Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][C:23]([N:27]([CH3:28])[CH3:26])=[O:25])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCCCC(=O)O)cc2C1
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](NC(=O)OC(C)(C)C)CC2
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
(S)-4-[2-(tert-Butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]butyric acid (399 mg) was dissolved in tetrahydrofuran (5 ml), and N,N'-carbonyldiimidazole (204 mg) was added to the solution under ice-cooling with stirring. After reaction for 2 hours, a solution of dimethylamine (1.40 g) in tetrahydrofuran (2 ml) was added to the reaction mixture under ice-cooling with stirring. After reaction for 45 minutes and then at room temperature for 45 minutes, the reaction mixture was concentrated in vacuo. Water was added to the resulting residue and the mixture was extracted with diethyl ether. The extract was washed with 10% aqueous citric acid solution, water, a saturated aqueous sodium bicarbonate solution and water successively, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give (S)-4-[2-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylbutyramide (396 mg) having a melting point of 97-101° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[N:13][CH:12]=[CH:11]2)[CH3:7])[CH3:2].[ClH:19]>C(O)C>[ClH:19].[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C=C(C)c1ccc2cnccc2c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCNC2
Reaction time: 19 h

Procedure:
A solution of 3-(isoquinolin-6-yl)-but-2-enoic acid ethyl ester {0.5 g, Reference Example 3(a)} in ethanol (30 mL) was treated with concentrated hydrochloric acid (1.7 mL). This stirred solution was flushed with nitrogen then treated with platinum oxide (0.07 g) and then hydrogenated in the presence of hydrogen at 2 bar for 19 hours. The reaction mixture was filtered through Hyflo supercel and the filter pad was washed three times with ethanol (20 mL). The combined filtrate plus washings were evaporated to give the title compound as a pale green solid. MS (ES)=248 (M+H)+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>O>[C:13]([NH:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=1)(=[O:15])[CH3:14]
Reactant: Cc1cc(N)n[nH]1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cc(C)[nH]n1
Yield: 59.6 %

Procedure:
50.4 g (0.6 mol) of sodium bicarbonate were added in small amounts at room temperature to a solution of 19.4 g (0.2 mol) of 3-amino-5-methyl-1H-pyrazole in 200 cm3 of water. 37.8 cm3 (0.4 mol) of acetic anhydride were added dropwise to this solution and then the mixture was heated at reflux for 2 hours. The solution was subsequently brought back to room temperature, a white solid crystallized and was pulled dry on sintered glass and then washed with 100 cm3 of water. After drying under vacuum at 40° C., 16.6 g of the expected product were obtained in the form of pearlescent-white crystals, the melting point of which was between 210° C. and 212° C.
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[I:13][C:14]1C(C)=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18].IC.Cl>O1CCCC1>[I:13][C:14]1[C:12]([CH2:10][CH3:11])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18]
Reactant: Cc1c(I)cccc1C(=O)O
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCc1c(I)cccc1C(=O)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
A n-butyllithium-1.58M n-hexane solution (36.2 ml, 57.2 mmol) was added dropwise to a solution of diisopropylamine (8.02 ml, 57.2 mmol) in tetrahydrofuran (114 ml) under ice-cooling, and the mixture was further stirred for 30 minutes. After the reaction mixture was cooled to −50° C., a solution of 3-iodo-2-methylbenzoic acid (5.00 g, 19.1 mmol) in tetrahydrofuran (38 ml) was added thereto. After the mixture was stirred for 1 hour, iodomethane (9.51 ml, 153 mmol) was added thereto and the temperature of the mixture was raised from −50° C. to −20° C. over 1 hour. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was successively washed with 1N hydrochloric acid, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-iodo-2-ethylbenzoic acid (5.48 g, yield: 100%).
Reaction SMILES: [CH2:1]([SiH:9]([CH3:11])[Cl:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:12]([Si:30]([CH:33]=[CH2:34])([CH3:32])[Cl:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[CH2:12]([Si:30]([CH3:32])([Cl:31])[CH2:33][CH2:34][Si:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH3:11])[Cl:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC[SiH](C)Cl
Reactant: C=C[Si](C)(Cl)CCCCCCCCCCCCCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC[Si](C)(Cl)CC[Si](C)(Cl)CCCCCCCC

