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. Author manuscript; available in PMC: 2023 Apr 1.
Published in final edited form as: Mol Divers. 2021 Apr 2;26(2):993–1004. doi: 10.1007/s11030-021-10218-2

One-pot Parallel Synthesis of 1,3,5-Trisubstituted 1,2,4-Triazoles

Dmytro S Radchenko 1,2, Vasyl S Naumchyk 3, Igor Dziuba 4, Andrii A Kyrylchuk 5,6, Yurii S Moroz 7,8, Kateryna E Gubina 9, Oleksandr O Grygorenko 10,11
PMCID: PMC8486894  NIHMSID: NIHMS1706368  PMID: 33797670

Abstract

An implementation of the three-component one-pot approach to unsymmetrical 1,3,5-trisubstituted-1,2,4-triazoles into combinatorial chemistry is described. The procedure is based on the coupling of amidines with carboxylic acids and subsequent cyclization with hydrazines. After the preliminary assessment of the reagent scope, the method had 81% success rate in parallel synthesis. It was shown that over a billion-sized chemical space of readily accessible (“REAL”) compounds may be generated based on the proposed methodology. Analysis of physico-chemical parameters shows that the library contains significant fractions of both drug-like and “beyond-rule-of-five” members. More than 10 million of accessible compounds meet the strictest lead-likeness criteria. Additionally, 195 Mln of sp3-enriched compounds can be produced. This makes the proposed approach a valuable tool in medicinal chemistry.

Keywords: heterocycles, multicomponent reactions, combinatorial chemistry, virtual libraries, chemical space

Graphical Abstract

graphic file with name nihms-1706368-f0009.jpg

Introduction

1,2,4-Triazole scaffold is a core moiety of a substantial part of marketed and investigational drugs [1, 2], including antifungal drugs and pesticides, anticancer and anti-inflammatory agents, substances for treatment microbial and viral infections [3], and even food intake suppressors [4–8]. In particular, prominent examples of biologically active 1,3,5-trisubstituted 1,2,4-triazoles include marketed antihypertensive agent forasartan [9], first FDA-approved oral medication for chronic iron overload (deferasirox) [10], a benzodiazepine prodrug rilmazafone [11], and some anticancer drug candidates (bemcentinib [12] and taselisib [13]) (Fig. 1).

Fig. 1.

Fig. 1

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Drug molecules featuring the 1,3,5-substituted 1,2,4-triazole core

With recent advances in virtual screening techniques, it becomes possible to navigate very large fractions of chemical space in silico [14–18]. However, in silico screening is typically followed by in vitro biological tests that require the pre-identified hits to be synthesized in a fast and efficient manner. This issue can be addressed with ultra-large virtual libraries with controlled and reliable synthetic accessibility [18–22]. Synthetic methods envisaged to background the design of such libraries should comply with the parallel chemistry requirements, i.e. involve minimum preparation and workup efforts, be undemanding to variations of the starting materials, and avoid the use of air-, moisture-sensitive, gaseous, or extremely toxic reagents [23].

While numerous synthetic methods are known for the synthesis of polysubstituted 1,2,4-triazoles, not many of them are compatible with the aforementioned criteria. Several parallel solid-supported syntheses of 1,2,4-triazoles were developed earlier [24, 25], but they are difficult to adapt to the preparation of large compound libraries due to the harsh conditions and difficult work-up procedures employed. Recently, we have proposed a one-pot method for the parallel synthesis of 3-(di)alkylamino1,2,4-triazoles that provided reliable access to a 5M-large library of 3,4,5-trisubstituted derivatives [26]. To enrich the chemical space of the accessible 1,2,4-triazoles with other substitution patterns, we searched for the rapid pathway to isomeric 1,3,5-trisubstituted compounds.

Several general strategies to synthesize the title compounds bearing alkyl, aryl, or heteroaryl substituents are known to date (Scheme 1) [27]. The most straightforward pathway A – N-alkylation of a 3,5-substituted triazole – yields a mixture of N1- and N2-isomers which lowers the yield of the target compound and complicates the product purification [28, 29]. Still, it was adopted in a few combinatorial chemistry setups [30, 31].

Scheme 1.

Scheme 1

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Approaches to 1,3,5-trisubstituted 1,2,4-triazoles

Strategy B based on the reaction of hydrazones and nitriles (i.e. CNN + CN approach) typically requires either toxic catalysts or high reaction temperatures [32, 33]. To the best of our knowledge, this approach was not applied for the parallel synthesis so far.

Strategy C involving reaction of hydrazines and various CNC bielectrophiles appears to more attractive [34–36]. For example, this approach was employed in the parallel microwave-assisted preparation of 3-amino-1,2,4-triazoles [37]. Nevertheless, the scope of the procedure demonstrated by the authors was limited, and only a small compound set was obtained (less than 10 library members).

In this work, we have turned our attention to another method from this category developed by Castanedo and co-workers [38]. Their one-pot two-step procedure involved amidines 1, carboxylic acids 2, and hydrazines 3 as the starting materials and produced the desired 1,2,4-triazoles 4 in moderate to high yields for a number of alkyl, aryl, and heteroaryl substitutents. The method used standard peptide coupling reagents and mild reaction conditions, which allowed expecting for a cost-effective and robust implementation into a combinatorial chemistry setup. By efficient preparation of a nearly 400-member 1,3,5-trisubstituted 1,2,4-triazole library, we demonstrate herein that this methodology is indeed well-compatible with the parallel synthesis conditions and has very wide reaction scope. Furthermore, we apply this approach to the generation of nearly a billion-sized REadily AccessibLe (REAL) virtual chemical space, which is a powerful extension of synthetically tractable 1,2,4-triazoles available so far.

