Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])[C:24]([F:43])=[CH:23][N:22]=1>>[F:43][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:41][CH3:42])=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1F
Product: CNC(=O)CN1CCc2cc(Nc3ncc(F)c(Nc4ccc(N5CCN(C)CC5)cc4OC)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.041 g, 42%). MP: 95-136° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.15 (s, 1H), 7.92-7.89 (m, 1H), 7.39 (s, 1H), 7.38-7.32 (m, 1H), 7.20-7.17 (m, 1H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 6.54-6.49 (m, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.22-3.16 (m, 4H), 3.11 (s, 2H), 2.90 (d, 3H, J=5.1 Hz), 2.88-2.82 (m, 4H), 2.72-2.66 (m, 4H), 2.63-2.57 (m, 4H), 2.37 (s, 3H). MS: 579.30 (MH)+.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28]([C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1)=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:30]4[N:31]=[C:32]([CH3:35])[S:33][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: Cc1nc(C(=N)NO)cs1
Product: Cc1nc(-c2noc(N3CCC(N(C(=O)c4ccc(-c5cnco5)cc4)C4CC4)CC3)n2)cs1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-methyl-thiazole-4-carboxamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.64 min; Mass spectrum (ESI+): m/z=477 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.[O:18]1[CH2:20][CH:19]1[CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:17][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:20][CH:19]([OH:18])[CH2:21][CH2:22][NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:7]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:4]([Br:3])=[CH:5][CH:6]=3
Reactant: c1ccc(NCCC2CO2)cc1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCNc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
NaH (60% dispersed in mineral oil, 0.0018 g, 0.0452 mmol) was added to a solution of 3,6-dibromocarbazole (0.0147 g, 0.0452 mmol) in 0.5 mL anhydrous THF and the mixture was stirred for 15 min. N-(2-(oxiran-2-yl)ethyl)aniline (0.0067 g, 0.0410 mmol) in 1.5 mL anhydrous THF solution was added dropwise and the resulting mixture was stirred at 60° C. overnight. THF was removed under vacuum and the residue was dissolved in 10 mL EtOAc and washed with water 2×5 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0115 g colorless oil; yield 57.5%.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH:25]([CH2:27][C:28]([O:30]CC)=[O:29])[C:24]4[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=4[CH2:22][C:21]=3[CH:37]=2)[CH:7]=1)[CH3:4]>C(O)C>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH:25]([CH2:27][C:28]([OH:30])=[O:29])[C:24]4[CH:33]=[CH:34][CH:35]=[CH:36][C:23]=4[CH2:22][C:21]=3[CH:37]=2)[CH:7]=1)[CH3:4]
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3cc(OCC)ccn3)cc2Cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)c1
Temperature: 45 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
1.0 N NaOH (1.7 mL, 1.7 mmole) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-[3-(4-ethoxypyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (528.1 mg, 1.11 mmole) in absolute ethanol (11 mL) at RT, and the solution was warmed in an oil bath preset at 45° C. After 20 hr, the reaction was concentrated, and the residue was reconcentrated from H2O. The resulting residue was dissolved in H2O (10 mL) and the solution was filtered. The pH was adjusted to 7 with 1.0 N HCl, and the mixture was stirred briskly to convert the initially-formed gummy precipitate into a solid. Trituration with a glass rod and a spatula aided in this transformation. The pH of the resulting mixture was readjusted to 7, and the solid was collected and washed with plenty of H2O. The filtrate was concentrated and the residue was dissolved in H2O with the aid of a little 1.0 N NaOH. The pH was adjusted to 7 to afford a small second crop. The crops were combined and dried in vacuum (40-50° C.) to afford the title compound (453.7 mg, 82%) as an off-white solid: HPLC (Hamilton PRP-1®, 45% CH3CN/H2O containing 0.1% TFA) k′=1.32; 1H NMR (400 MHz, DMSO-d6) δ7.78 (d, J=6.6 Hz, 1 H), 7.35-7.65 (m, 1 H), 7.02-7.22 (m, 4 H), 6.97 (d, J=8.3 Hz, 1 H), 6.82 (d, J=2.4 Hz, 1 H), 6.68 (dd, J=8.3, 2.4 Hz, 1 H), 6.29 (dd, 1 H), 6.15 (narrow d, 1 H), 4.20 (d, J=14.6 Hz, 1 H), 3.93-4.12 (m, 4 H), 3.89 (d, J=14.6 Hz, 1 H), 3.60-3.71 (m, 1 H), 3.30-3.50 (m, 2 H), 3.20 (dd, J=15.1, 4.1 Hz, 1 H), 2.83 (dd, J=15.1, 10.1 Hz, 1 H), 2.60 (dd, J=16.0, 5.3 Hz, 1 H), 2.48 (dd, J=16.0, 8.9 Hz, 1 H, partially obscured by residual solvent signal), 1.90-2.05 (m, 2 H), 1.30 (t, J=6.9 Hz, 3 H); MS (ES) m/e 447 (M+H)+. Anal. Calcd for C27H30N2O4.1.5 HCl: C, 64.70; H, 6.33; N, 5.59. Found: C, 64.53; H, 6.14; N, 5.31.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][S:38]([C:35]3[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=3)(=[O:40])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-(trifluoromethyl)benzenesulfonyl chloride following the procedure of Example 61 as an off-white solid: MS (EI) m/z 601.1 (M+H)+; 1H NMR (DMSO-d6): δ 7.00-7.10 (m, 3H), 7.24 (d, J=8.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 2H), 7.50-7.60 (m, 3H), 7.70 (d, J=8.5 Hz, 1H), 7.75 (t, J=8.4 Hz, 1H), 7.87 (d, J=7.4 Hz, 2H), 7.96 (d, J=7.4 Hz, 2H), 8.34 (d, J=6.2 Hz, 1H), 9.11 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH:13](I)([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)cc1Cl
Product: CC(C)Oc1ccc(C(=O)O)c(Cl)c1

