Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](B(O)O)[CH:26]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:30])=[C:23]([C:2]2[CH:3]=[N:4][C:5]([N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=2)[CH:22]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ncc(Br)cn1
Reactant: OB(O)c1cc(Cl)ccc1O
Product: CS(=O)(=O)N(Cc1ccccc1)c1ncc(-c2cc(Cl)ccc2O)cn1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and 5-chloro-2-hydroxyphenyl-boronic acid, yield 0.25 g.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1>CN(C=O)C>[Cl-:1].[CH2:38]([O:37][C:35]([CH:32]1[CH2:33][CH2:34][N+:29]([CH3:28])([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:30][CH2:31]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)C1CCN(C)CC1
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC[N+](C)(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added ethyl 1-methyl-piperidine-4-carboxylate (206 mg). The mixture was stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 4-ethoxycarbonyl-1-methyl-1-[4—(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]piperidinium chloride (Compound 31) (185 mg, ratio of isomers=37:63) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.O.[CH3:21][NH2:22]>CO.C(O)C>[CH3:21][NH:22][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: O=CN1CCN(c2nc(Cl)nc3c2SCCC3)CC1
Reactant: CN
Solvent: CCO
Solvent: CO
Solvent: O
Product: CNc1nc2c(c(N3CCN(C=O)CC3)n1)SCCC2

Procedure:
7 g of 2-chloro-4-(N-formylpiperazino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine was dissolved in 100 ml of a mixture of methanol-ethanol (1:1 by volume), and 50 ml of a 40% aqueous solution of methylamine was added thereto, followed by gently stirring while warming for 7 hours. A large amount of water was added to the mixture which was then extracted with chloroform. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and PG,16 the resulting residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane, 1:1 by volume) to obtain 3 g of 2-methylamino-4-(N-formylpiperazino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless prisms having a melting point of 149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[NH2:13][CH:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1/[CH:5]=[N:13]/[CH:14]([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(N)C(C)C
Reactant: COc1cccc(OC)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1/C=N/C(C(C)C)C(C)C

Procedure:
A mixture of 25.0 g (150 mmol) 2,6-dimethoxybenzaldehyde, 19.1 g (165 mmol) 3-amino-2,4-dimethylpentane and 0.500 g p-toluenesulfonic acid in 100 ml toluene was heated in a Dean-Stark apparatus to reflux for 2 hours. Then the cooled reaction mixture was washed with aqueous NaHCO3 solution, brine dried over Na2SO4, filtered and evaporated. The crude product was filtered through a silica pad with heptane/ethyl acetate 2:1 as eluent: 22.0 g [1-(2,6-dimethoxy-phenyl)-meth-(E)-ylidene]-(1-isopropyl-2-methyl-propyl)-amine as slightly yellow crystals: MS (EI): 264.3 ((M+H)+.), 262.3 ((M-H)+.), 248.3 ((M−CH3)+.), 220.2 ((M−(CH3)2CH)+.), 100%).
Reaction SMILES: II.C(O)(=O)C.P(=O)(O)(O)O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=O)=[C:15]([Cl:28])[CH:14]=1>C(OCC)(=O)C.O>[Cl:28][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH2:19][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[NH2:12]
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Agent: II
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Cc2ccc(Cl)cc2)c(Cl)c1
Yield: 98.9 %