Through the paper, the numbering system common for combinatorial science was followed. In particular, the reagent series used for the library synthesis were addressed with bold Arabic numbers (i.e. 1–3), while each particular reagent was denoted by an additional number shown in brackets, e. g. 1{1}, 1{2}, 1{3}, etc. The product library was also designated by a bold Arabic number (4), whereas each particular library member prepared from the reagents 1{i}, 2{j}, and 3{j} was denoted as 4{i,j,k}. Synthesis success rate (SSR, i.e. fraction of the planned compound set that could be synthesized successfully) was used as a measure of the parallel synthesis efficiency along with average yield of the products.

Results and Discussion

Parallel synthesis setup and validation

The parallel synthesis setup was based on the original procedure of Castanedo and co-workers [38] with minor alterations. In particular, to ensure the complete conversion for a wide range of the starting materials, the amidine (1) loading was decreased from 1.5 to 1.2 equiv, the reaction time for the first step was increased from 3 to 24 h, and the temperature for the second step – from 80 to 90 °C. For the initial evaluation of the substrate scope, 128 amidines, 326 carboxylic acids, and 164 hydrazines with widely varied substitution patterns were used to generate 409 deliberately selected virtual library members 4, that were subjected to parallel synthesis. As a result of this initial experiment, 180 library members were obtained (44% SSR, 26% average yield).

These modest preliminary results showed that limitations should be applied to the starting reagents before the generation of ultra-large readily accessible chemical space. It was found that:

  • the products with one (het)aryl and two alkyl substituents, as well as two (het)aryl and one alkyl substituents, were obtained with substantially higher SSR (49% and 52%, respectively) as compared to other combinations of the reagents;

  • for the library members derived from three alkyl-substituted substrates, low SRR was observed (15%), mainly due to isolation/purification issues; therefore, at least one of the components should be (hetero)aromatic.

Some limitations were found for specific types of reagents. It has been revealed that:

  • hydrazines containing electron-withdrawing substituents perform poor in the second stage of the reaction (Fig. 2). For example, using pyrimidine-substituted hydrazines did not allow obtaining the target triazoles, while less electron-deficient pyridyl- and even o- or p-chlorophenyl-substituted derivatives gave low yields of the products. The same problems were observed with compounds 3{40} and 3{141};

  • analogously, electron-deficient amidines demonstrated poor performance. Thus, pyridine-, pyrimidine-substituted amidines, compounds 1{1}, 1{35} had low reactivity at the first step;

  • somewhat lower SSR was observed for alkyl-substituted amidines (36%); nevertheless, it was still acceptable to proceed with these reagents further;

  • amidines containing free hydroxy, amino, or active methylene units demonstrated poor or even zero SSR (as 1{34});

  • both R1 and R3 groups originating from amidine and hydrazine, respectively, were sensitive to steric effects, so that low SSR was observed for these reagents. Bulky carboxylic acids (e.g. 2{5}), also showed lower performance, although the steric effects were less critical in this case.

Fig. 2.

Fig. 2

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Examples of reagents 1–3 that showed good and poor efficiency in the preliminary studies

Formation of the triazoles 4 presumably occurs through the steps shown in Scheme 2. Firstly, the standard amide coupling between carboxylic acids 1 and amidines 2 proceeds assisted by HATU [39]. Resulting acylamidine intermediate 5 then undergoes acid-catalyzed formation of amidrazone derivatives 6 upon reaction with hydrazines 3, which subsequently cyclize to yield the target triazoles 4. The possibility of such ring closure was demonstrated earlier by Frohberg et al. for a bis-hydrazinylated derivative [40].

Scheme 2.

Scheme 2

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Proposed mechanism of the triazoles 4 formation

Having all the above information in hands, we have performed the second selection of the starting materials; in this case, 130 amidines 1, 451 carboxylic acids 2, and 152 hydrazines 3 were selected taking into account the aforementioned restrictions. Based on these reagents, 483 triazoles were randomly selected for the SSR validation of the methodology. We were pleased to found that 392 library members were successfully synthesized (81% SSR) in 26% average yield (see Fig. 3 for examples).

Fig. 3.

Fig. 3

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Examples of library members 4

Analysis of SSR and product yield as a function of the calculated physico-chemical properties of the 1,2,4-triazoles synthesized in the validation phase are shown in Fig. 4 (together with distribution of the library subset by these parameters). As it follows from the histograms, there is no clear correlation between most predicted physico-chemical parameters of the products (i.e., molecular weight (MW), octanol – water partition coefficient logarithm (LogP), hydrogen bond acceptor count (HAcc), and fraction of sp3-hybridized carbon atoms (Fsp3)) and the outcome of the reaction. In particular, zero “LogP drift” effect [41] (a differe nce between the predicted average LogP of the library and the corresponding value for the subset that could be synthesized) was observed, although the yield was typically lower for more hydrophilic compounds. Increasing hydrogen bond donor count (HDon) had negative effect on both SSR and the product yield, which is obviously related to the presence of free OH or NH groups in any of the reagents. On the contrary, compounds with higher rotatable bond count (RotB) were obtained with better efficiency; this might be related to increased steric effects in the conformationally restricted representatives. These data correlate with the results obtained in the preliminary studies. Importantly, Fsp3 had little effect on the reaction outcome; in fact, sp3-enriched compounds were prepared with even somewhat higher SSR, which might be addressed to higher nucleophilicity of aliphatic amidines 1 and hydrazines 3. All the above data show that despite some of the method’s features (i.e. inapplicability for all-alkyl-substituted 1,2,4-triazoles and modest tolerance to hydrogen bond donors) are not compatible with the spirit of lead-oriented synthesis concept [41], the strategy is still very useful to the preparation of lead-like compounds [42].

