Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)=O.C([O:11][CH:12]1[CH2:15][CH:14]([C:16]2[C:21](=[O:22])[NH:20][N:19]3[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])=[N:24][N:25]=[C:18]3[CH:17]=2)[CH2:13]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[N:19]2[NH:20][C:21](=[O:22])[C:16]([CH:14]3[CH2:13][CH:12]([OH:11])[CH2:15]3)=[CH:17][C:18]2=[N:25][N:24]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CO
Product: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Formic acid (8 ml) was added to a solution of 7-(3-benzyloxy-cyclobutyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.64 g, 1.64 mmol) and ammonium for-mate (1.034 g, 16.4 mmol) in methanol (40 ml). The solution was flushed with nitrogen and 10% palladium on carbon (0.3 g) was added. The resulting solution was stirred under an atmosphere of nitrogen for 2 hours at 60° C. The reaction was cooled, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica using 0-10% methanol/dichloromethane as eluent to give the required product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO), cis and trans isomers present in 5.5:1 ratio, δ 1.89-1.98 (1.7H, m), 2.21-2.29 (0.3H, m), 2.40-2.48 (0.3H, m), 2.55-2.65 (1.7H, m), 2.88-3.00 (1H, m), 4.06-4.14 (0.85H, m), 4.20-4.30 (0.15H, m), 7.38-7.47 (2H, m), 7.60-7.65 (1H, m), 7.80-7.85 (1H, m), 7.97 (0.85H, s), 8.12 (0.15H, s); MS (ES+) m/e 301 [H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:23]([O:25][CH3:26])=[O:24])[C:15](OC(=O)C(F)(F)F)=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:29]([O:31]/[CH:32]=[CH:33]/[Sn](CCCC)(CCCC)CCCC)[CH3:30].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:32]([O:31]/[CH:29]=[CH:30]/[C:15]1[C:14]([C:23]([O:25][CH3:26])=[O:24])=[N:13][CH:12]=[C:11]2[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH:8]=[CH:9][C:10]=12)[CH3:33]
Reactant: CCCC[Sn](/C=C/OCC)(CCCC)CCCC
Reactant: COC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C/c1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 140 °C
Yield: 35 %

Procedure:
To a stirred solution of methyl 1-(4-fluorobenzyl)-4-[(trifluoroacetyl)oxy]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (1.4 g, 3.24 mmol) and (E)-2-ethoxyvinyl tributyltin (E [prepared according to A. Leusik, H. A. Budding, J. W. Marsman, J. Organomet. Chem., 1967, 9, 285-294] (2.2 g, 6.48 mmol) in DMF (10 mL) under a nitrogen atmosphere were added triethylamine (0.48 mL, 3.24 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.24 g, 0.32 mmol). The resulting mixture was heated to 140° C. for 2 hours. It was quenched with water, and extracted with ethyl acetate three times. The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo and purified by Biotage flash chromatography. Elution with hexane:ethyl acetate (1:1) provided the title compound as brown glue (0.40 g, 35% yield). 1H NMR (MeOD) δ; 8.50 (s, 1H), 7.64 (d, 1H, J=3.3 Hz), 7.22 (t, 2H, J=6.8 Hz), 7.05 (t, 2H, J=6.8 Hz), 6.89 (d, 1H, J=3.3 Hz), 5.53 (s, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.37 (t, 3H, J=7.1 Hz). LCMS (APCl, M+H+): 355.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][N:11]1[C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1.C(OCC)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:16]([C:15]2[N:11]([CH3:10])[N:12]=[C:13]([CH3:19])[CH:14]=2)=[O:17])[CH:3]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(O)ccc2C)n(C)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63.6 %

