Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][NH:23][CH2:24][CH:25]3[CH2:28][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:32]=5[N:31]=4)[CH2:26]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1.[BH3-][C:53]#N.[Na+]>CO.C1COCC1>[CH3:3][C:4]1([CH3:51])[O:8][C@@H:7]2[C@@H:9]([CH2:22][N:23]([CH3:53])[CH2:24][CH:25]3[CH2:26][CH:27]([CH2:29][C:30]4[N:34]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:41])[CH3:42])[C:33]5[CH:43]=[CH:44][C:45]([C:47]([F:50])([F:48])[F:49])=[CH:46][C:32]=5[N:31]=4)[CH2:28]3)[CH2:10][C@@H:11]([N:12]3[C:16]4[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=4[CH:14]=[CH:13]3)[C@@H:6]2[O:5]1
Reactant: CC1(C)O[C@@H]2[C@@H](CNCC3CC(Cc4nc5cc(C(F)(F)F)ccc5n4COCC[Si](C)(C)C)C3)C[C@@H](n3ccc4c(N)ncnc43)[C@@H]2O1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CC1CC(Cc2nc3cc(C(F)(F)F)ccc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Formaldehyde (36 μl, 0.49 mmol, 37%(aq)) was added to a solution of 7-[(3aS,4R,6R,6aR)-2,2-dimethyl-6-({[(3-{[5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl]amino}methyl)-hexahydro cyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine in MeOH (5 ml) and THF (5 ml), and the reaction was stirred at RT for 30 mins. NaCNBH3 (18 mg, 0.29 mmol) was added portionwise, and the reaction stirred for a further 2 hours at RT after which LC MS showed the reaction to be complete. The reaction mixture was concentrated under in vacuo, and the residue partitioned between water (20 ml) and DCM (20 ml) and the layers were separated. The aqueous layer was extracted with DCM (2×20 ml), the combined organics were then dried over Na2SO4, and concentrated. Purification by prep. TLC, eluting with 7N NH3 in MeOH:DCM (5:95) gave the desired product (114 mg, 66%) as a colourless oil; MS (EST+) for C36H50F3N7O3Si m/z 714.45 [M+H]+; HPLC purity 100% (ret. time, 1.77 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm −0.14-0.05 (9H, m), 0.85-0.99 (2H, m), 1.18-1.35 (3H, m), 1.37-1.53 (2H, m), 1.52-1.64 (3H, m), 1.89-2.15 (3H, m), 2.18-2.28 (2H, m), 2.29-2.70 (6H, m), 2.72-2.96 (1H, m), 2.97-3.20 (2H, m), 3.48 (3H, s), 3.50-3.58 (2H, m), 4.37-4.58 (1H, m), 4.85-5.05 (2H, m), 5.11-5.38 (2H, m), 5.41-5.57 (2H, m), 6.35 (1H, d, J=3.63 Hz), 6.84-7.19 (1H, m), 7.50 (1H, d, J=8.35 Hz), 7.68 (1H, s), 7.78 (1H, d, J=8.35 Hz), 8.13-8.52 (1H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([S:15]([NH2:18])(=[O:17])=[O:16])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:5]1([S:15]([NH2:18])(=[O:16])=[O:17])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:27]
Reactant: NS(=O)(=O)C1c2ccccc2-c2ccc(Cl)cc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2ccccc2-c2ccc(Cl)cc21
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
Under nitrogen, (21) (2.6 g, 9.3 mmoL) was added portionwise to a stirred suspension of sodium hydride (465 mg of a 60% mineral oil dispersion, 1.25 eq) in dry dimethylformamide (60 mL , from CaH2). After 30 minutes, ethyl bromoacetate (1.3 g, 11.6mmoL, 1.25 eq) was added and stirring was continued overnight. The reaction was then diluted with water (200 mL), neutralized, and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (3×200 mL), dried (MgSO4), and concentrated. The crude solid was recrystallized twice from ethyl acetate/hexane to provide 1.7 g(50%) of product (22): mp 189°-191° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[C:20](=O)[CH:21]=[CH:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)(=O)C.[Pt]=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:27][O:26][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(=O)ccoc4c3O2)cc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1