Fig. 4.

Fig. 4

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Calculated physico-chemical parameters of 392 synthesized 1,2,4-triazoles and their correlation with the synthetic efficiency

Generation of the chemical space of synthetically feasible 1,2,4-triazoles

The SSR value obtained in the validation study (81%) shows that the discussed methodology can be applied for generation of large virtual chemical space of highly reliable synthetic feasibility. More than a decade ago, we have started a project on creating the registry of the “make-on-demand” molecules that can be readily prepared within short terms using well-established parallel chemistry procedures – the so-called REAL (REadily AccessibLe) Database [43]. To date, the project has grown to the multibillion-sized REAL Space [21]. The three-component approach to 1,3,5-substituted 1,2,4-triazoles can provide a substantial extension of this chemical space with compounds that are largely underrepresented in the current databases.

To demonstrate this, we have selected 334 amidines 1, 12,084 carboxylic acids 2, and 416 hydrazines 3 from the available stock of commercially accessible reagents. The criteria described above and used to generate the validation subset were applied to all the reagents. For the carboxylic acids 2, only compounds with the previously established efficiency in amide couplings were included. Virtual coupling of these reagents according to the aforementioned selection rule (i.e. at least one (het)aryl-substited reagent should be used) was performed as described in our previous work [21] and gave 1,097,242,556 library members.

Distribution of this chemical space according to the common physico-chemical parameters is shown in Fig. 5. It is clearly seen that there are many compounds that comply with drug-likeness criteria (i.e. Lipinski [44] and Veber [45] rules; 332 Mln, or nearly 30%) and those from the “beyond-the-Ro5” space[46] (460 Mln, or 42%, have MW > 500) (Table 1). These numbers substantially exceed the currently available 1,3,5-trisubstituted 1,2,4-triazole space deposited in ChEMBL [47] and ZINC15 [17] databases (4,061 and 2,277,290 hits by the substructure search, respectively, Fig. 6), as well as ca. 5 Mln aminotriazoles enumerated in our previous work [48]. Even if the most rigorous lead-likeness criteria by Churcher and co-workers are applied (MW = 200…350, LogP −1…3) [41], there are still 10.4 Mln library members remaining.

Fig. 5.

Fig. 5

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Calculated physico-chemical parameters of the generated REAL chemical space of 1,3,5-trisubstituted 1,2,4-triazoles

Table 1.

REAL chemical space of 1,3,5-trisubstituted 1,2,4-triazoles: compliance with drug- and lead-likeness rules

Cut-off rule Compounds Library %
None 1,097,242,556 100.00
Lipinski “rule of five” [44]
(MW < 500; LogP < 5; HAcc ≤ 10; HDon ≤ 5)		 338,860,904 30.88
Lipinski Ro5 and Veber rules [45]
(additionally, RotB ≤ 10; TPSA < 140 Å2)		 332,498,602 30.30
“Rule of 4.5” for lead-likeness
(MW < 450; LogP < 4.5) [49]		 178,819,784 16.30
“Rule of 4” for lead-likeness [50]
(MW < 400; LogP < 4)		 66,749,852 6.08
Lead-likeness by Churcher et al. [41]
(MW 200…350, LogP –1…3)		 10,350,947 0.94
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Fig. 6.

Fig. 6

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1,3,5-substituted 1,2,4-triazoles in REAL space as compared to ChemBL and ZINC15 databases

An interesting aspect of the generated chemical space is related to three-dimensionality of the molecules – a property that has been shown to correlate with the compound success as the drug candidate [51–53]. Despite all the library members obviously contain at least two (hetero)aromatic rings, a number of the compounds with Fsp3 > 0.5 is significant (195 Mln, or 18%, see Fig. 5). The average Fsp3 value for the whole 1,2,4-triazole space is 0.345.

Conclusions

The viability of the one-pot three-component reaction sequence involving amidines, carboxylic acids, and hydrazines, for the parallel synthesis of 1,3,5-substituted 1,2,4-triazoles was evaluated. Preliminary experiments for a randomly selected library of 409 members showed that without restrictions applied to the starting reagents, the method showed modest synthetic success rate (SSR, only 44%). It was shown that electron-poor and sterically demanding amidines and hydrazines had poor performance; so did amidines with free hydroxy, amino, or active methylene groups. Also, library members derived from three alkyl-substituted substrates were obtained with low SSR. Nevertheless, 1,2,4-triazoles featuring these substituents can be accessed either by custom synthesis, as in the original work of Castanedo et al. [38], or by the described parallel procedure after additional optimization. Currently, the procedure discussed in this work is still capable of yielding such triazoles with the success rate of ca. 33% from a single experiment; in our experience, this value can be somewhat improved by parallel synthesis set-up including several repetitive runs.

After applying the aforementioned exclusion filters to the starting reagents or combinations thereof, the SSR parameter could be substantially improved (81%), so that 392 randomly selected library members could be successfully obtained in 26% average yield. These results allowed application of the methodology to the construction of ultra-large REadily AvailabLe (REAL) chemical space with reliable synthetic feasibility. More than a billion 1,3,5-substituted 1,2,4-triazoles were generated by virtual coupling of commercial reagents according to the above exclusion rules. The resulting chemical space contained a substantial fraction of drug-like (332 Mln, Lipinski and Veber rules) and sp3-enriched (195 Mln) members, which significantly exceeds the numbers of currently accessible 1,2,4-triazoles according to the CheMBL and ZINC15 databases. Even if the strictest lead-likeness criteria (Churcher rules) are applied, there are still 10.4 Mln molecules remaining. Therefore, the proposed methodology and the generated chemical space of 1,3,5-substituted 1,2,4-triazoles can be considered as valuable tools for early drug discovery, especially in combination with virtual screening techniques.

