1,2,4-Triazole motif has been embedded into more than 30 approved and marketed medicines as well as more than 100 investigational and experimental drugs.1 Among them, ribavirin (Fig. 1) – an antiviral medication used to treat respiratory syncytial virus infection, hepatitis C, and many other viral diseases.2,3,4 Being one of the safest and most effective remedies needed in a health system, ribavirin has been included into the World Health Organization’s List of Essential Medicines.5 Moreover, recent studies confirmed the successful application of ribavirin as a cure of COVID-19.6,7,8 Voriconazole is another example of choice used to treat serious fungal infections.9,10,11,12,13

Figure 1.
figure 1

The chemical structures of ribavirin and voriconazole.

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On the other hand, 1,2,4-triazoles (especially bearing additional functional groups) are very promising ligands for coordination chemistry with multiple coordination modes possible.14,15 In this view, they were used to obtain coordination polymers,16 blue-emitting organic lightemitting diodes,17 chemodynamic therapy agents against cancer cells,18 spin crossover nanoparticles,19 and other (potentially) useful materials.

Taking into account importance of the 1,2,4-triazole scaffold in drug discovery20,21,22,23,24,25,26,27,28,29 and materials science, as well as in line with our ongoing efforts toward the synthesis of 1,2,4-triazole-derived building blocks,30,31,32 we have aimed at the expanding the chemical space of 5-functionalized 1,2,4-triazoles with a special focus on (but not limiting by) low molecular weight compounds bearing aliphatic substituents. Alkyl 1,2,4-triazole-5-carboxylates 1 were selected as the key intermediates to obtain the corresponding building blocks (i.e. carboxylates, nitriles, hydrazides, and hydroxamic acids).

Among the methods developed to date for the synthesis of alkyl 1,2,4-triazole-3(5)-carboxylates 1, the cyclization of β-acylamidrazones 2 is the most common one. Primarily, it proceeds via thermal activation (Scheme 1, i)33,34,35,36,37,38,39 or under either anhydride- (ii)40 or acyl chloride-promoted (iii)41,42 conditions. In its turn, the main synthetic precursor 2 can be obtained in several ways such as acylation with chlorides 4 of alkyl 2-hydrazinyl-2-iminoacetates 3 (Scheme 1, path a)38,39 and condensation of acyl hydrazides 5 with alkyl 2-alkoxy-2-iminoacetates 6 (path b),35,37,41,42 ethyl 2-amino-2-thioxoacetate (7) (path c),33,36,41 or alkyl 2-(alkylthio)-2-iminoacetates 8 (path d).34 Apart from that, 3-substituted alkyl 1,2,4-triazole-5-carboxylates 1 could be synthesized by reaction of acid chlorides with ethyl β-N-Boc-oxalamidrazone 9 (path e),43 thermal induced condensation of thioamides 10 with ethyl 2-hydrazinyl-2-oxoacetate (11) (path f),33 alkyl imidothioates 12 with alkyl 2-hydrazinyl-2-iminoacetates 3 (path g),44,45 as well as diethyl oxalate with carboximidhydrazides 13 (path h).46,47

Scheme 1.
scheme 1

The literature methods for the synthesis of 1,2,4-triazole-3(5)-carboxylates 1

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We commenced our study from the synthesis of a range of 3(5)-substituted ethyl 1,2,4-triazole-3(5)-carboxylates 1 following a previously described method.48 In particular, the reaction of readily available hydrazides 5 with ethyl 2-ethoxy-2-iminoacetate hydrochloride (6)35,49 under basemediated conditions afforded the corresponding ethyl 2-(2-acylhydrazono)-2-aminoacetates 2. Further thermal induced intramolecular condensation of acetates 2 in Ph2O media gave the desired ethyl triazolecarboxylates 1a–t (20 examples) in 35–89% overall yield (Table 1).

Table 1. Synthesis of 1,2,4-triazole-3(5)-carboxylates 1
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The use of Ph2O as the solvent at the cyclization step has several advantages such as: a) completeness of the cyclization reaction; b) prevention of the side reactions; c) decreasing reaction time up to 1 min (the original methods require up to 4 h) and simplification of the work-up procedure; d) reusability of the solvent. In particular, unlike solvent-free procedures (performed by melting at 160–215°C)33,34,35,37 and those with refluxing diglyme (bp 162°C)36 or xylenes (bp 139°C)38,39 as the media, the use of Ph2O (bp 259°C) allows achieving better yields (by an average of 10%). The work-up procedure included simple filtration of warm (40°C) reaction mixture followed by washing the precipitate with hexane and subsequent recrystallization of thus obtained target product. The scope of the given method should be readily adaptable to the substrates of type 2 with a variety of other substituents. Finally, following the green chemistry principles, Ph2O can be recovered via ordinary evaporation of the filtrate on a rotary evaporator and reused.

With compounds 1 in hands, we proceeded to evaluation of their chemical properties, concurrently expanding the library of 3(5)-functionalized 1,2,4-triazoles. The alkylation study was conducted first. As expected for the 1,2,4-triazole core, nearly equimolar mixtures of products 14 and 15 were obtained after reaction of compound 1 with MeI and K2CO3 in DMF media (Table 2, entries 1–6). The reaction was more selective with triazole 1q (R = 4-ClC6H4) leading to product 14q predominantly (ratio 14q:15q = ca. 3:1), which can be addressed to a steric factor of the aryl substituent. Further chromatographic separation of these mixtures allowed the isolation of pure regioisomers 14 and 15. Their structures were established by NOE, 1H–13C, and 1H–15N HMBC experiments (Fig. 2). An additional criterion was 1H NMR shifts of the N–CH3 protons that were by ca. 0.1–0.2 ppm higher for isomers 14 as compared to isomers 15.

Table 2. Alkylation of 1,2,4-triazole-3(5)-carboxylates 1
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Figure 2.
figure 2

Important correlations observed for compounds 14b and 15a,b,f.

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Considering the ratio of products 14 and 15 in the reaction mixture and their isolated yields, we also studied the alkylation reaction of triazole 1b with higher alkyl halides (i.e. EtI and i-PrI, Table 2, entries 7 and 8). It turned out that with EtI, nearly 1:1 mixture of regioisomers 16a and 17a was obtained, whereas in the case of sterically demanding i-PrI, product 16b was formed preferably (ratio 16b:17b = ca. 3:1). This result demonstrates importance of the electronic effect of the CO2Et moiety for the regioselectivity of the alkylation reaction with alkyl halides of lowered reactivity.

Saponification of esters 1, 14, and 15 proceeded smoothly with aqueous alkali at 80°C, but further isolation of the corresponding carboxylic acids was complicated by the partial decarboxylation. Therefore, the corresponding hydrolysis products were isolated as stable sodium or lithium salts 18, 19, and 20 in 80–93% yield (Table 3).

Table 3. Hydrolysis of esters 1, 14, and 15
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Esters 1, 14, and 15 also readily reacted with aqueous ammonia at 50°C (Table 4). In this way, the synthesis of N-1(2)-unsubstituted amides 21 as well as N-methylated amides 22 and 23 was achieved in 82–95% yield (Table 4, entries 1–5).

Table 4. Reaction of esters 1, 14, and 15 with N-nucleophiles
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The reaction of compounds 1, 14, and 15 with hydrazine hydrate and hydroxylamine was also carried out in a straightforward manner in refluxing alcohol media (Table 4, entries 6–14). The corresponding hydrazides 24–26 and hydroxamic acids 27–29 were isolated in good yields (84–89% and 73–78%, respectively).

Finally, the conversion of amides 21, 22, and 23 into the corresponding nitriles required some optimization studies. While N-methylated amides 22b and 23b were successively transformed into the corresponding nitriles 30b and 31b under TFAA-promoted conditions51,52,53,54,55 at 0–5°C (Scheme 2, method I), this method appeared to be inapplicable for N-1-unsubstituted triazole-derived amides 21 and did not afford the desired product. Another procedure, POCl3-mediated dehydration,56,57,58,59,60 worked well only for N-unsubstituted substrate 21p possessing aromatic substituent at the C-3 position; the corresponding nitrile 32p was obtained in 86% yield (Scheme 2, method II). However, this method was inefficient for amides with C-3-aliphatic substituent. Specifically, when amides 21b,h were subjected to these reaction conditions, they were converted into the corresponding nitriles 32b,h in 5 and 27% isolated yields, respectively.