Procedure:
[(2R)-7-Oxo-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-2-yl]methyl 4-methylbenzenesulfonate (1.0 g, 2.6 mmole) dissolved in acetic acid (50 mL) was hydrogenated at 40 psi in the presence of 0.30 g platinum oxide on a Parr shaker for 5 hours. The catalyst was filtered through celite and the filter cake washed with water. The filtrate was then extracted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate until neutral. The organic extracts were dried over magnesium sulfate, filtered and evaporated to give 0.78 g (81%) of the (R)-enantiomer of the title compound as a clear oil. 1H (CDCl3) doublet 7.8 δ (2H); doublet 7.4 δ (2H); singlet 6.5 δ (1H); singlet 6.4 δ (1H); multiplet 4.2 δ (1H); multiplet 4.1-4.3 δ (5H); multiplet 4.0 δ (1H); triplet 2.7 δ (2H); singlet 2.4 δ (3H); triplet 2.0 δ (2H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([N:15]=[C:16]=[S:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([N:24]2[C:25](=[S:26])[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:7])[NH:15][C:16]2=[S:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(N=C=S)c1ccccc1
Reactant: S=C=Nc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccccc2)NC(=S)N(c2ccccc2)C1=S
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
15.1 g (122 mmol) of potassium tert-butoxide are dissolved in 200 ml of tetrahydrofuran in a 500 ml, three-necked, round-bottomed flask under a dry argon atmosphere. The solution is cooled to -70° C. A solution containing 20 g (122 mmol) of alpha-methylbenzyl isothiocyanate, 16.55 g (122 mmol) of phenyl isothiocyanate and 50 ml of tetrahydrofuran is run in dropwise while keeping the temperature of the mixture below -60° C. On completion of addition, the mixture is held for 0.5 hour at -70° C. and then is left to return to room temperature. The mixture is poured into 500 ml of water. The mixture is acidified to pH=1 by addition of N hydrochloric acid. The product is extracted with ethyl acetate (2 extractions, each with 150 ml of solvent). The solution is dried over magnesium sulfate. The solution is concentrated under reduced pressure. The product is crystallized from 50 ml of ether. The precipitate is filtered. 21 g (yield: 58%) of 3,5-diphenyl-5-methyldithiohydantoin are thus obtained as a yellow powder melting at 157° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([NH:9][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
3-Chloropropylsulfonyl chloride 1 (1.456 g, 8.23 mmol) was dropwise added to a solution of aniline (0.5 ml, 8.23 mmol) in pyridine (5 ml) with cooling at −20° C. to −30° C. over about 5 minutes. After the completion of the addition, the reaction mixture was stirred for another 45 minutes at room temperature. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography on silica gel. From the fraction eluted with a mixture of ethyl acetate/n-hexane (1:2), 1.683 g (88%) of N-phenyl-3-chloropropylsulfonamide (intermediate 3j) was obtained as a yellow oil. From the intermediate 3j, the desired compound 4j (yield: 57%) was yielded as a pale yellow solid in a manner as described in Preparation 1. IR (CHCl3)cm−1: 3020, 1598, 1495, 1315, 1139. NMR (CDCl3) δ: 2.46-2.60 (2H, m, CH2), 3.34-3.42 (2H, m, CH2), 3.78 (2H, t, J=6.6 Hz, CH2), 7.10-7.40 (5H, m, C6H5).
Reaction SMILES: [CH2:1]([N:3]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:4]1[CH:5]=[C:6]([CH3:19])[C:7]([CH3:18])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9]2)[CH3:2].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH2:1]([N:3]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:4]1[CH:5]=[C:6]([CH3:19])[C:7]([CH3:18])=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)c(C)cc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1cc(C)c(C)c2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.3 %