Experimental Section

General

All chemicals and solvents were obtained from Enamine Ltd. and used without further purification. 1H, 13C, and 19F NMR spectra were acquired on Bruker Advance DRX 400, Bruker Avance DRX 500, and Agilent ProPulse 600 spectrometers using DMSO-d6 as a solvent (unless noted otherwise). Melting points were determined on a Buchi melting point apparatus. LCMS data were recorded on Agilent 1100 HPLC equipped with diode-matrix and mass-selective detector Agilent LC/MSD SL instrument, column: Zorbax SB-C18, 4.6 mm × 15 mm; gradient acetonitrile – water with 0.1% of TFA (95:5) (A) – water with 0.1% of TFA (B) as eluent; flow rate: 1.8 mL/min. Elemental analyses were performed at the Laboratory of Organic Analysis, Department of Chemistry, Kyiv National Taras Shevchenko University. Preparative HPLC was performed on Agilent 1260 Infinity systems equipped with DAD and mass-detector using Waters Sunfire C18 OBD Prep Column, 100 A, 5 μm, 19 mm × 100 mm with SunFire C18 Prep Guard Cartridge, 100 A, 10 μm, 19 mm × 10 mm.

The transformation of the reagents into the synthons was performed by our proprietary software; this can be also easily done using open-source software e.g. ChemAxon tools (www.chemaxon.com). Virtual coupling, InChi key generation and duplicate removal, calculation of descriptor values, filtering by physico-chemical parameters and structural features were performed using RDKit (www.rdkit.org) in Python (www.python.org) (for more details, see also [21]).

Syntheses of the libraries were typically performed in 8-mL vials; loading of the reagents, as well as work-up of the reaction mixtures was performed manually in a parallel fashion. The reactions were performed in ultrasonic baths or laboratory ovens with a shaker; up to 1,000 vials could be used simultaneously. Centrifugal evaporators were used to remove the solvents from the vials in a parallel fashion.

Characterization of the synthesized library members was performed according to principles common for combinatorial science. In particular, all 572 synthesized library members (180 – from preliminary experiments and 392 – from SSR validation tests) were characterized by LCMS. For 20 of them, full characterization was performed.

Synthesis of 1,3,5-Trisubstituted-1,2,4-Triazoles 4

1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (137 mg, 0.36 mmol) and N,N-diisopropylethylamine (97 mg, 0.75 mmol) were added to a solution of amidine 1 (0.36 mmol) and carboxylic acid 2 (0.30 mmol) in DMF (1 mL). If any of the reagents 1–3 was used as a salt, an additional amount of i-Pr2NEt (0.3 mmol per each equivalent of HCl or other acid) was added to the reaction mixture to convert the reagent into a free form at the corresponding step of the procedure. The reaction mixture was stirred at rt for for 24 h. After completion of the first stage, hydrazine 3 (0.45 mmol) and AcOH (270 mg, 4.5 mmol) were added. The resulting mixture was stirred at 90 °C for 16 h, then cooled to rt, and evaporated under vacuum. The residue was dissolved in DMSO (0.5 mL) and then subjected to HPLC (gradient deionized H2O (A) – HPLC-grade MeCN or MeOH (B) as eluent; in some cases, NH3 was used as an additive to improve the separation).

3-(3-(2-(1H-1,2,4-Triazol-1-yl)pyridin-4-yl)-5-(pentan-3-yl)-1H-1,2,4-triazol-1-yl)-N,N-dimethylpropan-1-amine 4{110,231,13}

Yield 77 mg (78%). Yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.59 (d, J = 5.1 Hz, 1H), 8.33 (m, 2H), 7.93 (dd, J = 5.1, 1.4 Hz, 1H), 4.23 (t, J = 7.1 Hz, 2H), 2.90 (quint, J = 7.0 Hz, 1H), 2.22 (t, J = 6.8 Hz, 2H), 2.10 (s, 6H), 1.95 (quint, J = 6.9 Hz, 2H), 1.72 (m, 4H), 0.78 (t, J = 7.4 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 160.4, 157.0, 153.0, 149.6, 149.5, 142.1, 141.9, 119.4, 108.6, 55.6, 45.7, 45.0, 38.6, 27.4, 26.7, 11.5. LC/MS(API-ES): m/z = 369 [M+H]+. Anal. Calcd. for C19H28N8: C 61.93; H 7.66; N 30.41. Found: C 61.95; H 8.03; N 30.39.

4-(3-Cyclopropyl-1-(4-ethylphenyl)-1H-1,2,4-triazol-5-yl)-N,N-dimethylcyclohexanecarboxamide 4{56,232,97}

Yield 76 mg (75%). Beige solid. M.p. 155–156 °C. 1H NMR (600 MHz, DMSO-d6) δ 7.35 (s, 4H), 2.94 (m, 4H), 2.77 (s, 3H), 2.66 (m, 3H), 1.94 (m, 1H), 1.88–1.79 (br.m., 4H), 1.54 (m, 2H), 1.38 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.89 (m, 2H), 0.80 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 174.9, 164.0, 159.2, 145.0, 135.8, 129.1, 125.7, 37.2, 36.7, 35.4, 32.0, 28.2, 27.8, 25.7, 15.8, 9.1, 7.9. LC/MS(API-ES): m/z = 367 [M+H]+. Anal. Calcd. for C22H30N4O: C 72.1; H 8.25; N 15.29. Found: C 72.17; H 8.41; N 14.91.