Scheme 2.
scheme 2

Synthesis of 1,2,4-triazole-derived carbonitriles 30b, 31b, and 32b,h,p

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Eventually, this was circumvented by one more alternative synthetic approach. In this way, N-unsubstituted ester 1b was treated with 4-methoxybenzyl chloride and K2CO3 in DMF media in order to install the PMB protecting group at the heterocyclic core and prevent side reactions at the dehydration step (Scheme 2, method III). The resulting crude mixture of N-protected regioisomers 33 and 34 was refluxed in ethanolic ammonia that gave a mixture of amides 35 and 36. Subsequent TFAA-mediated dehydratation provided a mixture of PMB-protected nitriles 37 and 38. Ultimately, TFA-promoted cleavage of PMB protecting group afforded the target N-unsubstituted nitrile 32b in 67% overall yield.

In summary, an efficient approach to the gram-scale preparation of 3(5)-functionalized 1,2,4-triazoles is described. Particularly, a set of 3(5)-substituted, 1,3- and 1,5-disubstituted 1,2,4-triazole-derived esters, carboxylate salts, amides, nitriles, hydrazides, and hydroxamic acids (73 examples, 60 novel compounds) were prepared through the convergent synthetic strategy starting from readily available acyl hydrazides and ethyl 2-ethoxy-2-iminoacetate hydro-chloride. Besides, the use of diphenyl ether as the solvent improved the outcome of the cyclization reaction of the key intermediate – ethyl 2-(2-acylhydrazono)-2-aminoacetates that eventually afforded 3(5)-substituted ethyl 1,2,4-triazole-3(5)-carboxylates in higher yields (by an average of 10%). Owing to low molecular weight and high hydrophilicity, the described compounds can be considered as building blocks for lead-oriented synthesis. They also represent an interest as ligands for coordination chemistry.

Experimental

1H and 13C NMR spectra were recorded on Agilent ProPulse 600 (600 and 151 MHz, respectively), Bruker 170 Avance 500 (500 and 126 MHz, respectively), or Varian Unity Plus 400 (400 and 101 MHz, respectively) spectrometers, using DMSO-d6, CDCl3, D2O or TFA-d as solvents. TMS was used as internal standard. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (APCI)) and an Agilent 5890 Series II 5972 GCMS instrument (electron impact ionization (EI)). High-resolution mass spectra were obtained on an Agilent 1260 Infinity UHPLC instrument coupled with an Agilent 6224 Accurate Mass TOF mass spectrometer. Elemental analysis was performed on a CHNOS elementary Vario MICRO cube analyzer. All melting points were measured on a MPA100 OptiMelt automated melting point system. Analytical TLC was performed using Polychrom SI F254 plates. Compounds 14–17 were separated by column chromatography on silica gel (particle size 40–63 μm) using hexanes–t-BuOMe, 7:3 as eluent, MeCN, or CH2Cl2–EtOAc, gradient 0–100% as eluent.

Reactions requiring anhydrous conditions were performed with the usual precautions for rigorous exclusion of moisture. All the starting materials were obtained from Enamine Ltd. and UORSY. The solvents were purified according to the standard procedures.61

Synthesis of ethyl 1,2,4-triazole-3-carboxylates 1a–t (General method). Acyl hydrazide 5a–t (25.0 mmol) was added to a solution of ethyl 2-ethoxy-2-iminoacetate hydrochloride (6) (4.50 g, 25.0 mmol) and Et3N (4.20 ml, 3.07 g, 30.3 mmol) in anhydrous EtOH (50 ml), and obtained solution was stirred at room temperature for 12 h. The formed ethyl 2-(2-acylhydrazono)-2-aminoacetate intermediate 2a–t was filtered, washed with EtOH (3×20 ml), and dispersed (except for acetate 2a) in Ph2O (50 ml). The resulting mixture was brought to boil and refluxed for 1 min. After the temperature of the reaction mixture had dropped to 40°C, it was filtered. Thus obtained crude product was washed with hexane (3×50 ml) and recrystallized from PhMe to give the title compound 1b–t. Compound 1a was prepared by solvent-free melting of acetate 2a at 150°C for 2 min.

Ethyl 1 H -1,2,4-triazole-3-carboxylate (1a) was synthesized from compound 5a (1.5 g). Yield 3.14 g (89%), white powder, mp 176–177°C (mp 169–171°C (absolute EtOH)35). Physical and spectral data were in accordance with the previously reported.33,35,36,48

Ethyl 5-methyl-1 H -1,2,4-triazole-3-carboxylate (1b) was synthesized from compound 5b (1.85 g). Yield 3.06 g (79%), colorless crystals, mp 187–189°C (mp 186°C41). Physical and spectral data were in accordance with the previously reported.33,34,37,41,44,48

Ethyl 5-ethyl-1 H -1,2,4-triazole-3-carboxylate (1c) was synthesized from compound 5c (2.2 g). Yield 3.21 g (76%), white powder, mp 107–108°C (mp 103–105°C41). Physical and spectral data were in accordance with the previously reported.41,42

Ethyl 5-propyl-1 H -1,2,4-triazole-3-carboxylate (1d) was synthesized from compound 5d (2.55 g). Yield 3.39 g (74%), white powder, mp 125–127°C (mp 128–130°C41). Physical and spectral data were in accordance with the previously reported.41

Ethyl 5-( tert -butyl)-1 H -1,2,4-triazole-3-carboxylate (1e) was synthesized from compound 5e (2.9 g). Yield 3.84 g (78%), white powder, mp 193–195°C (mp 184–186°C41). Physical and spectral data were in accordance with the previously reported.41

Ethyl 5-(methoxymethyl)-1 H -1,2,4-triazole-3-carboxylate (1f) was synthesized from compound 5f (2.6 g). Yield 3.94 g (85%), colorless crystals, mp 84–86°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.71 (1H, br. s, NH); 4.56 (2H, s, OCH2); 4.31 (2H, q, J = 7.1, CH2CH3); 3.33 (3H, s, OCH3); 1.30 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 160.0; 155.3; 154.5; 65.5; 61.4; 58.6; 14.5. Mass spectrum (CI), m/z (Irel, %): 184 [M–H]– (100). Found, m/z: 186.0873 [M+H]+. C7H12N3O3. Calculated, m/z: 186.0879.

Ethyl 5-(cyanomethyl)-1 H -1,2,4-triazole-3-carboxylate (1g) was synthesized from compound 5g (2.48 g). Yield 2.84 g (63%), yellow powder, mp 111–112°C (mp 111–112°C50). Physical and spectral data were in accordance with the previously reported.50

Ethyl 5-cyclopropyl-1 H -1,2,4-triazole-3-carboxylate (1h) was synthesized from compound 5h (2.5 g). Yield 2.72 g (60%), yellow powder, mp 130–131°C (mp 110–112°C41). Physical and spectral data were in accordance with the previously reported.41

Ethyl 5-phenyl-1 H -1,2,4-triazole-3-carboxylate (1i) was synthesized from compound 5i (3.40 g). Yield 4.67 g (86%), white powder, mp 164–165°C (mp 161–163°C41). Physical and spectral data were in accordance with the previously reported.33,37,41,48

Ethyl 5-benzyl-1 H -1,2,4-triazole-3-carboxylate (1j) was synthesized from compound 5j (3.75 g). Yield 4.68 g (81%), white powder, mp 150–152°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.44 (1H, br. s, NH); 7.37–7.19 (5H, m, H Ph); 4.29 (2H, q, J = 7.1, CH2CH3); 4.13 (2H, s, CH2Ph); 1.28 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 160.4; 157.2; 154.7; 136.9 (2C); 129.1 (3C); 127.3 (2C); 61.2; 32.3; 14.6. Mass spectrum (CI), m/z (Irel, %): 230 [M–H]– (100). Found, %: C 62.38; H 5.99; N 17.79. C12H13N3O2. Calculated, %: C 62.33; H 5.67; N 18.17.

Ethyl 5-(phenoxymethyl)-1 H -1,2,4-triazole-3-carboxylate (1k) was synthesized from compound 5k (4.15 g). Yield 5.13 g (83%), white powder, mp 122–124°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 14.88 (1H, br. s, NH); 7.30 (2H, t, J = 7.7, H-3,5 Ph); 7.03 (2H, d, J = 7.7, H-2,6 Ph); 6.96 (1H, t, J = 7.7, H-4 Ph); 5.23 (2H, s, CH2OPh); 4.32 (2H, q, J = 7.3, CH2CH3); 1.29 (3H, t, J = 7.3, CH2CH3). 13C NMR spectrum (126 MHz, TFA-d), δ, ppm: 155.7; 155.5; 154.9; 146.7; 129.1; 122.9; 113.7; 65.4; 59.4; 11.4. Mass spectrum (CI), m/z (Irel, %): 246 [M–H]– (100). Found, m/z: 248.1022 [M+H]+. C12H14N3O3. Calculated, m/z: 248.1035.

