Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:13][C:14](=[CH2:18])[C:15](Cl)=[O:16].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:3]=1[CH2:13][CH:14]([CH3:18])[C:15]2=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1Cc2c(Br)ccc(Br)c2C1=O
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
94.37 g (0.40 mol) 1,4-Dibromobenzene and 106.7 g (0.80 mol) anhydrous aluminum trichloride were placed in a 1000 ml round bottom flask equipped with a mechanical stirrer. 62.72 g (0.60 mol) 2-Methyl-acryloyl chloride were added under heat evolution (50-55° C.). The mixture was heated, starting at 105° C. a strong gas evolution was observed and the temperature rose to 135° C. Heating of the now solid mass was continued for 3 h at 110° C. After cooling to room temperature 200 g ice was added very carefully, followed by the careful addition of 200 ml cone. HCl. The mixture was extracted three times with 250 ml dichloromethane each. The combined organic layers were washed with 250 ml water and 250 ml of a saturated sodium bicarbonate solution, dried over magnesium sulfate, and the solvent was removed in vacuo. Flash chromatography using silica and heptane/dichloromethane (1:2) yielded 19.3 g (63 mmol, 16%) of the desired indanone as a white solid. 1H-NMR (500 MHz, CDCl3): δ=7.67, 7.54 (2×d, 2H, aromatic), 3.30 (m, 1H, COCHCH3), 2.74-2.64 (m, 2H, benzylic), 1.30 (d, 3H, CH3) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15](OCC)=[O:16])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[BH4-]>C1COCC1>[OH:16][CH2:15][C:12]1([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC1(CO)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
To a stirred solution of ethyl 1-(benzyloxycarbonylamino)cyclopropanecarboxylate (8.7 g, 33.0 mmol) in 50 mL of THF was slowly added at room temperature LiBH4 (2.26 g, 103.76 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled to 0° C. and quenched by adding a 50% HOAc solution (10 mL). The reaction mixture was partitioned between 70 mL of water and 70 mL of diethyl ether. The organic phase was washed with saturated aqueous NaHCO3 solution (15 mL), brine (10 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated at 40° C. under reduced pressure to give a crude product, which was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:1, v/v) to give benzyl 1-(hydroxymethyl)cyclopropylcarbamate (6.36 g, 87.1%) as a white solid. MS: (M+H)+=222.1; 1H NMR (300 MHz, CDCl3): δ 7.46-7.35 (m, 5H), 5.38 (brs, 1H), 5.19 (s, 2H), 3.71 (s, 2H), 0.96 (s, 4H).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 107.4 %

Procedure:
A mixture of tert-butyl (2S)-2-{[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]methyl}pyrrolidine-1-carboxylate 94 (0.30 g, 0.63 mmol) and Pd/C (0.10 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 95 (0.26 g, quant. yield) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].[Sn](Cl)(Cl)(Cl)Cl.Cl>C(OCC)(=O)C>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([C:15]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C(Nc1ccc2c(c1)CCC2)c1ccccc1Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2c(cc1C(=O)c1ccccc1Cl)CCC2)c1ccccc1Cl
Temperature: 130 °C
Yield: 66.2 %