5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-(1-ethoxyethyl)-1-(4-isopropylphenyl)-1H-1,2,4-triazole 4{87,669,7}

Yield 36 mg (34%). Yellowish oil. 1H NMR (600 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 1H), 4.54 (q, J = 6.6 Hz, 1H), 3.68 (s, 3H), 3.54 – 3.41 (m, 2H), 2.96 (sept, J = 6.9 Hz, 1H), 2.04 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.9 Hz, 6H), 1.08 (t, J = 7.0 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 164.2, 149.8, 149.3, 147.1, 136.1, 131.9, 127.8, 125.7, 107.6, 70.9, 63.9, 38.9, 33.6, 24.2, 20.5, 15.7, 13.1. LC/MS(API-ES): m/z = 354 [M+H]+. Anal. Calcd. for C20H27N5O: C 67.96; H 7.7; N 19.81. Found: C 68; H 7.59; N 19.96.

5-(2-(1H-1,2,4-Triazol-1-yl)ethyl)-1-(4-chlorophenyl)-3-cyclohexyl-1H-1,2,4-triazole 4{109,229,125}

Yield 61 mg (61%). Yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.89 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 4.58 (t, J = 7.0 Hz, 2H), 3.31 (t, J = 7.0 Hz, 2H), 2.67 (tt, J = 11.5, 3.8 Hz, 1H), 1.98 – 1.90 (m, 2H), 1.79 – 1.70 (m, 2H), 1.70 – 1.62 (m, 1H), 1.55 – 1.44 (m, 2H), 1.42 – 1.29 (m, 2H), 1.29 – 1.18 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 166.9, 152.4, 151.4, 144.3, 135.7, 133.0, 129.4, 126.2, 46.1, 36.7, 31.2, 26.6, 25.6, 25.4. LC/MS(API-ES): m/z = 357 [M+H]+. Anal. Calcd. for C18H21ClN6: C 60.58; H 5.93; N 23.55; Cl 9.93. Found: C 60.29; H 6.14; N 23.76; Cl 10.18.

3-(3-(2-(1H-1,2,4-Triazol-1-yl)pyridin-4-yl)-5-(2-ethylbutyl)-1H-1,2,4-triazol-1-yl)-N,N-dimethylpropan-1-amine 4{110,742,13}

Yield 69 mg (58%). Brown oil. 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.34 (s, 2H), 7.94 (dd, J = 5.1, 1.5 Hz, 1H), 4.21 (t, J = 7.0 Hz, 2H), 2.77 (d, J = 7.1 Hz, 2H), 2.21 (t, J = 6.6 Hz, 2H), 2.12 (s, 6H), 2.03 – 1.92 (m, 2H), 1.85 – 1.74 (m, 1H), 1.42 – 1.29 (m, 4H), 0.87 (t, J = 7.4 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 157.1, 156.8, 153.0, 149.6, 149.5, 142.1, 141.8, 119.3, 108.5, 55.4, 45.8, 45.0, 39.3, 28.7, 27.2, 25.0, 10.6. LC/MS(API-ES): m/z = 383 [M+H]+. Anal. Calcd. for C20H30N8: C 62.8; H 7.91; N 29.29. Found: C 62.47; H 8.3; N 29.18.

1-Cyclobutyl-3-(3-methoxybenzyl)-5-(4-methyl-1H-pyrazol-3-yl)-1H-1,2,4-triazole 4{177,716,58}

Yield 65 mg (62%). Yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 13.08 (s, 1H), 7.71 (s, 1H), 7.20 (t, J = 7.8 Hz, 1H), 6.94 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 5.63 (quint, J = 8.4 Hz, 1H), 3.99 (s, 2H), 3.72 (s, 3H), 2.61 – 2.47 (m, 2H), 2.39 – 2.29 (m, 2H), 2.21 (s, 3H), 1.86 – 1.70 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 160.9, 159.2, 148.1, 140.1, 138.6, 129.2, 128.9, 120.8, 115.6, 114.3, 111.6, 54.8, 51.9, 34.0, 29.7, 14.1, 9.3. LC/MS(API-ES): m/z = 324 [M+H]+. Anal. Calcd. for C18H21N5O: C 66.85; H 6.55; N 21.66. Found: C 67.16; H 6.95; N 21.69.

3-(1-Ethoxyethyl)-1-(2-methoxyethyl)-5-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)-1H-1,2,4-triazole 4{84,722,68}

Yield 65 mg (58%). Yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.92 (s, 1H), 7.90 (s, 1H), 7.76 – 7.69 (m, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 4.54 (q, J = 6.6 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 3.87 (s, 3H), 3.76 (t, J = 5.2 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 3.17 (s, 3H), 1.47 (d, J = 6.6 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 163.3, 155.3, 136.3, 133.1, 129.3, 128.6, 128.2, 126.3, 125.2, 121.1, 70.5, 70.0, 63.3, 58.2, 48.6, 38.7, 20.1, 15.2. LC/MS(API-ES): m/z = 356 [M+H]+. Anal. Calcd. for C19H25N5O2: C 64.2; H 7.09; N 19.7. Found: C 63.92; H 6.95; N 19.68.

3-(1-Butyl-3-(pyridin-3-yl)-1H-1,2,4-triazol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine 4{71,727,119}

Yield 67 mg (61%). Colorless solid. M.p. 85–88 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.61 (d, J = 4.8 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.50 (dd, J = 7.9, 4.8 Hz, 1H), 4.30 (t, J = 7.3 Hz, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 6.3 Hz, 2H), 2.06 – 1.97 (m, 2H), 1.89 – 1.70 (m, 4H), 1.33 (h, J = 7.4 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 157.5, 149.8, 149.6, 146.7, 140.2, 136.6, 132.9, 126.9, 123.8, 104.9, 48.5, 47.7, 31.2, 22.6, 22.4, 19.3, 19.2, 13.4. LC/MS(API-ES): m/z = 323 [M+H]+. Anal. Calcd. for C18H22N6: C 67.06; H 6.88; N 26.07. Found: C 66.69; H 6.94; N 26.08.