Procedure:
Compound B (61.3 g) and 0.05M H2PtCl6, 0.04 mole percent of a chloroplantinic acid/ethyl acetate solution was stirred and heated at 50° to 60° while the 134 g of compound A was added over 45 minutes. The mixture was kept at 60° C. for an additional hour to yield 1-(octadecyl methylchlorosilyl)-2-(octyl methylchlorosilyl) ethane (compound C), as a pale-yellow oil. The analysis calculated for this product (C30H64Cl2Si2): C, 65.28; H, 11.69%. Elemental analysis showed: C, 65.80; H, 11.56%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([NH2:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:44][C:35]([CH3:37])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36])=[O:7]
Reactant: CC(C)(N)c1ccccc1
Reactant: COc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 97.6 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methoxybenzoic acid (1.00 g, 5.36 mmol) was dissolved in DMF (20 mL), and the solution was treated with EDCI (2.06 g, 10.7 mmol), HOBT monohydrate (724 mg, 5.36 mmol) and cumylamine (1.54 mL, 10.7 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-chloro-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (1.59 g, yield 97%).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13](C(C)(C)C)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH:12]=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28.66 g, 108.4 mmol) was dissolved with stirring in 430 mL glacial acetic acid and the resulting mixture was treated drop wise with fuming nitric acid (90%, 179.26 mL). When the addition was complete, the resulting mixture was stirred for 2.5 h. The reaction mixture was poured into a 2.0 L of crushed ice and allowed to stand 30 min. Afterwards, 1.0 L of water was added and the ice water mixture was allowed to melt. The mixture was then filtered, washed with water and dried to provide the title compound (24.57 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[C:26]1([NH:36][C:37](=[O:38])[NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:11][C:10]4[CH:22]=[CH:23][CH:24]=[N:25][C:9]3=4)[CH:5]=[CH:6][CH:7]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=C=Nc1cccc2ccccc12
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Solvent: C1COCCO1
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (150 mg) and 1-naphthyl isocyanate (94 mg) in dry dioxane (3 ml) was stirred at room temperature for 3 hours. The precipitates were collected and washed with isopropyl ether to give 4-[3-[3-(1-naphthyl)ureido]phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:7](=[NH:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C1COCC1>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15]2)/[C:7](=[N:16]/[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:25]=2[F:24])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(F)c(C(=O)Cl)c1
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)/N=c2\cc(C(C)(C)C)n(C)n2CC2CCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.9 %

Procedure:
To a solution of Example 113C (0.30 g, 1.4 mmol) and Et3N (0.56 mL, 4.1 mmol) in THF (10 mL) was added 2-fluoro-5-methylbenzoyl chloride (0.23 g, 1.4 mmol). The mixture was stirred at ambient temperature for 4 hours then partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous phase was extracted EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes in EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) afforded the title compound (0.24 g, 0.67 mmol, 50% yield). MS (ESI+) m/z 358 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([S:18]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cc2[nH]ccc2cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
A 100 mL round-bottomed flask was charged with a solution of 1H-pyrrolo[3,2-c]pyridine (1.0 g, 8.4 mmol) in anhydrous THF (50 mL). NaH (60% in mineral oil, 0.41 g, 10.2 mmol) was added and the reaction mixture was stirred for 5 min at room temperature. To this solution was added dropwise, at 0° C., benzenesulfonyl chloride (1.35 mL, 10.2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (1.29 g, 55%). 1H NMR (DMSO, 300 MHz): δ 8.95 (s, 1 H); 8.49 (d, J=5.8 Hz, 1 H); 8.13-8.05 (m, 2 H); 8.02-7.94 (m, 2 H); 7.79-7.71 (m, 1 H); 7.69-7.59 (m, 2 H); 7.01 (dd, J=3.7, 0.9 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:7]2=[CH:8][CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ncnn2cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
4-Chloropyrrolo[2,1-f][1,2,4]triazine (4.1g, 27 mmol), 2-fluoro-4-nitrophenol (5.0 g, 32 mmol), and potassium carbonate (7.4 g, 53 mmol) in 100 mL of dimethylformamide was stirred at 60° C. for 15 h. After cooling to room temperature, the reaction mixture was filtered through a plug of silica gel with EtOAc. The filtrate was concentrated in vacuo and the resulting crude product was purified by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:4) to give the title compound (4.25 g, 58%) as a white solid. 1H NMR (CDCl3) δ 8.09 (m, 2H), 7.88 (s, 1H), 7.77 (dd, 1H, J=2.6, 1.2 Hz), 7.46 (t, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=4.6, 1.4 Hz), 6.84 (dd, 1H, J=4.5, 2.6 Hz); 13C NMR (CDCl3) δ 160.6, 154.3 (J=254 Hz), 146.5, 145.8, 144.8 (J=12.9 Hz), 125.0, 121.7, 120.7, 114.5, 113.9, 113.6 (J=23.2 Hz), 103.6.
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:21])[C@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:29][NH:30][CH3:31].O>CN(C)C=O>[CH2:5]([C@@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C@@H:3]([CH3:21])[CH2:2][N:30]([CH3:31])[CH3:29])[CH3:6]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CCl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Yield: 90 %