Procedure:
A mixture of 5-(2-chlorobenzoylamino)indan (16 g), 2-chlorobenzoyl chloride (15.5 g) and tin tetrachloride (10.2 ml) was heated at 130° C. for 30 minutes and, then, diluted with ethyl acetate (150 ml), followed by addition of 3N HCl (150 ml). The organic layer was separated and washed with water, 2N NaOH and water in the order mentioned and the solvent was distilled off. The residue was chromatographed on silica gel and eluted with hexane-acetone (4:1) to give 6-(2-chlorobenzoyl)-5-(2-chlorobenzoylamino)indan as oil (16.0 g, 66.2%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH:13]=O)=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+]>[OH:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[C:11]([CH3:13])[CH:10]=[N:8]2
Reactant: CC(=O)C=O
Reactant: Nc1cccc(O)c1N
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnc2cccc(O)c2n1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 2,3-diaminophenol (2.93 g) in 2M aqueous acetic acid solution (47 ml) and 4M aqueous sodium acetate solution (29 ml) was added 40% aqueous pyruvic aldehyde solution (3.79 ml) at 60° C. The reaction mixture was stirred at 60° C. for 40 minutes. After cooling the reaction mixture was adjusted to pH 8 with saturated sodium hydrogen carbonate and extracted with dichloromethane (50 ml) twice. The organic layer was washed with saturated sodium hydrogen carbonate, water and brine. After dried over anhydrous magnesium sulfate, the solution was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel 450 ml) eluting with n-hexane/ethyl acetate (5/1, V/V) to give 8-hydroxy-2-methylquinoxaline (the less polar product) as crystals and with n-hexane/ethyl acetate (3/1, V/V) to give 8-hydroxy-3-methylquinoxaline (the more polar product) as crystals. The former was washed with n-hexane to afford pale yellow crystals (1.27 g). The latter was washed with isopropyl ether to afford pale yellow crystals (1.30 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([NH:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]1)(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) was dissolved in methylene chloride (10 ml) and triethylamine (0.86 ml) was added. Then, a solution of acetyl chloride (0.29 ml) in methylene chlride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 1-(2-acetylaminoethyl)-3-tert-butoxycarbonylaminomethylpyrrolidine.
Reaction SMILES: [C:1]([CH:3]1[O:7]C(=O)[NH:5][C@@:4]1([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)[CH3:9])#[CH:2].[OH-].[Na+].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:5][C:4]([CH3:9])([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)[C@H:3]([OH:7])[C:1]#[CH:2]
Reactant: C#CC1OC(=O)N[C@]1(C)CCc1ccc(OCCCCCCC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C#C[C@@H](O)C(C)(N)CCc1ccc(OCCCCCCC)cc1

Procedure:
To a stirred solution of (R)-5-Ethynyl-4-[2-(4-heptyloxy-phenyl)-ethyl]-4-methyl-oxazolidin-2-one in ethanol (1 ml) is added NaOH (1 ml, 1M aqueous solution). The mixture is heated at reflux temperature for 20 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted with AcOEt (3 times). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. The product is purified by RP-HPLC (ZORBAX Extend C-18) eluting with 5%→95% CH3CN in H2O (+0.1% TFA) to give the title compound.
Reaction SMILES: [N+]([O-])(O)=O.[Mn]([O-])(=O)(=O)=O.[K+].[O-2:11].[Mg+2].[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:28])[C:19]=2[CH:29]=1)[CH3:14]>O>[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:28])[C:19]=2[CH:29]=1)(=[O:11])[CH3:14]
Reactant: CCc1ccc2oc3ncccc3c(=O)c2c1
Reactant: [O-2]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 60 °C
Yield: 67 %

Procedure:
7.6 ml of nitric acid (specific gravity 1.38) and 7.9 g of potassium permanganate are added to a suspension of 2 g of magnesium oxide in 50 ml of water, and the mixture is heated to 60°C. To the mixture is added 4.5 g of 7-ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine over a period of 30 minutes with stirring, keeping the temperature at 60°-70°C. After the addition the mixture is stirred at 60°-70°C for 4.5 hours. After cooling, the reaction mixture is filtered under reduced pressure, and the residue containing manganese dioxide is extracted several times with chloroform. The chloroform layer is washed with water, dried, and the chloroform is distilled off. The residue is recrystallized from toluene to give 3.2 g of 7-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 195°-196°C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.COCCOC.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(-c3ccccc3)nc2)CC1

Procedure:
1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.89 g, 2.5 mmol), phenyl boronic acid (0.37 g, 3.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.12 mmol), 1.2-dimethoxyethane (50 ml), potassium carbonate (1.0 g, 7.5 mmol) and water (7.5 ml) was stirred at reflux overnight. Water (50 ml) was added and the mixture was extracted twice with ethyl acetate (40 ml). Chromatography on silica gel with a mixture of petroleum: ethyl acetate (1:1) gave the title compound as an oil. Yield 0.83 g. 94%.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([OH:39])([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:20]3[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=[O:27])[CH2:22][CH2:21]3)[CH:8]=2)[N:3]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C(Cl)(=O)C.CCN(CC)CC>C(Cl)Cl>[C:26]([N:23]1[CH2:22][CH2:21][CH:20]([C:19]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([Cl:1])[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]3[Cl:18])([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[OH:39])[CH2:25][CH2:24]1)(=[O:27])[CH3:40].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)CC1