3-((1H-1,2,4-Triazol-1-yl)methyl)-5-(4-methyl-1-phenyl-1H-pyrazol-3-yl)-1-(3-methylbutan-2-yl)-1H-1,2,4-triazole 4{13,743,187}

Yield 81 mg (67%). Yellowish oil. 1H NMR (600 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.52 (s, 1H), 7.98 (s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 5.54 (s, 2H), 5.18 – 5.10 (m, 1H), 2.25 (s, 3H), 2.17 – 2.08 (m, 1H), 1.45 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H), 0.70 (d, J = 6.7 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 157.5, 151.5, 148.4, 144.5, 140.2, 139.1, 129.7, 128.3, 126.7, 119.3, 118.2, 60.3, 46.4, 33.6, 19.3, 18.8, 17.7, 9.5. LC/MS(API-ES): m/z = 377 [M+H]+. Anal. Calcd. for C20H24N8: C 63.81; H 6.43; N 29.77. Found: C 63.57; H 6.26; N 29.5.

3,5-Dimethyl-4-(2-(1-phenyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)propyl)isoxazole 4{74,723,103}

Yield 60 mg (55%). Yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J = 6.0 Hz, 2H), 7.96 (d, J = 6.0 Hz, 2H), 7.61 – 7.53 (m, 3H), 7.29 (dd, J = 6.0, 2.9 Hz, 2H), 3.20 – 3.09 (m, 1H), 2.70 – 2.57 (m, 2H), 1.91 (s, 3H), 1.71 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.4, 160.7, 158.8, 158.4, 150.5, 137.6, 136.2, 129.6, 129.6, 125.7, 120.0, 110.7, 31.1, 28.4, 19.0, 10.0, 9.0. LC/MS(API-ES): m/z = 360 [M+H]+. Anal. Calcd. for C21H21N5O: C 70.17; H 5.89; N 19.48. Found: C 70.31; H 5.81; N 19.26.

4-Methyl-2-(5-(8-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)-1-(4H-1,2,4-triazol-3-yl)-1H-1,2,4-triazol-3-yl)morpholine 4{22,326,145}

Yield 60 mg (54%). Colorless solid. M.p. 217–220 °C. 1H NMR (500 MHz, DMSO-d6) δ 14.44 (br.s, 1H), 8.71 (s, 1H), 7.28 (d, J = 2.8 Hz, 1H), 4.58 (d, J = 11.0 Hz, 1H), 4.04 – 3.96 (m, 1H), 3.92 – 3.80 (m, 2H), 3.68 (t, J = 11.3 Hz, 1H), 2.92 (d, J = 11.0 Hz, 1H), 2.79 – 2.69 (m, 1H), 2.66 (d, J = 11.0 Hz, 1H), 2.37 (t, J = 11.2 Hz, 1H), 2.24 (s, 3H), 2.10 (t, J = 11.2 Hz, 1H), 2.00 – 1.91 (m, 2H), 1.86 – 1.74 (m, 1H), 1.41 (q, J = 11.3 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 161.5, 155.0, 152.0, 149.4, 144.8, 127.3, 120.3, 71.4, 66.0, 57.9, 54.2, 45.8, 44.8, 29.6, 28.9, 21.3, 19.0. LC/MS(API-ES): m/z = 370 [M+H]+. Anal. Calcd. for C17H23N9O: C 55.27; H 6.28; N 34.12. Found: C 55.28; H 6.11; N 34.2.

5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)propyl)-1-isopropyl-3-phenyl-1H-1,2,4-triazole 4{12,718,42}

Yield 63 mg (65%). Brownish oil. 1H NMR (600 MHz, DMSO-d6) δ 7.94 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.3 Hz, 2H), 7.40 – 7.34 (m, 1H), 5.61 (s, 1H), 4.83 – 4.74 (m, 1H), 4.47 (h, J = 6.5 Hz, 1H), 3.42 (dd, J = 15.0, 10.1 Hz, 1H), 3.14 (dd, J = 15.0, 4.2 Hz, 1H), 2.07 (s, 3H), 2.03 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H), 1.34 (d, J = 6.5 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 159.3, 152.8, 146.1, 138.3, 131.3, 128.8, 128.6, 125.5, 104.0, 51.9, 49.0, 32.2, 22.6, 21.6, 21.3, 13.5, 10.1. LC/MS(API-ES): m/z = 324 [M+H]+. Anal. Calcd. for C19H25N5: C 70.56; H 7.79; N 21.65. Found: C 70.73; H 7.47; N 21.35.

3-Methyl-5-(1-(2-methylbenzyl)-3-(tetrahydrofuran-2-yl)-1H-1,2,4-triazol-5-yl)-1H-indazole 4{73,731,137}

Yield 61 mg (55%). Yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.87 (s, 1H), 7.61 – 7.52 (m, 2H), 7.23 – 7.15 (m, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 5.49 (s, 2H), 4.91 (t, J = 6.9 Hz, 1H), 3.91 (q, J = 7.5 Hz, 1H), 3.78 (q, J = 7.5 Hz, 1H), 2.43 (s, 3H), 2.26 – 2.17 (m, 2H), 2.18 (s, 3H), 2.13 – 2.04 (m, 1H), 2.00 – 1.88 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 163.2, 155.6, 142.1, 140.8, 135.1, 134.8, 130.2, 127.6, 126.5, 126.1, 122.0, 120.6, 119.0, 110.5, 73.7, 67.6, 50.3, 30.5, 25.6, 18.6, 11.5. LC/MS(API-ES): m/z = 374 [M+H]+. Anal. Calcd. for C22H23N5O: C 70.76; H 6.21; N 18.75. Found: C 70.97; H 6.59; N 19.13.

