Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28]>>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH:28][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: CN(C)CCCN
Reactant: NCCOc1ccccc1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: CN(C)CCCNc1ccc2nc(NCCOc3ccccc3)ccc2c1

Procedure:
The title compound, MS: m/e=365.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and 3-dimethylamino-propylamine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:20])=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[ClH:20].[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:1][CH:2]2[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]2)=[O:19])=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: CCN1CC(N)CN1CC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CCN1CC(NC(=O)c2ccc([N+](=O)[O-])cc2)CN1CC
Product: Cl

Procedure:
The title compound was prepared as described in Example 4 of U.S. Pat. No. 4,207,327 from 4-amino-1,2-diethylpyrazolidine and p-nitrobenzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21].[Br:22]N1C(=O)CCC1=O.O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:14]([Br:22])=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[CH3:20])=[CH:4][C:3]=1[F:21]
Reactant: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)cc1C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC12CCC(=O)C(C)=C1c1cc(F)c(N)c(Br)c1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.138 g, 0.481 mmol) in anhydrous N,N-dimethylformamide (4.8 mL) was cooled in an ice bath, placed under a nitrogen atmosphere, treated with N-bromosuccinimide (0.94 g, 0.53 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was poured into a water solution of 10% K2CO3 and extracted with EtOAc. The organic layer was washed with water and evaporated under vacuum. The crude product was purified by preparative layer chromatography on a 0.05×20×20 cm silica gel GF plate, developing with 20% EtOAc in hexanes, to afford 7-amino-8-bromo-9a-butyl-6-fluoro-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (0.089 g, 50%) as a yellow solid.
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].[C:16]1([N:26]=[C:27](OCC)[CH2:28][CH3:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>C(O)CCC>[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/1=[N:15]\[C:27](=[N:26][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:28][CH3:29])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Reactant: CCOC(CC)=Nc1cccc2ccccc12
Agent: I
Solvent: CCCCO
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(CC)=Nc1cccc2ccccc12
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a 20-ml scintillation vial containing a magnetic stir bar were added the free base of Example 6A and the liquid imidate from Example 73A. Butanol was added to form a yellow solution. The reaction was heated to 85° C. in a heated shaker block and stirred for 48 h. The volatiles were removed by rotary evaporator to give a brown oil. Product purified by flash chromatography (silica gel: 5-40% ethyl acetate in hexanes) to give the title compound as a colorless oil. 1H NMR (DMSO-d6) δ0.96 (t, J=7.3 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H), 1.24 (s, 9H) 1.29-1.42 (m, 2H), 1.73-1.83 (m, 2H), 2.18 (q, J=7.5 Hz, 2H), 4.13 (t, J=7.1 Hz, 2H), 6.76 (dd, J=7.3, 1.2 Hz, 1H), 7.13 (s, 1H), 7.38-7.55 (m, 4H), 7.83-7.88 (m, 2H). MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]([Cu])#[N:11]>CN1C(=O)CCC1>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:10]#[N:11])=[CH:3][C:4]=1[F:9]
Reactant: Nc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)c(F)c1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
50 g (0.26 mol) of 4-bromo-2-fluoroaniline and 30 g (0.34 mol) of CuCN were dissolved in 130 cm3 of NMP and the solution was refluxed with a mantle heater for 2 hours. The reaction solution was cooled to room temperature. 42 cm3 of EDA was added to the cooled solution and the solution was poured into 300 cm3 of ice water. The resulting mixture was extracted with chloroform and washed with an aqueous EDA solution and water. The chloroform was distilled off the washed mixture. The distillation residue was dissolved in ether and washed with water to remove the NMP. The residue was distilled in a vacuum (b.p. 165° C./23 mmHg) to yield 28 g (0.21 mol) of 4-amino-3-fluorobenzonitrile. It was necessary to perform the distillation under an elevated degree of vacuum since the product was extremely sublimable and the crystals adhered to the output of the distillation tube and clogged the tube.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH:10]2[N:18]3[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH:12]3[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[CH:11]23)=[N:6][CH:7]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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(O)C>[CH3:23][N:20]1[C:21](=[O:22])[CH:11]2[CH:10](/[CH:9]=[CH:8]/[C:5]3[CH:4]=[CH:3][C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=4)=[CH:7][N:6]=3)[N:18]3[CH:13]([CH:12]2[C:19]1=[O:24])[CH2:14][CH2:15][CH2:16][CH2:17]3
Reactant: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(Br)cn1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture consisting of 42 mg of 4-[(E)-2-(5-bromopyridin-2-yl)vinyl]-2-methyloctahydropyrrolo[3,4-a]indolizine-1,3-dione (from Example 6, racemic mixture 1), 2.5 mg of tetrakis(triphenylphosphine)palladium(0), 25 mg of 3-trifluoromethylphenylboronic acid, 37 mg of potassium carbonate, 1.5 ml of toluene, 0.3 ml of ethanol and 0.75 ml of water is stirred at 100° C. for 5 h. After cooling, the mixture is taken up in 20 ml of water and the product is extracted by shaking with 20 ml of ethyl acetate. After drying and concentration of the organic phase, an oil is obtained. The crude product is purified by column chromatography (silica gel, MeOH:DCM=1:99).