Ethyl 5-(3-methylphenyl)-1 H -1,2,4-triazole-3-carboxylate (1l) was synthesized from compound 5l (3.75 g). Yield 4.39 g (76%), yellowish powder, mp 137–139°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 15.05 (1H, br. s, NH); 7.87 (1H, s, H-2 Ph); 7.82 (1H, d, J = 7.7, H-6 Ph); 7.41 (1H, t, J = 7.7, H-5 Ph); 7.30 (1H, d, J = 7.7, H-4 Ph); 4.36 (2H, q, J = 7.1, CH2CH3); 2.37 (3H, s, CH3); 1.32 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (126 MHz, TFA-d), δ, ppm: 155.3; 154.6; 145.1; 141.0; 136.2; 129.5; 127.4; 124.3; 116.5; 65.6; 18.7; 11.4. Mass spectrum (CI), m/z (Irel, %): 230 [M–H]– (100). Found, m/z: 232.1088 [M+H]+. C12H14N3O2. Calculated, m/z: 232.1086.

Ethyl 5-(4-methylphenyl)-1 H -1,2,4-triazole-3-carboxylate (1m) was synthesized from compound 5m (3.75 g). Yield 4.68 g (81%), white powder, mp 208–210°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 14.99 (1H, br. s, NH); 7.91 (2H, d, J = 7.8, H-2,6 Ph); 7.33 (2H, d, J = 7.8, H-3,5 Ph); 4.34 (2H, q, J = 7.1, CH2CH3); 2.34 (3H, s, CH3); 1.31 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (126 MHz, TFA-d), δ, ppm: 155.4; 154.5; 148.3; 145.0; 130.3; 127.1; 113.5; 65.6; 19.5; 11.4. Mass spectrum (CI), m/z (Irel, %): 230 [M–H]– (100). Found, m/z: 232.1073 [M+H]+. C12H14N3O2. Calculated, m/z: 232.1086.

Ethyl 5-(2-methoxyphenyl)-1 H -1,2,4-triazole-3-carboxylate (1n) was synthesized from compound 5n (4.15 g). Yield 2.16 g (35%), white powder, mp 159–161°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 14.22 (1H, s, NH); 8.06 (1H, d, J = 7.7, H-6 Ph); 7.50 (1H, t, J = 7.7, H-4 Ph); 7.21 (1H, d, J = 7.7, H-3 Ph); 7.10 (1H, t, J = 7.7, H-5 Ph); 4.34 (2H, q, J = 7.1, CH2CH3); 3.95 (3H, s, OCH3); 1.31 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 160.4; 157.1; 154.0; 153.1; 132.6; 129.7; 121.3; 115.3; 112.3; 61.4; 56.1; 14.6. Mass spectrum (CI), m/z (Irel, %): 246 [M–H]– (100). Found, m/z: 248.1025 [M+H]+. C12H14N3O3. Calculated, m/z: 248.1035.

Ethyl 5-(3-cyanophenyl)-1 H -1,2,4-triazole-3-carboxylate (1o) was synthesized from compound 5o (4.03 g). Yield 4.3 g (71%), yellow powder, mp 207–209°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 15.32 (1H, br. s, NH); 8.34 (1H, s, H-2 Ph); 8.30 (1H, d, J = 7.8, H-6 Ph); 7.93 (1H, d, J = 7.8, H-4 Ph); 7.72 (1H, t, J = 7.8, H-5 Ph); 4.37 (2H, q, J = 7.1, CH2CH3); 1.33 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 158.8; 157.5; 157.2; 134.0; 131.1; 130.9 (2C); 129.9; 118.6; 112.7; 62.0; 14.5. Mass spectrum (CI), m/z (Irel, %): 241 [M–H]– (100). Found, %: C 59.58; H 4.26; N 23.05. C12H10N4O2. Calculated, %: C 59.50; H 4.16; N 23.13.

Ethyl 5-(3-bromophenyl)-1 H -1,2,4-triazole-3-carboxylate (1p) was synthesized from compound 5p (5.38 g). Yield 6.14 g (83%), white powder, mp 164–166°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 15.24 (1H, br. s, NH); 8.18 (1H, s, H-2 Ph); 8.02 (1H, d, J = 7.9, H-6 Ph); 7.69 (1H, d, J = 7.9, H-4 Ph); 7.49 (1H, t, J = 7.9, H-5 Ph); 4.36 (2H, q, J = 7.1, CH2CH3); 1.32 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (126 MHz, TFA-d), δ, ppm: 155.2; 153.6; 145.8; 137.8; 130.7; 130.1; 125.6; 123.7; 119.4; 65.7; 11.4. Mass spectrum (CI), m/z (Irel, %): 294 [M(79Br)–H]– (100), 296 [M(81Br)–H]– (100). Found, m/z: 296.0024 [M+H]+. C11H11BrN3O2. Calculated, m/z: 296.0034.

Ethyl 5-(4-chlorophenyl)-1 H -1,2,4-triazole-3-carboxylate (1q) was synthesized from compound 5q (4.27 g). Yield 5.35 g (85%), yellow powder, mp 221–223°C (mp 220–223°C (i-PrOH)46). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 15.23 (1H, br. s, NH); 8.04 (2H, d, J = 8.2, H-2,6 Ph); 7.61 (2H, d, J = 8.2, H-3,5 Ph); 4.37 (2H, q, J = 7.1, CH2CH3); 1.34 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 160.0; 158.8; 155.4; 135.5; 134.3; 129.7 (2C); 128.5 (2C); 61.8, 14.6. Mass spectrum (CI), m/z (Irel, %): 250 [M–H]– (100), 252 [M–H]– (32). Found, m/z: 252.0528 [M+H]+. C11H11ClN3O2. Calculated, m/z: 252.0540.

Ethyl 5-(pyridin-2-yl)-1 H -1,2,4-triazole-3-carboxylate (1r) was synthesized from compound 5r (3.43 g). Yield 4.47 g (82%), yellow powder, mp 163–164°C (mp 164–166°C43). Physical and spectral data were in accordance with the previously reported.43,47,48

Ethyl 5-(pyridin-3-yl)-1 H -1,2,4-triazole-3-carboxylate (1s) was synthesized from compound 5s (3.43 g). Yield 3.71 g (68%), yellow powder, mp 180–182°C (mp 161–163°C43). Physical and spectral data were in accordance with the previously reported.43,48

Ethyl 5-(pyridin-4-yl)-1 H -1,2,4-triazole-3-carboxylate (1t) was synthesized from compound 5t (3.43 g). Yield 4.2 g (77%), yellow powder, mp 164–166°C (mp 163–165°C43). Physical and spectral data were in accordance with the previously reported.43,48

Synthesis of ethyl 1-alkyl-1 H -1,2,4-triazole-3-carboxylates 14a,b,f–h,q, 16a,b and ethyl 1-alkyl-1 H -1,2,4-triazole-5-carboxylates 15a,b,f–h,q, 17a,b (General method). Ethyl 1,2,4-triazolecarboxylate 1a,b,f–h,q (10.0 mmol) was added to a dispersion of K2CO3 (2.08 g, 15.0 mmol) in DMF (20 ml), and the resulting mixture was stirred at room temperature for 15 min. After, MeI (1.78 g, 12.5 mmol), EtI (1.95 g, 12.5 mmol), or i-PrI (2.13 g, 12.5 mmol) was added and the obtained mixture was stirred at the same temperature (until TLC analyses indicated that the starting material was consumed (normally 14 h)). Reaction mixture was filtered, the filtrate was evaporated at reduced pressure, diluted with CH2Cl2 (50 ml), washed with H2O (2×10 ml), and evaporated. Thus obtained crude mixture of compounds 14–17 was subjected to column chromatography affording the title compounds 14a,b,f–h,q, 15a,b,f–h,q, 16a,b, and 17a,b.

Ethyl 1-methyl-1 H -1,2,4-triazole-5-carboxylate (14a) was synthesized from compound 1a (1.41 g). Yield 543 mg (35%), white powder, mp 37–39°C, Rf 0.71 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 8.10 (1H, s, CH); 4.37 (2H, q, J = 7.1, CH2CH3); 4.12 (3H, s, NCH3); 1.33 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 158.0; 150.7; 144.8; 62.3; 38.7; 14.3. Mass spectrum (EI), m/z (Irel, %): 83 [M–C2H4–CO2]+ (100), 155 [M]+ (12). Found, %: C 46.13; H 5.46; N 27.39. C6H9N3O2. Calculated, %: C 46.45; H 5.85; N 27.08.