Procedure:
To a mixed solution of ethyl 7-[ethyl(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carboxylate (210 mg) in tetrahydrofuran (8 ml)-methanol (8 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (100 mg), and the mixture was stirred at room temperature for 6 hr. The reaction solution was acidified with aqueous citric acid solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 7-[ethyl(2-thienylsulfonyl)amino]-4,5-dimethyl-1H-indole-2-carboxylic acid (200 mg, yield:quantitative) as colorless crystals. To a mixture of the obtained crystals (200 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (100 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (130 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed successively with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:1) to give the title compound (200 mg, yield: quantitative) as colorless prism crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=O)[CH:4]=[C:5]([CH3:7])[N:6]=1.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[Li]>>[C:23]([O:22][C:19](=[O:21])[CH2:20][C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([N:3]2[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]2[CH3:1])[CH:9]=1)=[O:13])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cccc(-n2cc(C)nc2C)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
Prepared from ethyl 3-(2,4-dimethyl-imidazol-1-yl)-benzoate [prepared by reaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloride in EtOH at 0° C., direct treatment with 2-aminopropionaldehyde dimethyl acetal in EtOH at 23° C., follwed by addition of conc. H2SO4 and refluxing.] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as a yellow-brown oil (6.00 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[NH:17][S:18](=[O:20])(=[O:19])[C:13]=3[CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>CN(C)C=O.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:24]=[CH:23][C:14]3[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH2:40][C:39]4[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=4)[S:18](=[O:19])(=[O:20])[C:13]=3[CH:12]=2)=[O:10])=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)NC(=O)N3C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)N(Cc2ccc([N+](=O)[O-])cc2)C(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
4-Methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazine-7-carboxylic acid 4-methoxy-benzylamide (1.0 g), and cesium carbonate (0.87 g) were mixed in 50 mL of N,N-dimethylformamide. 4-Nitrobenzylbromide (0.58 g) was added, and the resulting mixture was stirred for 16 hours at room temperature. The reaction was diluted with IM HCl and filtered to give a gummy solid. Recrystallization from ethyl alcohol gave the title compound as a white solid (0.77 g). 1H-NMR (CDCl3); δ 8.48 (s, 1H), 8.26 (d, 1H), 8.10 (m, 3H), 7.54 (d, 2H), 7.25 (m, 4H), 6.82 (t, 2H), 5.05 (s, 2H), 4.50 (d, 2H), 3.73 (d, 3H), and 3.48 (s, 3H) ppm. Anal. (C24H22N407S-1.01H2O) C,H,N. MS: M++1=511.2 Da
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[CH:28]([CH3:32])[C:29](=[O:31])[CH3:30]>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH:28]([CH3:32])[C:29](=[O:31])[CH3:30])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Reactant: CC(=O)C(C)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC(C)C(C)=O)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 2.76 g (0.01 mole) of 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine (D. E. Schwartz, W. Vetter, and G. Englert, Arzneim.-Forsch. (Drug Res.) 1970, 20, 1867; G. Rey-Bellet and R. Reiner, Helv. Chim. Acta 1970, 53, 945) in 40 mL of dry dimethyl sulfoxide was added 1.12 g (0.01 mole) of potassium t-butoxide. To the resulting suspension was added in one portion 1.16 g (0.0109 mole) of 3-chloro-2-butanone. The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum and the residue was partitioned between 100 mL of methylene chloride and 100 mL of 0.1N sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with an additional 100 mL of methylene chloride. The organic layers were combined, washed with 100 mL of water, dried (MgSO4) and concentrated to give a quantitative yield (3.58 g) of the title compound. Recrystallization from 95% ethanol gave an analytical sample; mp 167.5°-168.5°. Anal. Calc'd for C17H22N4O4 : C, 58.95; H, 6.40; N, 16.17. Found: C, 58.77; H, 6.42; N, 16.13.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[O:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][N:23]1[C:27]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[N:26][N:25]=[C:24]1[SH:33]>C(#N)C>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][S:33][C:24]3[N:23]([CH3:22])[C:27]([C:28]4[S:29][CH:30]=[CH:31][CH:32]=4)=[N:26][N:25]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cn1c(S)nnc1-c1cccs1
Reactant: COc1cccc(-c2nc(CCl)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cccc(-c2nc(CSc3nnc(-c4cccs4)n3C)no2)c1
Yield: 89.6 %