Procedure:
Iodine (1 g) and 50 mL of acetic acid were mixed together, 2.53 g of 50% phosphoric acid was added thereto, and the mixture was heated with stirring to reflux. Subsequently, a mixture composed of 3.2 g of (4-amino-2-chlorophenyl)-(4′-chlorophenyl)methanone and 15 mL of acetic acid were added dropwise to the mixed solution. This solution was heated under reflux for 134 hr, was then cooled and was poured into water. Ethyl acetate was added to the mixed solution followed by separation and washing with brine. The ethyl acetate layer was concentrated to give 3.0 g of 3-chloro-4-(4-chlorobenzyl)aniline (yield 100%).
Reaction SMILES: [N:1]([C@H:4]1[C@H:9]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C(OCC)(=O)C>[NH2:1][C@H:4]1[C@H:9]([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:8][CH2:7][N:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
A mixture of crude trans-tert-butyl 3-azido-4-(benzyloxycarbonylamino)piperidine-1-carboxylate (12 g, ˜32 mmol) and triphenylphosphine (41.9 g, 160 mmol) in THF (100 mL) and water (5 mL) was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (500 mL). The organic layer was washed with brine (50 mL) and directly evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1˜1:1) to afford trans-tert-butyl 3-amino-4-(benzyloxycarbonylamino)piperidine-1-carboxylate (5.0 g, 44%) as a yellow oil. MS (ES+) C18H27N3O4 requires: 349, found: 350 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br.[NH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].C([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=O)C>C(OCC)(=O)C.C(O)CCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:18][CH2:17][NH:16][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=2[OH:29])[CH2:11][CH2:10]1
Reactant: NCCBr
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(CCNC(=O)c2ccccc2O)CC1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To 1.92 g (0.01 mol) of 1-(2-methoxyphenyl)piperazine, 2.05 g (0.01 mol) of 2-aminoethyl bromide hydrobromide, 2.76 g (0.02 mol) of anhydrous potassium carbonate and 40 ml of n-butanol were added, and the mixture was refluxed for 6 hours. After the reaction, the mixture was concentrated under vacuum, and to the resulting residue, 2.5 g of anhydrous sodium carbonate, 20 ml of water and 20 ml of ethyl acetate were added. Under agitation with cooling on ice, 2.38 g (0.012 mol) of acetylsalicylic acid chloride as dissolved in a small amount of ethyl acetate was added dropwise to the mixture. Thereafter, the mixture was stirred for 30 minutes under cooling with ice and extracted with ethyl acetate by agitation for 30 minutes at room temperature. The separated organic layer was washed with water, and 1N HCl was added until the pH became 3.0. The aqueous layer was separated, neutralized with sodium hydroxide and extracted with ethyl acetate. The resulting organic layer was washed with water, dried with Glauber's salt and concentrated under vacuum. The residue was subjected to column chromatography on silica gel (solvent: chloroform/methanol=100:1) to provide 1.78 g (yield: 50%) of 1-(2-methoxyphenyl)-4-[2-(2-hydroxybenzoyl)aminoethyl]piperazine as an oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10])=[N:2]1.C1C=CC=CC=1.S(Cl)([Cl:28])=O>C(N(CC)CC)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:28])=[O:10])=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccon1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1-c1ccon1

Procedure:
To 0.55 g of 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 10 ml of benzene, then 0.17 ml of thionyl chloride and a drop of triethylamine to heat at reflux for 2 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C>[OH-].[Na+]>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Reaction time: 2 h
Yield: 80.4 %

Procedure:
4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h under reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale white solid (10.5 g, 92%). 1H NMR (d-DMSO) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][CH:20]=[CH:21][N:22]=1)CCC.O1CCOCC1.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=[C:2]([C:18]2[O:19][CH:20]=[CH:21][N:22]=2)[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(-c2ncco2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 66.1 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 6-chloro-2-methoxy-3-nitropyridine (0.50 g, 2.6 mmol), 2-tributylstannanyloxazole (1.20 g, 3.4 mmol) and 1,4-dioxane (10 mL) and then subjected to several cycles of evacuation-backfilling with argon. Tetrakis(triphenylphosphine)palladium (0.18 g, 0.16 mmol) was then added and, after three new cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 110° C. After stirring overnight, water and ethyl acetate were added and the organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (0.38 g, 67%) as a yellow solid.
Reaction SMILES: FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.N1C=CC=CC=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.Cl>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Reactant: Nc1ccccc1
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1ccccc1
Reaction time: 0.08 h
Yield: 53.9 %

