Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]1([NH:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:36])[C:24](C=O)=[CH:25][N:26]3[CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][C:20]=2[F:37])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:12]1([NH:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23](=[O:36])[C:24]([OH:9])=[CH:25][N:26]3[CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[CH:21][C:20]=2[F:37])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(O)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reaction time: 2 h
Yield: 99.6 %

Procedure:
6.1 g of metachloroperbenzoic acid was gradually added to a 100 ml of dichloromethane solution of 8.0 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde at room temperature, followed by stirring for 2 hours. Aqueous saturated sodium hydrogen carbonate and aqueous sodium hydrogenthiosulfate were added to the reaction mixture, followed by stirring for 30 minutes and then extraction with chloroform. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 7.7 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-hydroxyquinolin-4(1H)-one.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].Cl[C:8]1[N:9]=[CH:10][C:11]2[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1.Cl.C[C:33](C)([C:37]([O-:39])=[O:38])C([O-])=O>>[CH2:1]([O:39][C:37](=[O:38])[CH2:33][C:8]1[N:9]=[CH:10][C:11]2[CH2:12][N:13]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:15]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)[CH3:2]
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 0.25 h

Procedure:
To 20 ml of dimethylmalonate was added 1.9 g (16.8 mmol) of potassium tertiary butoxide with stirring under nitrogen, and after 15 min, 2.0 g (5.59 mmol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine was added. The reaction was kept at 110° C. for 2 hr and 140° C. for 4 hr. Ice was added to the reaction mixture which was then acidified with concentrated hydrochloric acid, and extracted with 100 ml of ether. The ether layer was extracted with 25 ml of 3N hydrochloric acid, and the combined acid layers were made basic with ammonium hydroxide and extracted with ether (2×100 ml). The solution was dried, charcoal filtered and concentrated to a small volume. Petroleum ether was added and the product was filtered and recrystallized from the same solvents to give white rods, mp 98°-103° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[CH2:6]([O:8][C:9]([C:11]([CH3:20])([O:13][N:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])[CH3:12])=[O:10])[CH3:7].O.N>CO>[C:1]([OH:4])(=[O:3])[CH3:2].[C:18]([C:15](=[N:14][O:13][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])([CH3:12])[CH3:20])[C:16]([NH2:5])=[NH:17])#[N:19]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(C)(C)ON=C(C#N)C#N
Reactant: [NH4+]
Agent: N
Solvent: CO
Solvent: O
Product: CC(=O)O
Product: CCOC(=O)C(C)(C)ON=C(C#N)C(=N)N
Temperature: 20 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a solution of ammonium acetate (1258 g) in methanol (8.54 l) were added 2-(1-ethoxycarbonyl-1-methylethoxyimino)propanedinitrile (854 g) and 28% ammonia water (568 ml). After the mixture was stirred at 20° C. for 15 hours, methanol was evaporated under reduced pressure. The residue was dissolved in a mixture of water (8 l) and tetrahydrofuran (8 l). After the aqueous layer was saturated with sodium chloride, the organic layer was separated and dried over magnesium sulfate. Acetic acid (368 g) was added to the solution, then the mixture was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether (8 l) to give 2-cyano-2-(1-ethoxycarbonyl-1-methylethoxyimino)acetamidine acetate (689.1 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:37][CH:38]1[CH:45]2[CH2:46][C:41]3([OH:48])[CH2:42][CH:43]([CH2:47][CH:39]1[CH2:40]3)[CH2:44]2.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[OH:48][C:41]12[CH2:46][CH:45]3[CH2:44][CH:43]([CH2:47][CH:39]([CH:38]3[NH:37][C:15]([C:13]3[CH:12]=[CH:11][C:10]4[N:6]([CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[CH:7]=[N:8][C:9]=4[CH:14]=3)=[O:17])[CH2:40]1)[CH2:42]2
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)NC3C4CC5CC3CC(O)(C5)C4)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.9 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (0.65 g, 0.0028 mol) in dry DMF (5.0 mL) was added with stirring HOBt (0.46 g, 0.0034 mol), DIPEA (2.5 mL, 0.014 mol), 4-aminoadamantan-1-ol (0.685 g, 0.0034 mol) at 0° C. To the resulting mixture was added EDCl (0.65 g, 0.0034 mol) and stirred for 15 h at ambient temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×50 mL) and the combined organic phases were washed with water, dried (Na2SO4) and the solvent evaporated affording (1.0 g, 93.5%) of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (5-hydroxyadamantan-2-yl)-amide. MS-ESI m/z 381 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([C:12]1[CH:13]=[C:14](C(C)(C)C)[C:15]2[O:19][C:18](=[O:20])[CH:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=3)[C:16]=2[CH:30]=1)(C)(C)C.CS(O)(=O)=[O:37]>C1(C)C(C)=CC=CC=1>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:17]2[C:16]3[CH:30]=[C:12]([O:37][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:13]=[CH:14][C:15]=3[O:19][C:18]2=[O:20])=[CH:22][CH:23]=1)[CH3:29]
Reactant: CS(=O)(=O)O
Reactant: CCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1C
Product: CCOc1ccc(C2C(=O)Oc3ccc(OC(=O)C(C)(C)C)cc32)cc1
Temperature: 95 °C
Yield: 55 %

