Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.[BH4-].[Na+]>C(O)C.ClCCl>[CH3:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([OH:16])[C:5]=2[N:6]=1
Reactant: COc1ccc(Cn2c(C)nc3c(=O)c4ccccc4ccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(Cn2c(C)nc3c2C=Cc2ccccc2C3O)cc1

Procedure:
To a stirred solution of the product from step (ii) (1 g) in ethanol (40 ml) and dichloromethane (20 ml) was added sodium borohydride (0.28 g). After 48 h the solvent was evaporated (without heat) under reduced pressure and the residue partitioned between dilute aqueous sodium hydroxide solution and dichloromethane. The organic phase was collected, dried, (MgSO4) and solvent evaporated under reduced pressure to leave a yellow foam.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[Cu](I)I.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]3[N:17]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:16]([C:18]([F:20])([F:21])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Ic1ccccc1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2c1ccccc1
Temperature: 150 °C

Procedure:
In a microwave tube, 425 mg of (S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e) are introduced into 1 ml of dimethylformamide, 422 mg of tripotassium phosphate, 380 mg of copper iodide and 2 ml of iodobenzene. The mixture obtained is heated in a microwave oven for 30 minutes at 150° C. The reaction mixture is then centrifuged. The separated supernatant is then rinsed with ethyl acetate and then evaporated to dryness. The residue is taken up with ethyl acetate and the solution obtained is washed with water. The organic phase is separated and then dried over magnesium sulphate, filtered, and concentrated under vacuum. After purification by silica chromatography (gradient of 5% to 15% of the eluent CH2Cl2/MeOH/NH4OH 28% 38/17/2 in dichloromethane), 150 mg of (8S)-2-(morpholin-4-yl)-9-phenyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([F:28])[CH:22]=1>C(O)(C)C>[ClH:2].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([C:13]#[N:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:23]([F:28])[CH:22]=1
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1C#N
Yield: 98 %

Procedure:
A mixture of 4-chloro-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (300 mg 1 mmol), (prepared as described for the starting material in Example 1), and 4-chloro-2-fluoroaniline (0.5 ml, 3.4 mmol) in isopropanol (20 ml) was heated at reflux for 3 hours. The mixture was allowed to cool, the solid product was collected by filtration, washed with acetone and dried to give 4-(4-chloro-2-fluoroanilino)-6-cyano-7-(2-methoxyethoxy)quinoline hydrochloride (400 mg, 98%).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=[O:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH2:14]([Mg]Cl)[CH2:15][CH2:16][CH3:17].[Cl-].[NH4+]>O1CCCC1>[OH:13][CH:12]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CCCC[Mg]Cl
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 65 %

Procedure:
Methyl-(3-oxopropyl)carbamic acid, 1,1-dimethylethyl ester (2.00 g, 10.7 mmol) was dissolved in tetrahydrofuran (20 ml) under nitrogen and cooled to 0° C. with stirring. To the resulting solution was added n-butylmagnesium chloride and the mixture stirred at 0° C. for a further 30 minutes and then allowed to warm to room temperature with stirring over 20 h. The mixture was then poured into saturated ammonium chloride solution and then extracted with diethyl ether three times. The combined organic fractions were then washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 40% diethyl ether/isohexane as eluent to give 1.70 g (65%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[CH3:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:26])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:21][CH:20]=1)(=[O:23])=[O:24]
Reactant: COC(=O)c1cccc(OCc2ccc(S(C)(=O)=O)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)c1ccc(COc2cccc(C(=O)O)c2C(=O)O)cc1

Procedure:
A solution of 3-(4-methanesulfonyl-benzyloxy)-phthalic acid dimethyl ester (2.3 g, 6.1 mmol) in reagent alcohol (140 mL) and 3 N sodium hydroxide (70 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(4-methanesulfonyl-benzyloxy)-phthalic acid as an off-white solid (2.15 g, 101% crude yield). The product was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[N:7]1)=[O:5])C.[OH-].[Na+]>C(OC)(C)(C)C>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:8]1[S:9][CH2:10][C@@H:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)[C@@H]1CSC(c2ccc(OC)cc2OC)=N1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: COc1ccc(C2=N[C@H](C(=O)O)CS2)c(OC)c1

Procedure:
Ethyl-2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylate is refluxed with aqueous sodium hydroxide in methyl tertiary-butyl ether (MTBE) to form 2-(2,4-dimethoxyphenyl)-4,5-dihydro-thiazole-4-(R)-carboxylic acid.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1)=[O:2].[CH3:16][Mg]Cl>O1CCCC1>[OH:2][CH:1]([C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1)[CH3:16]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)C(=O)Nc1cccc(C=O)n1
Solvent: C1CCOC1
Product: CC(O)c1cccc(NC(=O)C(C)(C)C)n1
Temperature: 0 °C
Yield: 13 %

