Bae, Jong-Sup; Song, Kyung-Sik; Cho, Chang-Woo; Son, Youn Kyung; Baek, Dong Jae; Lee, Taeho

doi:10.3390/molecules201119673

Open AccessArticle

Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

by

Doohyun Lee

¹,

Daehun Kim

¹,

Seungyeon Lee

¹,

Taegeum Kim

¹,

Joobin Kim

¹,

Sohee Kim

¹,

Kwang-Hyeon Liu

¹,

Sangkyu Lee

¹,

Jong-Sup Bae

¹,

Kyung-Sik Song

¹,

Chang-Woo Cho

²,

Youn Kyung Son

³,

Dong Jae Baek

^4,* and

Taeho Lee

^1,*

¹

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea

²

Department of Chemistry, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea

³

National Institute of Biological Resources, Hwangyeong-ro 42, Seo-gu, Incheon 404-708, Korea

⁴

College of Pharmacy, Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-ro, Muan-gun, Jeonnam 534-729, Korea

^*

Authors to whom correspondence should be addressed.

Molecules 2015, 20(11), 19984-20013; https://doi.org/10.3390/molecules201119673

Submission received: 16 September 2015 / Revised: 28 October 2015 / Accepted: 29 October 2015 / Published: 5 November 2015

(This article belongs to the Collection Heterocyclic Compounds)

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Abstract

:

Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; S_N2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity points in excellent overall yields and purities using the reported solid- and solution-phase synthetic routes, respectively.

Keywords:

1,2,3-triazoloamide; solid-phase synthesis; solution-phase synthesis

Graphical Abstract

1. Introduction

Combinatorial chemistry has emerged as a powerful technique for the synthesis of biologically active small molecules for the purpose of medicinal chemistry programs within the pharmaceutical industry [1,2,3,4,5]. Recently, the 1,2,3-triazole moiety, produced by Cu(I)-catalyzed [3 + 2] cycloaddition reactions, has been used as a scaffold for generating combinatorial libraries [6,7,8,9,10]. 1,2,3-Triazoles can mimic the topological and electronic features of an amide bond, and this be used as bioisosteres of the amide moiety. They are particularly stable to reduction, oxidation, and hydrolysis conditions.

Various α-1,2,3-triazoloamide derivatives have been shown to exhibit a wide range of biological activities [11,12,13,14,15,16,17,18,19]. In recent examples, α-1,2,3-triazoloamide related compounds have been developed and studied as tropomysin receptor kinase A (TrkA) inhibitors [11], as inhibitors of Mycobacterium tuberculosis [12], as phosphodiesterase 4B (PDE4B) inhibitor for anticancer agents [13], as quorum sensing modulators [14], as β-haematin inhibitors for antimalarial agents [15], as γ-secretase modulators [16], as protein tyrosine phosphatase (PTPs) inhibitors [17], as lymphoid tyrosin phosphatase (Lyp, PTPN22) inhibitors [18], and as glucokinase (GK) acitvators [19].

Previously, we have reported a solid-phase synthetic protocol for the preparation of secondary α-1,2,3-triazoloamides 1 (R² = H, Figure 1) [20]. However, an expanded α-1,2,3-triazoloamide library was needed for our drug discovery project, which includes the secondary and tertiary 1,2,3-triazoloamides. Herein, we describe the construction of expanded libraries of secondary α-1,2,3-triazoloamides 1 on solid-phase and of tertiary 1,2,3-triazoloamides 2 in parallel solution-phase, which is applicable to high-throughput construction of drug-like compound libraries.

Figure 1. Structure and use of 1,2,3-triazoloamides 1 and 2.

2. Results and Discussion

The synthetic sequence for secondary α-1,2,3-triazoloamides 1 (R² = H) is shown in Scheme 1 [20]. According to the solid-phase synthetic approach with the polymer-bound amines 3, which were prepared by reductive amination reaction from Acid sensitive Methoxy Benzaldehyde (AMEBA) [20,21] resin 4 and primary amines 5 (the first diversity element R¹; Figure 2), polymer-bound chloroamides 7 can be easily prepared by the reaction of amine resin 3 with chloro-acid chloride 6 (the second diversity element A; Figure 3) and triethylamine in CH₂Cl₂ at room temperature. Treatment of solid supported chloroamides 7 (R = Cl, A = CH₂ or CHCH₃) with sodium azide in DMF at room temperature, provides the α-azidoamide resin 8 (R = N₃).

Scheme 1. Solid-phase synthesis of secondary α-1,2,3-triazoloamide derivatives 1.

Figure 2. Diversity reagents 5 for secondary α-1,2,3-triazoloamides 1.

Figure 3. Diversity reagents 6 for 1,2,3-triazoloamides 1 and 2.

In the case of β-chloroamide 7ac, which was prepared by the reaction of amine resin 3a and 3-chloropropionyl chloride (6c), the S_N2 reaction with sodium azide gave the undesired acrylamide 12 because of an elimination of β-chloroamide (Scheme 2). The reaction was confirmed by ATR-FTIR analysis of resin 11 and the cleavage of the resin 11 under 30% TFA in CH₂Cl₂ at room temperature provided an N-phenylacrylamide (12) [22,23] as a major product.

Scheme 2. Reaction of amine resin 3a and 3-chloropropionyl chloride (6c).

The selective [3 + 2] Hüisgen cycloaddition [24,25,26,27,28,29] was performed with α-azidoamide resin 8 and terminal acetylene 9 (the third diversity element R³; Figure 4) according to optimized reaction condition (3 equiv. CuI, 3 equiv. sodium ascorbate, DMF/piperidine (4:1), room temperature) [20]. The well-known methods for the synthesis of 1,2,3-triazoles (catalytic CuSO₄/sodium ascorbate or CuI/diisopropylethylamine as reagents and H₂O/t-BuOH, EtOH, or THF as solvent) were not very efficient. Under the general cleavage conditions of AMEBA resin (30% TFA, CH₂Cl₂, room temperature), the resulting polymer-bound product 10aaa gave the desired α-1,2,3-triazoloamide 1aaa (44%) and by-product 13 (30%), while unreacted resin 10aaa remained as was confirmed by ATR-FTIR analysis (Scheme 3).

Figure 4. Diversity reagents 9 for 1,2,3-triazoloamides 1 and 2.

Scheme 3. Cleavage of α-1,2,3-triazoloamide resin 10aaa.

Finally, the α-1,2,3-triazoloamide resin 10aaa was cleaved from the solid support under 30% TFA in CH₂Cl₂ at 45 °C to provide the desired α-1,2,3-triazoloamide 1aaa [24,27,30] (93% over six steps, from Merrifield resin) without formation of by-product 13.

The reaction progress on solid-phase was monitored by ATR-FTIR (Figure 5). The progress of reductive amination of AMEBA resin 4 and amine 5a (R¹ = Ph) was checked by the appearance of the weak NH stretching band at 3424 cm⁻¹ and the disappearance of the aldehyde stretching band at 1678 cm⁻¹. The progression of amide formation for 7aa (R¹ = Ph, A = CH₂) was monitored by ATR-FTIR which displayed the disappearance of the characteristic NH band at 3424 cm⁻¹ and appearance of the amide carbonyl stretching band at 1666 cm⁻¹. The S_N2 reaction of 7aa (R¹ = Ph, A = CH₂) with sodium azide was monitored by the appearance of the azide stretching band at 2101 cm⁻¹. The completion of selective [3 + 2] Hüisgen cycloaddition of 7aa and 9a was confirmed by the disappearance of the azide stretching band.

Figure 5. ATR-FTIR spectra of resins 3, 4, 7, 8 and 10 (R¹ = R² = Ph, A = CH₂).

Table 1. Prepared secondary α-1,2,3-triazoloamide derivatives 1 ^a. Molecules 20 19673 i001

**Table 1.** Prepared secondary α-1,2,3-triazoloamide derivatives 1 ^a.
Entry	Products	R¹	A	R³	Yield (%) ^b	Entry	Products	R¹	A	R³	Yield (%) ^b
1	1aaa	Ph	CH₂	Ph	93	41	1dan	2-MeO-Ph	CH₂	2,4-di-F-Ph	94
2	1aab	Ph	CH₂	4-MeO-Ph	91	42	1dao	2-MeO-Ph	CH₂	Bn	88
3	1aac	Ph	CH₂	4-CN-Ph	83	43	1eaa	n-Bu	CH₂	Ph	81
4	1aad	Ph	CH₂	3-thiophenyl	82	44	1eab	n-Bu	CH₂	4-MeO-Ph	88
5	1aae	Ph	CH₂	2-pyridyl	85	45	1eac	n-Bu	CH₂	4-CN-Ph	83
6	1aaf	Ph	CH₂	n-Bu	92	46	1ead	n-Bu	CH₂	3-thiophenyl	80
7	1baa	4-MeO-Ph	CH₂	Ph	92	47	1eae	n-Bu	CH₂	2-pyridyl	89
8	1bab	4-MeO-Ph	CH₂	4-MeO-Ph	94	48	1eaf	n-Bu	CH₂	n-Bu	89
9	1bac	4-MeO-Ph	CH₂	4-CN-Ph	89	49	1faa	i-Pr	CH₂	Ph	79
10	1bad	4-MeO-Ph	CH₂	3-thiophenyl	85	50	1fab	i-Pr	CH₂	4-MeO-Ph	87
11	1bag	4-MeO-Ph	CH₂	3-MeO-Ph	87	51	1fac	i-Pr	CH₂	4-CN-Ph	75
12	1baj	4-MeO-Ph	CH₂	3-Me-Ph	89	52	1fad	i-Pr	CH₂	3-thiophenyl	77
13	1bak	4-MeO-Ph	CH₂	2-Me-Ph	84	53	1fae	i-Pr	CH₂	2-pyridyl	84
14	1bal	4-MeO-Ph	CH₂	4-NMe₂-Ph	79	54	1faf	i-Pr	CH₂	n-Bu	83
15	1bam	4-MeO-Ph	CH₂	4-PhO-Ph	92	55	1dba	2-MeO-Ph	CHCH₃	Ph	88
16	1ban	4-MeO-Ph	CH₂	2,4-di-F-Ph	87	56	1dbb	2-MeO-Ph	CHCH₃	4-MeO-Ph	91
17	1bao	4-MeO-Ph	CH₂	Bn	85	57	1dbc	2-MeO-Ph	CHCH₃	4-CN-Ph	87
18	1caa	3-MeO-Ph	CH₂	Ph	91	58	1dbd	2-MeO-Ph	CHCH₃	3-thiophenyl	80
19	1cab	3-MeO-Ph	CH₂	4-MeO-Ph	90	59	1dbe	2-MeO-Ph	CHCH₃	2-pyridyl	83
20	1cac	3-MeO-Ph	CH₂	4-CN-Ph	87	60	1dbg	2-MeO-Ph	CHCH₃	3-MeO-Ph	94
21	1cad	3-MeO-Ph	CH₂	3-thiophenyl	76	61	1dbh	2-MeO-Ph	CHCH₃	2-MeO-Ph	89
22	1cae	3-MeO-Ph	CH₂	2-pyridyl	81	62	1dbi	2-MeO-Ph	CHCH₃	4-Me-Ph	94
23	1cah	3-MeO-Ph	CH₂	2-MeO-Ph	83	63	1dbj	2-MeO-Ph	CHCH₃	3-Me-Ph	83
24	1caj	3-MeO-Ph	CH₂	3-Me-Ph	93	64	1dbk	2-MeO-Ph	CHCH₃	2-Me-Ph	74
25	1cak	3-MeO-Ph	CH₂	2-Me-Ph	90	65	1dbl	2-MeO-Ph	CHCH₃	4-NMe₂-Ph	82
26	1cal	3-MeO-Ph	CH₂	4-NMe₂-Ph	91	66	1dbm	2-MeO-Ph	CHCH₃	4-PhO-Ph	87
27	1cam	3-MeO-Ph	CH₂	4-PhO-Ph	91	67	1dbn	2-MeO-Ph	CHCH₃	2,4-di-F-Ph	92
28	1can	3-MeO-Ph	CH₂	2,4-di-F-Ph	92	68	1dbo	2-MeO-Ph	CHCH₃	Bn	86
29	1cao	3-MeO-Ph	CH₂	Bn	88	69	1eba	n-Bu	CHCH₃	Ph	83
30	1daa	2-MeO-Ph	CH₂	Ph	94	70	1ebb	n-Bu	CHCH₃	4-MeO-Ph	81
31	1dab	2-MeO-Ph	CH₂	4-MeO-Ph	90	71	1ebc	n-Bu	CHCH₃	4-CN-Ph	79
32	1dac	2-MeO-Ph	CH₂	4-CN-Ph	86	72	1ebd	n-Bu	CHCH₃	3-thiophenyl	78
33	1dad	2-MeO-Ph	CH₂	3-thiophenyl	91	73	1ebe	n-Bu	CHCH₃	2-pyridyl	84
34	1dae	2-MeO-Ph	CH₂	2-pyridyl	84	74	1ebf	n-Bu	CHCH₃	n-Bu	81
35	1dag	2-MeO-Ph	CH₂	3-MeO-Ph	86	75	1fba	i-Pr	CHCH₃	Ph	88
36	1dah	2-MeO-Ph	CH₂	2-MeO-Ph	80	76	1fbb	i-Pr	CHCH₃	4-MeO-Ph	83
37	1dai	2-MeO-Ph	CH₂	4-Me-Ph	78	77	1fbc	i-Pr	CHCH₃	4-CN-Ph	78
38	1daj	2-MeO-Ph	CH₂	3-Me-Ph	85	78	1fbd	i-Pr	CHCH₃	3-thiophenyl	75
39	1dal	2-MeO-Ph	CH₂	4-NMe₂-Ph	88	79	1fbe	i-Pr	CHCH₃	2-pyridyl	81
40	1dam	2-MeO-Ph	CH₂	4-PhO-Ph	92	80	1fbf	i-Pr	CHCH₃	n-Bu	82

^a All reactions were performed on 150–200 mg scale of resin 10 and the purities of compounds 1 were over 95% as judged from LC-MS traces (integration of diode array 200–400 nm traces); ^b Six-step overall yield from Merrifield resin (loading capacity = 0.94 mmol/g).

Following the optimized solid-phase synthetic route, the secondary α-1,2,3-triazoloamide derivatives 1 were prepared starting from Merrifield resin and appropriate primary amines 5 (R¹NH₂; Figure 2), α-chloroacetyl chlorides 6a and 6b (Cl-A-COCl; Figure 3), and terminal acetylenes 9 (R³C≡CH; Figure 4) and the products displayed in Table 1. In most cases, secondary α-1,2,3-triazoloamide derivatives 1 (80 examples) were obtained with high yields (94%–75%) and high purities, >95% as judged from LC-MS traces (integration of 200–400 nm diode array traces).

With a successful synthetic route for secondary α-1,2,3-triazoloamides 1, the stage progressed to the tertiary 1,2,3-triazoloamides 2 (R² ≠ H) (Scheme 4). The chloroamides 15 [31,32,33,34,35,36,37] were prepared from the reaction of secondary amines 14 (the first diversity elements R¹ and R²; Figure 6) and chloro-acid chlorides 6a and 6c (the second diversity element A; see Figure 3) with triethylamine in CH₂Cl₂ at room temperature (99%–92% yields). Followed by S_N2 reaction of tertiary amides 15 with sodium azide to generated the corresponding azidoamides 16 [15,17,38,39,40,41] in high yields (99%–94% yields) (Figure 7). In contrast to the solid-phase synthesis of secondary 1,2,3-triazoloamides 1, treatment of tertiary β-chloroamide 15ac with sodium azide in DMF at room temperature, provided the corresponding β-azidoamide 16ac in high yield (94% yield) without formation of the undesired acrylamide. Under the general conditions [6,7,8,9,10,24,25,26,27,28] of the Cu-catalyzed 1,3-dipolar cycloaddition (catalytic CuSO₄/sodium ascorbate) of azidoamide 16aa and terminal acetylene 9a in H₂O/t-BuOH, the desired tertiary 1,2,3-triazoloamide 2aaa is generated in high yield (96%).