Procedure:
To a solution of 3-amino-4-methylphenol (930 mg, 7.5 mmol) in N,N-dimethylacetamide (10 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1370 mg, 8.7 mmol) in N, N-dimethylacetamide (5 mL), and the mixture was stirred at 0° C. for 20 min. To the mixture were added ethyl acetate/tetrahydrofuran, saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer was extracted 4 times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1170 mg, 63%) as a white solid. To a suspension of lithium aluminum hydride (1130 mg, 24 mmol) in tetrahydrofuran (35 mL) was slowly added dropwise a solution of N-(5-hydroxy-2-methylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1170 mg, 4.8 mmol) in tetrahydrofuran (10 mL) under ice-cooling. After dropwise addition, the reaction mixture was heated under reflux for 5 hr. A saturated aqueous sodium sulfate solution was added to the mixture under cooling, magnesium sulfate was added and the insoluble material was filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (570 mg, 52%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[NH2:13].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[NH:13][C:17]1[CH:18]=[C:19]([F:21])[CH:20]=[CH:15][C:16]=1[S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: NC1CCOc2ccc(Cl)cc21
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A solution of 6-chlorochroman-4-amine hydrochloride (551.0 mg, 2.50 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (496.0 mg, 2.50 mmol) and diisopropylethylamine (1.29 g, 10.0 mmol) in N,N-dimethylformamide (10 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was purified by silica chromatography (20% ethyl acetate in hexanes) to yield 143.0 mg (16%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, 1H), 7.19 (m, 2H), 6.83 (d, 1H), 6.57 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 4.28 (m, 1H), 3.01 (s, 3H), 2.19 (m, 2H).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[CH2:23][C:24]1[CH:25]=[C:26]([NH2:29])[NH:27][N:28]=1>O1CCCC1>[CH3:19][C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[CH2:23][C:24]1[CH:25]=[C:26]([NH:29][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:27][N:28]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: Cc1cccc(Cc2cc(N)[nH]n2)c1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cccc(Cc2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c1

Procedure:
The named compound is prepared by substituting 5-(3-methyl-benzyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.240 gms. 5-(3-methyl-benzyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL) overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=3)[CH2:14][NH:15]C(=O)OC(C)(C)C)[C:3]=12>Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:14][NH2:15])[CH:23]=[CH:24][CH:25]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
tert-butyl 3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzylcarbamate (50 mg) was dissolved in a solution of HCl in ethyl acetate, the reaction solution was stirred at room temperature overnight, the most of solvent was removed on a rotary evaporator and filtered to give the 31 mg of (3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)methanamine as HCl salt. yield: 72.1%.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46](C(OC(C)(C)C)=O)[CH:47]=2)O1>O>[CH3:12][C:6]1([CH3:13])[N:5]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[N:45][NH:46][CH:47]=3)[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1CC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC1(C)NC(=O)c2sc(-c3cn[nH]c3)cc2N1CC(=O)N1CCOCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
A flask was charged with 6-bromo-2,2-dimethyl-1-(2-(morpholin-4-yl)-2-oxoethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (115 mg, 0.296 mmol), Na2CO3 (89 mg, 1.48 mmol), 1,2-dimethoxyethane (2 mL), water (1 mL) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (261 mg, 0.888 mmol). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (24 mg, 0.0296 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 3 h, water and EtOAc were added to quench the reaction. The insoluble materials were filtered off, and NaCl was added to the filtrate. The organic materials were extracted with EtOAc/THF, and the extract was concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (31 mg, 27%) as a pale brown solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH:16]([C:18]([O:20]C)=[O:19])[CH2:15][CH2:14][N:13]1[C:22]([O:24][CH3:25])=[O:23].[Br-].[Li+].CCN(CC)CC.CC(OC)(C)C>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][N:13]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2F)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)cc1F
Yield: 94.1 %