Procedure:
Using methyl 2-chloro-4-hydroxybenzoate and isopropyl iodide, 2-chloro-4-isopropoxybenzoic acid was obtained in the same method as in Production Example 277b).
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23]CC2C=CC=CC=2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6]>C(O)C>[F:31][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6]
Reactant: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: CCO
Product: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
3-({(1S)-2-[(Difluoromethyl)oxy]-1-methylethyl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (0.1 g, 0.23 mmol) was dissolved in ethanol (3 mL) and THF (3 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (0.01 g) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at RT for 20 hours until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite and the filtrate concentrated in vacuo to give the desired compound (70 mg). 1H NMR δ (CDCl3): 1.28 (d, 3H), 3.71 (s, 3H), 3.80-3.95 (m, 2H), 4.51 (sextet, 1H), 5.96-6.36 (t, 1H), 6.53 (s, 1H), 6.73 (s, 1H), 6.91 (s, 1H), 6.96 (s, 1H), 7.22 (s, 1H), 8.83 (s, 1H). m/z 342 (M+H)+.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:31]#[N:32])[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2[CH:30]=[C:31]([NH2:32])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: N#CC=Cc1cc(Cl)cc(Cl)c1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Product: Nc1cc(-c2cc(Cl)cc(Cl)c2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, mp. 257-260° C. and MS m/e (%): 345 (M+H+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-(3,5-dichloro-phenyl)-acrylonitrile
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=2[CH3:29])=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([Br:14])[CH:10]=[CH:9]2)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[Br:14][C:11]1[CH:10]=[CH:9][N:8]2[C:13]([CH:12]=1)=[C:5]([C:3]([OH:4])=[O:2])[C:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[CH3:29])=[C:7]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(Cc2cccc(F)c2C)c(-c2ccccc2)n2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(C(=O)O)c2cc(Br)ccn2c1-c1ccccc1
Temperature: 90 °C

Procedure:
The compound of step 1 (450 mg, 0.99 mmol) was dissolved in 1,4-dioxane (10 ml) and treated with 10 ml of an aqueous 10 N solution of sodium hydroxide. The mixture was heated to 90° C. for 12 h, cooled to room temperature and neutralized with dilute hydrochloric acid. The aqueous phase was extracted with DCM, and the combined organic phase were dried over sodium sulfate. The crude title product obtained after evaporation was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[C@@:8]2([CH3:24])[CH2:9][C@@H:10](O)[C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]4)=[O:18])[CH2:14][CH2:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[Cl-].[Li+].[Cl:27]C(F)C(N(CC)CC)(F)F>O1CCCC1>[Cl:27][C@H:10]1[CH2:9][C@@:8]2([CH3:24])[C@@H:7]([CH2:6][CH2:5][C@@H:4]2[C:2](=[O:3])[CH3:1])[C@H:12]2[C@H:11]1[C@:21]1([CH3:22])[C:15]([CH2:14][CH2:13]2)=[CH:16][C:17](=[O:18])[CH2:19][CH2:20]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Reactant: CCN(CC)C(F)(F)C(F)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](Cl)C[C@]12C
Reaction time: 5 h