Procedure:
tert-Butyl 4-[(2,4-dichloro-3-phenylquinolin-6-yl)(hydroxy)pyridin-3-ylmethyl]piperidine-1-carboxylate (149 mg, 0.264 mmol, Example 91) was treated with TFA (1 mL) at room temperature for 1 hour and concentrated. A part of the residue (10 mg, 0.027 mmol), acetyl chloride (10 mg, 0.13 mmol), and Et3N (0.030 mL, 0.22 mmol) in CH2Cl2 (1 mL) was stirred overnight and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a white solid. 1H NMR (400 MHz, MeOH-d4) δ 9.11 (s, 1H), 8.80 (t, J=7.33 Hz, 1H), 8.70 (d, J=5.56 Hz, 1H), 8.59-8.65 (m, 1H), 8.08-8.15 (m, 1H), 8.01-8.06 (m, 1H), 7.94-8.01 (m, 1H), 7.47-7.57 (m, 3H), 7.33 (t, J=6.57 Hz, 2H), 4.59 (d, J=13.14 Hz, 1H), 3.97 (d, J=13.14 Hz, 1H), 3.10-3.28 (m, 2H), 2.63-2.76 (m, 1H), 1.37-1.67 (m, 4H); MS m/e 506.1 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:49])[CH3:48])[CH2:39][CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c10) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: N#CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: N#CCc1cccc(NC(=O)c2cccc(-c3ccc(F)cc3)n2)c1

Procedure:
The pyridyl bromide (91) (150 mg, 0.47 mmol) was coupled to 4-fluoro-phenylboronic acid (73 mg, 0.52 mmol) using Method E. The crude residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:32])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=1)=[O:21])=[CH:11]2.C(=O)=O.CC(C)=O>C(Cl)Cl>[Br:5][C:6]1[C:15]([OH:16])=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH2:18][N:19]([CH3:32])[C:20]([C:22]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=1)=[O:21])=[CH:11]2
Reactant: COc1ccc2cc(CN(C)C(=O)c3cn(C)c4ccccc34)ccc2c1Br
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1cn(C)c2ccccc12
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A solution of 1.0 M boron tribromide in methylene chloride (55.0 mL, 54.9 mmol) in 50 mL of methylene chloride was added under nitrogen dropwise over 1.5 h to a solution of 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (8.0 g, 18.3 mmol), prepared in the previous step, in 300 mL of methylene chloride at dry ice-acetone temperature. The dry ice-acetone bath was replaced with an ice bath immediately after the addition. The reaction stirred at ice bath temperature for 2 h. At ice bath temperature, the reaction was quenched by the dropwise with water. The reaction was partitioned between methylene chloride and water. A solid formed in the organic layer and was collected by filtration. The solid was dried under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (6.5359 g, 84%) as a white solid, mp 189-190° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[C:11](=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH3:11])=[CH:5][C:3]=1[NH2:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(F)c(N)cc1S
Agent: [K+]
Solvent: CI
Solvent: O
Product: CSc1cc(N)c(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
9.2 g of 2-fluoro-4-methyl-5-mercaptoaniline disclosed in WO2006/043635 was dissolved in 70 mL of water, and 9.7 g of potassium carbonate and 8.3 g of iodomethane were added under cooling with ice, followed by stirring at room temperature for 2 hours. The formed crystals were collected by filtration and washed with water to obtain 10.0 g of 2-fluoro-4-methyl-5-methylthioaniline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([F:10])[N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:40]=[C:41]([CH3:43])[CH:42]=1)[C:27]([C:29]1[NH:34][C:33](=[O:35])[NH:32][C:31](=[O:36])[C:30]=1[CH:37]([CH3:39])[CH3:38])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+]>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]([CH:40]=[C:41]([CH3:43])[CH:42]=1)[C:27]([C:29]1[N:34]([CH2:8][C:6]2[CH:7]=[C:2]([F:1])[N:3]=[C:4]([F:10])[CH:5]=2)[C:33](=[O:35])[NH:32][C:31](=[O:36])[C:30]=1[CH:37]([CH3:38])[CH3:39])=[O:28]
Reactant: OCc1cc(F)nc(F)c1
Reactant: Cc1cc(Cl)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)nc(F)c2)c1
Yield: 40.3 %