Procedure:
The title compound was prepared from 3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (50 mg, 0.22 mmol), potassium carbonate (92.4 mg, 0.67 mmol), 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.8 mg, 0.27 mmol) in acetonitrile (1 ml) at room temperature. Purification was performed by SPE (flash) chromatography using 30-40% ethyl acetate in hexanes afforded 76 mg (90%) of the title compound as a white solid. 1H NMR (CDCl3), δ (ppm): 7.68 (d, 1H), 7.57 (t, 1H), 7.49 (m, 2H), 7.41 (t, 1H), 7.15 (m, 2H), 4.53 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H). LC-MS (M+1)+ 386.3.
Reaction SMILES: [NH:1]=[C:2](SC)[C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:15])[CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[CH3:19][O:20][CH2:21][C:22]([NH:24][NH2:25])=O>C(O)(=O)C>[CH:13]([C:6]1[CH:5]=[C:4]([CH3:16])[C:3]([C:2]2[NH:1][C:22]([CH2:21][O:20][CH3:19])=[N:24][N:25]=2)=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(C(=N)SC)c(C)cc1C(C)C
Reactant: COCC(=O)NN
Solvent: CC(=O)O
Product: COCc1nnc(-c2cc(C(=O)OC)c(C(C)C)cc2C)[nH]1
Yield: 27.4 %

Procedure:
A solution of methyl 5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate (compound 196.5, 800 mg, 3.01 mmol, 1.00 equiv) and 2-methoxyacetohydrazide (compound 190.6, 1.90 g, 18.3 mmol, 5.00 equiv) in acetic acid (30 mL) was stirred for 2 h at 80° C. in an oil bath, then concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50-1:2) as eluent to yield 250 mg (27%) of methyl 2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate as a clear oil.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)c1cc(C=Cc2ccccc2OCC2CO2)on1
Product: CC(C)c1cc(C=Cc2ccccc2OCC(O)CNC(C)(C)C)on1

Procedure:
7 g (0.025 mole) of 3-isopropyl-5-[2-(2,3-epoxypropoxy)-styryl]-isoxazole and 3.6 g (0.05 mole) of tert.-butylamine are reacted by the method described in Example 4. 5.8 g (59% of theory) of colorless crystals are obtained. Melting point 191°-193° C.
Reaction SMILES: Br[C:2]1(Br)[CH2:4][C:3]1(Br)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([Li])CCC.CN(C)CCN(C)C.Br[CH2:26][CH:27]=[CH:28][CH2:29][CH3:30]>O1CCCC1.O>[CH2:26]([C:2]1[CH2:4][C:3]=1[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:27]=[CH:28][CH2:29][CH3:30]
Reactant: CCC=CCBr
Reactant: CCCCCC1(Br)CC1(Br)Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCC=CCC1=C(CCCCC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
A solution of 1.00 g (0.00287 mol) of 1,1,2-tribromo-2-pentyl-cyclopropane in 4 ml of tetrahydrofuran was placed under an inert atmosphere of nitrogen via a Firestone valve. To this mixture, cooling in an ice water bath, was added via syringe 3.58 ml (0.00861 mol) of 1.6M n-butyllithium in hexanes. After 30 minutes, 0.432 ml (0.00287 mol) of tetramethylethylene diamine and 0.339 ml (0.00287 mol) of 1-bromo-2-pentene were added by syringe. The reaction stirred for one hour while warming to room temperature, then for three hours at room temperature. To the resulting mixture was added 2 ml of water. This residue was extracted with diethyl ether. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 0.200 g (39.1% of theory) of 1-pent-2-enyl-2-pentyl-cyclopropene as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12]>O>[CH3:12][C:11]1([CH3:13])[S:14][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:9][C@H:10]1[C:15]([OH:17])=[O:16]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1cccnc1
Solvent: O
Product: CC1(C)SC(c2cccnc2)N[C@H]1C(=O)O
Reaction time: 0.17 h