Scheme 4. Solution-phase synthesis of tertiary 1,2,3-triazoloamide derivatives 2.

Figure 6. Diversity reagents 14 for tertiary 1,2,3-triazoloamides 2.

Figure 7. Prepared tertiary amides 15 and sodium azidoamide 16.

By using the parallel solution-phase synthetic route, we were able to prepare a number of tertiary 1,2,3-triazoloamide derivatives 2 displayed in Table 2 starting from appropriate secondary amines 14 (R¹R²NH; Figure 6), chloro-acid chlorides 6a and 6c (Cl-A-COCl; Figure 3), and terminal acetylenes 9 (R³C≡CH; Figure 4). In most cases, tertiary 1,2,3-triazoloamide derivatives 1T (80 examples) were obtained with high yields (99%–84%) from azidoamide 16 and in high purities, >95% as judged from LC-MS traces (integration of 200–400 nm diode array traces).

Table 2. Prepared tertiary 1,2,3-triazoloamide derivatives 2. ^a Molecules 20 19673 i002

**Table 2.** Prepared tertiary 1,2,3-triazoloamide derivatives 2. ^a
Entry	Products	NR¹R²	A	R³	Yield (%) ^b	Entry	Products	NR¹R²	A	R³	Yield (%) ^b
1	2aaa	morpholine	CH₂	Ph	91	41	2can	pyrrolidine	CH₂	2,4-di-F-Ph	86
2	2aab	morpholine	CH₂	4-MeO-Ph	91	42	2cao	pyrrolidine	CH₂	Bn	81
3	2aac	morpholine	CH₂	4-CN-Ph	88	43	2daa	azepine	CH₂	Ph	87
4	2aad	morpholine	CH₂	3-thiophenyl	87	44	2dab	azepine	CH₂	4-MeO-Ph	78
5	2aae	morpholine	CH₂	2-pyridyl	80	45	2dac	azepine	CH₂	4-CN-Ph	88
6	2aag	morpholine	CH₂	3-MeO-Ph	89	46	2dad	azepine	CH₂	3-thiophenyl	89
7	2aah	morpholine	CH₂	2-MeO-Ph	88	47	2dae	azepine	CH₂	2-pyridyl	78
8	2aai	morpholine	CH₂	4-Me-Ph	86	48	2dag	azepine	CH₂	3-MeO-Ph	84
9	2aaj	morpholine	CH₂	3-Me-Ph	89	49	2dah	azepine	CH₂	2-MeO-Ph	80
10	2aak	morpholine	CH₂	2-Me-Ph	88	50	2dai	azepine	CH₂	4-Me-Ph	88
11	2aal	morpholine	CH₂	4-NMe₂-Ph	81	51	2daj	azepine	CH₂	3-Me-Ph	83
12	2aam	morpholine	CH₂	4-PhO-Ph	94	52	2dak	azepine	CH₂	2-Me-Ph	78
13	2aan	morpholine	CH₂	2,4-di-F-Ph	87	53	2dal	azepine	CH₂	4-NMe₂-Ph	82
14	2aao	morpholine	CH₂	Bn	89	54	2dam	azepine	CH₂	4-PhO-Ph	90
15	2baa	piperidine	CH₂	Ph	93	55	2dan	azepine	CH₂	2,4-di-F-Ph	89
16	2bab	piperidine	CH₂	4-MeO-Ph	80	56	2dao	azepine	CH₂	Bn	86
17	2bac	piperidine	CH₂	4-CN-Ph	92	57	2eaa	NPhMe	CH₂	Ph	95
18	2bad	piperidine	CH₂	3-thiophenyl	93	58	2eab	NPhMe	CH₂	4-MeO-Ph	95
19	2bae	piperidine	CH₂	2-pyridyl	95	59	2eac	NPhMe	CH₂	4-CN-Ph	95
20	2bag	piperidine	CH₂	3-MeO-Ph	97	60	2ead	NPhMe	CH₂	3-thiophenyl	85
21	2bah	piperidine	CH₂	2-MeO-Ph	88	61	2eae	NPhMe	CH₂	2-pyridyl	95
22	2bai	piperidine	CH₂	4-Me-Ph	97	62	2eag	NPhMe	CH₂	3-MeO-Ph	89
23	2baj	piperidine	CH₂	3-Me-Ph	93	63	2eah	NPhMe	CH₂	2-MeO-Ph	90
24	2bak	piperidine	CH₂	2-Me-Ph	86	64	2eai	NPhMe	CH₂	4-Me-Ph	95
25	2bal	piperidine	CH₂	4-NMe₂-Ph	84	65	2eaj	NPhMe	CH₂	3-Me-Ph	93
26	2bam	piperidine	CH₂	4-PhO-Ph	93	66	2eak	NPhMe	CH₂	2-Me-Ph	94
27	2ban	piperidine	CH₂	2,4-di-F-Ph	93	67	2aca	morpholine	CH₂CH₂	Ph	84
28	2bao	piperidine	CH₂	Bn	89	68	2acb	morpholine	CH₂CH₂	4-MeO-Ph	80
29	2caa	pyrrolidine	CH₂	Ph	81	69	2acc	morpholine	CH₂CH₂	4-CN-Ph	80
30	2cab	pyrrolidine	CH₂	4-MeO-Ph	77	70	2acd	morpholine	CH₂CH₂	3-thiophenyl	88
31	2cac	pyrrolidine	CH₂	4-CN-Ph	81	71	2ace	morpholine	CH₂CH₂	2-pyridyl	79
32	2cad	pyrrolidine	CH₂	3-thiophenyl	76	72	2acg	morpholine	CH₂CH₂	3-MeO-Ph	88
33	2cae	pyrrolidine	CH₂	2-pyridyl	75	73	2ach	morpholine	CH₂CH₂	2-MeO-Ph	88
34	2cag	pyrrolidine	CH₂	3-MeO-Ph	80	74	2aci	morpholine	CH₂CH₂	4-Me-Ph	83
35	2cah	pyrrolidine	CH₂	2-MeO-Ph	77	75	2acj	morpholine	CH₂CH₂	3-Me-Ph	88
36	2cai	pyrrolidine	CH₂	4-Me-Ph	83	76	2ack	morpholine	CH₂CH₂	2-Me-Ph	80
37	2caj	pyrrolidine	CH₂	3-Me-Ph	83	77	2acl	morpholine	CH₂CH₂	4-NMe₂-Ph	88
38	2cak	pyrrolidine	CH₂	2-Me-Ph	79	78	2acm	morpholine	CH₂CH₂	4-PhO-Ph	88
39	2cal	pyrrolidine	CH₂	4-NMe₂-Ph	81	79	2acn	morpholine	CH₂CH₂	2,4-di-F-Ph	82
40	2cam	pyrrolidine	CH₂	4-PhO-Ph	86	80	2aco	morpholine	CH₂CH₂	Bn	88

^a All reactions were performed on 0.1 mmol scale of 16 and the purities of compounds 2 were over 95% as judged from LC-MS traces (integration of diode array 200–400 nm traces); ^b Three-step overall yield from secondary amine 14.

3. Experimental Section

3.1. General

All chemicals were reagent grade and used as purchased. The Merrifield resin (loading capacity 1.29 mmol/g, 100–200 mesh) was purchased from BeadTech (Seoul, Korea). Reactions were monitored by TLC analysis using silica gel 60 F-254 thin layer plates (Merck, Darmstadt, Germany) or ATR-FRIR analysis using a Cary 630 instrument (Agilent Technologies, Santa Clara, CA, USA). Flash column chromatography was carried out on Merck silica gel 60 (230–400 mesh). The crude products were purified by parallel chromatography using CombiFlash (Isco, Lincoln, NE, USA). ¹H-NMR (500 MHz) and ¹³C-NMR (125 MHz) spectra were recorded in δ units relative to deuterated solvent (CDCl₃, DMSO-d₆, etc.) as internal reference on a 500 MHz NMR instrument (Bruker, Billerca, MA, USA). LC-MS analysis was performed on ESI mass spectrometer with PDA detection. LC-MS area% purities of all products were determined by LC peak area analysis (XBD C18 column, 4.6 mm × 100 mm; PDA detector at 200–400 nm; isocratic, 5 mM ammonium formate/CH₃CN (30:70)).

3.2. General Procedure for the Preparation of Secondary α-1,2,3-Triazoloamides 1 on Solid-Phase

A typical procedure for the desired secondary α-1,2,3-triazoloamides 1, as exemplified for N-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1aaa; R¹ = R³ = Ph, A = CH₂) follows.

3.2.1. Preparation of AMEBA Resin 4

Merrifield resin (53.2 g, 50.0 mmol, 0.94 mmol/g) was treated with 4-formyl-3-methoxyphenol (22.8 g, 150.0 mmol), potassium iodide (83.0 mg, 0.5 mmol), and potassium carbonate (20.7 g, 150.0 mmol) in DMF (300 mL). The mixture was shaken at room temperature for 10 h, and then filtered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuo to give AMEBA resin 4 (59.0 g): On-bead ATR-FTIR (neat) υ_max 1678, 1598, 1259 (cm⁻¹).

3.2.2. Preparation of Secondary Amine Resin 3

A mixture of AMEBA resin 4 (10 g, theoretically 8.5 mmol), aniline (5a; (2.3 mL, 25.5 mmol), sodium triacetoxyborohydride (5.4 g, 25.5 mmol), and acetic acid (0.49 mL, 8.5 mmol) in 1,2-dichloroethane was heated at 50 °C for 12 h. The reaction mixture was cooled to room temperature, and then filtered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuum oven to give secondary amine resin 3a (10.6 g): On-bead ATR-FTIR (neat) υ_max 3424, 1597, 1489 (cm⁻¹).

3.2.3. Preparation of α-Chloroamide Resin 7

The amine resin 3a (3.0 g, theoretically 2.4 mmol) was treated with 2-chloroacetyl chloride (6a; 0.57 mL, 7.2 mmol) and triethylamine (1.0 mL, 7.2 mmol) in CH₂Cl₂ at 0 °C. The reaction mixture was shaken at room temperature for 5 h, and then filtered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuum oven to give α-chloroamide resin 7aa (3.16 g): On-bead ATR-FTIR (neat) υ_max 1666, 1593, 1489 (cm⁻¹).

3.2.4. Preparation of α-Azidoamide Resin 8

The α-chloroamide resin 7aa (2.8 g, theoretically 2.1 mmol) was treated with sodium azide (0.47 g, 7.2 mmol) in DMF. The reaction mixture was shaken at room temperature for 12 h, and then filtered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuum oven to give α-azidoamide resin 8aa (2.8 g): On-bead ATR-FTIR (neat) υ_max 2101, 1670, 1590, 1491 (cm⁻¹).

3.2.5. Preparation of α-1,2,3-Triazoloamide Resin 10

To a mixture of α-azidoamide resin 8aa (570 mg, theoretically 0.42 mmol) and phenylacetylene (9a, 0.07 mL, 0.6 mmol) in DMF/piperidine (4:1) was added copper(I) iodide (229 mg, 1.27 mmol) and sodium ascorbate (57 mg, 1.27 mmol) at room temperature. The reaction mixture was shaken at room temperature for 12 h, and then filtered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuum oven to give α-1,2,3-triazoloamide resin 10aaa (606 mg): On-bead ATR-FTIR (neat) υ_max 1669, 1590, 1489 (cm⁻¹).

3.2.6. Preparation of α-1,2,3-Triazoloamide 1

The α-1,2,3-triazoloamide resin 10aaa (157 mg, theoretically 0.10 mmol) was added 30% TFA in CH₂Cl₂ (3 mL). The reaction mixture was stirred at 45 °C for 1day and the mixture was filtered and washed with CH₂Cl₂ and MeOH. The filtrate was evaporated in vacuo and the residue was dissolved in CH₂Cl₂ and extracted with saturated NaHCO₃. The aqueous layer was extracted with CH₂Cl₂ twice and the combined organic extracts were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to give the target N-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1aaa) was obtained as a light yellow solid (23 mg, 93% from Merrifield resin). Mp 247–249 °C; ¹H-NMR (DMSO-d₆) δ 5.39 (s, 2H), 7.09 (m, 1H), 7.33–7.36 (m, 3H), 7.46 (m, 2H), 7.60 (m, 2H), 7.88 (m, 2H), 8.60 (s, 1H), 10.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 119.3, 123.1, 123.8, 125.1, 127.9, 128.9, 130.7, 138.4, 146.2, 164.2; IR (ATR) υ_max 3273, 3061, 1677, 1601, 1545, 1442, 1365, 1253, 1202, 1080, 753 (cm⁻¹); LC-MS (ESI) m/z 279 ([M + 1]⁺); HRMS (FAB) calcd for C₁₆H₁₅N₄O ([M + H]⁺) 279.1240, found 279.1239.

3.3. Characterization Data of Secondary α-1,2,3-Triazoloamides 1

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-N-phenylacetamide (1aab). White solid; Yield: 91%. ¹H-NMR (DMSO-d₆) δ 3.79 (s, 3H), 5.36 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.09 (m, 1H), 7.35 (m, 2H), 7.60 (m, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.48 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.2, 114.4, 119.3, 122.1, 123.3, 123.8, 126.5, 128.9, 138.4, 146.2, 159.0, 164.2; LC-MS (ESI) m/z 309 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-phenylacetamide (1aac). Light brown solid; Yield: 83%. ¹H-NMR (DMSO-d₆) δ 5.43 (s, 2H), 7.09 (m, 1H), 7.34 (m, 2H), 7.59 (m, 2H), 7.93 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 8.82 (s, 1H), 10.53 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.5, 110.1, 118.8, 119.2, 123.8, 124.8, 125.7, 128.9, 133.0, 135.2, 138.4, 144.7, 164.0; LC-MS (ESI) m/z 304 ([M + 1]⁺).

N-Phenyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1aad). White solid; Yield: 82%. ¹H-NMR (DMSO-d₆) δ 5.37 (s, 2H), 7.09 (m, 1H), 7.34 (m, 2H), 7.55 (dd, J = 1.2, 5.0 Hz, 1H), 7.59 (m, 2H), 7.66 (dd, J = 3.0, 5.0 Hz, 1H), 7.88 (dd, J = 1.2, 2.9 Hz, 1H), 8.46 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 119.2, 120.8, 122.8, 123.8, 125.8, 127.1, 128.9, 132.0, 138.4, 142.8, 164.2; LC-MS (ESI) m/z 285 ([M + 1]⁺).

N-Phenyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1aae). White solid; Yield: 85%. ¹H-NMR (DMSO-d₆) δ 5.42 (s, 2H), 7.09 (m, 1H), 7.33–7.36 (m, 3H), 7.59 (m, 2H), 7.91 (t, J = 7.7 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.62 (s, 2H), 10.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 119.2, 119.4, 123.0, 123.8, 125.0, 128.9, 137.2, 138.4, 147.1, 149.7, 150.0, 164.1; LC-MS (ESI) m/z 280 ([M + 1]⁺).