Procedure:
(2,6-Difluoro-pyridin-4-yl)-methanol (145 mg, 1 mmol) was dissolved in chloroform (10 ml) and cooled in an ice bath under nitrogen atmosphere. With stirring, triethylamine (210 μl, 1.5 mmol) was added and methanesulfonyl chloride (90 μl, 1.2 mmol) was added dropwise. After stirring for 1.1 hr., the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was further dried in high vacuo for ca. 20 min. and mixed with 6-(3-Chloro-5-methyl-benzoyl)-5-isopropyl-1H-pyrimidine-2,4-dione (306 mg, 1 mmol), powdered anhydrous potassium carbonate (138 mg, 1 mmol), and lithium iodide (134 mg, 1 mmol). DMF (5 ml) was then added to the mixture at room temperature and stirred for ca. 4 hr. After evaporation of DMF, the residue was dissolved in methanol-chloroform (1:9) and filtered through celite pad. The filtrate was then evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2)) to afford 175 mg (40%) of a white solid. 1H-NMR (300 MHz, CDCl3) δ 1.18 (3H, d, J=6.7 Hz), 1.25 (3H, d, J=6.8 Hz), 2.26 (1H, m), 4.76 (3H, s), 6.57 (2H, s), 7.67 (3H, s), 9.21 (1H, s); m/z (EI) 433 (M+).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 79.8 %

Procedure:
4-Diphenylmethylenepiperidine (9.5 g), N-(4-bromobutyl)phthalimide (16 g), sodium iodide (8 g) and potassium carbonate (9 g) are added to methyl ethyl ketone (200 ml) and the mixture is refluxed with stirring for 4 hours. The reaction mixture is concentrated and water (150 ml) is added to the residue. The aqueous layer is extracted three times with chloroform (each 100 ml). The combined extracts are dried over anhydrous magnesium sulfate and then concentrated. The residue is subjected to silica gel column chromatography, followed by elution with chloroform to give N-[4-(4-diphenylmethylene-1-piperidyl)butyl]phthalimide (13.7 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([C:8]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9]N(C)C)=O.Cl.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[NH:29])=[CH:26][CH:25]=1.C[O-].[Na+]>CO>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]2[N:30]=[C:6]([C:5]3[CH:17]=[CH:18][CH:19]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)[C:8]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:9][N:29]=2)=[CH:26][CH:25]=1
Reactant: CN(C)C=C(C(=O)c1cccc(C(F)(F)F)c1)S(C)(=O)=O
Reactant: N=C(N)c1ccc(F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1cnc(-c2ccc(F)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 81.1 %

Procedure:
6 g of 1-(3-trifluoromethylbenzoyl)-1-methanesulfonyl-2-(N,N-dimethylamino)ethene and 4 g of 4-fluorobenzamidine hydrochloride were dissolved in 30 ml of methanol at room temperature. After adding 1.2 of sodium methoxide thereto, the mixture was heated under reflux for 1 hour. The solvent was distilled away under reduced pressure. The residue was washed with water, and then dried to obtain 6 g of 2-(4-fluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine (Compound 112).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[N:19]3[C@H:14]([CH2:15][CH2:16][CH2:17][C:18]3=[O:20])[CH2:13][C@@H:12]3[O:21][C@H:11]23)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C([BH-](CC)CC)C.[Li+].O.C(OCC)(=O)C>C1COCC1>[OH:21][C@H:11]1[CH2:12][CH2:13][C@@H:14]2[N:19]([C:18](=[O:20])[CH2:17][CH2:16][CH2:15]2)[C@@H:10]1[C:4]1[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1
Reactant: O=C1CCC[C@@H]2C[C@@H]3O[C@@H]3[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCC[C@@H]2CC[C@H](O)[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A solution of (1aR*,2R*,6aR*,7aS*)-2-(3,4,5-trifluorophenyl)octahydro-1-oxa-2a-aza-cyclopropa[b]naphthalen-3-one (123 mg) in THF (4.0 mL) was cooled to −78° C. Lithium triethyl borohydride (1 M solution in THF, 620 μL) was added to the reaction solution, which was then stirred at 0° C. for one hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 125 mg of the title compound. The property values of the compound are as follows.