Procedure:
2.41 g (20.0 mmol) of pivaloyl chloride are added dropwise over a period of 10 minutes to a suspension of 2.70 g (10.0 mmol) of 3-(4-ethoxyphenyl)-5-hydroxybenzofuran-2-one (compound (136), Table 1, Example 1) in 10 ml of xylene and 0.1 ml of methanesulfonic acid which is stirred at 95° C. under a nitrogen atmosphere. The clear, homogeneous reaction mixture is then refluxed for 2.5 hours and then concentrated under a slight vacuum. The residue is taken up in dichloromethane and washed with saturated sodium bicarbonate solution and water. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. The residue gives 1.95 g (55%) of 3-(4-ethoxyphenyl)-5-pivaloyloxybenzofuran-2-one, oil (compound (135), Table 1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=O.[C:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C[O-].[Li+].Cl>CN(C)C=O.CO.O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1/[CH:4]=[CH:18]/[C:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)=[O:19]
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
2-Hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-29B, 0.10 g, 0.43 mmol) and 4-acetylbenzoic acid (0.070 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2.8 mL, 7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting red slurry was stirred in the dark at room temperature for 18 h. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. Note: the compound appears to decompose with heating. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.025 g (15%) of the title compound as a dark yellow solid, mp 125° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.18–8.22 (m, 3H), 8.09 (d, 2H, J=8.1 Hz), 8.05 (s, 1H), 7.87 (d, 1H, J=14.7 Hz), 7.60 (d, 1H, J=3.0 Hz), 7.49 (d, 1H, J=4.2 Hz), 7.11 (dd, 1H, J=4.2, 3.0 Hz), 6.67 (s, 1H), 3.90 (s, 3H). MS (ESI) m/z=381 ([M+H]+, 100%). Anal. Calcd. for C21H16O5S.EtOH: C, 64.77; H, 5.20; S, 7.52. Found: C, 64.68; H, 5.00; S, 7.77.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:16](F)(F)[C:17]([OH:19])=O.[C:22]1(C)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>O>[C:1]1([NH:7][C:8]2[CH:13]=[C:12]3[C:11]([NH:14][C:24]4[CH2:23][CH2:22][CH2:27][CH2:26][C:16]=4[C:17]3=[O:19])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1c2c([nH]c3ccc(Nc4ccccc4)cc13)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 73.6 g (0.4 mol) of N-phenyl-p-phenylenediamine, 72 g (0.4 mol) of a mixture of the methyl and ethyl esters of 2-cyclohexanonecarboxylate (Aldrich Chemical Co., 40% methyl, 60% ethyl ester) 0.8 ml of trifluoroacetic acid and 1200 ml of toluene was refluxed for 1 hour in a flask equipped with a Dean-Stark water separator. The solvent was removed under vacuum and the resultant oil was dissolved in 500 ml of Dowtherm® A. This solution was added over 1 hour to 100 ml of refluxing Dowtherm® A in a flask equipped with mechanical stirrer, nitrogen flow and a steam heated condenser. Reflux was continued for 1 hour after the addition was complete. The mixture was cooled to room temperature and the precipitated product was filtered. The product was washed with four 200 ml aliquots of methanol. Vacuum oven drying at 80° C. overnight gave 99.9 g (89% yield) of 1,2,3,4-tetrahydro-7-(phenyl)amino-9(10H)acridinone. The product was identified by microanalysis.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=O)C.[H-].[Na+].CI.O>CN(C)C=O>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH3:1])=[CH:6][C:7]([O:24][C:25]([F:40])([F:39])[C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:8]1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
0.45 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole was dissolved in 5 mL of N,N-dimethylformamide, the solution was dropwise added to a suspension having 40 mg of sodium hydride suspended in 10 mL of N,N-dimethylformamide under cooling with ice, and after completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.15 g of methyl iodide was added, followed by stirring at room temperature for one hour. Then, water was injected, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of ethanol, and 10 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for one hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.39 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methylamino-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]45[CH2:30][CH:25]6[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]6)[CH2:22]4)[CH2:28]5)=[CH:17][CH:16]=3)=[N:10][C:9]=2[CH:31]=1)=[O:4].[Br-].[Al+3].[Br-].[Br-].O.Cl>CSC.ClCCl>[C:21]12([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:11]4[O:12][C:8]5[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:31][C:9]=5[N:10]=4)=[CH:16][CH:17]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: COC(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
To a solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester (100 mg, 0.24 mmol) in dimethyl sulfide (5 ml) and dichloromethane (5 ml) was added aluminum bromide (1.02 g, 3.84 mmol). The reaction mixture was stirred at room temperature for 2.5 h, after which water and 10% HCl were added. After stirring at room temperature for 1 h, the mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2Cl2:MeOH=4:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid as a white solid (63.8 mg, 66.0% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[N:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:18]2[C:13]([N:10]3[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]3)=[N:14][CH:15]=[CH:16][N:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nccnc2OCc2ccncc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2nccnc2OCc2ccncc2)C1
Reaction time: 1 h
Yield: 170.1 %