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])OC.[H-].[Na+].[Br:9][C:10]1[S:14][C:13]([C:15](=O)[CH3:16])=[CH:12][CH:11]=1.C1C[O:21]CC1>>[CH3:5][O:4][C:1](=[O:6])[CH:15]([C:13]1[S:14][C:10]([Br:9])=[CH:11][CH:12]=1)[CH:16]=[O:21]
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(Br)s1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C=O)c1ccc(Br)s1
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of dimethyl carbonate (33.67 mL, 400 mmol) in anhydrous THF (200 mL) was added NaH (12.0 g, 300 mmol, 60% dispersion), which was pre-washed with anhydrous hexane. A solution of 1-(5-bromo-thiophen-2-yl)ethanone (20.51 g, 10 mmol) in THF was added dropwise via an additional funnel. The reaction mixture was stirred under nitrogen atmosphere for overnight. The reaction mixture was cooled off with an ice water bath and quenched with water and acidified to pH 3 with 6.0 M HCl. The organic layer was separated from the aqueous layer, which was washed with DCM three times. The combined organic layer was dried over anhydrous Na2SO4 and concentrated, resulting in the product 3-(5-bromo-thiophen-2-yl-3-oxo-propionic acid methyl ester (25.8 g, 98% yield) as dark brown oil. The crude β-ketoester product was relatively pure by analysis of the 1H NMR spectrum. 1H-NMR (CDCl3): δ 7.48 (d, J=4.1 Hz, 1H), 7.13 (d, J=4.1 Hz, 1H), 3.87 (s, 2H), 3.75 (S, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.Cl[Si:13]([CH3:20])([CH3:19])[O:14][Si:15]([CH3:18])([CH3:17])Cl.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[O:9]1[CH:10]=[CH:11][C:7]([Si:13]([CH3:20])([CH3:19])[O:14][Si:15]([CH3:18])([CH3:17])[C:23]2[CH:24]=[CH:25][O:21][CH:22]=2)=[CH:8]1
Reactant: C1CCOC1
Reactant: Brc1ccoc1
Reactant: C[Si](C)(Cl)O[Si](C)(C)Cl
Agent: [Li]CCCC
Product: C[Si](C)(O[Si](C)(C)c1ccoc1)c1ccoc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Fifty (50) ml of n-butyl lithium (1.55 in hexane) were transferred via a syringe to a one-necked, round-bottomed flask, under nitrogen, equipped with a magnetic stirrer. Ten (10) grams of 3-Bromofuran in 10 ml of dry tetrahydrofuran (THF) were then added dropwise under nitrogen. Once this addition was complete, the resulting solution was stirred at -78 degrees C. for 1 hour. A pale yellow precipitate formed, and 6.5 g of 1,3-dichlorotetramethyl disiloxane in 10 ml dry THF were then added dropwise at -78 degrees C. under nitrogen. The precipitate slowly disappeared. The solution was then stirred for 4 hours at -78 degrees C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[C:25]1([C:35](O)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:35]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:36]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccc2ccccc12
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1cccc2ccccc12
Yield: 77 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1-naphthyl)carbonyl]-L-phenylalanine methyl ester was prepared in 77% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 1-naphthoic acid using the general procedure described in example 3. HR MS: Obs. mass, 521.1024. Calcd. mass. 521.1053 (M+H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:27])[CH:11]([N:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH3:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2.[Cl:28][CH2:29][C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:31]>C(OCC)(=O)C>[Cl-:28].[F:26][C:23]1[CH:24]=[CH:25][C:20]([N:18]([CH3:19])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]([O:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:29][C:30](=[O:31])[C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[O:27])=[CH:21][CH:22]=1
Reactant: O=C(CCl)c1cccs1
Reactant: CN(c1ccc(F)cc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Solvent: CCOC(C)=O
Product: CN(c1ccc(F)cc1)C(C(=O)O[C@H]1C[N+]2(CC(=O)c3cccs3)CCC1CC2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 84 h
Yield: 84 %

Procedure:
To a solution of [(4-fluoro-phenyl)-methyl-amino]-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (C120) (100 mg, 0.27 mmol) in ethyl acetate (2.7 mL), is added 2-chloro-1-(thiophen-2-yl)ethanone (48.0 mg, 0.30 mmol). The reaction is stirred at RT for 3.5 days. The suspension is evaporated and the residue is triturated with Et2O (8 mL). The solid is filtered on a buckner funnel and the sticky solid is dissolved in DCM. The solution is evaporated giving the title compound as a pale yellow solid (120 mg, 84% yield, chloride salt, mixture of diastereoisomers).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1[Br:7].S(=O)(=O)(O)O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:16])=[O:9])[O:5][C:6]=1[Br:7]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(Br)o1
Temperature: 50 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a solution of 4,5-dibromo-2-furancarboxylic acid (25 g, 93 mmol) in methanol (185 ml) was added sulfuric acid (24.7 ml, 463 mmol). The resulting solution stirred at 50° C. over 12 h. The solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification providing methyl 4,5-dibromo-2-furancarboxylate (23.67 g, 83 mmol, 90% yield), LCMS (ES) m/e 283, 285, 287 (M, M+2, M+4)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc(O)cc1
Product: Cc1nc(Nc2ccc(O)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (818 mg, 4.58 mmol), 4-hydroxy-aniline (500 mg, 4.58 mmol) by a procedure similar to example 1b to give 498 mg (43%) of off white solids. 1H NMR (DMSO-d6): 9.51 (s, 1H), 9.34 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.67-7.48 (m, 4H), 6.79 (d, J=7.8 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:30]=[C:25]([OH:24])[CH:26]=[CH:27][CH:28]=2)[CH:3]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(O)c2)n1
Reaction time: 15 h
Yield: 116.9 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [1.47 g, 4.2 mmol, see Example 52, step 1], (3-hydroxy-phenyl)-boronic acid, (637 mg, 4.62 mmol), and Cs2CO3 (3.4 g, 10.5 mmol) in ethylene glycol dimethyl ether (20 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (243 mg, 0.21 mmol) at room temperature. After 15 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford 3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (2 g). LCMS: RT=2.32 minutes; MS: 408 (M+H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@H:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:16][CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][NH:39][CH3:40])=[CH:32][C:31]=1[CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[C@H:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:16][CH2:17][N:39]([CH2:38][CH2:37][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([F:29])=[C:31]([CH3:41])[CH:32]=1)[CH3:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Reactant: CNCCCc1ccc(F)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(CCCN(C)CC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(4-fluoro-3-methylphenoxy)-4-oxobutanal (35 mg, 0.091 mmol) in 3 mL DCE was added 3-(4-Fluoro-3-methylphenyl)-N-methylpropan-1-amine (22 mg, 0.12 mmol) followed by NaBH(OAc)3 (29.5 mg, 0.14 mmol) and AcOH (7.2 mg, 0.12 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 10 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)(=[O:12])[CH3:11]>[Cu]I.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>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][S:13][C:10](=[O:12])[CH3:11])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: C#Cc1ccc(CSC(C)=O)cc1
Reactant: O=Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(=O)SCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reaction time: 0.05 h
Yield: 88.3 %

Procedure:
Samples of 4-iodobenzaldehyde (1.18 g, 5.00 mmol), 7 (950 mg, 5.00 mmol), CuI (52 mg, 270 μmol) and Pd(PPh3)2Cl2 (23 mg, 33 μmol) were placed in a Schlenk flask. The flask was evacuated via vacuum pump for 3 min and then the flask was backflushed with argon for 3 min. The process of evacuation and flushing was repeated 3 times. At this point the argon flow rate was increased and the threaded stopcock was removed. Deareated THF (5.0 mL) and DIEA (5.0 mL) were added in succession to the flask by gastight syringe. The threaded stopcock was replaced, the argon flow rate was reduced and the flask was immersed in an oil bath thermostated at 40° C. The reaction was stopped after 40 h. The mixture was then filtered and evaporated. The resulting orange-brown solid was chromatographed (silica, CH2Cl2/hexanes, 2:3, then 1:1, then 3:2) to afford yellowish-white crystals. Recrystallization (ethyl acetate/heptane) gave 1.30 g (88.2%) of white crystals. mp 128–129° C.; 1H NMR δ 2.49 (s, 3H), 4.07 (s, 2H), 7.25, 7.43 (AA′BB′, 2×2H), 7.59, 7.79 (AA′BB′, 2×2H), 9.95 (s, 1H); 13C NMR δ 30.9, 33.9, 89.5, 93.9, 122.1, 129.8, 130.1, 130.2, 132.7, 132.7, 136.1, 139.5, 192.0, 195.4; FAB-MS obsd 294.0717, calcd exact mass 294.0715; Anal. Calcd. for C18H14O2S: C, 73.44; H, 4.79; S, 10.89; Found: C, 73.18; H, 4.82; S, 10.88.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[CH:7]([CH3:18])[CH2:6]1.FC(F)(F)C(O)=O.CC1C=CC=C(C)C=1CN1C2C(=CC=C(CC(O)=O)C=2)[C@H](C)C1>CCCCCC.C(O)(C)C>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C@@H:7]([CH3:18])[CH2:6]1
Reactant: Cc1cccc(C)c1CN1CC(C)c2ccc(CC(=O)O)cc21
Agent: Cc1cccc(C)c1CN1C[C@@H](C)c2ccc(CC(=O)O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1cccc(C)c1CN1C[C@H](C)c2ccc(CC(=O)O)cc21
Yield: 57.7 %

Procedure:
The compound [78] obtained in Example 78 (26 mg) was optically resolved by chiral column chromatography (CHIRALCEL (registered trademark) OD (CHRALCEL OD) manufactured by Daicel Corporation, 2 cm×25 cm; 0.1% trifluoroacetic acid, hexane/isopropyl alcohol=85/15; flow rate 20 mL/min). (3R*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetic acid [79A] (15 mg) as a pale brown solid was obtained from the preceding fraction (retention time: 5.3 minutes), and (3S*)-2-[1-(2,6-dimethylbenzyl)-2,3-dihydro-3-methyl-1H-indole-6-yl]acetic acid [79B] of the same (16 mg) as a pale brown solid was obtained from the posterior fraction (retention time: 10.8 minutes). (Both of them were un-identified, and thus one of them was referred to as 3R*, and the other one as 3S* for convenience.)
Reaction SMILES: [F:1][C:2]1[C:20]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15](N)=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[OH2:28]>>[F:1][C:2]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:28])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: O
Reactant: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(N)=O)cn4C)CC1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC1
Temperature: 20 °C

Procedure:
7-Fluoro-8-(4-methyl-1-piperazinyl)-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Application Example 2, but starting with 0.3 g of 7-fluoro-1-methyl-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxamide. After cooling to approximately 20° C., the reaction mixture is treated with 50 cm3 of water; the insoluble matter is drained and washed with twice 10 cm3 of water.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([O:13][C:14](=[O:35])[N:15]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][N:23]2[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)C>[C:9]([O:13][C:14](=[O:35])[N:15]([C:17]1[CH:25]=[C:24]2[C:20]([C:21]([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Br:1])=[CH:22][N:23]2[CH2:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)=[CH:19][CH:18]=1)[CH3:16])([CH3:12])([CH3:10])[CH3:11]
Reactant: Sc1ccccc1Br
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2ccn(Cc3cc(F)cc(F)c3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3Br)cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
—Sulfuryl chloride (1.08 ml, 13.4 mmol) was added to a solution of 2-bromobenzenethiol (1.27 g, 6.69 mmol) in dichloromethane (45 ml). The reaction mixture was stirred at room temperature for 15 min. and concentrated under reduced pressure. The resulting material was dissolved in diethyl ether and added dropwise to a solution of [1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (Example 6, method 1, step i; 2.50 g, 6.71 mmol) in diethyl ether (45 ml). The reaction mixture was stirred for 3.5 h and then poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→8:2) afforded [3-(2-bromo-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (3.02 g).