Procedure:
A mixture of 11α-hydroxy progesterone (6 g., 0.018 mole), anhydrous lithium chloride (6 g., 0.14 mole), N-(2-Chloro-1,1,2-trifluoroethyl)diethylamine (6 ml., 0.036 mole) and dry tetrahydrofuran (120 ml.) was stirred at -20° for 5 hr. and then room temperature for 16 hr. The reaction mixture was partitioned between methylene chloride and water. Evaporation of the organic layer and chromatography of the residue on magnesium silicate afforded, after recrystallisation from acetone/petroleum ether (b.p. 60°-80°), 11β-chloropregn-4 -ene-3,20-dione (0.26 g., 4%), m.p. 185°-188° [α]D + 252° (c 1.0 CHCl3), λmax. (EtOH) 238 nm. (ε 17,150).
Reaction SMILES: [O:1]1[CH2:7][CH:2]1[C:3]([O:5][CH3:6])=[O:4].[C:8](=[O:10])=[O:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>[CH3:6][O:5][C:3]([CH:2]1[CH2:7][O:1][C:8](=[O:9])[O:10]1)=[O:4]
Reactant: COC(=O)C1CO1
Reactant: O=C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COC(C)(C)C
Product: COC(=O)C1COC(=O)O1
Reaction time: 96 h
Yield: 94 %

Procedure:
20 g of the methyl epoxypropionate were mixed with 20 g of tert-butyl methyl ether and 1 g of tetrabutylammonium bromide. The homogeneous mixture was transferred to a 100 ml pressurized reactor and carboxylated for 4 days at 40° C. and a CO2 pressure of 20 bar. After the carboxylation, a two-phase system was obtained; the upper phase consisted of tert-butyl methyl ether, and the lower phase consisted of 4-methoxycarbonyl-2-oxo-1,3-dioxolane (purity 94% (GC), yield 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl

Procedure:
The title compound was prepared from {2-amino-4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-carbamic acid tert.-butyl ester (Example J4) (165 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example K1) (165 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (167 mg).
Reaction SMILES: C([N:4]1[C:8]([CH3:9])=[N:7][C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[N:5]1)(=O)C>O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:6]2[N:7]=[C:8]([CH3:9])[NH:4][N:5]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)n1nc(-c2ccc(Cl)cc2)nc1C
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
27 g (114 mM) 1-Acetyl-3-(4-chlorophenyl)-5-methyl-1H-1,2,4-triazole is refluxed in 800 ml of water for 9 hours and stirred overnight at room temperature. The product is filtered out, washed with water, and dried at 90° under vacuum overnight to give 23.4 g of the title compound, m.p. 173°-175°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[Br:19]Br.O>C(O)(=O)C>[Br:19][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]#[N:13])[CH:7]=[C:8]([CH3:9])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(CCC#N)cc1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)cc(CCC#N)cc1Br
Reaction time: 8 h

Procedure:
62.8 g (358.4 mmol) of 3-(4-methoxy-5-methylphenyl)propanenitrile are dissolved in 390 mL of acetic acid. There are then added, all at once, 58.8 g (716.8 mmol/2 eq.) of sodium acetate and then, dropwise, 20.2 mL (394.2 mmol/1.1 eq.) of bromine, and stirring is carried out at ambient temperature overnight. The reaction mixture is then poured into 2 liters of water, and the aqueous phase is extracted 3 times with 500 mL of dichloromethane. The combined organic phases are washed successively with 500 mL of water, 500 mL of saturated aqueous sodium hydrogen carbonate solution and 500 mL of water, and are dried over magnesium sulphate. After concentration, the expected product is collected.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([C:26](=[O:35])[CH2:27][C:28]2[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH2:24][CH3:25])[CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1>[Cl:34][C:31]1[N:30]=[CH:29][C:28]([CH2:27][C:26]([N:23]([CH2:22][C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=2[C:10]2[CH:11]=[C:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:7]=[N:8][CH:9]=2)[CH2:24][CH3:25])=[O:35])=[CH:33][CH:32]=1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cc2ccc(Cl)nc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)O)c1)C(=O)Cc1ccc(Cl)nc1
Temperature: 50 °C