2-(4-Butyl-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (1aaf). White solid; Yield: 92%. ¹H-NMR (DMSO-d₆) δ 0.90 (t, J = 7.3 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H), 2.64 (m, 2H), 5.26 (s, 2H), 7.08 (m, 1H), 7.33 (m, 2H), 7.58 (m, 2H), 7.86 (s, 1H), 10.43 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.7, 21.7, 24.6, 31.1, 52.1, 119.2, 123.4, 123.7, 128.9, 138.4, 146.7, 164.4; LC-MS (ESI) m/z 259 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1baa). White solid; Yield: 92%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.34 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.34 (m, 1H), 7.44–7.47 (m, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.87-7.88 (m, 2H), 8.59 (s, 1H), 10.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.2, 114.1, 120.9, 123.1, 125.2, 127.9, 129.0, 130.7, 131.5, 146.2, 155.6, 163.7; LC-MS (ESI) m/z 309 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1bab). Yellow solid; Yield: 94%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 3.79 (s, 3H), 5.31 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.79 (d, J = 8.9 Hz, 2H), 8.47 (s, 1H), 10.36 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.18, 55.21, 114.1, 114.4, 120.9, 122.1, 123.4, 126.5, 131.5, 155.6, 158.0, 159.0, 163.7; LC-MS (ESI) m/z 339 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(4-methoxyphenyl)acetamide (1bac). Yellow solid; Yield: 89%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.38 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.50 (d, J = 9.1 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.81 (s, 1H), 10.39 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.9, 55.7, 110.6, 114.5, 119.3, 121.3, 125.2, 126.2, 131.9, 133.5, 135.6, 145.1, 156.1, 163.9; LC-MS (ESI) m/z 334 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1bad). Light brown solid; Yield: 85%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.33 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.51 (d, J = 9.1 Hz, 2H) 7.55 (dd, J = 1.3, 5.0 Hz, 1H), 7.65 (dd, J = 3.0, 5.0 Hz, 1H), 7.88 (dd, J = 1.2, 2.9 Hz, 1H), 8.45 (s, 1H), 10.36 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.2, 114.0, 120.8, 122.7, 125.8, 127.1, 131.5, 132.0, 142.8, 155.6, 163.6; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1bag). White solid; Yield: 87%. ¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 3.88 (s, 3H), 5.23 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 6.93 (ddd, J = 1.3, 2.5, 7.9 Hz, 1H), 7.34–7.40 (m, 4H), 7.46 (m, 1H), 7.78 (br s, 1H), 7.97 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.1, 55.2, 110.3, 113.6, 114.0, 117.5, 120.8, 123.2, 130.0, 131.5, 132.1, 146.1, 155.6, 159.7, 163.6; LC-MS (ESI) m/z 339 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1baj). White solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 2.42 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 9.1 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.83 (br s, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.0, 52.3, 55.2, 114.0, 120.8, 122.3, 122.9, 125.7, 128.5, 128.8, 130.6, 131.5, 138.0, 146.3, 155.6, 163.6;LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1bak). Light yellow solid; Yield: 84%. ¹H-NMR (CDCl₃) δ 2.50 (s, 3H), 3.79 (s, 3H), 5.25 (s, 2H), 6.86 (d, J = 9.1 Hz, 2H), 7.30–7.32 (m, 3H), 7.38 (d, J = 9.0 Hz, 2H), 7.80 (m, 1H), 7.86 (br s, 1H), 7.87 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 52.2, 55.2, 114.0, 120.8, 124.9, 126.0, 127.8, 128.1, 130.0, 130.9, 131.5, 134.8, 145.3, 155.6, 163.7; LC-MS (ESI) m/z 323 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(4-methoxyphenyl)acetamide (1bal). Brown solid; Yield: 79%. ¹H-NMR (DMSO-d₆) δ 2.94 (s, 6H), 3.72 (s, 3H), 5.32 (s, 2H), 6.68 (dd, J = 1.9, 8.3 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 7.11 (dd, J = 1.0, 8.1 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H), 7.67 (d, J = 8.9 Hz, 2H), 8.36 (s, 1H), 10.48 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 40.1, 52.2, 55.2, 112.4, 114.1, 118.7, 121.2, 126.1, 131.5, 146.9, 150.1, 155.6, 163.8; LC-MS (ESI) m/z 352 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1bam). Light yellow solid; Yield: 92%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.34 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.06–7.10 (m, 4H), 7.17 (m, 1H), 7.40–7.44 (m, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 8.55 (s, 1H), 10.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.2, 114.1, 118.9, 119.0, 120.9, 122.7, 123.7,126.1,127.0, 130.2, 131.5, 145.8, 155.6, 156.5, 163.7; LC-MS (ESI) m/z 401 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-N-(4-methoxyphenyl)acetamide (1ban). Light yellow solid; Yield: 87%. ¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 5.24 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 6.93 (ddd, J = 2.4, 8.6, 11.0 Hz, 1H), 7.03 (m, 1H), 7.36 (d, J = 9.1 Hz, 2H), 7.70 (br s, 1H), 8.10 (d, J = 3.6 Hz, 1H), 8.30 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.2, 104.6 (t, J_CF = 26.0 Hz), 112.3 (dd, J_CF = 21.2, 3.5 Hz), 115.2 (dd, J_CF = 13.3, 3.6 Hz), 114.0, 125.2 (d, J_CF = 10.8 Hz), 120.8, 128.5 (dd, J_CF = 9.8, 5.1 Hz), 131.5, 138.8 (d, J_CF = 2.6 Hz), 155.5, 158.5 (dd, J_CF = 250.3, 12.7 Hz), 161.7 (dd, J_CF = 247.4, 12.7 Hz), 163.6; LC-MS (ESI) m/z 345 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide (1bao). White solid; Yield: 85%. ¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 4.13 (s, 2H), 5.09 (s, 2H), 6.84 (d, J = 9.0 Hz, 2H), 7.22–7.34 (m, 7H), 7.37 (s, 1H), 7.81 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 31.3, 52.1, 55.2, 114.0, 120.8, 124.2, 126.2, 128.4, 128.6, 131.5, 139.6, 145.9, 155.6, 163.8; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1caa). Light yellow solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 5.24 (s, 2H), 6.70 (dd, J = 2.2, 8.1 Hz, 1H), 6.97 (dd, J = 1.5, 7.9 Hz, 1H), 7.19–7.23 (m, 2H), 7.37 (m, 1H), 7.44–7.47 (m, 2H), 7.85–7.87 (m, 2H), 7.95 (s, 1H), 7.98 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.0, 105.0, 109.3, 111.5, 123.0, 125.1, 127.8, 128.9, 129.7, 130.7,139.5, 146.2, 159.6, 164.2; LC-MS (ESI) m/z 309 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1cab). White solid; Yield: 90%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 3.86 (s, 3H), 5.22 (s, 2H), 6.70 (dd, J = 2.3, 7.9 Hz, 1H), 6.96–6.99 (m, 3H), 7.18 (t, J = 2.2 Hz, 1H), 7.21 (t, J = 8.2 Hz, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.88 (s, 1H), 7.91 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.0, 55.1, 105.0, 109.3, 111.5, 114.3, 122.1, 123.3, 126.5, 129.7, 139.6, 146.1, 159.0, 159.6, 164.3; LC-MS (ESI) m/z 339 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(3-methoxyphenyl)acetamide (1cac). White solid; Yield: 87%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.41 (s, 2H), 6.68 (dd, J = 1.9, 8.3 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.29 (t, J = 2.1 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.81 (s, 1H), 10.52 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.5, 55.0, 105.0, 109.3, 110.1, 111.5, 124.7, 125.7, 129.7, 133.0, 135.2, 139.5, 144.6, 159.6, 164.0; LC-MS (ESI) m/z 334 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1cad). Light brown solid; Yield: 76%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.36 (s, 2H), 6.68 (dd, J = 2.2, 7.9 Hz, 1H), 7.11 (dd, J = 0.9, 8.1 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H), 7.55 (dd, J = 1.3, 5.0 Hz, 1H), 7.66 (dd, J = 3.0, 5.0 Hz, 1H), 7.88 (dd, J = 1.2, 3.0 Hz, 1H), 8.46 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.0, 105.0, 109.3, 111.5, 120.8, 122.8, 125.8, 127.1, 129.7, 132.0, 139.5, 142.8, 159.6, 164.2; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1cae). Brown solid; Yield: 81%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 5.26 (s, 2H), 6.70 (dd, J = 2.1, 8.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 7.18–7.22 (m, 2H), 7.28 (m, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.87 (s, 1H), 8.19 (d, J = 7.4 Hz, 1H), 8.33 (s, 1H), 8.61 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.1, 105.1, 109.4, 115.6, 119.5, 123.1, 125.1, 129.9, 137.4, 139.6, 147.1, 149.8, 150.0, 159.7, 164.3; LC-MS (ESI) m/z 310 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1cah). Light yellow solid; Yield: 83%. ¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 3.96 (s, 3H), 5.24 (s, 2H), 6.96 (dd, J = 1.3, 8.1 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 7.11 (dt, J = 0.9, 7.6 Hz, 1H), 7.17 (t, J = 2.2 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.36 (m, 1H), 7.92 (br s, 1H), 8.24 (s, 1H), 8.36 (dd, J = 1.7, 7.8 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.0, 55.5, 105.0, 109.2, 111.4, 111.5, 119.1, 120.6, 125.6, 126.5, 128.8, 129.7, 139.6, 141.6, 155.3, 159.5, 164.4; LC-MS (ESI) m/z 339 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1caj). White solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 2.42 (s, 3H), 3.79 (s, 3H), 5.23 (s, 2H), 6.70 (dd, J = 2.2, 8.1 Hz, 1H), 6.97 (dd, J = 1.3, 8.0 Hz, 1H), 7.19–7.23 (m, 3H), 7.34 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.94 (br s, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.0, 55.1, 105.0, 109.3, 110.3, 111.5, 113.6, 117.5, 123.7, 129.7, 130.0, 132.0, 139.5, 146.1, 159.6, 159.7, 164.2; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1cak). Light yellow solid; Yield: 90%. ¹H-NMR (CDCl₃) δ 2.50 (s, 3H), 3.79 (s, 3H), 5.26 (s, 2H), 6.71 (dd, J = 2.1, 8.3 Hz, 1H), 6.98 (dd, J = 1.3, 8.0 Hz, 1H), 7.19–7.24 (m, 2H), 7.28-7.32 (m, 3H), 7.79 (m, 1H), 7.87 (s, 1H), 8.00 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 52.3, 55.0, 105.0, 109.3, 111.5, 124.9, 126.1, 127.8, 128.1, 129.7, 123.0, 130.9, 134.8, 139.6, 145.4, 159.6, 164.3; LC-MS (ESI) m/z 323 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(3-methoxyphenyl)acetamide (1cal). Brown solid; Yield: 91%. ¹H-NMR (DMSO-d₆) δ 2.94 (s, 6H), 3.72 (s, 3H), 5.32 (s, 2H), 6.68 (dd, J = 1.9, 8.3 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 7.11 (dd, J = 1.0, 8.1 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H), 7.67 (d, J = 8.9 Hz, 2H), 8.36 (s, 1H), 10.48 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 40.0, 52.3, 55.0, 105.0, 109.3, 111.5, 112.4, 118.6, 121.2, 126.1, 129.7, 139.6, 146.8, 150.1, 159.6, 164.3; LC-MS (ESI) m/z 352 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1cam). Yellow solid; Yield: 91%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.37 (s, 2H), 6.68 (dd, J = 1.8, 8.3 Hz, 1H), 7.06–7.10 (m, 4H), 7.12 (dd, J = 1.0, 8.1 Hz, 1H), 7.17 (m, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.2 Hz, 1H), 7.40–7.44 (m, 2H), 7.88 (d, J = 8.8 Hz, 2H), 8.55 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.0, 105.0, 109.3, 111.5, 118.8, 118.9, 122.7, 123.7, 126.0, 126.9, 129.7, 130.1, 139.5, 145.7, 156.4, 159.6, 164.2; LC-MS (ESI) m/z 401 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-N-(3-methoxyphenyl)acetamide (1can). Light yellow solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 5.25 (s, 2H), 6.70 (dd, J = 2.0, 8.4 Hz, 1H), 6.93 (ddd, J = 2.5, 8.7, 11.1 Hz, 1H), 6.95 (dd, J = 1.7, 7.7 Hz, 1H), 7.03 (m, 1H), 7.19 (t, J = 2.2 Hz, 1H), 7.22 (t, J = 8.2 Hz, 1H), 7.81 (br s, 1H), 8.10 (d, J = 3.5 Hz, 1H), 8.30 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.0, 104.6 (t, J_CF = 26.1 Hz), 105.0, 109.27, 111.4, 112.3 (dd, J_CF = 21.4, 3.5 Hz), 115.2 (dd, J_CF = 13.4, 3.7 Hz), 125.2 (d, J_CF = 10.9 Hz), 128.5 (dd, J_CF = 9.8, 5.3 Hz), 129.7, 138.9 (d, J_CF = 2.6 Hz), 139.6, 158.5 (dd, J_CF = 250.7, 12.8), 159.6, 161.7 (dd, J_CF = 247.5, 12.5 Hz), 164.2; LC-MS (ESI) m/z 345 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(3-methoxyphenyl)acetamide (1cao). White solid; Yield: 88%. ¹H-NMR (CDCl₃) δ 3.77 (s, 3H), 4.12 (s, 2H), 5.10 (s, 2H), 6.68 (dd, J = 2.1, 8.2 Hz, 1H), 6.94 (dd, J = 1.1, 7.9 Hz, 1H), 7.17–7.32 (m, 7H), 7.39 (s, 1H), 8.15 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 31.2, 52.1, 55.0, 105.0, 109.2, 111.4, 124.1, 126.1, 128.4, 128.5, 129.7, 139.56, 139.59, 145.9, 159.5, 164.3; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1daa). Light yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 3.80 (s, 3H), 5.27 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.96 (dt, J = 1.1, 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.37 (m, 1H), 7.44–7.47 (m, 2H), 7.86–7.88 (m, 2H), 7.99 (s, 1H), 8.24 (s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 111.3, 120.3, 121.7, 123.0, 124.9, 125.1, 126.6, 127.8, 128.9, 130.7, 146.2, 149.6, 164.4; LC-MS (ESI) m/z 309 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dab). White solid; Yield: 90%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 3.85 (s, 3H), 5.25 (s, 2H), 6.84 (dd, J = 1.0, 8.2 Hz, 1H), 6.95 (dt, J = 1.1, 7.7 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.07 (dt, J = 1.5, 7.9 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.90 (s, 1H), 8.24 (s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.1, 55.7, 111.3, 114.3, 120.3, 121.7, 122.1, 123.3, 124.9, 126.5, 126.6, 146.1, 149.6, 159.0, 164.5; LC-MS (ESI) m/z 339 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)acetamide (1dac). White solid; Yield: 86%. ¹H-NMR (DMSO-d₆) δ 3.88 (s, 3H), 5.52 (s, 2H), 6.91 (m, 1H), 7.08–7.13 (m, 2H), 7.92–7.94 (m, 3H), 8.08 (d, J = 8.4 Hz, 2H), 8.80 (s, 1H), 9.81 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.7, 110.1, 111.3, 120.3, 121.8, 124.8, 125.0, 125.7, 126.5, 132.6, 132.6, 133.0, 135.2, 144.6, 149.6, 164.3; LC-MS (ESI) m/z 334 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1dad). Light brown solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 5.25 (s, 2H), 6.85 (dd, J = 1.0, 8.2 Hz, 1H), 6.96 (dt, J = 1.1, 7.9 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.41 (dd, J = 3.0, 5.0 Hz, 1H), 7.49 (dd, J = 1.2, 5.1 Hz, 1H), 7.74 (dd, J = 1.2, 3.0 Hz, 1H), 7.89 (s, 1H), 8.22 (br s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 111.3, 120.3, 120.8, 121.7, 122.8, 124.9, 125.8, 126.6, 127.1, 132.0, 142.7, 149.6, 164.4; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1dae). Light brown solid; Yield: 84%. ¹H-NMR (CDCl₃) δ 3.80 (s, 3H), 5.28 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.95 (m, 1H), 7.07 (dt, J = 1.4, 7.9 Hz, 1H), 7.27 (m, 1H), 7.80 (dt, J = 1.7, 7.8 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.25 (br s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H), 8.34 (s, 1H), 8.61 (d, J = 4.2 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.8, 111.4, 119.5, 120.4, 121.9, 123.1, 125.06., 125.10, 126.6, 137.3, 147.1, 149.7, 150.1, 164.5; LC-MS (ESI) m/z 310 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dag). White solid; Yield: 86%. ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 3.88 (s, 3H), 5.26 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.92 (ddd, J = 1.0, 2.6, 8.1 Hz, 1H), 6.96 (dt, J = 1.0, 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.40 (td, J = 1.2, 7.6 Hz, 1H), 7.48 (dd, J = 1.5, 2.4 Hz, 1H), 7.98 (s, 1H), 8.23 (br s, 1H), 8.27 (dd, J = 1.3, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.1, 55.7, 110.3, 111.3, 113.6, 117.5, 120.3, 121.8, 123.3, 124.9, 126.6, 130.1, 132.1, 146.1, 149.6, 159.7, 164.4; LC-MS (ESI) m/z 339 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dah). Light yellow solid; Yield: 80%. ¹H-NMR (CDCl₃) δ 3.77 (s, 3H), 3.95 (s, 3H), 5.26 (s, 2H), 6.83 (dd, J = 1.1, 8.2 Hz, 1H), 6.95 (dt, J = 1.2, 7.8 Hz, 1H), 7.00 (dd, J = 0.6, 8.3 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.11 (dt, J = 1.0, 7.6 Hz, 1H), 7.35 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.25 (s, 1H), 8.27 (br s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.39 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.5, 55.7, 111.3, 111.5, 119.1, 120.3, 120.7, 121.7, 124.9, 125.6, 126.5, 126.6, 128.9, 141.6, 149.6, 155.3, 164.6; LC-MS (ESI) m/z 339 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1dai). Light yellow solid; Yield: 78%. ¹H-NMR (CDCl₃) δ 2.39 (s, 3H), 3.80 (s, 3H), 5.25 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 7.07 (dt, J = 1.4, 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H), 8.23 (br s, 1H), 8.27 (dd, J = 1.5, 8.0 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 52.3, 55.7, 111.3, 120.3, 121.7, 122.6, 124.9, 125.1, 126.6, 128.0, 129.5, 137.1, 146.2, 149.6, 164.5; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1daj). Light yellow solid; Yield: 85%. ¹H-NMR (CDCl₃) δ 2.42 (s, 3H), 3.80 (s, 3H), 5.26 (s, 2H), 6.85 (dd, J = 0.9, 8.2 Hz, 1H), 6.95 (dt, J = 1.0, 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.97 (s, 1H), 8.25 (br s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 52.3, 55.7, 111.3, 120.3, 121.7, 122.3, 123.0, 124.9, 125.7, 126.6, 128.5, 128.8, 130.6, 138.1, 146.3, 149.6, 164.4; LC-MS (ESI) m/z 323 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(2-methoxyphenyl)acetamide (1dal). Brown solid; Yield: 88%. ¹H-NMR (CDCl₃) δ 3.00 (s, 6H), 3.78 (s, 3H), 5.23 (s, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.84 (dd, J = 1.0, 8.1 Hz, 1H), 6.95 (dt, J = 1.1, 7.8 Hz, 1H), 7.07 (dt, J = 1.4, 7.8 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.83 (s, 1H), 8.24 (br s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 40.0, 52.3, 55.7, 111.3, 112.4, 118.6, 120.3, 121.1, 121.7, 124.9, 126.0, 146.8, 149.6, 150.0, 164.5; LC-MS (ESI) m/z 352 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dam). Yellow solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 5.26 (s, 2H), 6.86 (dd, J = 1.0, 8.2 Hz, 1H), 6.96 (dt, J = 1.1, 7.8 Hz, 1H), 7.02–7.09 (m, 5H), 7.14 (m, 1H), 7.35–7.38 (m, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H), 8.24 (br s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 111.3, 118.8, 120.3, 121.7, 122.7, 123.6, 124.9, 126.1, 126.6, 126.9, 130.1, 145.7, 149.6, 156.40, 156.41, 166.4; LC-MS (ESI) m/z 401 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)acetamide (1dan). Light yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 3.82 (s, 3H), 5.28 (s, 2H), 6.86 (dd, J = 1.0, 8.2 Hz, 1H), 6.93 (ddd, J = 2.5, 8.6, 11.0 Hz, 1H), 6.96 (dt, J = 1.1, 7.8 Hz, 1H), 7.03 (m, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 8.12 (d, J = 3.6 Hz, 1H), 8.21 (br s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H), 8.31 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 104.6 (t, J = 26.0 Hz), 111.3, 112.3 (dd, J = 21.4, 3.5 Hz), 115.2 (dd, J = 13.5, 3.7 Hz), 120.3, 121.8, 124.9, 125.2 (d, J = 11.1 Hz), 126.6, 128.5 (dd, J = 9.7, 5.3 Hz), 138.8 (d, J = 2.9 Hz), 149.6, 158.5 (dd, J_CF = 250.5, 12.5 Hz), 161.7 (dd, J_CF = 247.4, 12.5 Hz), 164.4; LC-MS (ESI) m/z 345 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (1dao). White solid; Yield: 88%. ¹H-NMR (CDCl₃) δ 3.77 (s, 3H), 4.14 (s, 2H), 5.14 (s, 2H), 6.84 (dd, J = 0.9, 8.2 Hz, 1H), 6.94 (dt, J = 1.1, 7.8 Hz, 1H), 7.07 (dt, J = 1.4, 7.9 Hz, 1H), 7.20–7.32 (m, 5H), 7.40 (s, 1H), 8.20 (br s, 1H), 8.25 (dd, J = 1.4, 8.0 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 31.2, 52.1, 55.7, 111.3, 120.3, 121.6, 124.1, 124.8, 126.1, 126.5, 128.4, 128.5, 139.6, 145.8, 149.5, 164.5; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-Butyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1eaa). White solid; Yield: 81%. ¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.12 (m, 2H), 5.11 (s, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.86 (d, J = 7.5 Hz, 2H), 8.32 (br s, 1H), 8.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 19.5, 31.0, 38.4, 51.8, 122.9, 125.1, 127.8, 128.9, 130.7, 146.1, 165.1; LC-MS (ESI) m/z 259 ([M + 1]⁺).