Procedure:
Dimethyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (5.33 g, 14.67 mmol) was dissolved in acetonitrile (35 mL) and water (0.700 mL), then lithium bromide (10.19 g, 117.37 mmol) was added. Et3N (8.18 mL, 58.68 mmol) was added and the resulting yellow suspension was heated under reflux for 1 h. Water (50 mL) and MTBE (150 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE (2 times). The combined organic layer was dried over Na2SO4, filtered and evaporated yielding 2-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.82 g, 94%) as a slightly yellow solid. MS m/z 348 (M−H)−
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]([CH:12]=1)=[N:9][O:10][N:11]=2.[ClH:13].[CH3:14][S:15]([NH:18][C:19]1[CH:20]=[CH:21][C:22]2[O:32][C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:25][C:24](=[O:33])[C:23]=2[CH:34]=1)(=[O:17])=[O:16].C(=O)(O)[O-].[Na+]>C(O)C>[ClH:13].[N:11]1[O:10][N:9]=[C:8]2[CH:12]=[C:4]([CH2:3][CH2:2][N:29]3[CH2:30][CH2:31][C:26]4([CH2:25][C:24](=[O:33])[C:23]5[CH:34]=[C:19]([NH:18][S:15]([CH3:14])(=[O:16])=[O:17])[CH:20]=[CH:21][C:22]=5[O:32]4)[CH2:27][CH2:28]3)[CH:5]=[CH:6][C:7]=12
Reactant: BrCCc1ccc2nonc2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc4nonc4c3)CC1)O2
Yield: 41.2 %

Procedure:
A suspension of 5-(2-bromoethyl)benzofurazan (0.39 g, 1.72 mmol), 3,4-dihydro-6-methanesulfonamido spiro[(2H)-1-benzopyran-2,4'-piperidine]4-one hydrochloride (0.24 g, 0.69 mmol) and sodium bicarbonate (0.21 g, 2.55 mmol) in ethanol (13.2 ml) was heated at reflux temperature for 24 hr. Solvent evaporation and chromatography (silica gel, chloroform-methanol-ammonium hydroxide, 97/3/0.3) gave an oil; conversion to the hydrochloride gave the hydrochloride (0.14 g, 41%); mp>250° C. Anal. Calcd for C22H24N4O3.HCl: C, 53.59; H, 5.12; N, 11.37. Found: C, 53.55; H, 5.15; N, 11.12.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26]>O>[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][N:12]([C:25](=[O:26])[NH:24][CH3:23])[CH2:11][CH2:10]2)[C:5]1=[O:15]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: CN=C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC2(CC1)CC(=O)N(OC)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in water (20 ml) was added triethylamine (1 ml), followed by methyl isocyanate (1 ml), and this was followed by stirring at room temperature for 30 minutes. The water was then evaporated off under reduced pressure. The residue was directly subjected to silica gel column chromatography (eluent; chloroform-acetone-methanol=10:3:2 (v/v)), and the solvent for the solution containing the desired product was evaporated off under reduced pressure to obtain 1.4 g of a colorless oily compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:19][N+:16]([O-:18])=[O:17])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C=O)ccc1O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1cc(C=C[N+](=O)[O-])ccc1O
Temperature: 45 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Commercially available 3-methyl-4-hydroxybenzaldehyde (1.00 g, 7.34 mmol), ammonium acetate (850 mg, 11.0 mmol), and nitromethane (7.00 mL) were mixed, and the mixture was stirred at 45° C. for 5 hours. Then, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-methyl-4-(2-nitrovinyl)phenol (1.05 g, yield 80%). This compound (1.05 g, 5.86 mmol) was dissolved in THF (30.0 mL), then lithium aluminum hydride (642 mg, 16.9 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Subsequently, sodium sulfate decahydrate (5.45 g, 16.9 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The resulting precipitate was filtered out, and the filtrate was concentrated under reduced pressure. A hydrogen chloride-ethyl acetate solution (4.00 mol/L, 10.0 mL, 40.0 mmol) was added thereto, and precipitated crystals were collected by filtration to give 2-methyl-4-(2-aminoethyl)phenol hydrochloride (188 mg, yield 17%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([BH3-])#N.[Na+]>>[Cl:1][C:2]1[C:10]([S:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: CSc1ccc2[nH]ccc2c1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CSc1ccc2c(c1Cl)CCN2
Yield: 100.4 %