3-(5-((Tetrahydro-2H-pyran-4-yl)methyl)-1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)pyridine 4{71,476,75}

Yield 71 mg (61%). Beige solid. M.p. 79–81 °C. 1H NMR (600 MHz, DMSO-d6) δ 9.22 (d, J = 2.0 Hz, 1H), 8.66 (dd, J = 4.8, 2.0 Hz, 1H), 8.38 (dt, J = 8.0, 2.0 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.53 (dd, J = 8.0, 4.8 Hz, 1H), 3.78 (dd, J = 11.6, 4.5 Hz, 2H), 3.25 (t, J = 11.6 Hz, 2H), 2.81 (d, J = 7.0 Hz, 2H), 2.11 – 2.01 (m, 1H), 1.60 (d, J = 12.9 Hz, 2H), 1.22 (dd, J = 12.1, 4.4 Hz, 1H), 1.18 (dd, J = 12.1, 4.4 Hz, 1H). 13C NMR (151 MHz, DMSO-d6) δ 158.5, 156.3, 150.4, 147.0, 137.6, 133.3, 131.0, 130.3 (q, J = 33.0 Hz), 129.5, 126.3, 126.0, 124.0, 122.6 (q, J = 272.2 Hz), 122.4, 66.8, 33.6, 32.6, 32.2. 19F NMR (564 MHz, DMSO-d6) δ −61.14. LC/MS(API-ES): m/z = 389 [M+H]+. Anal. Calcd. for C20H19F3N4O: C 61.85; H 4.93; N 14.43. Found: C 61.86; H 5.01; N 14.29.

5-(3,3-Difluorobutyl)-1-(3-methoxyphenyl)-3-(phenoxymethyl)-1H-1,2,4-triazole 4{129,463,82}

Yield 63 mg (56%). Yellowish oil. 1H NMR (600 MHz, DMSO-d6) δ 7.50 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 8.3 Hz, 2H), 7.17 – 7.13 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.96 (t, J = 7.2 Hz, 1H), 5.10 (s, 2H), 3.82 (s, 3H), 2.96 (t, J = 8.0 Hz, 2H), 2.37 (tt, J = 16.5, 8.0 Hz, 2H), 1.60 (t, J = 19.0 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 159.8, 158.6, 158.1, 155.3, 137.7, 130.4, 129.5, 123.3 (d, J = 238.3 Hz), 120.9, 117.0, 114.9, 114.6, 110.7, 62.8, 55.6, 34.6 (t, J = 25.5 Hz), 22.9 (t, J = 26.5 Hz), 19.6 (t, J = 5.4 Hz). 19F NMR (564 MHz, DMSO-d6) δ −89.99 (h, J = 18.2 Hz). LC/MS(API-ES): m/z = 374 [M+H]+. Anal. Calcd. for C20H21F2N3O2: C 64.33; H 5.67; N 11.25. Found: C 64.54; H 5.91; N 11.37.

2-(4-(5-(1,5-Dimethyl-1H-pyrazol-4-yl)-1-(4-methoxyphenyl)-1H-1,2,4-triazol-3-yl)-1H-pyrazol-1-yl)ethanol 4{39,464,194}

Yield 64 mg (56%). Beige solid. M.p. 164–166 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.87 (s, 1H), 7.39 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 4.93 (t, J = 5.4 Hz, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.83 (s, 3H), 3.77 (q, J = 5.5 Hz, 2H), 3.74 (s, 3H), 2.47 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 159.5, 155.9, 149.3, 139.3, 136.9, 136.4, 130.8, 129.3, 127.5, 114.5, 113.3, 106.9, 59.9, 55.5, 54.1, 36.2, 10.2. LC/MS(API-ES): m/z = 380 [M+H]+. Anal. Calcd. for C19H21N7O2: C 60.15; H 5.58; N 25.84. Found: C 60.15; H 5.83; N 25.84.

4-(5-(3-(1H-Indol-3-yl)propyl)-1-(2-(pyridin-2-yl)ethyl)-1H-1,2,4-triazol-3-yl)pyrazolo[1,5-a]pyrazine 4{156,479,196}

Yield 89 mg (66%). Yellowish oil. 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.81 (d, J = 4.7 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.98 (d, J = 4.7 Hz, 1H), 7.63 (td, J = 7.7 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.20 – 7.12 (m, 3H), 7.07 (t, J = 7.7 Hz, 1H), 6.97 (t, J = 7.7 Hz, 1H), 4.60 (t, J = 6.8 Hz, 2H), 3.34 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 2.04 (quint, J = 7.5 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 157.6, 157.4, 157.0, 149.1, 143.7, 142.3, 136.6, 136.3, 133.0, 128.6, 127.1, 123.4, 122.3, 121.9, 121.8, 120.8, 118.3, 118.1, 113.7, 111.3, 101.4, 47.3, 37.2, 27.4, 24.5, 24.1. LC/MS(API-ES): m/z = 449 [M+H]+. Anal. Calcd. for C26H24N8: C 69.62; H 5.39; N 24.98. Found: C 69.91; H 5.73; N 24.71.