Procedure:
The product of Example 42 (2.4 g, 8 mmol) was dissolved in N,N-dimethylformamide, potassium carbonate (2.7 g, 20 mmol) and dimethylamine hydrochloride (0.7 g, 8 mmol) were added therein, then it was reacted at room temperature for 12 hours. After that, the reaction solution was poured into water, the aqueous phase was extracted with dichloromethane twice, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated through silica gel column chromatography to give target 2.2 g, yield: 90%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:28][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([NH:27][C:30](=[O:31])[O:32][CH3:33])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: COC(=O)Cl
Reactant: Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Agent: Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To a solution of 2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepin-8-amine HCl salt (0.2 g, 0.464 mmol) in 10 ml of dried DCM was added TEA (0.32 mL, 2.3 mmol). The mixture was stirred at 0° C. for 20 min and 0.2 ml of methyl chloroformate was added. The reaction mixture was stirred for 10 min and the solution was quenched with water and evaporated to the crude product, which was purified by preparative HPLC to give 113 (81 mg, 38%). 1HNMR (DMSO-d6, 400 MHz): δ 9.78 (s, 1H), 8.81 (s, 1H), 7.79-7.12 (m, 7H), 6.53 (s, 1H), 4.15 (t, J=5.2 Hz, 2H), 3.63 (s, 3H), 2.93 (t, J=5.2 Hz, 2H). MS: (ESI+) 453.1
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])(=[O:16])=[O:15])[S:11][CH:12]=1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)C>[N:25]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])(=[O:16])=[O:15])[S:11][CH:12]=1)=[N+:26]=[N-:27]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN=[N+]=[N-])cs1
Yield: 72.8 %

Procedure:
A mixture of EXAMPLE 191A (1.00 g, 2.43 mmol) and sodium azide (791 mg, 12.17 mmol) in ethanol (30 mL) was refluxed for 2.5 h. The solvent was evaporated and the crude material was extracted with ethyl acetate. The organic phase was dried (Sodium sulfate) and the solvent was evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 2-5% acetone in DCM to yield the title product (633 mg, 1.77 mmol, 70%): MS (Ionspray, [M+H]+) m/z 357.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)N[C@H]1CCCNC1
Product: COC(=O)c1cccc(N2CCC[C@H](NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 49.6 %

Procedure:
Using (S)—N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazol-5-carboxamide (336 mg, 1.00 mmol) and 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol), the same procedure was followed as in Example 2 to give 233 mg (50%) of the desired compound as a colorless powder.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(O)C=CC=CC=1.[H][H]>[Ni].C(O)C>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [Ni]
Solvent: Oc1ccccc1
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](O)CC2)CC1

Procedure:
Ten % by weight (20 g) of Raney nickel was added to 4-(trans-4'-pentylcyclohexyl)phenol (200 g), and ethanol (1.8 l) was added to dissolve the phenol, followed by absorbing 3 mols of hydrogen based on one mol of the raw material phenol, into the solution at 100° C. under a hydrogen pressure of 20 Kg/cm2G. After completion of the hydrogenation, the catalyst was filtered off and ethanol was vaporized to concentrate the solution so as to give a volume of about 0.3 l, followed by adding fresh ethanol, recrystallization and filtration to obtain trans-4-(trans-4'-pentylcyclohexyl)cyclohexanol (77 g) (yield: 37.6%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)[CH2:41][C:37]1[NH:36][CH:40]=[CH:39][N:38]=1
Reactant: CCCN(CCC)CCCCOCc1ccc(CNCc2ncc[nH]2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCOCc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
The compound (81.2 mg) obtained in Example 60-4 was dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (27.4 mg), acetic acid (3.00 ml), and 2-imidazole carboxaldehyde (31.4 mg), followed by stirring under a nitrogen atmosphere at 60° C. for 4 days. After completion of the reaction, the solvent was distilled off. Then, the residue was dissolved in chloroform and added with a saturated aqueous sodium bicarbonate solution, followed by stirring. The aqueous layer was washed with chloroform and then evaporated to dryness. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (63.0 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:19]I.[Cl-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccccn1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of 2-[2-(N-t-butoxycarbonylamino)ethyl]-pyridine (1.8 g) in N,N-dimethylformamide (7 ml) was added dropwise to a suspension of sodium hydride (0.39 g) in N,N-dimethylformamide (7 ml) which was cooled at 0° C. The mixture was stirred at 0° C. for 1 hour. Methyl iodide (1.4 g) was added to this solution at the same temperature. After stirring at 0° C. for 1 hour and at ambient temperature for 2 hours, the mixture was poured into ice water, saturated with sodium chloride, and extracted with ethyl acetate 3 times. The combined organic layer was washed with saturated sodium thiosulfate, saturated sodium bicarbonate and saturated sodium chloride successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel chromatography (ethyl acetate:n-hexane, 3:1, V/V, as eluent) to give 2-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]-pyridine (1.47 g) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[N:38]=[C:9]2[C:10]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)=[C:11]([CH3:27])[C:12]([C:14]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)[N:16]=[CH:17][CH:18]=3)=[CH:13][N:8]2[N:7]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([N:15]2[C:14]([C:12]3[C:11]([CH3:27])=[C:10]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)[C:9]4[N:8]([N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)[N:38]=4)[CH:13]=3)=[CH:18][CH:17]=[N:16]2)=[CH:20][CH:21]=1)#[N:26]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CN3CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
2-Chloro-N-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 17, 150 mg, 0.28 mmol) was stirred in dry DMF (3 mL), then K2CO3 (83 mg, 0.60 mmol) and 1-methylpiperazine (56 mg, 0.56 mmol) were added. Stirring was continued for 2 hrs at RT then the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with water followed by saturated brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography eluting with a gradient of 2-5% MeOH in DCM followed by 10% (2M NH3 in MeOH) in DCM to give the title compound as a white solid (128 mg).