Procedure:
4-Chloro-5-methylthioindole (D47) (0.89 g, 4.49mmol) was treated with sodium cyanoborohydride according to the procedure of Description 10 to afford the title compound (0.90 g, 100%) as a pale yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Br>>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH2:12][N:11]([CH3:21])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)CN(C)CC2c1cccc(Cl)c1
Agent: Br
Agent: Cl
Product: CN1Cc2cc(O)ccc2C(c2cccc(Cl)c2)C1

Procedure:
The free base isolated from 4.00 g. of rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride is heated for an hour at 150° (bath temperature) with 80 ml. of 48% hydrobromic acid. After concentration, it is extracted with ethyl acetate and sodium bicarbonate solution. By acidification of the ethyl acetate extract with ethanolic hydrogen chloride and by crystallization and recrystallization from methanol-ether there is obtained rac.-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol hydrochloride, m.p. 258°-259°. The base released therefrom displays a m.p. of 196°-197° after recrystallization from ether-petroleum ether.
Reaction SMILES: [O:1]1[CH2:4][CH2:3][C@@H:2]1[CH2:5][CH2:6][OH:7].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][CH2:5][C@H:2]2[CH2:3][CH2:4][O:1]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OCC[C@H]1CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2CCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The mixture of (S)-2-(oxetan-2-yl)ethanol (408 mg, 4 mmol), TsCl (1.15 g, 6 mmol), TEA (0.85 g, 6 mmol) and DMAP (92 mg, 0.8 mmol) in DCM (20 mL) was stirred at RT for 18 h. Then the mixture was concentrated, the residue was dissolved into EtOAc (15 mL), washed with sat. NaHCO3 aqueous solution, water and brine, then the EtOAc layers was dried with Na2SO4, then the solvent was removed under the reduced pressure. The crude product was purified with Combiflash (PE/EtOAc=5/1, silica gel) to give the titled compound.
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.[Br-].[CH3:32][CH:33]([CH3:37])[CH2:34][CH2:35][Zn+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH3:32][CH:33]([CH3:37])[CH2:34][CH2:35][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Reactant: CC(C)CC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: CC(C)CCc1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 31.3 %