N-Butyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1eab). White solid; Yield: 88%. ¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.11 (m, 2H), 3.79 (s, 3H), 5.09 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 8.31 (br s, 1H), 8.39 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 19.5, 31.0, 38.4, 51.7, 55.1, 114.3, 121.9, 123.4, 126.4, 146.0, 158.9, 165.2; LC-MS (ESI) m/z 289 ([M + 1]⁺).

N-Butyl-2-[4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl]acetamide (1eac). White solid; Yield: 83%. ¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.09 (m, 2H), 5.15 (s, 2H), 7.92 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 8.36 (br s, 1H), 8.74 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 19.5, 31.0, 38.5, 51.9, 110.0, 118.8, 124.6, 125.6, 133.0, 135.2, 144.5, 164.9; LC-MS (ESI) m/z 284 ([M + 1]⁺).

N-Butyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1ead). White solid; Yield: 80%. ¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.11 (m, 2H), 5.10 (s, 2H), 7.53 (dd, J = 1.3, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 4.9 Hz, 1H), 7.86 (dd, J = 1.2, 2.9 Hz, 1H), 8.32 (br s, 1H), 8.38 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 13.7, 19.5, 21.6, 24.6, 31.0, 31.1, 38.4, 51.5, 123.2, 146.5, 165.3; LC-MS (ESI) m/z 265 ([M + 1]⁺).

N-Butyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1eae). Light yellow solid; Yield: 89%. ¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.11 (m, 2H), 5.15 (s, 2H), 7.34 (dd, J = 5.1, 6.6 Hz, 1H), 7.89 (dt, J = 1.7, 7.7 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H),8.31 (br s, 1H), 8.51 (s, 1H), 8.60 (d, J = 4.4 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6,19.5, 31.0, 38.4, 51.8, 119.3, 122.9, 124.8, 137.1, 146.9, 149.6, 150.0, 165.0; LC-MS (ESI) m/z 260 ([M + 1]⁺).

N-Butyl-2-(4-butyl-1H-1,2,3-triazol-1-yl)acetamide (1eaf). White solid; Yield: 89%. ¹H-NMR (DMSO-d₆) δ 0.87 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 1.31 (m, 4H), 1.40 (m, 2H), 1.57 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 3.09 (m, 2H), 4.99 (s, 2H), 7.76 (s, 1H), 8.23 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 19.5, 31.0, 38.5, 51.7, 120.7, 122.7, 125.8, 127.1, 132.1, 142.7, 165.1; LC-MS (ESI) m/z 239 ([M + 1]⁺).

N-Isopropyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1faa). White solid; Yield: 79%. ¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.86 (m, 1H), 5.08 (s, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.86 (d, J = 7.1 Hz, 1H), 8.29 (d, J = 7.4 Hz, 1H), 8.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 22.3, 40.9, 51.8, 122.9, 125.1, 127.8, 128.9, 130.8, 146.1, 164.2; LC-MS (ESI) m/z 245 ([M + 1]⁺).

N-Isopropyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1fab). Light yellow solid; Yield: 87%. ¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.79 (s, 3H), 3.85 (m, 1H), 5.05 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 8.28 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 22.3, 40.9, 51.8, 55.1, 114.3, 122.0, 123.4, 126.5, 146.0, 159.0, 164.3; LC-MS (ESI) m/z 275 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-isopropyl-acetamide (1fac). Light brown solid; Yield: 75%. ¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.85 (m, 1H), 5.12 (s, 2H), 7.92 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6 Hz, 2H), 8.32 (d, J = 7.4 Hz, 1H), 8.73 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 22.2, 41.0, 51.9, 110.1, 118.8, 124.7, 125.7, 133.0, 135.2, 144.5, 164.0; LC-MS (ESI) m/z 270 ([M + 1]⁺).

N-Isopropyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1fad). White solid; Yield: 77%. ¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.85 (m, 1H), 5.07 (s, 2H), 7.53 (dd, J = 1.2, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 5.0 Hz, 1H), 7.86 (dd, J = 1.2, 2.9 Hz, 1H), 8.28 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 22.3, 40.9, 51.7, 120.7, 122.7, 125.8, 127.1, 132.1, 142.7, 164.2; LC-MS (ESI) m/z 251 ([M + 1]⁺).

N-Isopropyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1fae). White solid; Yield: 84%. ¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.85 (m, 1H), 5.11 (s, 2H), 7.34 (ddd, J = 1.2, 4.8, 7.5 Hz, 1H), 7.89 (dt, J = 1.8, 7.7 Hz, 1H), 8.03 (td, J = 1.0, 7.9 Hz, 1H),8.28 (d, J = 7.5 Hz, 1H), 8.51 (s, 1H), 8.60 (m, 1H); ¹³C-NMR (DMSO-d₆) δ 22.3, 41.0, 51.8, 119.4, 122.9, 124.8, 137.2, 146.9, 149.6, 150.0, 164.2; LC-MS (ESI) m/z 246 ([M + 1]⁺).