Procedure:
To {5-[2-({N-[2-(6-chloro-pyridin-3-yl)-acetyl]-N-ethyl-amino}-methyl)-4-trifluoromethyl-phenyl]-pyridin-3-yl}-acetic acid ethyl ester (0.085 g, 0.16 mmol) in THF (2 mL) was added 1N aqueous LiOH (2 mL), and the reaction was stirred at 50° C. The mixture was neutralized with 1N aqueous HCl to pH 3-4 and extracted three times with EtOAc. The combined organic layers were dried and concentrated to give Compound 31.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Cl.[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][C:1]#[N:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCc1nccn1Cc1ccccc1
Temperature: 23 °C
Yield: 70 %

Procedure:
Dry, powdered sodium cyanide (14 gm, 280 mmole) was added to 80 ml of dry dimethylsulfoxide with stirring at 23° C. Then 1-benzyl-2-chloromethylimidazole hydrochloride (14 gm, 63 mmole) was added portionwise over 10 minutes while maintaining the temperature below 40° C. After the addition was complete, the mixture was stirred at 40° C. for an additional hour. It was diluted with 250 ml methylene chloride and the resulting solution was washed with 4×200 ml of water, dried over MgSO4 and the solvent removed in vacuo. The residue was collected by filtration, dissolved in warm methanol and precipitated with ether to obtain needle-like crystals (8.7 g) of N-benzyl-2-cyanomethylimidazole. m.p. 102.5°-104° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](/[C:10](=[CH:16]\[CH3:17])/[C:11]([O:13]CC)=[O:12])[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](/[C:10](=[CH:16]\[CH3:17])/[C:11]([OH:13])=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: C/C=C(/C(=O)OCC)c1csc(NC(C)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C=C(/C(=O)O)c1csc(NC(C)=O)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
22 parts by weight of ethyl E-2-(2-acetamidothiazol-yl)-2-butenoate are added to a solution of 12 parts by weight of sodium hydroxide in 130 parts by volume of water. After the mixture has been stirred at 25° C. for 90 minutes, 750 parts by volume of water are added, while cooling with ice, and the pH is brought to 2.8 with 2N hydrochloric acid. The product precipitated is filtered off with suction, washed twice with 50 parts by volume of water each time and dried. 17.9 parts by weight of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18](Cl)(=[O:20])=[O:19].[NH4+:22]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:22])(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(=O)(=O)Cl)c2)cc1
Reactant: [NH4+]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.45 g, 1.0 mmol) in methylene chloride is added aqueous ammonium solution (1 mL). The reaction mixture is stirred for 10 min at room temperature. The solvent is removed and the residue is redissolved in ethyl acetate and extracted with water. The organic layers are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. The residue is recrystallized with methylene chloride-hexane to give 100 mg (32% yield) of the title compound as pale yellow solid. 1H NMR (CDCl3): δ 8.40 (m, 1H), 8.05 (m, 1H), 7.80 (d, J=8 Hz, 2H), 7.32 (t, 1H), 7.00 (d, J=8 Hz, 2H), 5.15 (s, 1H), 3.90 (s, 3H). Analytics calculated for C14H12FNO4S: C, 54.36; H, 3.91; N, 4.53. Found: C, 53.89; H, 3.50; N, 4.50.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=O)=O.[OH-].[K+]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:7]1[NH:8][CH:9]=[CH:10][N:6]=1
Reactant: CN(C)S(=O)(=O)n1ccnc1Cc1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(Cc2ncc[nH]2)nc1
Yield: 42.2 %

Procedure:
To a solution of 0.21 g of N,N-dimethyl[2-(pyridin-2-ylmethyl)imidazol-1-yl]sulfonamide in ethanol (2 ml) was added a 2% aqueous solution (20 ml) of potassium hydroxide and the resulting mixture was heated under reflux for 11 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.053 g of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:31]=[N:32][CH:33]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccc(OC(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethoxy)phenyl]amino]piperidine (721 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.