Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][NH2:14])=[CH:8][CH:7]=2.[Br:17][C:18]1[N:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([NH:14][CH2:13][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4]([C:3]([F:2])([F:15])[F:16])=[CH:12]3)=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.4 %

Procedure:
A mixture of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine hydrochloride (Intermediate 5, 1 g, 3.99 mmol), 6-bromo-3-pyridinecarboxylic acid (Matrix Scientific; 0.887 g, 4.39 mmol), EDC (0.841 g, 4.39 mmol), HOBT (0.672 g, 4.39 mmol) and DIPEA (2.8 ml, 16.03 mmol) in DCM (50 ml) was stirred at room temperature for 18 hrs. The mixture was stirred well with saturated aqueous NaHCO3 solution, the organics separated and the aqueous further extracted (EtOAC×3). The combined organics were dried (Phase-Sep cartridge) and evaporated under reduced pressure to a white solid. Trituration with diethyl ether overnight and filtration afforded a crude white solid (1.16 g). A portion (88 mg) was further purified via MDAP to afford the title compound as a white solid (54 mg);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:28][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][N:10]([CH3:20])[S:11]([C:14]1[S:15][C:16]([Br:19])=[CH:17][CH:18]=1)(=[O:13])=[O:12]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CC(F)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Temperature: 0 °C

Procedure:
To a solution of 5-bromothiophene-2-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 71) (210 mg) in dichloromethane (2 mL) was added dropwise (diethylamino)sulfur trifluoride (DAST) (0.1 mL) at −70° C., After gradually warming slowly to 0° C. over 1.5 hours, an aqueous solution of saturated sodium bicarbonate was added, and the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and was dried with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (169 mg) was obtained as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([CH:20](OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:33][S-:34].[Na+]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:18]([CH:20]([S:34][CH3:33])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(C)n2c(C)c(C(=O)OC(C)(C)C)c3ccccc32)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 110 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
A mixture of compound tert-butyl 2-methyl-1-(3-(tosyloxy)butan-2-yl)-1H-indole-3-carboxylate (200 mg, 0.43 mmol) in N,N-dimethyl formamide (2 mL) was added sodium methanethiolate (994 mg, 1.44 mmol). The reaction mixture was stirred at 110° C. for 4 hours. The reaction was quenched by adding water (6 mL). The aqueous layer was extracted with ethyl acetate (30 mL×3), and the organic layer was concentrated. The crude product was purified by preparative TLC (elute: petroleum/ethyl acetate:5:1) to give product tert-butyl 2-methyl-1-(3-(methylthio)butan-2-yl)-1H-indole-3-carboxylate (100 mg, yield: 68%). LRMS (M+H+) m/z: calc'd 333.18. found 334.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].[CH3:32][C:33]([CH3:40])([CH2:37][CH2:38]Br)[CH2:34][CH2:35]Br.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:38][CH2:37][C:33]([CH3:40])([CH3:32])[CH2:34][CH2:35]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(C)(CCBr)CCBr
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCC(C)(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 3,3-dimethyl-1,5-dibromopentane (0.322 g, 1.25 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4-dimethylcyclohexanecarboxylate (230 mg).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:13]SC)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CI>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC1CCCCC1
Solvent: CI
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(CC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
tert-Butyl [(1R)-1-{[(cyclohexylmethyl)amino]carbonyl}-3-(methylthio)propyl]carbamate (5.12 g) was dissolved in methyl iodide (23 mL) and stirred at room temperature for 18 hours. The excess methyl iodide was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (50 mL), added lithium bis(trimethylsilyl)amide 1.0M solution in hexane (16.3 mL) at o 0° C., and then allowed to warm to room temperature and stirred for 5 hours. The resulting mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=from 80/20 (v/v) to 60/40 (v/v)) to give tert-butyl [(3R)-1-(cyclohexylmethyl)-2-oxo-3-pyrrolidinyl]carbamate (2.0 g) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([N:20]2[C:29]3[C:24](=[CH:25][C:26]([F:32])=[C:27](F)[C:28]=3[F:30])[C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21]2)[CH2:19][CH2:18]1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:11]2([CH2:12][CH2:13][N:14]([C:27]3[C:28]([F:30])=[C:29]4[C:24]([C:23](=[O:33])[C:22]([C:34]([OH:36])=[O:35])=[CH:21][N:20]4[CH:17]4[CH2:19][CH2:18]4)=[CH:25][C:26]=3[F:32])[CH2:15][CH2:16]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC12CCNCC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CC(C)(C)OC(=O)NC1CC12CCN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)CC2
Yield: 99.9 %