2-(4-Butyl-1H-1,2,3-triazol-1-yl)-N-isopropylacetamide (1faf). White solid; Yield: 83%. ¹H-NMR (DMSO-d₆) δ 0.89 (t, J = 7.3 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.32 (m, 2H), 1.57 (m, 2H), 2.61 (d, J = 7.6 Hz, 2H), 3.82 (m, 1H), 4.96 (s, 2H), 7.76 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 13.7, 21.7, 22.2, 24.6, 31.1, 40.8, 51.5, 123.2, 146.5, 164.4; LC-MS (ESI) m/z 251 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide (1dba). Yellow solid; Yield: 88%. ¹H-NMR (CDCl₃) δ 1.98 (d, J = 7.3 Hz, 3H), 3.81 (s, 3H), 5.50 (q, J = 7.2 Hz, 1H), 6.84 (dd, J = 1.2, 8.2 Hz, 1H), 6.95 (dt, J = 1.1, 7.8 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.36 (m, 1H), 7.43–7.46 (m, 2H), 7.85–7.87 (m, 2H), 8.01 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.32 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.5, 111.3, 120.2, 120.8, 122.1, 125.1, 127.8, 128.9, 146.1, 149.9, 167.6; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbb). White solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 3.85 (s, 3H), 5.25 (s, 2H), 6.84 (dd, J = 1.0, 8.2 Hz, 1H), 6.95 (dt, J = 1.1, 7.7 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.07 (dt, J = 1.5, 7.9 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.90 (s, 1H), 8.24 (s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.1, 55.8, 58.5, 111.3, 114.3, 119.9, 120.2, 122.1, 123.4, 125.2, 126.38, 126.44, 146.0, 149.9, 158.9, 167.6; LC-MS (ESI) m/z 353 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)propanamide (1dbc). Light yellow solid; Yield: 87%. ¹H-NMR (CDCl₃) δ 1.98 (d, J = 7.2 Hz, 3H),5.53 (q, J = 7.2 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 8.15 (s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H), 8.30 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.7, 110.1, 111.4, 118.8, 120.2, 122.2, 122.7, 125.3, 125.6, 126.3, 133.0, 135.2, 144.6, 150.0, 167.5; LC-MS (ESI) m/z 348 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propanamide (1dbd). Light brown oil; Yield: 80%. ¹H-NMR (CDCl₃) δ 1.94 (d, J = 7.3 Hz, 3H), 3.78 (s, 3H), 5.52 (q, J = 7.2 Hz, 2H), 6.83 (dd, J = 1.1, 8.2 Hz, 1H), 6.90 (dt, J = 1.2, 8.4 Hz, 1H), 7.05 (m, 1H), 7.38 (dd, J = 3.0, 5.0 Hz, 1H), 7.47 (dd, J = 1.2, 5.0 Hz, 1H), 7.71 (dd, J = 1.2, 3.0 Hz, 1H), 7.95 (s, 1H), 8.26 (dd, J = 1.5, 8.1 Hz, 1H), 8.38 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.1, 55.8, 58.4, 111.4, 120.3, 120.6, 120.7, 122.1, 125.2, 125.8, 127.1, 132.1, 142.7, 149.9, 167.6; LC-MS (ESI) m/z 329 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide (1dbe). Colorless oil; Yield: 83%. ¹H-NMR (CDCl₃) δ 1.97 (d, J = 7.2 Hz, 3H), 3.78 (s, 3H), 5.53 (q, J = 7.2 Hz, 1H), 6.82 (dd, J = 1.1, 8.2 Hz, 1H), 6.92 (dt, J = 1.1, 7.8 Hz, 1H), 7.04 (dt, J = 1.5, 7.9 Hz, 1H), 7.24 (ddd, J = 1.2, 4.9, 7.6 Hz, 1H), 7.78 (dt, J = 1.8, 7.8 Hz, 1H), 8.18 (dd, J = 0.9, 8.8 Hz, 1H), 8.26 (dd, J = 1.6, 8.1 Hz, 1H), 8.36 (br s, 1H), 8.39 (s, 1H), 8.59 (ddd, J = 0.9, 1.7, 4.8 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.7, 111.4, 119.4, 120.3, 122.2, 122.7, 123.0, 125.2, 126.4, 137.2, 147.0, 149.6, 149.9, 150.0, 167.5; LC-MS (ESI) m/z 324 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbg). Light yellow oil; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.95 (d, J = 7.2 Hz, 3H), 3.77 (s, 3H), 3.85 (s, 3H), 5.53 (q, J = 7.2 Hz, 1H), 6.82 (dd, J = 1.2, 8.2 Hz, 1H), 6.89 (ddd, J = 1.0, 2.6, 8.2 Hz, 1H), 6.92 (dt, J = 1.2, .8 Hz, 1H), 7.04 (dt, J = 1.6, 7.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.39 (td, J = 1.3, 7.7 Hz, 1H), 7.46 (dd, J = 1.5, 2.5 Hz, 1H), 8.04 (s, 1H), 8.26 (dd, J = 1.6, 8.1 Hz, 1H), 8.39 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.1, 55.8, 58.5, 110.3, 111.4, 113.7, 117.4, 120.3, 121.2, 122.1, 125.2, 126.4, 130.0, 132.1, 146.0, 149.9, 159.7, 167.6; LC-MS (ESI) m/z 353 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbh). Light yellow oil; Yield: 89%. ¹H-NMR (CDCl₃) δ 1.98 (d, J = 7.3 Hz, 3H), 3.75 (s, 3H), 3.92 (s, 3H), 5.51 (q, J = 7.3 Hz, 1H), 6.80 (dd, J = 1.2, 8.2 Hz, 1H), 6.92 (dt, J = 1.2, 7.8 Hz, 1H), 6.97 (dd, J = 0.6, 8.3 Hz, 1H), 7.03 (dt, J = 1.5, 7.9 Hz, 1H), 7.08 (dt, J = 1.0, 7.5 Hz, 1H), 7.32 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.25 (s, 1H), 8.27 (dd, J = 1.6, 8.1 Hz, 1H), 8.37 (dd, J = 1.7, 7.7 Hz, 1H), 8.41 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.1. 55.5. 55.8. 58.5. 111.4. 111.5. 119.0. 120.3. 120.6. 122.1. 123.0. 125.2. 126.4. 126.6. 128.9. 141.7. 149.9. 155.4. 167.6; LC-MS (ESI) m/z 353 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)propanamide (1dbi). Light yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.97 (d, J = 7.3 Hz, 3H), 2.38 (s, 3H), 3.80 (s, 3H), 5.49 (q, J = 7.2 Hz, 1H), 6.84 (dd, J = 1.0, 8.2 Hz, 1H), 6.94 (dt, J = 1.1, 7.8 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.33 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 20.8, 55.8, 58.5, 111.3, 120.2, 120.4, 122.1, 125.0, 125.2, 126.4, 128.0, 129.4, 137.1, 146.2, 149.9, 167.6; LC-MS (ESI) m/z 337 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)propanamide (1dbj). Light yellow solid; Yield: 83%. ¹H-NMR (CDCl₃) δ 1.97 (d, J = 7.3 Hz, 3H), 2.41 (s, 3H), 3.80 (s, 3H), 5.51 (q, J = 7.2 Hz, 1H), 6.84 (dd, J = 1.1, 8.2 Hz, 1H), 6.94 (dt, J = 1.2, 7.8 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 8.00 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.34 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 20.8, 55.8, 58.5, 111.3, 120.2, 120.4, 122.1, 125.0, 125.1, 126.4, 128.0, 129.4, 137.1, 146.2, 149.9, 167.6; LC-MS (ESI) m/z 337 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)propanamide (1dbk). Light yellow solid; Yield: 74%. ¹H-NMR (acetone-d₆) δ 1.97 (d, J = 7.2 Hz, 3H), 2.52 (s, 3H), 3.84 (s, 3H), 5.85 (q, J = 7.3 Hz, 1H), 6.93 (m, 1H), 7.02 (d, J = 7.1 Hz, 1H), 7.25–7.32 (m, 3H), 7.82 (m, 1H), 8.26 (m, 1H), 8.41 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.5, 21.5, 56.3, 59.1, 111.8, 120.8, 122.6, 123.2, 125.7, 126.5, 127.0, 128.3, 128.8, 130.5, 131.3, 135.5, 146.0, 150.4, 166.3; LC-MS (ESI) m/z 337 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(2-methoxyphenyl)propanamide (1dbl). Brown solid; Yield: 82%. ¹H-NMR (CDCl₃) δ 1.96 (d, J = 7.3 Hz, 3H), 3.00 (s, 6H), 3.79 (s, 3H), 5.47 (q, J = 7.2 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.83 (dd, J = 1.1, 8.2 Hz, 1H), 6.94 (dt, J = 1.2, 7.8 Hz, 1H), 7.05 (dt, J = 1.5, 7.9 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.85 (s, 1H), 8.28 (dd, J = 1.6, 8.1 Hz, 1H), 8.32 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 40.0, 55.8, 58.4, 111.3, 112.3, 118.7, 118.9, 120.3, 122.0, 125.1, 126.0, 126.4, 146.7, 149.9, 150.0, 167.7; LC-MS (ESI) m/z 366 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbm). Light yellow oil; Yield: 87%. ¹H-NMR (CDCl₃) δ 1.97 (d, J = 7.3 Hz, 3H), 3.80 (s, 3H), 5.52 (q, J = 7.2 Hz, 1H), 6.84 (dd, J = 1.2, 8.2 Hz, 1H), 6.94 (m, 1H), 7.02–7.08 (m, 5H), 7.15 (m, 1H), 7.34–7.37 (m, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.99 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.37 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 80.0, 111.3, 118.2, 118.81, 118.86, 119.4, 120.3, 120.5, 123.6, 126.9, 130.1, 130.2, 133.6, 145.7, 149.9, 156.39, 156.42, 167.6; LC-MS (ESI) m/z 415 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)propanamide (1dbn). Light yellow solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 1.99 (d, J = 7.3 Hz, 3H), 3.82 (s, 3H), 5.51 (q, J = 7.2 Hz, 2H), 6.85 (dd, J = 1.2, 8.2 Hz, 1H), 6.92 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.95 (dt, J = 1.1, 7.8 Hz, 1H), 7.01 (m, 1H), 7.07 (dt, J = 1.5, 7.9 Hz, 1H), 8.12 (d, J = 3.5 Hz, 1H), 8.28 (dd, J = 1.6, 8.1 Hz, 1H), 8.29 (dt, J = 6.5, 8.6 Hz, 1H), 8.31 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.7, 104.6 (t, J_CF = 25.9 Hz), 111.4, 112.30 (dd, J_CF = 21.6, 3.6 Hz), 115.20 (dd, J_CF = 13.4, 3.8 Hz), 120.3, 122.2, 122.8 (d, J_CF = 10.3 Hz), 125.3, 126.3, 128.7 (dd, J_CF = 9.8, 5.2 Hz), 139.1 (d, J_CF = 2.6 Hz), 150.0, 158.5 (dd, J_CF = 250.5, 12.8 Hz), 161.86 (dd, J_CF = 247.8, 12.6 Hz), 167.5; LC-MS (ESI) m/z 359 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)propanamide (1dbo). Light yellow oil; Yield: 86%. ¹H-NMR (CDCl₃) δ 1.88 (d, J = 7.3 Hz, 3H), 3.77 (s, 3H), 4.12 (s, 2H), 5.39 (q, J = 7.3 Hz, 1H), 6.83 (dd, J = 1.1, 8.2 Hz, 1H), 6.93 (dt, J = 1.2, 7.8 Hz, 1H), 7.05 (dt, J = 1.5, 7.9 Hz, 1H), 7.23 (m, 1H), 7.26–7.31 (m, 4H), 7.42 (s, 1H), 8.25 (dd, J = 1.5, 8.1 Hz, 1H), 8.33 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 31.2, 55.7, 58.3, 111.3, 120.2, 121.8, 122.0, 125.1, 126.1, 126.4, 128.4, 128.5, 139.6, 145.8, 149.9, 167.6; LC-MS (ESI) m/z 337 ([M + 1]⁺).

N-Butyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide (1eba). White solid; Yield: 83%. ¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.41 (m, 2H), 1.71 (d, J = 7.2 Hz, 3H), 3.10 (m, 2H), 5.38 (q, J = 7.2 Hz, 1H),, 7.33(t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.88 (d, J = 7.1 Hz, 2H), 8.38 (br s, 1H), 8.68 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.4, 58.4, 120.6, 125.1, 127.8, 128.9, 130.9, 146.0, 168.3; LC-MS (ESI) m/z 273 ([M + 1]⁺).

N-Butyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1ebb). White solid; Yield: 81%. ¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.70 (d, J = 7.2 Hz, 3H), 3.79 (s, 3H), 5.36 (q, J = 7.2 Hz, 1H), 7.01(d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.36 (br s, 1H), 8.56 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.4, 55.1, 58.3, 114.3, 119.6, 123.5, 126.4, 146.0, 158.9, 168.4; LC-MS (ESI) m/z 303 ([M + 1]⁺).

N-Butyl-2-[4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl]propanamide (1ebc). White solid; Yield: 79%. ¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.72 (d, J = 7.2 Hz, 3H), 3.09 (m, 2H), 5.42 (q, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.6 Hz, 2H), 8.40 (br s, 1H), 8.92 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.5, 58.5, 110.0, 118.8, 122.5, 125.6, 133.0, 135.3, 144.5, 168.2; LC-MS (ESI) m/z 298 ([M + 1]⁺).

N-Butyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propanamide (1ebd). Light yellow solid; Yield: 78%. ¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.69 (d, J = 7.2 Hz, 3H), 3.08 (m, 2H), 5.37 (q, J = 7.1 Hz, 1H), 7.55 (dd, J = 1.2, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 5.0 Hz, 1H), 7.86 (dd, J = 1.2, 2.9 Hz, 1H), 8.38 (br s, 1H), 8.55 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.4, 58.3, 120.3, 120.6, 125.8, 127.0, 132.2, 142.7, 168.3; LC-MS (ESI) m/z 279 ([M + 1]⁺).

N-Butyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide (1ebe). White solid; Yield: 84%. ¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.73 (d, J = 7.2 Hz, 3H), 3.09 (m, 2H), 5.42 (q, J = 7.2 Hz, 1H), 7.35 (m, 1H), 7.89 (dt, J = 1.7, 7.7 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 8.37 (br s, 1H), 8.61 (m, 1H), 8.62 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.5, 58.5, 119.4, 122.4, 123.0, 137.2, 147.0, 149.6, 150.0, 168.2; LC-MS (ESI) m/z 274 ([M + 1]⁺).

N-Butyl-2-(4-butyl-1H-1,2,3-triazol-1-yl)propanamide (1ebf). White solid; Yield: 81%. ¹H-NMR (DMSO-d₆) δ 0.85(t, J = 7.3 Hz, 3H), 0.89(t, J = 7.4 Hz, 3H), 1.26 (m, 2H), 1.32 (m, 2H), 1.37 (m, 2H), 1.59 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H), 2.60 (d, J = 7.6 Hz, 2H), 3.06 (m, 2H), 5.27 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 8.29 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 13.7, 18.0, 19.4, 21.7, 24.7, 30.9, 31.1, 38.4, 58.0, 120.7, 146.6, 168.4; LC-MS (ESI) m/z 253 ([M + 1]⁺).

N-Isopropyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide (1fba). White solid; Yield: 88%. ¹H-NMR (DMSO-d₆) δ 1.07 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.70 (d, J = 7.2 Hz, 3H), 3.81 (m, 1H), 5.35 (q, J = 7.1 Hz, 1H), 7.33 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.88 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 7.5 Hz, 1H), 8.68 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 58.3, 120.6, 125.1, 127.8, 128.9, 130.9, 146.0, 167.5; LC-MS (ESI) m/z 259 ([M + 1]⁺).

N-Isopropyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1fbb). Light brown solid; Yield: 83%. ¹H-NMR (DMSO-d₆) δ 1.06 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.69 (d, J = 7.2 Hz, 3H), 3.79 (s, 3H), 3.82 (m, 1H), 5.33 (q, J = 7.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.32 (d, J = 7.5 Hz, 1H), 8.56 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 55.1, 58.3, 114.3, 119.6, 123.5, 126.4, 145.9, 158.9, 167.5; LC-MS (ESI) m/z 289 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-isopropyl-propanamide (1fbc). White solid; Yield: 78%. ¹H-NMR (DMSO-d₆) δ 1.07 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.71 (d, J = 7.3 Hz, 3H), 3.80 (m, 1H), 5.38 (q, J = 7.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 8.36 (d, J = 7.3 Hz, 1H), 8.93 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 58.4, 110.0, 118.8, 122.5, 125.6, 133.0, 135.3, 144.5, 167.3; LC-MS (ESI) m/z 284 ([M + 1]⁺).

N-Isopropyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propanamide (1fbd). White solid; Yield: 75%. ¹H-NMR (DMSO-d₆) δ 1.06 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.68 (d, J = 7.2 Hz, 3H), 3.81 (m, 1H), 5.34 (q, J = 7.1 Hz, 1H), 7.55 (dd, J = 1.2, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 5.0 Hz, 1H), 7.86 (dd, J = 1.2, 3.0 Hz, 1H), 8.33 (d, J = 7.4 Hz, 1H), 8.55 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.1, 22.1, 40.9, 58.2, 120.3, 120.6, 125.8, 127.0, 132.2, 142.6, 167.5; LC-MS (ESI) m/z 265 ([M + 1]⁺).

N-Isopropyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide (1fbe). White solid; Yield: 81%. ¹H-NMR (DMSO-d₆) δ 1.06 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.72 (d, J = 7.2 Hz, 3H), 3.82 (m, 1H), 5.38 (q, J = 7.2 Hz, 1H), 7.35 (ddd, J = 1.2, 4.8, 7.5 Hz, 1H), 7.89 (dt, J = 1.8, 7.7 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.60 (m, 1H), 8.61 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 58.4, 119.4, 122.3, 122.9, 137.2, 146.9, 149.6, 150.0, 167.3; LC-MS (ESI) m/z 260 ([M + 1]⁺).

2-(4-Butyl-1H-1,2,3-triazol-1-yl)- N-isopropyl-propanamide (1fbf). White solid; Yield: 82%. ¹H-NMR (DMSO-d₆) δ 0.89 (t, J = 7.43 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H), 1.32 (m, 2H), 1.57 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H), 2.60 (t, J = 7.6 Hz, 2H), 3.79 (m, 1H), 5.24 (q, J = 7.2 Hz, 1H), 7.88 (s, 1H), 8.24 (d, J = 7.4 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 13.7, 18.1, 21.7, 22.1, 24.7, 31.1, 40.8, 58.0, 120.7, 146.5, 167.6; LC-MS (ESI) m/z 239 ([M + 1]⁺).

3.4. General Procedure for the Preparation of Tertiary 1,2,3-Triazoloamides 2 in Solution-Phase

A typical procedure for the desired tertiary 1,2,3-triazoloamide 2, as exemplified for 1-morpholino-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone (2aaa; R¹R²N = morpholine, A = CH₂, R³ = Ph).

3.4.1. Preparation of Chloro-Amide 15

To a solution of morpholine (14a; 4.50 mL, 51.45 mmol) and triethylamine (7.90 mL, 56.68 mmol) in CH₂Cl₂ (80 mL) was slowly added 2-chloroacetyl chloride (6a; 3.70 mL, 46.45 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 6 h, and then diluted with CH₂Cl₂, washed with saturated NaHCO₃ and brine, dried over MgSO₄ and filtered. The residue was concentrated under reduced pressure to afford α-chloroamide 15aa (7.55 g, 99%) as a light yellow liquid: ¹H-NMR (CDCl₃) δ 3.54 (t, J = 4.5 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H), 3.70–3.74 (m, 4H), 4.07 (s, 2H); ¹³C-NMR (CDCl₃) δ 40.7, 42.5, 46.8, 66.6, 66.7, 165.3; LC-MS (ESI) m/z 164 ([M + 1]⁺).

3.4.2. Preparation of Azidoamide 16

To a solution of α-chloroamide 15aa (1.41 g, 8.62 mmol) in acetonitrile (20 mL) and H₂O (1 mL) was added sodium azide (700 mg, 10.77 mmol). The reaction mixture was stirred at room temperature for 1 day, and then diluted with EtOAc, washed with brine, dried over MgSO₄ and filtered. The solvent was removed, and the residue was passed through a short plug of silica to give α-azidoamide 16aa (1.40 g, 99%) as a colorless oil: ¹H-NMR (CDCl₃) δ 3.38 (t, J = 4.8 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H), 3.67–3.71 (m, 4H), 3.92 (s, 2H); ¹³C-NMR (CDCl₃) δ 42.3, 45.6, 50.6, 66.5, 66.8, 165.9; LC-MS (ESI) m/z 171 ([M + 1]⁺).

3.4.3. Preparation of Tertiary 1,2,3-Triazoloamide 2

To a mixture of α-azidoamide 16aa (34 mg, 0.20 mmol) and phenylacetylene (9a; 24 μL, 0.20 mmol) in t-BuOH/H₂O (2 mL, 1:1) were added 0.5 M CuSO₄ (0.020 mL, 0.010 mmol) and 1.0 M sodium ascorbate (0.020 mL, 0.020 mmol). The reaction mixture was stirred at room temperature for 1 day, and then the resulting reaction mixture was filtered. The separated solid was washed with H₂O and hexanes, and triturated with hexane/EtOAc (10:1) to give the 1-morpholino-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone (2aaa; 52 mg, 96%) as a white solid: Mp 229–231 °C; ¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.71 (m, 4H), 5.28 (s, 2H), 7.34 (m, 1H), 7.41–7.45 (m, 2H), 7.84–7.86 (m, 2H), 7.99 (s, 1H); ¹³C-NMR (CDCl₃) δ 42.7, 46.0, 51.0, 66.5, 66.7, 121.3, 125.9, 128.4, 129.0, 130.5, 148.3, 163.7; IR (ATR) υ_max 3134, 2984, 2858, 1661, 1643, 1471, 1426, 1236, 1112, 1036, 768 (cm⁻¹); LC-MS (ESI) m/z 273 ([M + 1]⁺); HRMS (FAB) calcd for C₁₄H₁₇N₄O₂ ([M + H]⁺) 273.1346, found 273.1342.