Ethyl 1,3-dimethyl-1 H -1,2,4-triazole-5-carboxylate (14b) was synthesized from compound 1b (1.55 g). Yield 676 mg (40%), colorless crystals, mp 92–93°C, Rf 0.63 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.34 (2H, q, J = 7.1, CH2CH3); 4.04 (3H, s, NCH3); 2.27 (3H, s, CH3); 1.32 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 159.2; 158.0; 144.7; 62.2; 38.3; 14.3; 13.7. Mass spectrum (CI), m/z (Irel, %): 170 [M+H]+ (100). Found, %: C 49.48; H 6.33; N 24.48. C7H11N3O2. Calculated, %: C 49.70; H 6.55; N 24.84.

Ethyl 3-(methoxymethyl)-1-methyl-1 H -1,2,4-triazole-5-carboxylate (14f) was synthesized from compound 1f (1.85 g). Yield 816 mg (41%), colorless crystals, mp 34–35°C, Rf 0.59 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.40 (2H, s, CH2O); 4.36 (2H, q, J = 7.2, CH2CH3); 4.10 (3H, s, OCH3); 3.28 (3H, s, NCH3); 1.33 (3H, t, J = 7.2, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 159.6; 157.9; 145.2; 66.8; 62.3; 58.2; 38.7; 14.3. Mass spectrum (CI), m/z (Irel, %): 200 [M+H]+ (100), 168 [M–CH3O]+ (65). Found, m/z: 200.1026 [M+H]+. C8H14N3O3. Calculated, m/z: 200.1035.

Ethyl 3-(cyanomethyl)-1-methyl-1 H -1,2,4-triazole-5-carboxylate (14g) was synthesized from compound 1g (1.80 g). Yield 815 mg (42%), yellow powder, mp 80–81°C, Rf 0.68 (MeCN). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.37 (2H, q, J = 7.1, CH2CH3); 4.22 (2H, s, CH2CN); 4.10 (3H, s, NCH3); 1.33 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 157.5; 154.0; 145.6; 117.3; 62.5; 38.8; 17.5; 14.3. Mass spectrum (CI), m/z (Irel, %): 195 [M+H]+ (100). Found, %: C 49.29; H 5.50; N 28.97. C8H10N4O2. Calculated, %: C 49.48; H 5.19; N 28.85.

Ethyl 3-cyclopropyl-1-methyl-1 H -1,2,4-triazole-5-carboxylate (14h) was synthesized from compound 1h (1.81 g). Yield 741 mg (38%), colorless liquid, Rf 0.81 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.33 (2H, q, J = 7.1, CH2CH3); 4.02 (3H, s, NCH3); 2.04–1.94 (1H, m, CH cyclopropyl); 1.31 (3H, t, J = 7.1, CH2CH3); 0.97–0.88 (2H, m, CH2 cyclopropyl); 0.83–0.75 (2H, m, CH2 cyclopropyl). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 164.3; 157.9; 144.6; 62.2; 38.4; 14.4; 8.9; 8.1 (2C). Mass spectrum (CI), m/z (Irel, %): 196 [M+H]+ (100). Found, m/z: 196.1078 [M+H]+. C9H14N3O2. Calculated, m/z: 196.1086.

Ethyl 3-(4-chlorophenyl)-1-methyl-1 H -1,2,4-triazole-5-carboxylate (14q) was synthesized from compound 1q (2.52 g). Yield 1.6 g (60%), colorless crystals, mp 129–131°C, Rf 0.65 (CH2Cl2–EtOAc, gradient 0–100%). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 8.00 (2H, d, J = 8.4, H-2,6 Ph); 7.54 (2H, d, J = 8.4, H-3,5 Ph); 4.40 (2H, q, J = 7.1, CH2CH3); 4.17 (3H, s, NCH3); 1.36 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 159.1; 157.8; 145.8; 134.7; 129.4 (2C); 129.3; 128.0 (2C); 62.5; 39.1; 14.4. Mass spectrum (CI), m/z (Irel, %): 266 [M+H]+ (100), 268 [M+H]+ (32). Found, m/z: 266.0683 [M+H]+. C12H13ClN3O2. Calculated, m/z: 266.0696.

Ethyl 1-methyl-1 H -1,2,4-triazole-3-carboxylate (15a) was synthesized from compound 1a (1.41 g). Yield 667 mg (43%), colorless crystals, mp 114–115°C, Rf 0.16 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 8.63 (1H, s, CH); 4.31 (2H, q, J = 7.1, CH2CH3); 3.95 (3H, s, NCH3); 1.29 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 159.9; 154.3; 146.7; 61.4; 37.0; 14.5. Mass spectrum (EI), m/z (Irel, %): 110 [M–C2H5O]+ (100), 83 [M–C2H4–CO2]+ (53). Found, m/z: 156.0764 [M+H]+. C6H10N3O2. Calculated, m/z: 156.0773.

Ethyl 1,5-dimethyl-1 H -1,2,4-triazole-3-carboxylate (15b) was synthesized from compound 1b (1.55 g). Yield 810 mg (48%), beige crystals, mp 93–94°C, Rf 0.14 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 4.28 (2H, q, J = 7.1, CH2CH3); 3.84 (3H, s, NCH3); 2.42 (3H, s, CH3); 1.28 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 160.1; 154.5; 152.4; 61.2; 36.1; 14.5; 11.8. Mass spectrum (EI), m/z (Irel, %): 169 [M]+ (10), 124 [M–C2H5O]+ (100). Found, %: C 49.96; H 6.24; N 24.97. C7H11N3O2. Calculated, %: C 49.70; H 6.55; N 24.84.

Ethyl 5-(methoxymethyl)-1-methyl-1 H -1,2,4-triazole-3-carboxylate (15f) was synthesized from compound 1f (1.85 g). Yield 876 mg (44%), colorless crystals, mp 46–48°C, Rf 0.24 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.62 (2H, s, CH2O); 4.30 (2H, q, J = 7.1, CH2CH3); 3.92 (3H, s, NCH3); 3.30 (3H, s, OCH3); 1.29 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 159.8; 154.0; 152.7; 64.3; 61.4; 58.5; 36.6; 14.5. Mass spectrum (CI), m/z (Irel, %): 200 [M+H]+ (100), 154 [M+H–C2H5OH]+ (42). Found, m/z: 200.1027 [M+H]+. C8H14N3O3. Calculated, m/z: 200.1035.

Ethyl 5-(cyanomethyl)-1-methyl-1 H -1,2,4-triazole-3-carboxylate (15g) was synthesized from compound 1g (1.80 g). Yield 757 mg (39%), yellow crystals, mp 111–113°C, Rf 0.14 (MeCN). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.49 (2H, s, CH2CN); 4.32 (2H, q, J = 7.1, CH2CH3); 3.88 (3H, s, NCH3); 1.30 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 159.6; 152.8; 149.0; 115.9; 61.5; 36.5; 16.3; 14.5. Mass spectrum (CI), m/z (Irel, %): 195 [M+H]+ (100). Found, %: C 49.48; H 5.35; N 29.11. C8H10N4O2. Calculated, %: C 49.48; H 5.19; N 28.85.

Ethyl 5-cyclopropyl-1-methyl-1 H -1,2,4-triazole-3-carboxylate (15h) was synthesized from compound 1h (1.81 g). Yield 800 mg (41%), colorless oil, Rf 0.4 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.27 (2H, q, J = 7.1, CH2CH3); 3.94 (3H, s, NCH3); 2.18 (1H, tt, J = 8.5, J = 4.8, CH cyclopropyl); 1.27 (3H, t, J = 7.1, CH2CH3); 1.12–1.03 (2H, m, CH2 cyclopropyl); 0.96–0.89 (2H, m, CH2 cyclopropyl). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 160.1; 159.4; 152.3; 61.2; 35.8; 14.6; 8.8 (2C); 6.2. Mass spectrum (CI), m/z (Irel, %): 196 [M+H]+ (100). Found, m/z: 196.1077 [M+H]+. C9H14N3O2. Calculated, m/z: 196.1086.

Ethyl 5-(4-chlorophenyl)-1-methyl-1 H -1,2,4-triazole-3-carboxylate (15q) was synthesized from compound 1q (2.52 g). Yield 400 mg (15%), white powder, mp 115–117°C, Rf 0.18 (CH2Cl2–EtOAc, gradient 0–100%). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 7.84 (2H, d, J = 8.4, H-2,6 Ph); 7.65 (2H, d, J = 8.4, H-3,5 Ph); 4.34 (2H, q, J = 7.1, CH2CH3); 4.04 (3H, s, NCH3); 1.31 (3H, t, J = 7.1, CH2CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 159.9; 154.8; 152.9; 135.9; 131.0 (2C); 129.4 (2C); 126.2; 61.5; 38.2; 14.5. Mass spectrum (CI), m/z (Irel, %): 266 [M+H]+ (100), 268 [M+H]+ (32). Found, m/z: 266.0687 [M+H]+. C12H13ClN3O2. Calculated, m/z: 266.0696.