Procedure:
According to the procedure of example 1A, 1-tert-butoxycarbonylamino-6-azaspiro[2.5]octane (181.2 mg, 0.80 mmol) and 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (239.8 mg, 0.72 mmol) were reacted to generate the title product (352.2 mg, crude).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[C:11]([CH:13]=[CH:14][O:15][CH3:16])[CH:10]=[CH:9][C:8]=1[CH:17]([CH3:19])[CH3:18].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[CH:17]([C:8]1[CH:9]=[CH:10][C:11]([CH:13]=[CH:14][O:15][CH3:16])=[CH:12][C:7]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:19])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: COC=Cc1ccc(C(C)C)c(Br)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C=COC)ccc1C(C)C
Reaction time: 1 h
Yield: 220.9 %

Procedure:
tert-BuLi solution (1.7 M in pentane, 800 mL; 1.59 M in pentane, 2L; 4.5 mol total) was added via cannula over 135 minutes under nitrogen into a solution of 1-Bromo-6-isopropyl-3-(2-methoxyvinyl)benzene (C) (500 g, 1.96 mol) in anhydrous THF (3 L) at −50 to −75° C. The mixture was stirred for 1 hour after addition was complete. The solution was then transferred via cannula into a chilled (kept below −50° C.) solution of ethyl chloroformate (562 mL, 5.88 moles) in anhydrous THF (2 L), and the resultant solution was stirred for 68 minutes. The reaction was quenched by addition of 1 L of saturated aqueous NH4Cl with stirring, followed by the addition of 2 L of water. The organic phase was separated, washed with a 10% NaCl solution. The solution was concentrated under vacuum to approximately. Evaporation furnished the crude product as a light yellow or greenish yellow liquid. A total of 3 batches were produced according to the above procedures, and 1.7 kg of crude product was obtained. The crude liquid product was distilled under high vacuum (0.9 mm Hg) and distillates in the range of 158 to 165° C. were collected to obtain 1075 g (yield 73%) of product. The following values were obtained by nuclear magnetic resonance spectroscopy:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:25][C:26]#[N:27])[CH2:18][CH2:17][N:16]([S:19]([CH:22]4[CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:28]1([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[CH:22]1([S:19]([N:16]2[CH2:17][CH2:18][C:13]([CH2:25][C:26]#[N:27])([N:11]3[CH:12]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]5[CH:35]=[CH:34][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[N:29]6)=[CH:39][CH:38]=5)[N:7]=4)[CH:9]=[N:10]3)[CH2:14][CH2:15]2)(=[O:21])=[O:20])[CH2:24][CH2:23]1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCN(S(=O)(=O)C2CC2)CC1
Reactant: Nc1ccc(-n2cccn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(-n5cccn5)cc4)n3)cn2)CCN(S(=O)(=O)C2CC2)CC1

Procedure:
A mixture of (4-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)piperidin-4-yl)acetonitrile (30 mg, 0.08 mmol), 4-(1H-pyrazol-1-yl)aniline (18.9 mg, 0.119 mol), and p-toluenesulfonic acid (12 mg, 0.067 mmol) in dry 1,4-dioxane (0.6 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as free base (30 mg, 72%). LCMS (M+H) 530.1.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:24]3[CH2:26][CH2:25]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH:24]3[CH2:25][CH2:26]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][N:15]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1C1CC1)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2C2CC2)C2CCCCC2)cc1
Yield: 24.6 %

Procedure:
Using cyclohexyl{3-cyclopropyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized in Example 9(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.34 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.19 g, 25%) was obtained as a white solid.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[N:6]1([C:22]([O-:24])=[O:23])[CH:18]2[CH:9]([CH:10]([C:19]([O-:21])=O)[NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>O1CCCC1CCO.O1CCCC1.C(OCC)(=O)C>[OH:21][CH2:19][C@H:10]1[C@H:9]2[CH2:8][CH2:7][N:6]([C:22]([O:24][C:9]([CH3:18])([CH3:10])[CH3:8])=[O:23])[C@H:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]1
Reactant: O=C([O-])C1Nc2ccccc2C2C1CCN2C(=O)[O-]
Agent: O=C([O-])O
Agent: OCCC1CCCO1
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](CO)Nc3ccccc3[C@@H]21
Reaction time: 0.5 h
Yield: 4.6 %