Procedure:
Into a dry microwave vial under N2 was added 6-bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(dppf)Cl2 (about 5 mol %), and CuI (about 6 mol %) in dry THF (0.5 mL) followed by 3-methylbutyl zinc bromide (0.273 mL, 0.138 mmol (0.5M in THF)) dropwise. The solution was heated in the microwave for 10 minutes at 160° C., filtered, and was purified by Prep HPLC to give 6.2 mg (25%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 431 (M+H)+; 1H NMR (300 MHz, MeOH) δ ppm 0.97 (d, 6H), 1.52-1.64 (m, 3H), 1.97 (br q, 2H), 2.40 (br d, 2H), 2.72 (br t, 2H), 3.23 (br t, 2H), 3.73 (d, 2H), 3.93-3.97 (m, 3H), 5.42 (s, 1H), 6.30-6.40 (m, 1H), 6.95 (d, 1H), 7.23-7.54 (m. 8H), 7.86 (d, 1H).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[Br-].C([PH3+])CC.[N:12]1[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.O>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=1)[CH2:1][CH2:2][CH3:3]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)[O-]
Agent: CCC[PH3+]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccncc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
4-Butylpyridine was prepared by adding potassium-t-butoxide (0.68 g, 6 mmol) to propylphosphonium bromide (Aldrich) (2.4 g, 6.0 mmol) in THF (10 mL), at 0° C. and stirring at room temperature for 1 hour. Pyridine-4-carbaldehyde (428 mg, 4 mmol) was added and the reaction mixture stirred for 2 h. The reaction mixture was then poured into water and extracted with ethyl acetate. The product obtained after removing the solvent was taken as such in methanol (30 mL) to which palladium on carbon (10%, 300 mg) was added and hydrogenated at 1 atm pressure over night. Removal of solvent and purification on column chromatography using ethyl acetate resulted in pure product 4-butylpyridine (500 mg, 92%):
Reaction SMILES: [CH3:1][C:2]1([CH2:36][OH:37])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14]CC3C=CC=CC=3)=[CH:10][CH:9]=2)=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28]CC3C=CC=CC=3)=[CH:24][CH:23]=2)[CH2:3]1>C(Cl)Cl.C(OCC)(=O)C.O.Cl[Ti](Cl)(Cl)Cl>[CH3:1][C:2]1([CH2:36][OH:37])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[C:4]([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)[CH2:3]1
Reactant: CC1(CO)CCC(c2ccc(OCc3ccccc3)cc2)=C(c2ccc(OCc3ccccc3)cc2)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(CO)CCC(c2ccc(O)cc2)=C(c2ccc(O)cc2)C1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a solution of (1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-enyl)-methanol (150 mg, 0.306 mmol) in DCM (5.0 mL) at −10° C. was added TiCl4 (0.102 mL, 3.0 eq.) and the reaction mixture stirred at −10° C. for 3 h. The reaction mixture was then diluted with ethyl acetate (20 mL and H2O (10 mL). The organic layer was separated, dried over MgSO4, and purified by SiO2 (50˜100% ethyl acetate/hexane) to yield a lower TLC spot of (1-methyl-3,4-di(4-hydroxy-phenyl)-cyclohex-3-enyl)-methanol.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([P:10]([OH:14])([O:12][CH3:13])=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[OH-].[Na+].[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:19]1([CH2:25][C:26]([NH:1][CH:2]2[C:15](=[O:16])[N:4]3[CH:5]([P:10]([OH:14])([O:12][CH3:13])=[O:11])[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]23)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COP(=O)(O)C1N2C(=O)C(N)[C@H]2SC1(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COP(=O)(O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred slurry of 532 mg. (0.002 mole) of 6-amino-2,2-dimethyl-3-(O-methylphosphono)penam in 10 ml. of water is cooled to 0° C., and the pH is then adjusted to 8.0 using 1N sodium hydroxide. To this solution is then added 0.27 ml. (310 mg., 0.002 mole) of phenylacetyl chloride, in portions, with the pH of the solution being maintained between 7 and 8 during the addition, using 0.1 N sodium hydroxide. The solution is stirred in additional 30 minutes at 0° C. and pH 7. It is concentrated in vacuo to a small volume and the title compound purified by Sephadex LH-20 chromatography, eluting with water.
Reaction SMILES: N1CCC(NC(=O)OC(C)(C)C)C1.CN(C1CCCNC1)C(=O)OC(C)(C)C.[ClH:29].[CH2:30]([N:34]1[C:42]2[C:41](=[O:43])[N:40]([CH3:44])[C:39]([C:45]#[N:46])=[N:38][C:37]=2[N:36]=[C:35]1[N:47]1C[CH2:51][CH2:50][CH:49]([NH:53]C)[CH2:48]1)[C:31]#[C:32][CH3:33]>>[ClH:29].[NH2:53][CH:49]1[CH2:50][CH2:51][N:47]([C:35]2[N:34]([CH2:30][C:31]#[C:32][CH3:33])[C:42]3[C:41](=[O:43])[N:40]([CH3:44])[C:39]([C:45]#[N:46])=[N:38][C:37]=3[N:36]=2)[CH2:48]1
Reactant: CC#CCn1c(N2CCCC(NC)C2)nc2nc(C#N)n(C)c(=O)c21
Agent: CC(C)(C)OC(=O)NC1CCNC1
Agent: CN(C(=O)OC(C)(C)C)C1CCCNC1
Agent: Cl
Product: CC#CCn1c(N2CCC(N)C2)nc2nc(C#N)n(C)c(=O)c21

Procedure:
In Example 254, the title compound was synthesized by using t-butyl pyrrolidin-3-ylcarbamate, instead of t-butyl N-methyl-N-(piperidin-3-yl)carbamate, according to the method described in Examples 254(b), (c), and (d).