Ethyl 1-ethyl-3-methyl-1 H -1,2,4-triazole-5-carboxylate (16a) was synthesized from compound 1b (1.55 g). Yield 770 mg (42%), colorless crystals, mp 47–48°C, Rf 0.57 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 4.44 (2H, q, J = 7.2, OCH2CH3); 4.33 (2H, q, J = 7.2, NCH2CH3); 2.26 (3H, s, CH3); 1.33 (3H, t, J = 7.2, OCH2CH3); 1.30 (3H, t, J = 7.2, NCH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 159.0; 157.5; 143.6; 61.8; 45.5; 15.1; 13.9; 13.4. Mass spectrum (CI), m/z (Irel, %): 184 [M+H]+ (100). Found, m/z: 184.1079 [M+H]+. C8H14N3O2. Calculated, m/z: 184.1086.

Ethyl 1-isopropyl-3-methyl-1 H -1,2,4-triazole-5-carboxylate (16b) was synthesized from compound 1b (1.55 g). Yield 1.34 g (68%), colorless oil, Rf 0.61 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 5.30 (1H, hept, J = 6.8, CH(CH3)2); 4.33 (2H, q, J = 7.1, OCH2CH3); 2.27 (3H, s, CH3); 1.38 (6H, d, J = 6.8, CH(CH3)2); 1.30 (3H, t, J = 7.1, OCH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 158.9; 157.7; 143.3; 61.8; 51.6; 22.3; 13.9; 13.6. Mass spectrum (CI), m/z (Irel, %): 198 [M+H]+ (100). Found, m/z: 198.1235 [M+H]+. C9H16N3O2. Calculated, m/z: 198.1242.

Ethyl 1-ethyl-5-methyl-1 H -1,2,4-triazole-3-carboxylate (17a) was synthesized from compound 1b (1.55 g). Yield 878 mg (48%), colorless crystals, mp 34–36°C, Rf 0.38 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm (J, Hz): 4.26 (2H, q, J = 7.1, OCH2CH3); 4.16 (2H, q, J = 7.3, NCH2CH3); 2.42 (3H, s, CH3); 1.32 (3H, t, J = 7.3, NCH2CH3); 1.26 (3H, t, J = 7.1, OCH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 159.6; 153.3; 152.2; 60.7; 43.4; 14.5; 14.1; 11.3. Mass spectrum (CI), m/z (Irel, %): 184 [M+H]+ (100). Found, m/z: 184.1080 [M+H]+. C8H14N3O2. Calculated, m/z: 184.1086.

Ethyl 1-isopropyl-5-methyl-1 H -1,2,4-triazole-3-carboxylate (17b) was synthesized from compound 1b (1.55 g). Yield 394 mg (20%), colorless oil, Rf 0.61 (hexanes–t-BuOMe, 7:3). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 4.65 (1H, hept, J = 6.6, CH(CH3)2); 4.28 (2H, q, J = 7.1, OCH2CH3); 2.45 (3H, s, CH3); 1.38 (6H, d, J = 6.6, CH(CH3)2); 1.28 (3H, t, J = 7.1, OCH2CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 160.2; 153.2; 152.7; 61.2; 50.5; 22.5; 14.6; 11.9. Mass spectrum (CI), m/z (Irel, %): 198 [M+H]+ (100). Found, m/z: 198.1238 [M+H]+. C9H16N3O2. Calculated, m/z: 198.1242.

Syntesis of lithium or sodium 1,2,4-triazole carboxylates 18b,c,e,f,h–k,n,r, 19a,b,f,h, and 20a,b,f,h (General method). Ethyl 1,2,4-triazolecarboxylate 1b,c,e,f,h–k,n,r, 14a,b,f,h, or 15a,b,f,h (5.00 mmol) was added to a solution of NaOH (200 mg, 5.00 mmol) or LiOH·H2O (210 mg, 5.00 mmol) in H2O (10 ml), and the resulting mixture was stirred at 80°C for 10 h. Then solvent was evaporated under reduced pressure, the residue was dispersed in i-PrOH (10 ml), brought to reflux, cooled, filtered, and dried to constant weight at 120°C thus affording the title compounds 18b,c,e,f,h–k,n,r, 19a,b,f,h, and 20a,b,f,h.

Lithium 5-methyl-1 H -1,2,4-triazole-3-carboxylate (18b) was synthesized from compound 1b (775 mg). Yield 678 mg (91%), white powder, mp 275–277°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 2.22 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 160.9; 156.1; 151.5; 13.6. Mass spectrum (CI), m/z (Irel, %): 128 [M–Li+2H]+ (100). Found, m/z: 126.0306 [M–Li]–. C4H4N3O2. Calculated, m/z: 126.0304.

Sodium 5-ethyl-1 H -1,2,4-triazole-3-carboxylate (18c) was synthesized from compound 1c (845 mg). Yield 710 mg (87%), white powder, mp 220–222°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 2.58 (2H, q, J = 7.6, CH2CH3); 1.16 (3H, t, J = 7.6, CH2CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 162.7; 161.8; 155.8; 21.2; 13.1. Mass spectrum (CI), m/z (Irel, %): 140 [M–Na]– (51), 96 [M–Na–CO2]– (100). Found, m/z: 140.0466 [M–Na]–. C5H6N3O2. Calculated, m/z: 140.0460.

Sodium 5-( tert -butyl)-1 H -1,2,4-triazole-3-carboxylate (18e) was synthesized from compound 1e (985 mg). Yield 860 mg (90%), white powder, mp 208–210°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 1.27 (9H, s, C(CH3)3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 169.5; 161.7; 155.4; 32.6; 30.0. Mass spectrum (CI), m/z (Irel, %): 170 [M–Na+2H]+ (100). Found, %: C 44.32; H 4.88; N 21.58. C7H10N3NaO2. Calculated, %: C 43.98; H 5.27; N 21.98.

Sodium 5-(methoxymethyl)-1 H -1,2,4-triazole-3-carboxylate (18f) was synthesized from compound 1f (925 mg). Yield 814 mg (91%), white powder, mp 180–182°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 4.35 (2H, s, CH2O); 3.25 (3H, s, OCH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 160.9; 159.2; 155.8; 67.2; 57.9. Mass spectrum (CI), m/z (Irel, %): 158 [M–Na+2H]+ (100), 126 [M–Na–CH3O+H]+ (58). Found, m/z: 156.0415 [M–Na]–. C5H6N3O3. Calculated, m/z: 156.0409.

Sodium 5-cyclopropyl-1 H -1,2,4-triazole-3-carboxylate (18h) was synthesized from compound 1h (905 mg). Yield 744 mg (85%), white powder, mp 179–181°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 1.92 (1H, tt, J = 8.5, J = 5.1, CH cyclopropyl); 0.90–0.73 (4H, m, 2CH2 cyclopropyl). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 163.5; 161.7; 155.7; 9.1; 7.9 (2C). Mass spectrum (CI), m/z (Irel, %): 154 [M–Na+2H]+ (100), 136 [M–Na+2H–H2O]+ (42). Found, m/z: 152.0458 [M–Na]–. C6H6N3O2. Calculated, m/z: 152.0460.

Sodium 5-phenyl-1 H -1,2,4-triazole-3-carboxylate (18i) was synthesized from compound 1i (1.09 g). Yield 970 mg (92%), white powder, mp >300°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm: 7.75–7.65 (2H, m, H-2,6 Ph); 7.38–7.26 (3H, m, H-3,4,5 Ph). 13C NMR spectrum (151 MHz, D2O), δ, ppm: 164.2; 158.7; 155.3; 130.3; 128.9; 127.7; 126.2. Mass spectrum (CI), m/z (Irel, %): 190 [M–Na+2H]+ (100), 172 [M–Na+2H–H2O]+ (72). Found, m/z: 188.0456 [M–Na]–. C9H6N3O2. Calculated, m/z: 188.0460.

Sodium 5-benzyl-1 H -1,2,4-triazole-3-carboxylate (18j) was synthesized from compound 1j (1.16 g). Yield 1.05 g (93%), white powder, mp 105–106°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 13.80 (1H, br. s, NH); 7.45–7.02 (5H, m, H Ph); 3.91 (2H, s, CH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 172.2; 160.6 (2C); 139.3; 129.1; 128.6; 126.4; 34.3. Mass spectrum (CI), m/z (Irel, %): 204 [M–Na+2H]+ (100). Found, %: C 53.66; H 3.63; N 18.56. C10H8N3NaO2. Calculated, %: C 53.34; H 3.58; N 18.66.