3.5. Characterization Data of Tertiary 1,2,3-Triazoloamides 2

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aab). White solid; Yield: 96%. ¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.70 (m, 4H), 3.85 (s, 3H), 5.26 (s, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.9, 65.87, 65.94, 114.3, 122.1, 123.4, 126.4, 146.0, 158.9, 164.5; LC-MS (ESI) m/z 303 ([M + 1]⁺).

4-[1-(2-Morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl]benzonitrile (2aac). Yellow solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.8 Hz, 2H), 3.67 (t, J = 4.8 Hz, 2H), 3.72–3.76 (m, 4H), 5.31 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 8.10 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9. 44.7. 50.9. 65.86. 65.92. 110.2. 118.8. 124.8. 125.7. 133.0. 135.3. 144.6. 164.3; LC-MS (ESI) m/z 298 ([M + 1]⁺).

1-Morpholino-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2aad). Light brown solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 3.60–3.62 (m, 2H), 3.65–3.66 (m, 2H), 3.69–3.71 (m, 4H), 5.26 (s, 2H), 7.39 (dd, J = 3.0, 5.0 Hz, 1H), 7.46 (dd, J = 1.2, 5.0 Hz, 1H), 7.70 (dd, J = 1.3, 3.0 Hz, 1H), 7.88 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.6, 65.86, 65.93, 120.6, 122.8, 125.8, 127.1, 132.1, 142.7, 164.4; LC-MS (ESI) m/z 279 ([M + 1]⁺).

1-Morpholino-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanone (2aae). Light brown solid; Yield: 84%. ¹H-NMR (CDCl₃) δ 3.55 (t, J = 4.8 Hz, 2H), 3.61 (t, J = 4.7 Hz, 2H), 3.65–3.68 (m, 4H), 4.11 (s, 2H), 5.15 (s, 2H), 7.22 (m, 1H), 7.25–7.31 (m, 4H), 7.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.8, 65.8, 65.9, 119.3, 122.9, 125.0, 137.2, 147.0, 149.6, 150.0, 164.4; LC-MS (ESI) m/z 274 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aag). White solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 3.62 (m, 2H), 3.66 (m, 2H), 3.69–3.71 (m, 4H), 3.87 (s, 3H), 5.27 (s, 2H), 6.89 (ddd, J = 1.1, 2.6, 8.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.38 (td, J = 1.3, 7.6 Hz, 1H), 7.45 (dd, J = 1.5, 2.5 Hz, 1H), 7.97 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.8, 50.7, 55.1, 65.87, 65.94, 110.3, 113.5, 117.4, 123.3, 130.0, 132.1, 146.0, 159.7, 164.4; LC-MS (ESI) m/z 303 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aah). White solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 3.62 (m, 2H), 3.66-3.69 (m, 6H), 3.94 (s, 3H), 5.27 (s, 2H), 6.98 (dd, J = 0.8, 8.3 Hz, 1H), 7.08 (dt, J = 1.0, 7.6 Hz, 1H), 7.32 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.23 (s, 1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.6, 55.4, 65.8, 65.9, 111.5, 119.1, 120.6, 125.6, 126.4, 128.8, 141.5, 155.3, 164.6; LC-MS (ESI) m/z 303 ([M + 1]⁺).

1-Morpholino-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2aai). White solid; Yield: 91. ¹H-NMR (CDCl₃) δ 2.38 (s, 3H), 3.62 (m, 2H), 3.66 (m, 2H), 3.70 (m, 4H), 5.26 (s, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 41.9, 44.7, 50.7, 65.86, 65.93, 122.6, 125.0, 128.0, 129.4, 137.1, 146.1, 164.5; LC-MS (ESI) m/z 287 ([M + 1]⁺).

1-Morpholino-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2aaj). Light yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 2.40 (s, 3H), 3.62 (m, 2H), 3.66 (m, 2H), 3.69 (m, 4H), 5.27 (s, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.97 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 41.9, 44.8, 50.7, 65.88, 65.94, 122.3, 123.0, 125.7, 128.4, 128.8, 130.7, 138.0, 146.2, 164.4; LC-MS (ESI) m/z 287 ([M + 1]⁺).

1-Morpholino-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2aak). White solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 2.49 (s, 3H), 3.62 (m, 2H), 3.66 (m, 2H), 3.69–3.71 (m, 4H), 5.30 (s, 2H), 7.27–7.29 (m, 3H), 7.79 (m, 1H), 7.87 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 41.9, 44.7, 50.6, 65.86, 65.94, 125.0, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.2, 164.5; LC-MS (ESI) m/z 287 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-morpholinoethanone (2aal). Light green solid; Yield: 86%. ¹H-NMR (CDCl₃) δ 2.99 (s, 6H), 3.60–3.62 (m, 2H), 3.66–3.70 (m, 6H), 5.24 (s, 2H), 6.77 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.84 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 40.5, 41.9, 44.8, 50.6, 65.87, 65.94, 112.4, 118.7, 121.2, 126.0, 146.7, 150.0, 164.6; LC-MS (ESI) m/z 316 ([M + 1]⁺).

1-Morpholino-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2aam). Yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.70–3.72 (m, 4H), 5.27 (s, 2H), 7.04–7.08 (m, 4H), 7.15 (m, 1H), 7.34-7.38 (m, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.8, 50.7, 65.87, 65.94, 118.8, 118.9, 122.7, 123.7, 126.1, 126.9, 130.1, 145.6, 156.36, 156.44, 164.4; LC-MS (ESI) m/z 365 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aan). White solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 3.60–3.62 (m, 2H), 3.65–3.67 (m, 2H), 3.70–3.73 (m, 4H), 5.29 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 7.00 (m, 1H), 8.09 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.8, 65.8, 65.9, 104.6 (t, J_CF = 26.0 Hz), 112.3 (dd, J_CF = 21.2, 3.6 Hz), 115.3 (dd, J_CF = 13.3, 3.7 Hz), 125.2 (d, J_CF = 11.1 Hz), 128.4 (dd, J_CF = 9.7, 5.3 Hz), 138.8 (d, J_CF = 2.6 Hz), 158.5 (dd, J_CF = 250.1, 12.6 Hz), 161.7 (dd, J_CF = 247.5, 12.6 Hz), 164.4; LC-MS (ESI) m/z 309 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-morpholinoethanone (2aao). White solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 3.60 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.70–3.72 (m, 4H), 5.28 (s, 2H), 7.24 (m, 1H), 7.78 (m, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H), 8.59 (d, J = 4.2 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 31.2, 41.9, 44.7, 50.4, 65.8, 65.9, 124.2, 126.1, 128.4, 128.5, 139.7, 145.7, 164.6; LC-MS (ESI) m/z 287 ([M + 1]⁺).

2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(piperidin-1-yl)ethanone (2baa). Light yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.68 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 5.28 (s, 2H), 7.33 (m, 1H), 7.41–7.44 (m, 2H), 7.84–7.86 (m, 2H), 8.00 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.9, 123.1, 125.1, 127.8, 128.9, 130.9, 146.0, 163.7; LC-MS (ESI) m/z 271 ([M + 1]⁺).

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bab). White solid; Yield: 85%. ¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.67 (m, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.5 Hz, 2H), 3.84 (s, 3H), 5.28 (s, 2H), 6.96 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 55.1, 114.3, 122.1, 123.5, 126.4, 146.0, 158.9, 163.8; LC-MS (ESI) m/z 301 ([M + 1]⁺).

4-{1-[2-Oxo-2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}benzonitrile (2bac). Yellow solid; Yield: 98%. ¹H-NMR (CDCl₃) δ 1.59–1.67 (m, 4H), 1.70 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 5.30 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 8.10 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 51.0, 110.0, 118.8, 124.8, 125.6, 133.0, 135.3, 144.5, 163.6; LC-MS (ESI) m/z 296 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2bad). Light brown solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 1.57–1.62 (m, 4H), 1.65–1.69 (m, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.38 (dd, J = 3.0, 5.0 Hz, 1H), 7.46 (dd, J = 0.9, 5.0 Hz, 1H), 7.69 (dd, J = 1.0, 2.9 Hz, 1H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 120.6, 122.9, 125.8, 127.1, 132.2, 142.6, 163.4; LC-MS (ESI) m/z 277 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanone (2bae). White solid; Yield: 90%. ¹H-NMR (CDCl₃) δ 1.52–1.58 (m, 4H), 1.61–1.66 (m, 2H), 3.45 (t, J = 5.5 Hz, 2H), 3.54 (t, J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.19 (ddd, J = 1.2, 4.9, 7.5 Hz, 1H), 7.74 (dt, J = 1.8, 7.8 Hz, 1H), 8.11 (td, J = 1.0, 7.9 Hz, 1H), 8.29 (s, 1H), 8.56 (ddd, J = 0.9, 1.7, 4.9 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.9, 119.3, 122.8, 125.0, 137.2, 146.9, 149.6, 150.1, 163.7; LC-MS (ESI) m/z 272 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bag). White solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 1.57–1.62 (m, 4H), 1.67 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 3.87 (s, 3H), 5.27 (s, 2H), 6.89 (ddd, J = 1.0, 2.6, 8.1 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.38 (td, J = 1.3, 7.6 Hz, 1H), 7.46 (dd, J = 1.5, 2.5 Hz, 1H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.9, 55.1, 110.2, 113.5, 117.4, 123.4, 130.0, 132.2, 145.9, 159.7, 163.7; LC-MS (ESI) m/z 301 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bah). White solid; Yield: 95%. ¹H-NMR (CDCl₃) δ 1.52–1.58 (m, 4H), 1.65 (m, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H), 3.92 (s, 3H), 5.26 (s, 2H), 6.97 (dd, J = 0.6, 8.3 Hz, 1H), 7.07 (dt, J = 1.0, 7.6 Hz, 1H), 7.30 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.23 (s, 1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.7, 22.4, 111.5, 119.2, 120.6, 125.6, 126.4, 128.7, 141.4, 155.3, 163.9; LC-MS (ESI) m/z 301 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2bai). Light yellow solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 1.57–1.60 (m, 4H), 1.67 (m, 2H), 2.38 (s, 3H), 3.52 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.95 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 122.7, 125.0, 128.1, 129.4, 137.0, 146.1, 163.8; LC-MS (ESI) m/z 285 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2baj). Light yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.67 (m, 2H), 2.40 (s, 3H), 3.51 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.97 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 122.3, 123.0, 125.6, 128.4, 128.8, 130.8, 138.0, 146.1, 163.7; LC-MS (ESI) m/z 285 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2bak). Light yellow solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 1.57–1.61 (m, 4H), 1.68 (m, 2H), 2.49 (s, 3H), 3.53 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 5.29 (s, 2H), 7.27–7.28 (m, 3H), 7.79 (m, 1H), 7.88 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 125.0, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.2, 163.8; LC-MS (ESI) m/z 285 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(piperidin-1-yl)ethanone (2bal). Light green solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 1.53-1.57 (m, 4H), 1.64–1.68 (m, 2H), 2.99 (s, 6H), 3.51 (t, J = 5.5 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H), 5.24 (s, 2H), 6.77 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.84 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 40.0, 42.5, 45.2, 50.7, 112.4, 118.8, 121.2, 126.0, 146.6, 149.9, 163.9; LC-MS (ESI) m/z 314 ([M + 1]⁺).

2-[4-(4-Phenoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bam). Light yellow solid; Yield: 99%.¹H-NMR (CDCl₃) δ 1.59–1.62 (m, 4H), 1.66–1.71 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.5 Hz, 2H), 5.27 (s, 2H), 7.04–7.07 (m, 4H), 7.13 (m, 1H), 7.34–7.37 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 118.8, 118.9, 122.7, 123.6, 126.2, 126.8, 130.1, 145.6, 156.3, 156.4, 163.7; LC-MS (ESI) m/z 363 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2ban). Yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 1.58–1.64 (m, 4H), 1.66–1.71 (m, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 5.29 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (m, 1H), 8.09 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.7, 42.5, 45.2, 50.9, 104.6 (t, J_CF = 26.0 Hz), 112.3 (d, J_CF = 24.6 Hz), 115.3 (dd, J_CF = 13.1, 4.0 Hz), 125.2 (d, J_CF = 11.9 Hz), 128.4 (dd, J_CF = 9.4, 5.7 Hz), 138.7 (d, J_CF = 2.4 Hz), 158.5 (dd, J_CF = 250.0, 12.6 Hz), 161.6 (dd, J_CF = 247.5, 12.6 Hz), 163.7; LC-MS (ESI) m/z 307 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-(piperidin-1-yl)ethanone (2bao). White solid; Yield: 95%. ¹H-NMR (CDCl₃) δ 1.52–1.57 (m, 4H), 1.63–1.67 (m, 2H), 3.45 (t, J = 5.5 Hz, 2H), 3.56 (t, J = 5.6 Hz, 2H), 4.10 (s, 2H), 5.15 (s, 2H), 7.20 (m, 1H), 7.24–7.30 (m, 4H), 7.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.7, 31.2, 42.4, 45.2, 50.5, 124.2, 126.1, 128.4, 128.5, 139.7, 145.6, 163.9; LC-MS (ESI) m/z 285 ([M + 1]⁺).

2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(pyrrolidin-1-yl)ethanone (2caa). Light yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.7, 7.0 Hz, 2H), 2.05 (tt, J = 6.8, 7.0 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 5.19 (s, 2H), 7.33 (m, 1H), 7.41–7.44 (m, 2H), 7.84–7.86 (m, 2H), 8.06 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 123.0, 125.1, 127.8, 128.9, 130.8, 146.0, 163.7; LC-MS (ESI) m/z 257 ([M + 1]⁺).

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cab). White solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 1.91 (tt, J = 6.8, 7.1 Hz, 2H), 2.03 (tt, J = 6.8, 7.0 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 5.17 (s, 2H), 6.96 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.9 Hz, 2H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 55.1, 114.3, 122.0, 1234, 126.4, 146.0, 158.9, 163.7; LC-MS (ESI) m/z 287 ([M + 1]⁺).

4-{1-[2-Oxo-2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}benzonitrile (2cac). Yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.93 (tt, J = 6.9, 7.1 Hz, 2H), 2.07 (tt, J = 6.8, 6.9 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H), 3.60 (t, J = 6.9 Hz, 2H), 5.21 (s, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 8.17 (s, 1H); ¹³C- NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.9, 51.5, 110.0, 118.8, 124.7, 125.7, 133.0, 135.3, 144.5, 163.5; LC-MS (ESI) m/z 282 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2cad). Light green solid; Yield: 88%. ¹H-NMR (CDCl₃) δ 1.91 (tt, J = 6.7, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 5.18 (s, 2H), 7.38 (dd, J = 3.0, 5.0 Hz, 1H), 7.47 (dd, J = 1.2, 5.0 Hz, 1H), 7.69 (dd, J = 1.3, 3.0 Hz, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.3, 120.6, 122.7, 125.8, 127.1, 132.2, 142.6, 163.7; LC-MS (ESI) m/z 263 ([M + 1]⁺).