Procedure:
Pentafluorophenyl trifluoroacetate (0.867 g, 3.10 mmol) was added dropwise, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.800 g, 2.21 mmol) and pyridine (0.245 g, 3.10 mmol) in dimethylformamide (8 ml). After stirring for 5 minutes, aniline (0.412 g, 4.43 mmol) was added and the reaction mixture was stirred for 2 hours. The mixture was poured into dilute hydrochloric acid (0.2N, 25 ml) and the resultant solid filtered and then washed with water. The residue was stirred in dilute aqueous sodium hydroxide solution and filtered and the residue washed successively with water, methanol and diethylether to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-phenylacetamide (0.520 g, 54% yield): MS (+ve ESI): 437 (M+H)+.
Reaction SMILES: F[C:2]1[N:26]=[CH:25][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[C:13]([CH3:24])[CH:12]=3)[C:4]=2[CH:3]=1.C(OC(=O)[NH:33][CH:34]1[CH:39]2[CH:35]1[CH2:36][NH:37][CH2:38]2)(C)(C)C>C(O)C.C(Cl)(Cl)Cl>[NH2:33][CH:34]1[CH:39]2[CH:35]1[CH2:36][N:37]([C:2]1[N:26]=[CH:25][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=5)=[C:13]([CH3:24])[CH:12]=4)[C:4]=3[CH:3]=1)[CH2:38]2
Reactant: CC(C)(C)OC(=O)NC1C2CNCC21
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccnc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2ncnc3cnc(N4CC5C(N)C5C4)cc23)ccc1Oc1cccnc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A solution of 2.71 g (7.83 mmol) of (6-fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(pyridin-3-yloxy)-phenyl]-amine and 31.0 g (156.5 mmol) of (3-aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester in 20 mL of ethanol in a sealed tube was heated at 105° C. for 24 hours. The mixture was cooled to room temperature and diluted with chloroform. The organics were washed sequentially with 3×150 mL saturated sodium bicarbonate and 1×50 mL of saturated sodium chloride, dried over sodium sulfate and evaporated. Chromatography over silica gel, eluting with 5% methanol/chloroform afforded 1.79 g (43%) of the title compound. 1H NMR (CDCl3): δ 8.93 (s, 1), 8.53 (s, 1), 8.33 (m, 2), 7.60 (m, 3), 7.21 (m, 2), 6.96 (d, 1), 6.24 (m, 1), 4.83 (m, 1), 3.81 (m, 2), 3.51 (m, 2), 3.47 (m, 1), 2.36 (m, 1), 2.26 (s, 3), 1.88 (m, 1).
Reaction SMILES: CO[N:3]([CH3:21])[C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])=O.[CH3:22]NC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:22][N:3]([CH2:4][CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])[CH3:21]
Reactant: CNC
Reactant: CON(C)C(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1CC1Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 2-(3-cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (0.029 g, 0.13 mmol), dimethylamine (0.7 ml, 1.4 mmol, 2M/THF), and methyl alcohol (5 ml) was treated with sodium triacetoxyborohydride (0.28 g, 1.13 mmol) and stirred at ambient temperature for 1 h. The solution was concentrated in vacuo and the residue applied directly to a silica gel column and eluted with chloroform, methyl alcohol, triethylamine 95:5:0.1 to afford 5-(2-Dimethylaminomethyl-cyclopropylmethyl)-1H-indole-3-carbonitrile (23 mg, 69%) as a light salmon colored solid. 1H-NMR (400 MHz, CDCl3) 8.88 (1H, br s), 7.66 (2H, dd, J=19.4, 2.3 Hz), 7.33 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4, 1.5 Hz), 2.72 (2H, m), 2.25 (6H, s), 2.24 (2H, m), 0.88 (2H, m), 0.53 (1H, m), 0.45 (1H, m). LC-MS: 0.90; 254.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]1=2.C(N(CC)CC)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3[CH:21]=[CH:22][CH:23]=[CH:24][C:15]2=3)(=[O:10])=[O:9])[CH:7]=1
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1cc(Br)c(Cl)cc1F)N1CCCCc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of DCM (20 mL) containing 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride (2.82 g, 9.2 mmol) was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.35 g, 9.2 mmol) and triethylamine (2.8 mL, 21 mmol). The mixture was stirred for 16 hrs. The mixture was then diluted with 50 mL of DCM and repartioned with 50 mL of water. The organic layer was further washed with water (2×30 mL) and dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (9/1 to 6/1) yielded 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine as the pale yellow solid (2.70 g). NMR (CDCl3), δ, 8.059 (1H, d, J=7.2 Hz), 7.404 (1H, d, J=9.3 Hz), 7.202-7.218 (2H, q), 7.073-7.129 (1H, m), 7.860 (1H, d, J=7.8 Hz), 3.746 (2H, m), 2.750-2.813 (2H, m), 1.906-1.982 (2H, m), 1.639-1.678 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:6]([C:14]([O:16]CCC)=[O:15])[C:5]=1[C:20]1[C:25]([C:26]([O:28]C)=[O:27])=[CH:24][C:23]([O:30][CH3:31])=[C:22]2[O:32][CH2:33][O:34][C:21]=12)[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=1[C:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]([O:30][CH3:31])=[C:22]2[O:32][CH2:33][O:34][C:21]=12)[CH3:2]
Reactant: CCCOC(=O)c1cc(OC)c(OC)c(OCC)c1-c1c(C(=O)OC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1c(OC)c(OC)cc(C(=O)O)c1-c1c(C(=O)O)cc(OC)c2c1OCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In 4 ml of dioxane was dissolved 48 mg of methyl 2-ethoxy-2',3'-methylenedioxy-6-propoxycarbonyl-3,4,4'-trimethoxy-1,1'-biphenyl-6'-carboxylate obtained in Example 9, and 1 ml of a 5% aqueous solution of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight, the pH value was adjusted to 1 by 3N hydrochloric acid, and the mixture was extracted with chloroform. The solvent was removed from the extract to obtain 36 mg of 2-ethoxy-2',3'-methylenedioxy-3,4,4'-trimethoxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 86%).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4](C)[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[S:13]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=1[CH3:25])(=[O:15])=[O:14].[OH-].[Li+]>O.CO>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH3:25])[C:16]([S:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])(=[O:14])=[O:15])=[C:21]([CH3:22])[CH:20]=1
Reactant: COC(=O)C(C)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CCCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-(1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)butanoic acid methyl ester (1.65 g, 4.3 mmol) was dissolved in water (10 ml) and methanol (35 ml), and lithium hydroxide was added (0.3 g, 12.9 mmol). The mixture was stirred at room temperature for 3 days, the methanol was then distilled off in vacuo and ethyl acetate (50 ml) and HCl solution (1 mol/l, 10 ml) were added to the residue. The phases were then separated, extraction was carried out with ethyl acetate (2×50 ml) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The yield was 1.56 g (98%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>C1C=CC=CC=1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:4][C:3](=[O:5])[C@@H:2]2[CH2:6][CH2:7][CH2:8][NH:1]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@@H]1CCCN1
Yield: 118.3 %