Procedure:
To a solution of calcium chloride (12.5 g, 113.1 mmol) in a mixture of tetrahydrofuran-ethanol (200 ml-200 ml) was added sodium borohydride (8.5 g, 226.2 mmol) at 0° C. and the mixture was stirred for 30 min. A solution of 1-tert-butyl 4-ethyl(3aR*,4R*,9bR*)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1,4-dicarboxylate (14.6 g, 46.6 mmol) in tetrahydrofuran (50 ml) was added at 0° C., and the mixture was stirred at room temperature for 16 hrs. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, and the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (over anhydrous MgSO4) and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:9, v/v) to give the title compound (326 mg, 96%) as an oil.
Reaction SMILES: [CH2:1]([C@@:3]1([CH3:18])[NH:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[N:11][C:12](F)=[C:13]([CH3:15])[CH:14]=2)[C:4]1=[O:17])[CH3:2].[CH3:19][C:20]1([CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[CH2:22][O:21]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][C:20]1([CH3:30])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:12]3[N:11]=[CH:10][C:9]([N:5]4[C:4](=[O:17])[C@:3]([CH2:1][CH3:2])([CH3:18])[NH:7][C:6]4=[O:8])=[CH:14][C:13]=3[CH3:15])[CH:27]=2)[CH2:22][O:21]1
Reactant: CC[C@@]1(C)NC(=O)N(c2cnc(F)c(C)c2)C1=O
Reactant: CC1(C)OCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC[C@@]1(C)NC(=O)N(c2cnc(Oc3ccc4c(c3)C(C)(C)OC4)c(C)c2)C1=O
Temperature: 110 °C
Reaction time: 10 h
Yield: 26.6 %

Procedure:
To a solution of (5R)-5-ethyl-3-(6-fluoro-5-methyl-3-pyridyl)-5-methyl-imidazolidine-2,4-dione (Intermediate 5, 48 mg, 0.19 mmol) in DMF (1 ml) 3,3-dimethyl-1H-isobenzofuran-5-ol (Intermediate 18, 45 mg, 0.27 mmol) and dipotassium carbonate (75.7 mg, 0.55 mmol) were added and the reaction mixture was stirred at 110° C. for 10 hours. The reaction was quenched with an aqueous saturated solution of ammonium chloride (5 ml) and extracted with ethyl acetate (10 ml). The organic layer was washed with brine (3×10 ml) dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (Biotage system) using a SNAP 10 g as column and cyclohexane/ethyl acetate from 85:15 to 20:80 as eluent to afford the title compound (20 mg) as white solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[NH2:11][C:9]1[N:10]=[C:3]2[C:2]([C:21]3[CH:20]=[CH:19][C:18]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:23][CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: CN(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Product: CN(c1ccc(-c2cccn3nc(N)nc23)cc1)S(C)(=O)=O

Procedure:
To a suspension of N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (0.50 g, 1.7 mmol) and potassium carbonate (0.28 g, 2.0 mmol) in acetone (10 mL) was added methyl iodide (0.12 mL, 2.0 mmol). The mixture was stirred at room temperature for 18 hours under an atmosphere of nitrogen then diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a yellow solid (0.50 g, 95%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 3.34 (s, 3H), 2.82 (s, 3H), 1.34 (s, 12H). MS=312 (MH)+. 62b) N-[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300.0 mg, 1.408 mmol) and N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (500.0 mg, 1.607 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.33 g, 73%). MP=245-247° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.55 (d, J=5.8 Hz, 1H), 8.12 (d, J=7.5 Hz, 2H), 7.72 (d, J=7.1, 1H), 7.52 (d, J=7.2 Hz, 2H), 6.98 (t, J=6.2 Hz, 1H), 6.11 (s, 2H), 3.29 (s, 3H), 2.98 (s, 3H). MS=318 (MH)+. 62c) N-Methyl-N-(4-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[4-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (70.0 mg, 0.274 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (26.0 mg, 0.0476 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a tan solid (0.027 g, 23%). MP=205-206° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=6.5 Hz, 1H), 8.04 (d, J=7.7 Hz, 2H), 7.57-7.46 (m, 5H), 6.99-6.91 (m, 3H), 6.66 (s, 1H), 3.38 (s, 3H), 3.19-3.14 (m, 4H), 2.90 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=492 (MH)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Mn]([O-])(=O)(=O)=[O:15].[K+].S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[O:15]=[C:9]1[C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]([NH:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(=O)NC1CCCc2sccc21
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(=O)NC1CCC(=O)c2sccc21