2-[4-(Pyridin-2-yl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cae). Light yellow solid; Yield: 87%. ¹H-NMR (CDCl₃) δ 1.89 (tt, J = 6.9, 7.0 Hz, 2H), 2.02 (tt, J = 6.8, 6.9 Hz, 2H), 3.52 (t, J = 6.9 Hz, 2H), 3.54 (t, J = 6.8 Hz, 2H), 5.20 (s, 2H), 7.21 (ddd, J = 1.2, 4.9, 7.5 Hz, 1H), 7.76 (dt, J = 1.8, 7.7 Hz, 1H), 8.14 (td, J = 1.0, 7.9 Hz, 1H), 8.35 (s, 1H), 8.58 (ddd, J = 0.9, 1.7, 4.9 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.2, 45.9, 51.5, 119.4, 122.9, 124.8, 137.2, 146.9, 149.6, 150.1, 163.6; LC-MS (ESI) m/z 258 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cag). White solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.8, 6.8 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 3.87 (s, 3H), 5.19 (s, 2H), 6.88 (ddd, J = 1.0, 2.6, 8.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.39 (td, J = 1.3, 7.6 Hz, 1H), 7.46 (dd, J = 1.6, 2.5 Hz, 1H), 8.05 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.2, 45.8, 51.4, 55.1, 110.3, 113.5, 117.5, 123.2, 130.1, 132.2, 146.0, 159.7, 163.7; LC-MS (ESI) m/z 287 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cah). White solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 1.90 (tt, J = 6.8, 6.9 Hz, 2H), 2.02 (tt, J = 6.8, 6.8 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.56 (t, J = 6.9 Hz, 2H), 3.93 (s, 3H), 5.19 (s, 2H), 6.72 (dd, J = 0.7, 8.3 Hz, 1H), 7.07 (dt, J = 1.0, 7.5 Hz, 1H), 7.31 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.29 (s, 1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C- NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.2, 55.5, 111.5, 119.2, 120.7, 125.5, 126.4, 128.8, 141.5, 155.3, 163.9; LC-MS (ESI) m/z 287 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2cai). White solid; Yield: 96%. ¹H-NMR (CDCl₃) δ 1.91 (tt, J = 6.9, 6.9 Hz, 2H), 2.04 (tt, J = 6.8, 6.8 Hz, 2H), 2.38 (s, 3H), 3.53 (t, J = 7.0 Hz, 2H), 3.57 (t, J = 6.9 Hz, 2H), 5.18 (s, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 8.01 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 23.7, 25.6, 45.2, 45.8 51.4, 122.5, 125.0, 128.1, 129.5, 137.1, 146.1, 163.7; LC-MS (ESI) m/z 271 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2caj). White solid; Yield: 96%. ¹H-NMR (CDCl₃) δ 1.91 (tt, J = 6.8, 6.8 Hz, 2H), 2.03 (tt, J = 6.8, 6.8 Hz, 2H), 2.40 (s, 3H), 3.53 (t, J = 7.0 Hz, 2H), 3.57 (t, J = 6.8 Hz, 2H), 5.18 (s, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 8.03 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 23.7, 25.6, 45.1, 45.8, 51.4, 122.3, 122.9, 125.6, 128.4, 128.8, 130.7, 138.0, 146.1, 163.7; LC-MS (ESI) m/z 271 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2cak). White solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.8, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.8 Hz, 2H), 2.49 (s, 3H), 3.54 (t, J = 7.0 Hz, 2H), 3.59 (t, J = 6.9 Hz, 2H), 5.21 (s, 2H), 7.26–7.28 (m, 3H), 7.79 (m, 1H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 23.7, 25.6, 45.1, 45.8, 51.3, 124.8, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.2, 163.7; LC-MS (ESI) m/z 271 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(pyrrolidin-1-yl)ethanone (2cal). Light yellow solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.90 (tt, J = 6.7, 6.9 Hz, 2H), 2.02 (tt, J = 6.8, 6.9 Hz, 2H), 2.99 (s, 6H), 3.52 (t, J = 7.0 Hz, 2H), 3.56 (t, J = 6.9 Hz, 2H), 5.16 (s, 2H), 6.77 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.90 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 40.0, 45.1, 45.8, 51.3, 112.4, 118.8, 121.1, 126.0, 146.6, 150.0, 163.8; LC-MS (ESI) m/z 300 ([M + 1]⁺).

2-[4-(4-Phenoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cam). Light yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.8, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 5.19 (s, 2H), 7.04–7.07 (m, 4H), 7.12 (m, 1H), 7.34–7.37 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H), 8.00 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 118.8, 118.9, 122.6, 123.6, 126.2, 126.8, 130.1, 145.6, 156.3, 156.4, 163.7; LC-MS (ESI) m/z 349 ([M + 1]⁺).

2-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2can). Light yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ. 1.92 (tt, J = 6.7, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 5.20 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (m, 1H), 8.14 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 104.6 (t, J_CF = 26.0 Hz), 112.3 (dd, J_CF = 20.2, 4.8 Hz), 115.3 (dd, J_CF = 13.4, 3.8 Hz), 125.0 (d, J_CF = 11.1 Hz), 128.5 (dd, J_CF = 9.8, 5.3 Hz),138.7, 158.5 (dd, J_CF = 250.0, 12.6 Hz), 161.7 (dd, J_CF = 247.4, 12.7 Hz), 163.6; LC-MS (ESI) m/z 293 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-(pyrrolidin-1-yl)ethanone (2cao). White solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.86 (tt, J = 6.8, 7.0 Hz, 2H), 1.99 (tt, J = 6.8, 7.0 Hz, 2H), 3.46 (t, J = 7.0 Hz, 2H), 3.49 (t, J = 6.9 Hz, 2H), 4.08 (s, 2H), 5.05 (s, 2H), 7.19 (m, 1H), 7.24–7.29 (m, 4H), 7.42 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 31.2, 45.1, 45.7, 51.1, 124.0, 126.1, 128.4, 128.5, 139.7, 145.6, 163.8; LC-MS (ESI) m/z 271 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone (2daa). Light yellow solid; Yield: 95%. ¹H-NMR (CDCl₃) δ 1.58–1.63 (m, 4H), 1.72-1.77 (m, 2H), 1.78–1.83 (m, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.0 Hz, 2H), 5.27 (s, 2H), 7.33 (m, 1H), 7.41–7.44 (m, 2H), 7.84–7.86 (m, 2H), 8.04 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.7, 123.2, 125.1, 277, 128.9, 130.9, 146.0, 165.0; LC-MS (ESI) m/z 285 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dab). White solid; Yield: 86%. ¹H-NMR (CDCl₃) δ 1.59-1.63 (m, 4H), 1.72-1.76 (m, 2H), 1.77–1.82 (m, 2H), 3.53–3.59 (m, 4H), 3.84 (s, 3H), 5.25 (s, 2H), 6.95 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.95 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.7, 55.1, 114.3, 122.2, 123.5, 126.4, 145.9, 158.9, 165.0; LC-MS (ESI) m/z 315 ([M + 1]⁺).

4-{1-[2-(Azepan-1-yl)-2-oxoethyl]-1H-1,2,3-triazol-4-yl}benzonitrile (2dac). Yellow solid; Yield: 97%. ¹H-NMR (CDCl₃) δ 1.57–1.66 (m, 4H), 1.75 (tt, J = 5.9, 6.0 Hz, 2H), 1.84 (tt, J = 5.9, 6.0 Hz, 2H), 3.56–3.60 (m, 4H), 5.29 (s, 2H), 7.71 (d, J = 6.7 Hz, 2H), 7.96 (d, J = 6.7 Hz, 2H), 8.15 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.4, 27.0, 28.1, 45.5, 46.4, 50.9, 110.0, 118.8, 124.9, 125.6, 133.0, 133.3, 144.5, 164.8; LC-MS (ESI) m/z 310 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2dad). Light brown solid; Yield: 98%. ¹H-NMR (CDCl₃) δ 1.58–1.61 (m, 4H), 1.75 (tt, J = 5.8, 5.8 Hz, 2H), 1.80 (tt, J = 5.8, 5.9 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 5.9 Hz, 2H), 5.26 (s, 2H), 7.37 (dd, J = 3.0, 5.0 Hz, 1H), 7.47 (dd, J = 1.3, 5.0 Hz, 1H), 7.69 (dd, J = 1.2, 3.0 Hz, 1H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.7, 120.6, 122.9, 125.8, 127.0, 132.2, 142.6, 165.0; LC-MS (ESI) m/z 291 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanone (2dae). Light brown solid; Yield: 86%. ¹H-NMR (CDCl₃) δ 1.59–1.64 (m, 4H), 1.74 (tt, J = 5.9, 6.0 Hz, 2H), 1.80 (tt, J = 5.8, 6.0 Hz, 2H), 3.55 (t, J = 6.1 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 5.28 (s, 2H), 7.22 (ddd, J = 1.1, 4.9, 7.5 Hz, 1H), 7.76 (dt, J = 1.8, 7.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.59 (d, J = 4.3 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.0, 28.2, 45.5, 46.4, 50.8, 119.3, 122.9, 125.1, 137.2, 146.9, 149.6, 150.1, 164.9; LC-MS (ESI) m/z 286 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dag). Light yellow solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 1.58–1.61 (m, 4H), 1.75 (m, 2H), 1.80 (m, 2H), 3.56–3.59 (m, 4H), 3.87 (s, 3H), 5.27 (s, 2H), 6.88 (ddd, J = 1.0, 2.6, 8.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.39 (td, J = 1.2, 7.6 Hz, 1H), 7.46 (dd, J = 1.5, 2.5 Hz, 1H), 8.03 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.8, 55.1, 110.2, 113.5, 117.4, 123.4, 130.0, 132.2, 145.9, 159.7, 165.0; LC-MS (ESI) m/z 315 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dah). White solid; Yield: 88%. ¹H-NMR (CDCl₃) δ 1.55–1.61 (m, 4H), 1.72–1.78 (m, 4H), 3.56–3.59 (m, 4H), 3.93 (s, 3H), 5.27 (s, 2H), 6.97 (dd, J = 0.7, 8.3 Hz, 1H), 7.07 (dt, J = 1.0, 7.6 Hz, 1H), 7.31 (ddd, J = 1.8, 7.4, 8.3 Hz, 1H), 8.27 (s, 1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.1, 45.4, 46.4, 50.5, 55.5, 111.5, 119.2, 120.6, 125.7, 126.4, 128.7, 141.4, 155.3, 165.2; LC-MS (ESI) m/z 315 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2dai). White solid; Yield: 97%. ¹H-NMR (CDCl₃) δ 1.55–1.62 (m, 4H), 1.74 (m, 2H), 1.79 (m, 2H), 2.38 (s, 3H), 3.55–3.59 (m, 4H), 5.26 (s, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 26.2, 26.7, 27.1, 28.2, 45.5, 46.5, 50.7, 122.7, 125.0, 128.1, 129.4, 137.0, 146.1, 165.0; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2daj). White solid; Yield: 91%. ¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.74 (m, 2H), 1.79 (m, 2H), 2.40 (s, 3H), 3.55–3.59 (m, 4H), 5.26 (s, 2H), 7.15 (dd, J = 0.6, 7.6 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 8.02 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 26.2, 26.7, 27.0, 28.2, 45.5, 46.5, 50.7, 122.2, 123.1, 125.6, 128.4, 128.8, 130.8, 138.0, 146.1, 165.0; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2dak). Light yellow solid; Yield: 86%. ¹H-NMR (CDCl₃) δ 1.58–1.63 (m, 4H), 1.75 (m, 2H), 1.80 (m, 2H), 2.49 (s, 3H), 3.57–3.60 (m, 4H), 5.29 (s, 2H), 7.26–7.28 (m, 3H), 7.78 (m, 1H), 7.92 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.7, 125.1, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.1, 165.0; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1-(Azepan-1-yl)-2-{4-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}ethanone (2dal). Light brown solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 1.57–1.58 (m, 4H), 1.73–1.77 (m, 4H), 2.99 (s, 6H), 3.56 (t, J = 6.0 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 5.23 (s, 2H), 6.77 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 40.0, 45.5, 46.5, 50.6, 112.4, 118.8, 121.3, 126.0, 146.6, 150.0, 165.1; LC-MS (ESI) m/z 328 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dam). Light yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 1.59–1.66 (m, 4H), 1.73–1.77 (m, 2H), 1.7–1.83 (m, 2H), 3.57 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.0 Hz, 2H), 5.27 (s, 2H), 7.04–7.06 (m, 4H), 7.12 (m, 1H), 7.34–7.37 (m, 2H), 7.81 (d, J = 8.9 Hz, 2H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.5, 50.7, 118.8, 118.9 ,122.8, 123.6, 126.2, 126.8, 130.1, 145.6, 456.3, 156.4, 165.0; LC-MS (ESI) m/z 377 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(2,4-difluorophenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dan). Yellow solid; Yield: 98%. ¹H-NMR (CDCl₃) δ 1.57–1.65 (m, 4H), 1.75 (tt, J = 5.8, 5.9 Hz, 2H), 1.82 (tt, J = 5.8, 5.9 Hz, 2H), 3.56 (t, J = 6.1 Hz, 2H), 3.58 (t, J = 6.1 Hz, 2H), 5.28 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (dddd, J = 1.0, 2.5, 8.0, 10.4 Hz, 1H), 8.13 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.1, 45.5, 46.4, 50.8, 104.6 (t, J_CF = 26.0 Hz), 112.3 (dd, J_CF = 20.2, 4.8 Hz), 115.3 (dd, J_CF = 13.2, 3.7 Hz), 125.3 (d, J_CF = 10.9 Hz), 128.5 (dd, J_CF = 9.7, 5.4 Hz), 138.7 (d, J_CF = 2.4 Hz), 158.5 (dd, J_CF = 249.9, 12.5 Hz), 161.7 (dd, J_CF = 247.4, 12.7 Hz), 165.0; LC-MS (ESI) m/z 321 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-benzyl-1H-1,2,3-triazol-1-yl)ethanone (2dao). White solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.55–1.57 (m, 4H), 1.68–1.75 (m, 4H), 3.50 (t, J = 6.1 Hz, 2H), 3.52 (t, J = 6.1 Hz, 2H), 4.10 (s, 2H), 5.15 (s, 2H), 7.21 (m, 1H), 7.26–7.30 (m, 4H), 7.41 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.1, 31.3, 45.5, 46.5, 50.5, 124.3, 126.1, 128.4, 128.6, 139.7, 145.7, 165.1; LC-MS (ESI) m/z 299 ([M+1]⁺).

N-Methyl-N-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (2eaa). White solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 4.97 (s, 2H), 7.31–7.34 (m, 3H), 7.40–7.43 (m, 2H), 7.45 (m, 1H), 7.51–7.54 (m, 2H), 7.82–7.84 (m, 2H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 37.3, 51.1, 123.0, 125.1, 127.5, 127.8, 128.4, 129.0, 130.1, 130.8, 141.9, 146.0, 164.9; LC-MS (ESI) m/z 293 ([M + 1]⁺).

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-N-methyl-N-phenylacetamide (2eab). Yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 3.84 (s, 3H), 4.95 (s, 2H), 6.95 (d, J = 8.9 Hz, 2H), 7.30–7.32 (m, 2H), 7.45 (m, 1H), 7.50-7.53 (m, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 37.3, 51.0, 55.2, 114.3, 122.0, 123.4, 126.5, 127.5, 128.4, 130.1, 141.9, 146.0, 159.0, 164.9; LC-MS (ESI) m/z 323 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-methyl-N-phenylacetamide (2eac). White solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 4.98 (s, 2H), 7.30–7.34 (m, 2H) ,7.47 (m, 1H), 7.56–7.51 (m, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 8.10 (s, 1H); ¹³C-NMR (CDCl₃) δ 37.9, 51.4, 111.4, 118.9, 122.9, 126.2, 127.3, 129.2, 130.6, 132.7, 135.1, 141.7, 146.0, 164.7; LC-MS (ESI) m/z 318 ([M + 1]⁺).

N-Methyl-N-phenyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (2ead). White solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 3.34 (s, 3H), 4.97 (s, 2H), 7.21 (ddd, J = 1.1, 4.9, 7.5 Hz, 1H), 7.32 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.75 (dt, J = 1.8, 7.7 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.29 (s, 1H), 8.58 (ddd, J = 4.9, 1.6, 0.9 Hz, 1H; ¹³C-NMR (CDCl₃) δ 37.9, 51.3, 121.1, 121.4, 126.0, 126.3, 127.4, 129.1, 130.6, 132.0, 141.9, 144.1, 164.9; LC-MS (ESI) m/z 294 ([M + 1]⁺).