Sodium 5-(phenoxymethyl)-1 H -1,2,4-triazole-3-carboxylate (18k) was synthesized from compound 1k (1.24 g). Yield 1.08 g (90%), white powder, mp >300°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm (J, Hz): 7.15 (2H, t, J = 8.1, H-3,5 Ph); 6.93–6.79 (3H, m, H-2,4,6 Ph); 5.02 (2H, s, OCH2). 13C NMR spectrum (126 MHz, D2O), δ, ppm: 164.9; 157.7; 157.0; 155.9; 129.4; 121.5; 114.7; 62.3. Mass spectrum (CI), m/z (Irel, %): 220 [M–Na+2H]+ (100). Found, m/z: 218.0573 [M–Na]–. C10H8N3O3. Calculated, m/z: 218.0566.

Sodium 5-(2-methoxyphenyl)-1 H -1,2,4-triazole-3-carboxylate (18n) was synthesized from compound 1n (1.24 g). Yield 1.02 g (85%), beige powder, mp >300°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 7.98 (1H, d, J = 7.7, H-6 Ph); 7.36 (1H, t, J = 7.7, H-4 Ph); 7.09 (1H, d, J = 7.7, H-3 Ph); 6.96 (1H, t, J = 7.7, H-5 Ph); 3.84 (3H, s, OCH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 162.0; 157.1; 156.8; 155.9; 130.1; 120.3; 119.3; 111.8; 55.6. Mass spectrum (CI), m/z (Irel, %): 220 [M–Na+2H]+ (100), 202 [M–Na+2H–H2O]+ (14). Found, m/z: 218.0559 [M–Na]–. C10H8N3O3. Calculated, m/z: 218.0566.

Sodium 5-(pyridin-2-yl)-1 H -1,2,4-triazole-3-carboxylate (18r) was synthesized from compound 1r (1.09 g). Yield 931 mg (87%), white powder, mp >300°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm (J, Hz): 8.39 (1H, d, J = 4.9, H-6 Py); 7.81–7.76 (1H, m, H-3 Py); 7.73 (1H, t, J = 7.7, H-4 Py); 7.33–7.23 (1H, m, H-5 Py). 13C NMR spectrum (151 MHz, D2O), δ, ppm: 164.5; 158.8; 155.8; 149.1; 146.9; 138.2; 124.9; 122.0. Mass spectrum (CI), m/z (Irel, %): 191 [M+H]+ (100). Found, m/z: 189.0410 [M–Na]–. C8H5N4O2. Calculated, m/z: 189.0413.

Sodium 1-methyl-1 H -1,2,4-triazole-5-carboxylate (19a) was synthesized from compound 14a (775 mg). Yield 648 mg (87%), white powder, mp 312–315°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm: 7.79 (1H, s, CH); 3.94 (3H, s, CH3). 13C NMR spectrum (151 MHz, D2O), δ, ppm: 163.3; 150.5; 149.1; 37.1. Mass spectrum (CI), m/z (Irel, %): 126 [M–Na]– (100). Found, %: C 32.61; H 2.84; N 28.54. C4H4N3NaO2. Calculated, %: C 32.23; H 2.70; N 28.19.

Lithium 1,3-dimethyl-1 H -1,2,4-triazole-5-carboxylate (19b) was synthesized from compound 14b (845 mg). Yield 647 mg (88%), white powder, mp 336–338°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 4.00 (3H, s, NCH3); 2.17 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 160.1; 156.8; 152.8; 37.0; 13.8. Mass spectrum (CI), m/z (Irel, %): 142 [M–Li+2H]+ (100), 98 [M–Li+2H–CO2]+ (35). Found, %: C 40.71; H 3.95; N 28.73. C5H6LiN3O2. Calculated, %: C 40.84; H 4.11; N 28.57.

Sodium 3-(methoxymethyl)-1-methyl-1 H -1,2,4-triazole-5-carboxylate (19f) was synthesized from compound 14f (995 mg). Yield 772 mg (80%), white powder, mp 238–241°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 4.30 (2H, s, CH2O); 4.06 (3H, s, NCH3); 3.25 (3H, s, OCH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 160.3; 157.7; 153.4; 67.1; 57.9; 37.6. Mass spectrum (CI), m/z (Irel, %): 172 [M–Na+2H]+ (100). Found, m/z: 170.0565 [M–Na]–. C6H8N3O3. Calculated, m/z: 170.0566.

Sodium 3-cyclopropyl-1-methyl-1 H -1,2,4-triazole-5-carboxylate (19h) was synthesized from compound 14h (975 mg). Yield 822 mg (87%), white powder, mp 310–312°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 3.99 (3H, s, NCH3); 1.87 (1H, tt, J = 8.1, J = 5.2, CH cyclopropyl); 0.90–0.71 (4H, m, 2CH2 cyclopropyl). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 162.2; 160.5; 152.8; 37.4; 9.1; 7.7 (2C). Mass spectrum (CI), m/z (Irel, %): 166 [M–Na]– (100), 122 [M–Na–CO2]– (20). Found, %: C 44.42; H 3.91; N 22.18. C7H8N3NaO2. Calculated, %: C 44.45; H 4.26; N 22.22.

Sodium 1-methyl-1 H -1,2,4-triazole-3-carboxylate (20a) was synthesized from compound 15a (775 mg). Yield 572 mg (90%), white powder, mp >300°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm: 8.08 (1H, s, H-5); 3.70 (3H, s, CH3). 13C NMR spectrum (126 MHz, D2O), δ, ppm: 166.3; 158.6; 145.4; 36.1. Mass spectrum (CI), m/z (Irel, %): 126 [M–Na]– (100). Found, %: C 32.28; H 2.30; N 28.52. C4H4N3NaO2. Calculated, %: C 32.23; H 2.70; N 28.19.

Lithium 1,5-dimethyl-1 H -1,2,4-triazole-3-carboxylate (20b) was synthesized from compound 15b (845 mg). Yield 670 mg (91%), white powder, mp 318–322°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 3.73 (3H, s, NCH3); 2.33 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 163.2; 159.9; 152.1; 35.5; 11.7. Mass spectrum (CI), m/z (Irel, %): 142 [M–Li+2H]+ (49), 124 [M–Li+2H–H2O]+ (100). Found, m/z: 140.0464 [M–Li]–. C5H6N3O2. Calculated, m/z: 140.0460.

Sodium 5-(methoxymethyl)-1-methyl-1 H -1,2,4-triazole-3-carboxylate (20f) was synthesized from compound 15f (995 mg). Yield 840 mg (87%), white powder, mp 131–134°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm: 4.55 (2H, s, CH2O); 3.79 (3H, s, NCH3); 3.29 (3H, s, OCH3). 13C NMR spectrum (126 MHz, D2O), δ, ppm: 165.7; 156.9; 152.4; 63.2; 57.7; 35.1. Mass spectrum (CI), m/z (Irel, %): 172 [M–Na+2H]+ (100). Found, m/z: 170.0566 [M–Na]–. C6H8N3O3. Calculated, m/z: 170.0566.

Sodium 5-cyclopropyl-1-methyl-1 H -1,2,4-triazole-3-carboxylate (20h) was synthesized from compound 15h (975 mg). Yield 803 mg (85%), white powder, mp 230–233°C. 1H NMR spectrum (400 MHz, D2O), δ, ppm: 3.77 (3H, s, NCH3); 1.98–1.81 (1H, m, CH cyclopropyl); 1.05–0.92 (2H, m, CH2 cyclopropyl); 0.90–0.75 (2H, m, CH2 cyclopropyl). 13C NMR spectrum (126 MHz, D2O), δ, ppm: 166.0; 158.8; 156.3; 34.4; 6.9 (2C); 5.2. Mass spectrum (CI), m/z (Irel, %): 166 [M–Na]– (100), 122 [M–Na–CO2]– (80). Found, m/z: 166.0614 [M–Na]–. C7H8N3O2. Calculated, m/z: 166.0617.

Synthesis of 1,2,4-triazole carboxamides 21b,h,p, 22b, and 23b (General method). Ethyl 1,2,4-triazolecarboxylate 1b,h, 14b, or 15b (5.00 mmol) was dissolved in 25% aqueous NH3 (10 ml) while triazole 1p was dissolved in a mixture EtOH – 25% aqueous NH3, 1:1 (10 ml), and the resulting solution was stirred at 50°C for 24 h. The formed precipitate was filtered to give the title compounds 21p, 22b, or 23b. Alternatively, the reaction mixture was evaporated at reduced pressure, and the residue was recrystallized from H2O thus affording the title compounds 21b,h.