Procedure:
To compound {1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (1 g, 2.6 mmole) was added 50% TFA/DCM. The mixture was stirred for 1 hour, and concentrated in vacuo to give 1-[3-(Pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine (1.2 g, 100% yield).
Reaction SMILES: [Cl:1][CH2:2]CC1C2C(=CC=CC=2)CCO1.O.[ClH:15].Cl.[CH:17]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3OC)[CH2:31][CH2:30]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][O:18]1.C(N(C(C)C)CC)(C)C>C(O)CO>[ClH:1].[ClH:15].[CH:17]1([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:2])[CH2:33][CH2:34]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][O:18]1
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: ClCCC1OCCc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: OCCO
Product: Cc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reaction time: 72 h

Procedure:
A mixture of 1-(2-chloroethyl)isochroman (LXIV, PREPARATION 2, 0.2466 g, 1.25 mmol), 1-(2-methylphenyl)piperazine dihydrochloride (XI, 0.5327 g, 2.14 mmol), diisopropylethylamine (0.98 ml, 5.63 mmol) and ethylene glycol (2.5 ml) is stirred under nitrogen at 100° for 3 days. The reaction mixture is cooled and partitioned between aqueous sodium bicarbonate and ethyl acetate. The combined organic phase is washed with saline, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the free base of the title compound. The dihydrochloride salt is formed using hydrochloric acid/methanol to give the title compound, mp 207.5°-210.5°; MS (m/z) 336; IR (mineral oil) 770, 2406, 2435, 2992, 2364 and 1489 cm-1.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[CH:3][CH:2]=1
Reactant: COc1cccc2c1cc(C)n2Cc1ccc(-c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(O)cccc2n1Cc1ccc(-c2ccccc2)cc1
Yield: 77.4 %