Procedure:
0.94 ml (1.07 g, 10 mmoles) of pyridine-3-aldehyde is added to a solution containing 1.5 g (10 mmoles) of D-penicillamine in 30 ml of water at room temperature while stirring. After 10 minutes, the title product begins to crystallize. The mixture is stirred for 1 additional hour, the precipitate is filtered, washed with water and dried. The thus-obtained crude product is dissolved in hot water, filtered and cooled down to give the crystalline title compound in a yield of 1.9 g (79.7%), m.p.: 164°-165° C., [α]D20 =+145° (c=0.556, dimethylsulphoxide).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C[Si]([N:23]=[N+:24]=[N-:25])(C)C>COCCOC>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:16]3[NH:25][N:24]=[N:23][N:17]=3)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(C2(C#N)CCOCC2)cc1
Solvent: COCCOC
Product: COC(=O)c1ccc(C2(c3nnn[nH]3)CCOCC2)cc1

Procedure:
A solution of 4-(4-cyano-tetrahydro-pyran-4-yl)-benzoic acid methyl ester (400 mg, 1.63 mmol), trimethylsilyl azide (TMSN3) (40 mg, 2.1 eq), and Bu2Sn(O) (40 mg, 1.0 eq) in DME was heated in the microwave at 150° C. for 4 hours. After the reaction was done the mixture was washed with water and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(1H-tetrazol-5-yl)-tetrahydro-pyran-4-yl]-benzoic acid methyl ester.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH:1]1([NH:7][C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: NC1CCCCC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NC2CCCCC2)n1
Yield: 45 %

Procedure:
According to the general method described in step 5 of example 27, reaction of cyclohexylamine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (45%) as sticky yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[CH3:25]O>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:16][CH3:25])=[O:15])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: CC1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCC(C)CC2)c1
Yield: 75 %

Procedure:
3-((4-methylpiperidin-1-yl)sulfonyl)benzoic acid (120 mg, 0.424 mmol) was refluxed in the presence of con. Sulfuric acid (2.74 mg, 0.021 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 3-((4-methylpiperidin-1-yl)sulfonyl)benzoate (100 mg, 0.319 mmol, 75% yield). 1H NMR (CDCl3, 400 MHz): δ 8.39 (m, 1H), 8.25 (m, 1H), 7.94 (m, 1H), 7.62 (t, 1H, J=7.6 Hz), 3.95 (s, 3H), 3.77 (m, 2H), 2.25 (m, 2H), 1.67 (m, 2H), 1.29 (m, 3H), 0.90 (d, 3H, J=4.8 Hz). ESI-MS: 298.1[M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([O:21]CC)=O.C(OC([N:37]1CC[C@@H](NC2N=C3C(NC(=O)N3C3C=CC=CC=3OC)=C(C(OCC)=O)N=2)C1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17](=[O:18])[NH:16][C:15]2[C:10]1=[N:11][C:12]([NH:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:13][C:14]=2[C:19]([NH2:37])=[O:21]
Reactant: CCOC(=O)c1nc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@@H]2CCNC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@@H]3CCNC3)nc21
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-Ethyl 9-(2-methoxyphenyl)-8-oxo-2-(pyrrolidin-3-ylamino)-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate (0.333 g, 0.668 mmol) were dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The solution was stirred for two hours and condensed under reduced pressure to afford the crude title compound (0.300 g, 100%). MS (ESI) m/z 399.3 [M+1]+.