5-Methyl-1 H -1,2,4-triazole-3-carboxamide (21b) was synthesized from compound 1b (775 mg). Yield 536 mg (85%), white powder, mp 223–225°C (mp 221–225°C (MeCN)45). 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 14.09 (1H, br. s, NH); 7.81 (1H, br. s, NH2); 7.56 (1H, br. s, NH2); 2.35 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 160.8; 155.8; 154.4; 12.5. Mass spectrum (CI), m/z (Irel, %): 127 [M+H]+ (100), 110 [M+H–NH3]+ (49). Found, %: C 38.24; H 4.89; N 44.11. C4H6N4O. Calculated, %: C 38.09; H 4.80; N 44.42.

5-Cyclopropyl-1 H -1,2,4-triazole-3-carboxamide (21h) was synthesized from compound 1h (905 mg). Yield 623 mg (82%), white powder, mp 192–194°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.09 (1H, br. s, NH); 7.72 (1H, br. s, NH2); 7.55 (1H, br. s, NH2); 2.03 (1H, tt, J = 8.7, J = 4.9, CH cyclopropyl); 1.08–0.94 (2H, m, CH2 cyclopropyl); 0.94–0.78 (2H, m, CH2 cyclopropyl). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 160.7; 159.8; 157.9; 8.4 (2C); 7.8. Mass spectrum (CI), m/z (Irel, %): 153 [M+H]+ (100), 136 [M+H–NH3]+ (64). Found, m/z: 153.0773 [M+H]+. C6H9N4O. Calculated, m/z: 153.0776.

5-(3-Bromophenyl)-1 H -1,2,4-triazole-3-carboxamide (21p) was synthesized from compound 1p (1.48 g). Yield 1.24 g (93%), white powder, mp 262–264°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.81 (1H, br. s, NH); 8.21 (1H, s, H-2 Ph); 8.11 (1H, s, NH2); 8.03 (1H, d, J = 8.0, H-6 Ph); 7.86 (1H, s, NH2); 7.65 (1H, d, J = 8.0, H-4 Ph); 7.47 (1H, t, J = 8.0, H-5 Ph). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 159.6; 153.3; 145.4; 132.7; 132.5; 131.7; 129.0; 125.3; 122.6. Mass spectrum (CI), m/z (Irel, %): 266 [M(79Br)+H]+ (100), 268 [M(81Br)+H]+ (100). Found, m/z: 268.9852 [M+H]+. C9H8BrN4O. Calculated, m/z: 266.9881.

1,3-Dimethyl-1 H -1,2,4-triazole-5-carboxamide (22b) was synthesized from compound 14b (845 mg). Yield 630 mg (90%), white powder, mp 217–219°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 8.06 (1H, s, NH); 7.82 (1H, s, NH); 4.02 (3H, s, NCH3); 2.23 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 159.4; 158.2; 146.9; 37.8; 13.7. Mass spectrum (CI), m/z (Irel, %): 141 [M+H]+ (100). Found, m/z: 141.0772 [M+H]+. C5H9N4O. Calculated, m/z: 141.0776.

1,5-Dimethyl-1 H -1,2,4-triazole-3-carboxamide (23b) was synthesized from compound 15b (845 mg). Yield 595 mg (85%), white powder, mp 187–189°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 7.64 (1H, s, NH); 7.42 (1H, s, NH); 3.79 (3H, s, NCH3); 2.38 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 161.2; 155.3; 153.7; 35.8; 11.8. Mass spectrum (CI), m/z (Irel, %): 141 [M+H]+ (100). Found, m/z: 141.0771 [M+H]+. C5H9N4O. Calculated, m/z: 141.0776.

Synthesis of 1,2,4-triazole carbohydrazides 24a,b, 25a,b, and 26a,b (General method). Ethyl 1,2,4-triazolecarboxylate 1a,b, 14a,b, 15a,b (5.00 mmol) was dissolved in EtOH (10 ml) followed by addition of N2H4·H2O (313 mg, 0.31 ml, 6.25 mmol), and the resulting solution was refluxed for 1 h. Then it was cooled, the precipitate formed was filtered and washed with EtOH (10 ml) thus affording the title compounds 24a,b, 25a,b, or 26a,b.

1 H -1,2,4-Triazole-3-carbohydrazide (24a) was synthesized from compound 1a (705 mg). Yield 552 mg (87%), white powder, mp 282–284°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 13.91 (1H, br. s, NH); 9.84 (1H, br. s, NHNH2); 8.43 (1H, s, CH); 4.54 (2H, br. s, NHNH2). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 165.0; 157.5; 146.8. Mass spectrum (CI), m/z (Irel, %): 128 [M+H]+ (100). Found, %: C 28.55; H 3.87; N 55.46. C3H5N5O. Calculated, %: C 28.35; H 3.97; N 55.10.

5-Methyl-1 H -1,2,4-triazole-3-carbohydrazide (24b) was synthesized from compound 1b (775 mg). Yield 600 mg (85%), white powder, mp 213–215°C (mp 211–213°C62). 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 13.80 (1H, s, NH); 9.67 (1H, s, NHNH2); 4.51 (2H, s, NHNH2); 2.33 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 158.5; 154.9 (2C); 12.4. Mass spectrum (CI), m/z (Irel, %): 142 [M+H]+ (100). Found, m/z: 142.0725 [M+H]+. C4H8N5O. Calculated, m/z: 142.0729.

1-Methyl-1 H -1,2,4-triazole-5-carbohydrazide (25a) was synthesized from compound 14a (775 mg). Yield 627 mg (89%), white powder, mp 160–162°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 10.09 (1H, br. s, NHNH2); 8.01 (1H, s, H-5); 4.60 (2H, s, NHNH2); 4.10 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 156.4; 150.1; 146.2; 37.8. Mass spectrum (CI), m/z (Irel, %): 142 [M+H]+ (100). Found, m/z: 142.0723 [M+H]+. C4H8N5O. Calculated, m/z: 142.0651.

1,3-Dimethyl-1 H -1,2,4-triazole-5-carbohydrazide (25b) was synthesized from compound 14b (845 mg). Yield 651 mg (84%), white powder, mp 154–156°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 10.05 (1H, s, NHNH2); 4.58 (2H, s, NHNH2); 4.03 (3H, s, NCH3); 2.24 (3H, s, CH3). 13C NMR spectrum (101 MHz, DMSO-d6), δ, ppm: 158.4; 156.5; 146.4; 37.5; 13.8. Mass spectrum (CI), m/z (Irel, %): 156 [M+H]+ (100). Found, m/z: 156.0879 [M+H]+. C5H10N5O. Calculated, m/z: 156.0885.

1-Methyl-1 H -1,2,4-triazole-3-carbohydrazide (26a) was synthesized from compound 15a (775 mg). Yield 620 mg (88%), white powder, mp 200–202°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 9.62 (1H, br. s, NHNH2); 8.53 (1H, s, CH); 4.47 (2H, s, NHNH2); 3.89 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 158.8; 156.6; 145.8; 36.7. Mass spectrum (CI), m/z (Irel, %): 142 [M+H]+ (100). Found, m/z: 142.0721 [M+H]+. C4H8N5O. Calculated, m/z: 142.0729.

1,5-Dimethyl-1 H -1,2,4-triazole-3-carbohydrazide (26b) was synthesized from compound 15b (845 mg). Yield 660 mg (85%), white powder, mp 152–154°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 9.54 (1H, s, NHNH2); 4.43 (2H, s, NHNH2); 3.78 (3H, s, NCH3); 2.38 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 158.5; 154.2; 153.1; 35.4; 11.3. Mass spectrum (CI), m/z (Irel, %): 156 [M+H]+ (100). Found, m/z: 156.0880 [M+H]+. C5H10N5O. Calculated, m/z: 156.0885.

Synthesis of 1,2,4-triazole N-hydroxycarboxamides 27b, 28b, and 29b (General method). To a solution of MeONa (810 mg, 15.0 mmol) in anhydrous MeOH (50 ml), H2NOH·HCl (1.04 g, 15.0 mmol) was added, and the obtained mixture was stirred at room temperature for 30 min. Then ethyl 1,2,4-triazole-3-carboxylate 1b, 14b, or 15b (5.00 mmol) was added and the reaction mixture was refluxed for 12 h. After this time, solvent was evaporated at reduced pressure, obtained residue was diluted with H2O (25 ml) and acidified with AcOH (pH 7–8), followed by filtration of formed product thus affording the title compounds 27b, 28b, or 29b.