2-(2-(5-((2R*,4r,6S*)-2,6-Dimethyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1H-1,2,4-triazol-1-yl)ethyl)pyridine 4{86,475,114}

Yield 72 mg (63%). Colorless solid. M.p. 93–95 °C. 1H NMR (600 MHz, DMSO-d6) δ 8.53 (d, J = 5.0 Hz, 1H), 8.01 – 7.95 (m, 2H), 7.66 (td, J = 7.6, 1.9 Hz, 1H), 7.29 – 7.21 (m, 3H), 7.15 (d, J = 7.6 Hz, 1H), 4.57 (t, J = 6.6 Hz, 2H), 3.45 (dq, J = 12.5, 6.2 Hz, 2H), 3.29 (t, J = 6.6 Hz, 2H), 2.97 (tt, J = 12.1, 3.9 Hz, 1H), 1.37 (d, J = 12.1 Hz, 2H), 1.25 (q, J = 12.1 Hz, 2H), 1.07 (d, J = 6.2 Hz, 6H). 13C NMR (151 MHz, DMSO-d6) δ 162.5 (d, J = 245.5 Hz), 159.2, 158.9, 157.7, 149.2, 136.6, 127.7 (d, J = 8.3 Hz), 123.7, 121.9, 115.5 (d, J = 21.7 Hz), 71.8, 46.9, 37.6, 37.2, 31.5, 21.7. 19F NMR (564 MHz, DMSO-d6) δ −112.89. LC/MS(API-ES): m/z = 381 [M+H]+. Anal. Calcd. for C22H25FN4O: C 69.45; H 6.62; N 14.73. Found: C 69.46; H 6.61; N 15.05.

1-(4-(5-Isobutyl-1-(3,3,3-trifluoropropyl)-1H-1,2,4-triazol-3-yl)phenyl)piperidin-4-ol 4{163,472,156}

Yield 67 mg (56%). Beige solid. M.p. 138–140 °C. 1H NMR (600 MHz, DMSO-d6) δ 7.78 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 4.68 (s, 1H), 4.36 (t, J = 6.8 Hz, 2H), 3.68 – 3.61 (m, 1H), 3.63 – 3.56 (m, 2H), 2.95 – 2.84 (m, 4H), 2.64 (d, J = 7.0 Hz, 2H), 2.12 (sept, J = 7.0 Hz, 1H), 1.85 – 1.77 (m, 2H), 1.50 – 1.41 (m, 2H), 0.96 (d, J = 7.0 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 160.1, 155.6, 151.1, 127.4 (t, J = 277.1 Hz), 126.7, 120.8, 114.8, 66.0, 45.8, 40.7 (d, J = 4.0 Hz), 33.6, 33.3, 32.7 (q, J = 27.9 Hz), 27.2, 22.1. 19F NMR (564 MHz, DMSO-d6) δ −63.92 (t, J = 11.2 Hz). LC/MS(API-ES): m/z = 397 [M+H]+. Anal. Calcd. for C20H27F3N4O: C 60.59; H 6.86; N 14.13. Found: C 60.68; H 6.7; N 14.26.

1-(Bicyclo[1.1.1]pentan-1-yl)-3-(3-(methylsulfonyl)phenyl)-5-(2-phenylpropyl)-1H-1,2,4-triazole 4{116,478,66}

Yield 92 mg (76%). Colorless solid. M.p. 152–154 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.45 – 8.40 (m, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.32 – 7.25 (m, 4H), 7.22 – 7.15 (m, 1H), 3.41 – 3.33 (m, 1H), 3.27 (s, 3H), 3.18 – 3.07 (m, 2H), 2.63 (s, 1H), 2.30 (s, 6H), 1.33 (d, J = 6.9 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 157.7, 155.7, 145.5, 141.4, 131.9, 130.4, 130.1, 128.4, 127.5, 126.8, 126.3, 123.7, 53.0, 51.7, 43.6, 38.4, 34.0, 23.5, 21.3. LC/MS(API-ES): m/z = 408 [M+H]+. Anal. Calcd. for C23H25N3O2S: C 67.79; H 6.18; N 10.31; S 7.87. Found: C 67.92; H 6.03; N 10.2; S 7.95.

Acknowledgements

The authors thank Dr. Angelika Konovets for the compound QC management, Mr. Bohdan V. Vashchenko and Ms. Vladyslava Prykhodko for their help with TOC graphics preparation, and Prof. Andrey A. Tolmachev for his encouragement and support.

Funding The work was funded by Enamine Ltd. and NIH grant GM133836 (to Y.S.M.). O.O.G. was also funded by Ministry of Education and Science of Ukraine (grants No. 19BF037-03 and 21BF037-01M).

Footnotes

Declarations

Conflicts of interest The authors declare no competing interests apart from those indicated in the Funding and Affiliation sections.

Electronic supplementary material The online version of this article (https://doi.org/10.1007/) contains supplementary material, which is available to authorized users.

Availability of data and material Library member characterization data not presented in the supplementary material are available from authors upon request. Compound library members generated in this study can be made available on request, but payment and/or a completed Materials Transfer Agreement shall be required if there is potential for commercial application. There are restrictions on the availability of the synthon lists with the reactivity features that have been used to generate the chemical space owing to commercial confidentiality reasons.

Code availability Not applicable

This Author Accepted Manuscript is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication but has not been copyedited or corrected. The official version of record that is published in the journal is kept up to date and so may therefore differ from this version.

Contributor Information

Dmytro S. Radchenko, Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine.

Vasyl S. Naumchyk, Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine

Igor Dziuba, Chemspace (www.chem-space.com), Chervonotkatska Street 78, Kyiv 02094, Ukraine.

Andrii A. Kyrylchuk, Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine; Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02094, Ukraine.

Yurii S. Moroz, Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine; Chemspace (www.chem-space.com), Chervonotkatska Street 78, Kyiv 02094, Ukraine.

Kateryna E. Gubina, Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine

Oleksandr O. Grygorenko, Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine; Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine.

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