Procedure:
One molar equivalent of N-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)acetamide is oxidized in aqueous acetone at 10° C. to 15° C. with 2.66 moles of potassium permanganate in the pH range of 7 to 9 in the presence of magnesium sulfate buffer for a period of time from about 3 to 5 hours to afford N-(4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-yl)acetamide. The thus-obtained oxo-acetamide is hydrolyzed in aqueous hydrochloric acid to the corresponding amine. This amine is then reacted with sodium or potassium cyanate in an aqueous medium at about pH 6.5, and at a temperature of about 60° C. to 65° C., to afford the animal growth-promoting 4,5,6,7-tetrahydro-7-oxobenzo[b]thien-4-ylurea of formula (A). Oxidation of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea under reaction conditions, similar to those described above, also affords the aforesaid urea of formula (A). The above reaction sequence may be graphically illustrated as follows: ##STR10##
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH3:11])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[NH2:16]>CN1CCCC1=O>[CH3:11][N:10]1[C:3]2[C:2]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:20][C:21]4[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[C:13]([CH3:12])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Cn1ccc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccn(C)c34)cc2C)cn1
Yield: 51.4 %

Procedure:
To a solution of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1-methyl-2-pyrrolidone (1.0 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (192 mg). The title compound (106 mg) was obtained as white powder crystals by the reaction in the same manner as in Example 39 (ii).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11][C:10]=1[O:28][CH3:29]
Reactant: COc1cc(/C=C/COCCCN2CCCCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCCOCCCN2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A A suspension of 10% palladium on charcoal (25 mg) in a solution of trans-1-{3-[3-(4-benzyloxy-3-methoxyphenyl)allyloxy]propyl}piperidine (340 mg containing 28% wt dimethylsufoxide) in methanol (2.5 mL) is stirred overnight at room temperature under an atmosphere of dihydrogene. The suspension is filtered over a clarcel pad and the filtrate concentrated under reduced pressure. The product is dissolved in diethyl oxide and a solution of oxalic acid (61 mg) in acetone is added. The precipitate is filtered, washed with diethyl oxide and dried under vacuum to afford 150 mg of 1-{3-[3-(4-hydroxy-3-methoxyphenyl)propoxy]propyl}-piperidine, oxalate as a white solid melting at 110-111° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(=[O:5])[CH3:4]>C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])=[O:5]
Reactant: COC(=O)c1csc(C(C)=O)c1OC(=O)C1CCCCC1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1csc(C(=O)CBr)c1OC(=O)C1CCCCC1
Temperature: 0 °C
Yield: 29 %

Procedure:
A solution of 0.70 mL of bromine in 3.45 mL of acetic acid was added dropwise over a period of 60 minutes to a solution of 3.56 g of Compound 3A in 34.5 ml, of acetic acid at 20-25° C. while stirring. After stirring further for 2.5 hours at 20-25° C., the mixture was poured into ice water and extracted with diethyl ether (2×80 mL). The combined organic layers were washed with water (2×80 ml), 10% aqueous sodium carbonate (100 mL) and water (3×80 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude product was purified by flash chromatography in n-hexane/chloroform (6:4) to yield 1.31 g (29%) of Compound 3B.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[C@@H:11]([OH:12])[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][C:3]=1[F:22].Cl>CO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:8][NH:9][CH2:10][C@H:11]2[OH:12])=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)[C@H](Oc2ccc(Cl)c(F)c2)C1
Agent: Cl
Solvent: CO
Product: O[C@@H]1CNC[C@@H]1Oc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of 418 (0.560 g, 1.69 mmol) and MeOH (10 mL) was added a methanolic HCl solution (4 N, 5 mL). The mixture was stirred at RT for 3 h and the solvent was removed in vacuo. The residue was neutralized with satd. aq. NaHCO3 (20 mL) and extracted with DCM/IPA (3:1, 3×100 mL) to afford 0.35 g (90%) of cis-(±)-4-(4-chloro-3-fluorophenoxy)pyrrolidin-3-ol (420) as a yellow oil.