N -Hydroxy-5-methyl-1 H -1,2,4-triazole-3-carboxamide (27b) was synthesized from compound 1b (775 mg). Yield 520 mg (73%), white powder, mp 174–175°C. 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 2.26 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 157.6; 156.6; 154.5; 13.1. Mass spectrum (CI), m/z (Irel, %): 143 [M+H]+ (100). Found, m/z: 143.0564 [M+H]+. C4H7N4O2. Calculated, m/z: 143.0569.

N -Hydroxy-1,3-dimethyl-1 H -1,2,4-triazole-5-carboxamide (28b) was synthesized from compound 14b (845 mg). Yield 605 mg (78%), white powder, mp 192–194°C. 1H NMR (500 MHz, DMSO-d6), δ, ppm: 11.58 (1H, s, OH); 9.30 (1H, s, NH); 4.01 (3H, s, NCH3); 2.24 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 158.4; 155.2; 145.7; 37.4; 13.7. Mass spectrum (CI), m/z (Irel, %): 155 [M–H]– (100). Found, m/z: 157.0720 [M+H]+. C5H9N4O2. Calculated, m/z: 157.0725.

N -Hydroxy-1,5-dimethyl-1 H -1,2,4-triazole-3-carboxamide (29b) was synthesized from compound 15b (845 mg). Yield 580 mg (74%), white powder, mp 182–183°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 11.11 (1H, br. s, OH); 9.12 (1H, br. s, NH); 3.79 (3H, s, NCH3); 2.40 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 157.4; 154.2; 153.6; 35.8; 11.8. Mass spectrum (CI), m/z (Irel, %): 157 [M+H]+ (100). Found, m/z: 157.0712 [M+H]+. C5H9N4O2. Calculated, m/z: 157.0725.

Synthesis of 1,2,4-triazole carbonitriles 30b and 31b (General method I). TFAA (2.10 g, 10.0 mmol) was added to a stirred solution of 1,2,4-triazole carboxamide 22b, 23b (5.00 mmol) in CH2Cl2 (50 ml). Stirring was continued until TLC analyses indicated that the starting material was consumed (normally 6 h). Then reaction mixture was diluted with CH2Cl2 (10 ml), washed with H2O (3 × 10 ml), dried over Na2SO4, and evaporated at reduced pressure thus affording the title compounds 30b, 31b.

1,3-Dimethyl-1 H -1,2,4-triazole-5-carbonitrile (30b) was synthesized from compound 22b (700 mg). Yield 458 mg (75%), yellow crystals, mp 84–86°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 3.99 (3H, s, NCH3); 2.32 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 161.3; 130.3; 109.8; 37.3; 13.7. Mass spectrum (EI), m/z (Irel, %): 122 [M]+ (100). Found, m/z: 123.0670 [M+H]+. C5H7N4. Calculated, m/z: 123.0671.

1,5-Dimethyl-1 H -1,2,4-triazole-3-carbonitrile (31b) was synthesized from compound 23b (700 mg). Yield 494 mg (81%), yellow crystals, mp 74–76°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm: 3.88 (3H, s, NCH3); 2.46 (3H, s, CH3). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 155.7; 136.2; 113.2; 36.6; 11.8. Mass spectrum (CI), m/z (Irel, %): 123 [M+H]+ (100). Found, %: C 49.33; H 4.61; N 46.22. C5H6N4. Calculated, %: C 49.17; H 4.95; N 45.88.

Synthesis of 1,2,4-triazole carbonitriles 32b,h,p (General method II). 1,2,4-Triazole carboxamide 21b,h,p (5.00 mmol) was dispersed in POCl3 (16.4 g, 10 ml, 107 mmol), gradually heated, and refluxed for 2 h. Then the reaction mixture was cooled and poured onto ice. After POCl3 had been quenched, mixture was neutralized with aqueous 2 M NaOH (pH 6–7) and thus obtained mixture was either filtered affording compound 32p, or extracted with CH2Cl2 (3×10 ml). The combined organic layers were dried over Na2SO4 and evaporated at reduced pressure to give compounds 32b,h.

5-Methyl-1 H -1,2,4-triazole-3-carbonitrile (32b) was synthesized from compound 21b (630 mg). Yield 27 mg (5%), white solid, mp 132–133°C (mp 135–136°C (PhMe)63). 1H NMR spectrum (500 MHz, DMSO-d6), δ, ppm: 14.76 (1H, br. s, NH); 2.41 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 155.8; 138.0; 113.5; 11.9. Mass spectrum (CI), m/z (Irel, %): 109 [M+H]+ (100). Found, %: C 44.48; H 4.03; N 51.83. C4H4N4. Calculated, %: C 44.44; H 3.73; N 51.83.

5-Cyclopropyl-1 H -1,2,4-triazole-3-carbonitrile (32h) was synthesized from compound 21h (760 mg). Yield 180 mg (27%), white powder, mp 113–115°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 14.80 (1H, br. s, NH); 2.12 (1H, tt, J = 8.6, J = 4.8, CH cyclopropyl); 1.15–1.05 (2H, m, CH2 cyclopropyl); 0.99–0.90 (2H, m, CH2 cyclopropyl). 13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 161.5; 137.8; 113.5; 9.2 (2C); 7.2. Mass spectrum (CI), m/z (Irel, %): 135 [M+H]+ (100). Found, m/z: 135.0665 [M+H]+. C6H7N4. Calculated, m/z: 135.0671.

5-(3-Bromophenyl)-1 H -1,2,4-triazole-3-carbonitrile (32p) was synthesized from compound 21p (1.34 g). Yield 1.07 g (86%), beige powder, mp 212–214°C. 1H NMR spectrum (400 MHz, DMSO-d6), δ, ppm (J, Hz): 15.72 (1H, br. s, NH); 8.18 (1H, s, H-2 Ph); 8.00 (1H, d, J = 7.9, H-6 Ph); 7.78 (1H, d, J = 7.9, H-4 Ph); 7.55 (1H, t, J = 7.9, H-5 Ph). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 155.4; 138.7; 134.5; 132.0; 129.5; 128.2; 126.1; 122.8; 113.1. Mass spectrum (CI), m/z (Irel, %): 247 [M(79Br)–H]– (100), 249 [M(81Br)–H]– (100). Found, m/z: 248.9767 [M+H]+. C9H6BrN4. Calculated, m/z: 248.9776.

5-Methyl-1 H -1,2,4-triazole-3-carbonitrile (32b) (Method III). K2CO3 (10.4 g, 75.0 mmol) and 4-methoxybenzyl chloride (7.60 g, 6.90 ml, 60.0 mmol) were added to a stirred solution of ethyl 5-methyl-4H-1,2,4-triazole 3-carboxylate (1b) (7.76 g, 50.0 mmol) in anhydrous DMF (100 ml), and thus obtained mixture was stirred for 48 h. Reaction mixture was filtered, solvent was evaporated at reduced pressure, the residue was diluted with H2O (50 ml) and extracted with CH2Cl2 (3×50 ml). The combined extracts were dried over Na2SO4 and evaporated at reduced pressure yielding 17.7 g of a mixture of esters 33 and 34 that was dissolved in EtOH (250 ml) and refluxed under an atmosphere of NH3 for 2 h. Filtration of cooled reaction mixture afforded 13.2 g of a mixture of amides 35 and 36 that was dispersed in a solution of DIPEA (19.4 g, 150 mmol) in CH2Cl2 (250 ml) followed by addition of TFAA (13.7 g, 65.0 mmol) at 0–5°C. Thus obtained mixture was stirred at room temperature until TLC analyses indicated that the starting material was consumed (normally 24 h). Then it was washed with H2O (3×50 ml), dried over Na2SO4, and evaporated at reduced pressure affording 10.1 g of a mixture of nitriles 37 and 38. Thus obtained crude product was dissolved in CH2Cl2 (100 ml) followed by addition of TFA (23.0 g, 200 mmol), and the resulting mixture was stirred at room temperature until TLC analyses indicated that the starting material was consumed (typically 24 h). Reaction mixture was evaporated at reduced pressure, diluted with H2O (50 ml), and washed with CH2Cl2 (3×10 ml). The aqueous layer was treated with NaHCO3 (4.20 g, 50.0 mmol) and stirred at room temperature for 12 h. After, reaction mixture was evaporated at reduced pressure, diluted with MeCN (50 ml), brought to boil, and filtered. Finally, thus obtained filtrate was evaporated under reduced pressure affording 3.60 g (67%) of the title product 32b. This product was identical to the sample of product 32b synthesized as described above according to general method II.