N-Methyl-N-phenyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (2eae). White solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 3.34 (s, 3H), 4.94 (s, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.36 (ddd, J = 5.0, 3.0, 0.6 Hz, 1H), 7.42–7.48 (m, 2H), 7.48–7.54 (m, 2H), 7.67 (m, 1H), 7.88 (s, 1H); ¹³C-NMR (CDCl₃) δ 37.9, 51.4, 120.3, 122.8, 124.0, 127.4, 129.1, 130.6, 136.8, 142.0, 148.6, 149.5, 150.4, 164.7; LC-MS (ESI) m/z 299 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-N-phenylacetamide (2eag). White solid; Yield: 93%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 3.86 (s, 3H), 4.96 (s, 2H), 6.88 (ddd, J = 1.1, 2.6, 8.1 Hz, 1H), 7.30–7.33 (m, 3H), 7.37 (td, J = 1.3, 7.6 Hz, 1H), 7.44 (dd, J = 1.5, 2.6 Hz, 1H), 7.45 (m, 1H), 7.50–7.53 (m, 2H), 7.98 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 37.3, 51.1, 55.1, 110.3, 113.6, 117.5, 123.2, 127.5, 128.4, 130.1, 132.1 (2C), 141.9, 146.0, 159.7, 164.9; LC-MS (ESI) m/z 315 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-N-phenylacetamide (2eah). Light yellow solid; Yield: 95%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 3.93 (s, 3H), 4.97 (s, 2H), 6.97 (d, J = 8.3 Hz, 1H), 7.06 (dt, J = 0.9, 7.5 Hz, 1H), 7.28–7.33 (m, 3H), 7.45 (m, 1H), 7.50–7.53 (m, 2H), 8.22 (s, 1H), 8.33 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 37.5, 51.2, 55.7, 111.8, 119.2, 120.9, 125.9, 126.7, 127.7, 128.7, 129.2, 130.3, 141.7, 142.1, 155.5, 165.3; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-Methyl-N-phenyl-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)acetamide (2eai). White solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 2.37 (s, 3H), 3.35 (s, 3H), 4.95 (s, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.30–7.32 (m, 2H), 7.45 (m, 1H), 7.50–7.53 (m, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 37.2, 51.0, 122.5, 125.0, 127.4, 128.0, 128.4, 129.4, 130.0, 137.1, 141.9, 146.0, 164.9; LC-MS (ESI) m/z 299 ([M + 1]⁺).

N-Methyl-N-phenyl-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (2eaj). White solid; Yield: 87%. ¹H-NMR (CDCl₃) δ 2.39 (s, 3H), 3.33 (s, 3H), 4.95 (s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.27–7.31 (m, 3H), 7.44 (m, 1H), 7.49–7.52 (m, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.0, 37.3, 51.0, 122.3, 122.9, 125.6, 127.4, 128.4, 128.8, 130.0, 130.7, 138.0, 141.9, 146.1, 164.9; LC-MS (ESI) m/z 299 ([M + 1]⁺).

N-Methyl-N-phenyl-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)acetamide (2eak). Colorless oil; Yield: 98. ¹H-NMR (CDCl₃) δ 2.45 (s, 3H), 3.32 (s, 3H), 4.97 (s, 2H), 7.22–7.24 (m, 3H), 7.29–7.31 (m, 2H), 7.42 (m, 1H), 7.47–7.50 (m, 2H), 7.76 (m, 1H), 7.86 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 37.3, 51.0, 124.9, 126.0, 127.5, 127.7, 128.0, 128.4, 130.0, 130.9, 134.7, 141.9, 145.1, 164.9; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1-Morpholino-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-1-one (2aca). Colorless oil; Yield: 94%. ¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 4.74 (t, J = 6.2 Hz, 2H), 7.30 (m, 1H), 7.38–7.41 (m, 2H), 7.78–7.81 (m, 2H), 7.93 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.4, 41.5, 45.2, 45.8, 65.97, 65.98, 121.8, 125.1, 127.8, 128.9, 130.8, 146.0, 168.0; LC-MS (ESI) m/z 287 ([M + 1]⁺).

3-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2acb). Colorless oil; Yield: 90%. ¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 3.81 (s, 3H), 4.72 (t, J = 6.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.83 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.5, 41.5, 45.2, 45.7, 55.1, 65.97, 65.99, 114.3, 120.8, 123.4, 126.4, 146.0, 158.9, 168.1; LC-MS (ESI) m/z 317 ([M + 1]⁺).

4-[1-(3-Morpholino-3-oxopropyl)-1H-1,2,3-triazol-4-yl]benzonitrile (2acc). White solid; Yield: 90%. ¹H-NMR (500 MHz, CDCl₃) δ 3.01 (t, J = 5.9 Hz, 2H), 3.42 (t, J = 4.9 Hz, 2H), 3.59-3.65 (m, 6H), 4.80 (t, J = 5.9 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 8.08 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ 32.3, 41.5, 45.1, 46.0, 65.95, 65.97, 110.0, 118.8, 123.6, 125.6, 133.0, 135.3, 144.4, 168.0; LC-MS (ESI) m/z 312 ([M + 1]⁺).

1-Morpholino-3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propan-1-one (2acd). Yellow oil; Yield: 98%. ¹H-NMR (CDCl₃) δ 2.95 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.55–3.61 (m, 6H), 4.72 (t, J = 6.1 Hz, 2H), 7.34 (dd, J = 3.0, 5.0 Hz, 1H), 7.42 (dd, J = 1.3, 5.0 Hz, 1H), 7.63 (dd, J = 1.2, 3.0 Hz, 1H), 7.83 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.5, 41.5, 45.2, 45.7, 65.96, 65.98, 120.6, 121.6, 125.7, 127.1, 132.1, 142.6, 168.0; LC-MS (ESI) m/z 293 ([M + 1]⁺).

1-Morpholino-3-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propan-1-one (2ace). Light yellow oil; Yield: 89%. ¹H-NMR (CDCl₃) δ 2.99 (t, J = 6.5 Hz, 2H), 3.39 (t, J = 4.8 Hz, 2H), 3.57–3.63 (m, 6H), 4.77 (t, J = 6.5 Hz, 2H), 7.20 (ddd, J = 1.0, 4.9, 7.5 Hz, 1H), 7.74 (dt, J = 1.7, 7.7 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 32.4, 41.5, 45.1, 45.8, 65.97, 65.99, 119.3, 122.9, 123.6, 137.2, 147.0, 149.6, 150.0, 168.1; LC-MS (ESI) m/z 288 ([M + 1]⁺).

3-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2acg). Colorless oil; Yield: 98%. ¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 3.83 (s, 3H), 4.73 (t, J = 6.2 Hz, 2H), 6.85 (ddd, J = 1.2, 2.6, 8.0 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.33 (td, J = 1.3, 7.6 Hz, 1H), 7.40 (dd, J = 1.5, 2.5 Hz, 1H), 7.92 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.4, 41.5, 45.2, 45.8, 55.1, 65.98, 66.00, 110.3, 13.5, 117.5, 122.1, 130.1, 132.2, 146.0, 459.7, 168.0; LC-MS (ESI) m/z 317 ([M + 1]⁺).

3-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2ach). Light yellow oil; Yield: 99%. ¹H-NMR (CDCl₃) δ 3.00 (t, J = 6.5 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.56–3.61 (m, 6H), 3.91 (s, 3H), 4.74 (t, J = 6.5 Hz, 2H), 6.95 (dd, J = 0.7, 8.3 Hz, 1H), 7.05 (dt, J = 1.0, 7.5 Hz, 1H), 7.29 (ddd, J = 1.7, 7.3, 8.3 Hz, 1H), 8.11 (s, 1H), 8.28 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 32.6, 41.5, 45.2, 45.6, 55.4, 66.0 (2C), 111.5, 119.2, 120.6, 124.3, 126.5, 128.8, 141.6, 155.3, 168.1; LC-MS (ESI) m/z 317 ([M + 1]⁺).

1-Morpholino-3-(4-p-tolyl-1H-1,2,3-triazol-1-yl)propan-1-one (2aci). Colorless oil; Yield: 93%. ¹H-NMR (CDCl₃) δ 2.35 (s, 3H), 2.96 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.55–3.61 (m, 6H), 4.72 (t, J = 6.2 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.87 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 32.4, 41.5, 45.2, 45.8, 65.96, 65.98, 121.4, 125.0, 128.1, 129.4, 137.0, 146.1, 168.0; LC-MS (ESI) m/z 301 ([M + 1]⁺).

1-Morpholino-3-(4-m-tolyl-1H-1,2,3-triazol-1-yl)propan-1-one (2acj). Colorless oil; Yield: 98%. ¹H-NMR (CDCl₃) δ 2.37 (s, 3H), 2.96 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 4.74 (t, J = 6.2 Hz, 2H), 7.12 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.91 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 32.4, 41.5, 45.2, 45.8, 65.98, 66.00, 121.7, 122.3, 125.6, 128.4, 128.8, 130.7, 138.0, 146.2, 168.1; LC-MS (ESI) m/z 301 ([M + 1]⁺).

1-Morpholino-3-(4-o-tolyl-1H-1,2,3-triazol-1-yl)propan-1-one (2ack). Light yellow oil; Yield: 90%. ¹H-NMR (CDCl₃) δ 2.45 (s, 3H), 3.00 (t, J = 6.3 Hz, 2H), 3.40 (t, J = 4.9 Hz, 2H), 3.57–3.62 (m, 6H), 4.77 (t, J = 6.3 Hz, 2H), 7.21–7.27 (m, 3H), 7.73 (m, 1H), 7.82 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 32.5, 41.5, 45.2, 45.8, 66.0, 66.02, 123.6, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.4, 168.1; LC-MS (ESI) m/z 301 ([M + 1]⁺).

3-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-morpholinopropan-1-one (2acl). Light yellow solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.3 Hz, 2H), 2.97 (s, 6H), 3.38 (t, J = 4.9 Hz, 2H), 3.57–3.62 (m, 6H), 4.72 (t, J = 6.3 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.5, 40.0, 41.5, 45.2, 45.7, 65.97, 65.99, 112.4, 119.9, 126.0, 130.2, 146.7, 149.9, 168.1; LC-MS (ESI) m/z 330 ([M + 1]⁺).

1-Morpholino-3-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]propan-1-one (2acm). Light yellow oil; Yield: 99%. ¹H-NMR (CDCl₃) δ 2.98 (t, J = 6.1 Hz, 2H), 3.39 (t, J = 4.8 Hz, 2H), 3.58–3.63 (m, 6H), 4.75 (t, J = 6.1 Hz, 2H), 7.02–7.05 (m, 4H), 7.12 (m, 1H), 7.32–7.35 (m, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.44, 41.5, 45.2, 45.8, 65.96, 65.98, 118.8, 118.9, 123.6, 124.2, 126.2, 126.8, 130.1, 145.6, 156.3, 156.4, 168.0; LC-MS (ESI) m/z 379 ([M + 1]⁺).

3-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2acn). Light yellow solid; Yield: 92. ¹H-NMR (CDCl₃) δ 3.02 (t, J = 6.3 Hz, 2H), 3.41 (t, J = 4.9 Hz, 2H), 3.60–3.65 (m, 6H), 4.79 (t, J = 6.3 Hz, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (m, 1H), 8.03 (d, J = 3.8 Hz, 1H), 8.24 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 32.5, 41.5, 45.2, 45.9, 66.0 (2C), 104.5 (t, J_CF = 26.0 Hz), 112.3 (dd, J_CF = 21.1, 3.7 Hz), 115.3 (dd, J_CF = 11.8, 5.4 Hz), 123.9 (d, J_CF = 10.4 Hz), 128.5 (dd, J_CF = 9.6, 5.5 Hz), 138.8 (d, J_CF = 2.5 Hz), 158.4 (dd, J_CF = 250.1, 12.6 Hz), 161.7 (dd, J_CF = 247.5, 12.6 Hz), 168.1; LC-MS (ESI) m/z 323 ([M + 1]⁺).

3-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-morpholinopropan-1-one (2aco). Colorless oil; Yield: 98%. ¹H-NMR (CDCl₃) δ 2.92 (t, J = 6.4 Hz, 2H), 3.35 (t, J = 4.9 Hz, 2H), 3.53–3.59 (m, 6H), 4.04 (s, 2H), 4.63 (t, J = 6.4 Hz, 2H), 7.19 (m, 1H), 7.21–7.29 (m, 4H), 7.32 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 31.3, 32.5, 41.5, 45.2, 45.5, 66.0 (2C), 122.8, 126.1, 128.4, 128.5, 139.6, 145.8, 168.1; LC-MS (ESI) m/z 301 ([M + 1]⁺).

4. Conclusions

In summary, the yields for secondary α-1,2,3-triazoloamides (80 examples) produced by solid-phase synthetic route ranged from 75 to 94% for six linear steps starting with Merrifield resin (the average yield for each step was over 95%). The parallel solution-phase synthesis generated the target tertiary 1,2,3-triazoloamides (80 examples) with 97%–73% yields for three linear steps from the reaction of amines and chloro-acid chlorides. In addition, the target 1,2,3-triazoloamides were obtained in high purities (>95%) as judged from LC-MS and ¹H-NMR analyses. This investigation, has led to the development of the solid- and solution-phase route for the synthesis of various 1,2,3-triazoloamides that contain three diversity sites that were introduced in reactions involving amines (R¹ and R²), chloro-acid chlorides (A), and terminal acetylenes (R³). The strategy allows for a ready access to a large library and is potentially applicable to the preparation of other 1,2,3-triazole derivatives.

Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF) grants (NRF-2014R1A1A1037635 and NRF-2014R1A2A1A11052798) from the Basic Science Research Program, the Ministry of Science, ICT and Future Planning, Republic of Korea, and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI11C1300(A111345)).

Author Contributions

T.L. and D.J.B. conceived and designed the experiments; D.L., D.K., S.L., T.K., J.K., S.K., S.L., and J.-S.B. performed experiments; K.-H.L., K.-S.S., C.-W.C., and Y.K.S. analyzed data; T.L., D.L., and D.J.B. wrote the paper. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are not available.

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Lee, D.; Kim, D.; Lee, S.; Kim, T.; Kim, J.; Kim, S.; Liu, K.-H.; Lee, S.; Bae, J.-S.; Song, K.-S.; et al. Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches. Molecules 2015, 20, 19984-20013. https://doi.org/10.3390/molecules201119673

AMA Style

Lee D, Kim D, Lee S, Kim T, Kim J, Kim S, Liu K-H, Lee S, Bae J-S, Song K-S, et al. Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches. Molecules. 2015; 20(11):19984-20013. https://doi.org/10.3390/molecules201119673

Chicago/Turabian Style

Lee, Doohyun, Daehun Kim, Seungyeon Lee, Taegeum Kim, Joobin Kim, Sohee Kim, Kwang-Hyeon Liu, Sangkyu Lee, Jong-Sup Bae, Kyung-Sik Song, and et al. 2015. "Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches" Molecules 20, no. 11: 19984-20013. https://doi.org/10.3390/molecules201119673

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Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

Abstract

1. Introduction

2. Results and Discussion

3. Experimental Section

3.1. General

3.2. General Procedure for the Preparation of Secondary α-1,2,3-Triazoloamides 1 on Solid-Phase

3.2.1. Preparation of AMEBA Resin 4

3.2.2. Preparation of Secondary Amine Resin 3

3.2.3. Preparation of α-Chloroamide Resin 7

3.2.4. Preparation of α-Azidoamide Resin 8

3.2.5. Preparation of α-1,2,3-Triazoloamide Resin 10

3.2.6. Preparation of α-1,2,3-Triazoloamide 1

3.3. Characterization Data of Secondary α-1,2,3-Triazoloamides 1

3.4. General Procedure for the Preparation of Tertiary 1,2,3-Triazoloamides 2 in Solution-Phase

3.4.1. Preparation of Chloro-Amide 15

3.4.2. Preparation of Azidoamide 16

3.4.3. Preparation of Tertiary 1,2,3-Triazoloamide 2

3.5. Characterization Data of Tertiary 1,2,3-Triazoloamides 2

4. Conclusions

Acknowledgments

Author Contributions

Conflicts of Interest

References

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