Procedure:
Preparation 6 ##STR64## (a) A mixture solution of 5.0 g of L-proline, 9.91 g of p-toluenesulfonic acid monohydrate and 6.65 g of p-nitrobenzyl alcohol in 100 ml of benzene was refluxed for 2 days by using Dean-Stark trap. After reaction, the solvent was removed under reduced pressure and the resulting residue was washed with diethyl ether to give 21.7 g of L-proline p-nitrobenzyl ester p-toluenesulfonic acid salt as oil. Then, a mixture solution of 12.17 g of Boc-glycine and 13.32 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride in 150 ml of ethylene chloride was stirred for 25 minutes under ice-cooling at nitrogen atmosphere. To this reaction mixture was added a solution of 29.36 g of the compound obtained above in 100 ml ethylene chloride and the reaction mixture was stirred overnight at room temperature. After reaction, the reaction mixture was washed with 10% citric acid aqueous solution, 4% sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to give 8.00 g of [N-(t-butoxycarbonyl)glycyl]L-proline p-nitrobenzyl ester [Compound (22)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[C:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)N1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A solution of 5.23 g (0.0118 mole) of α,α-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol in 100 ml of acetic acid and 20 ml of 2M sulfuric acid was heated at reflux for 2.5 hours and then poured over ice. The mixture was made basic with 50% sodium hydroxide and the basic mixture was extracted with methylene chloride. The methylene chloride solution was dried (anhydrous sodium sulfate), and the solvent was removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g (64.4%) of white, crystalline, solid, m.p. 90°-92.5° C.