Procedure:
By the method used in Example 1, Part D, 1.3 g (4.0 mmol) of 1-([1,1'-biphenyl]-4-ylmethyl)-4-methoxy-2-methyl-1H-indole was O-demethylated by treating it with 16 mL of 1M BBr3 /CH2Cl2 to give 970 mg (77% yield) of crude 1-([1,1'-biphenyl]-4-ylmethyl)-4-hydroxy-2-methyl-1H-indole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.[H-].[Na+].[CH2:20]1[CH2:24]O[CH2:22][CH2:21]1>>[CH:20]1([CH2:24][NH:17][C:11](=[O:13])[C@@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:22][CH2:21]1.[CH:14]1([NH:17][C:11](=[O:12])[C@@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: C1CCOC1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1CC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC1CC1

Procedure:
(R)-tert-butoxycarbonylalanine cyclopropylamide (15) was prepared as described in General Procedure 1 using (R)-tert-butoxycarbonylalanine and cyclopropyl amine. Intermediate 16 was prepared as illustrated in General Procedure 7. A solution of 1.0 eq. of 15 in THF was prepared. While stirring, 1.5 eq. of 60% NaH in mineral oil was added.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[CH2:8]1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:17]=1)[C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)[CH2:8][C@H:9]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:28]
Reactant: Cc1ccc(C[C@@H]2CN(CCCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C[C@@H]2CN(CCCNC(=O)c3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a stirred mixture of (2R)-4-(3-aminopropyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (160 mg), nicotinic acid (33 mg) and triethylamine (0.17 ml) in dichloromethane (2 ml) was added 2-chloro-1-methylpyridinium iodide (78 mg) at room temperature. After stirring for 1.5 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on a silica gel with dichloromethane-methanol (40:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(nicotinoylamino)propyl]piperazine (70 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[C:33]([CH3:40])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCOCC1>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:34]4[CH:35]=[CH:36][C:31]([F:30])=[CH:32][C:33]=4[CH3:40])[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Reactant: Cc1cc(F)ccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(F)ccc1-c1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
3-Bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (600 mg, 1.31 mmol), 4-fluoro-2-methylphenyl boronic acid (271 mg, 1.98 mmol), cesium carbonate (730 mg, 2.24 mmol) and tetrakis triphenylphosphine palladium(0) (25 mg) in dioxane (10 ml) are heated to 100° C. under a nitrogen atmosphere for 16 hours. The mixture is cooled to room temperature then poured into ethyl acetate (100 ml). The organic layer is washed with water (100 ml), dried over anhydrous sodium sulfate and evaporated to dryness. The residue is then purified by column chromatography on silica gel to give 4′-fluoro-2′-methyl-biphenyl-3-carboxylic acid[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as pale purple needles (0.44 g). Mp: 95-7° C. 1H NMR 300 MHz (CDCl3) δ 8.35(d, 1H, J=7.5 Hz), 7.85-8.1(m, 5H), 7.75(d, 1H, J=7.5 Hz), 7.5-7.63(m, 4H), 7.2(m, 1H), 6.9-7.05(m, 2H), 6.85(d, 1H, J=12 Hz), 4.3(t, 2H), 3.75(m, 4H), 2.98(t, 2H), 2.6(m, 4H), 2.3(s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1COCC1.O.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>[Cl:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:10]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(Cl)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of commercially available 2-bromopyridine (294 mg; 1.86 mmol), 3-chloro-5-(methoxycarbonyl)phenylboronic acid (400 mg; 1.86 mmol), K2CO3 (515 mg; 3.73 mmol), and PdCl2(PPh3)2 (130 mg; 0.18 mmol) in THF (4 ml) and water (4 ml) was stirred at rt, under nitrogen, for 17 h. Water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=15/1) afforded methyl 3-chloro-5-(pyridin-2-yl)benzoate as a colorless solid. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 247.95 g/mol.