Procedure:
To an ice-cooled solution of N-(6-formylpyridin-2-yl)-2,2-dimethylpropanamide (4.0 g, 19.4 mmol) in tetrahydrofuran (30 mL) was added methylmagnesium chloride (13.6 mL, 40.7 mmol, 3 M in THF) dropwise. After 2 h the reaction was quenched with saturated aqueous NH4Cl solution (10 mL) and diluted with ethyl acetate (50 mL). The mixture was washed with saturated aqueous NaHCO3 solution (2×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (2:1 hexanes/EtOAc) to afford the intermediate as a clear oil (0.56 g, 49%). 1H NMR (400 MHz, CDCl3), δ: 8.14 (d, J=8.1 Hz, 1H), 8.00 (br s, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.00 (d, J=7.5 Hz, 1H), 4.82 (m, 1H), 3.81 (d, J=5.0 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.35 (s, 9H); LRMS (ESI): m/z: 223.2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([S:25](Cl)(=[O:27])=[O:26])[C:22]([C:29]([F:32])([F:31])[F:30])=[N:21]1>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:23]2[C:22]([C:29]([F:32])([F:30])[F:31])=[N:21][N:20]([CH3:19])[CH:24]=2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: Cn1cc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)c(C(F)(F)F)n1

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (0.5 mmol) to obtain N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 3.8 (s, 3H), 5.7 (s, 1H), 6.0 (dt, 1H), 7.0 (q, 1H), 7.2 (m, 2H), 7.4 (dd, 1H), 7.8 (s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[N:27]=2)[CH:20]=1.O>CN1C(=O)CCC1.[Cu]I>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([O:11][C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[N:27]=4)[CH:20]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2cc(Oc3ccc4c(c3)OCCO4)ncn2)n1
Temperature: 100 °C
Yield: 29 %

Procedure:
A stirred mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (0.137 g, 0.90 mmol), Cs2CO3 (0.734 g, 2.25 mmol), CuI (0.02 g, 10% w/w), and N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (0.29 g, 0.90 mmol) in NMP (1 mL) was heated at 100° C. for 16 h. The reaction mixture was cooled to rt and slowly added to demineralised water. The solid that precipitated was collected by filtration and was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 7/3) to give N2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)pyrimidin-4-yl)pyridine-2,6-diamine (0.088 g, 29%) as yellow solid.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C(P([Pd]P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[C:24]=1[F:25])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH]([Pd][PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cccc(F)c3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2,3-difluorophenyl)boronic acid (0.072 g, 0.46 mmol) in 1,4-dioxane (3 mL) was added a 1N solution of sodium carbonate in water (0.57 mL, 0.57 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl}palladium (0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-30% ethyl acetate/hexane) to give the desired product (83 mg). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1cccc(O)c1
Product: CCN(Cc1cccc(O)c1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-ethylaminomethyl-phenol
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NC(C)C)(C)C.C(OCC)(=O)C.[Cu]I>[N:14]1([C:12]([C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N2CCCC2)c(C#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
18 g (57.7 mmol) of methyl 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoate is placed under a nitrogen atmosphere together with 6.66 g (5.77 mmol) of tetrakis-triphenylphosphinepalladium(0) and 0.439 g (2.31 mmol) of copper(1) iodide in 150 mL of N,N-diisopropylamine, the mixture is heated to 80° C. and 16.6 mL (115 mmol) trimethylsilylethyne is added. The reaction mixture is stirred for 8 hours at 80° C. and then for 16 hours at ambient temperature. Then volatile constituents are eliminated in vacuo, the residue is taken up in ethyl acetate, insoluble matter is filtered off, and the solvent is eliminated in vacuo. The residue is purified by chromatography on silica gel (gradient: dichloromethane/ethanol 100:0□95:5). Yield: 7.7 g (41%); Rf value: 0.44 (silica gel; dichloromethane/ethanol=95:5); C18H23NO3Si (329.48); mass spectrum: (M+H)+=330.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[N:20]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]4[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]4)=[CH:7][CH:8]=3)=[CH:13][CH:14]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCCC1
Reactant: O[C@@H]1CCNC1
Product: O=C(c1ccc(-c2ccc(OCCCN3CC[C@@H](O)C3)cc2)cc1)N1CCCC1

Procedure:
1-{[4′-(3-Chloropropoxy)[1,1′-biphenyl]-4-yl]carbonyl}pyrrolidine and (3R)-3-pyrrolidinol were processed as described in Example 159 to provide the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCN=C=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: CCNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Yield: 55.6 %

Procedure:
The compound (0.20 g) obtained in Example 1 and ethyl isocyanate (0.047 g) were reacted and treated in the same manner as in the method described in Example 6 to obtain the title compound as colorless oil (0.12 g, 74%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH:22]=O.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.C(O)(=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[CH:24][C:21]=1[CH2:22][NH:1][C@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H]1CC[C@H](N)[C@@H]1c1ccc(F)cc1
Reactant: COc1ccc(-n2cnnn2)cc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](NCc2cc(-n3cnnn3)ccc2OC)[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of 100 mg of amine from Example 63 in 2 mL of methanol was added 0.040 mL of acetic acid, 1 g of 3A sieves and 94 mg 2-methoxy-5-(1-tetrazolyl)benzaldehyde (prepared according to the procedures given in PCT International Application WO 95/08549, published 30 Mar. 1995; p. 33). The reaction was stirred at room temperature for 30 min and then 0.080 g of sodium cyanoborohydride was added. The reaction was stirred further for 20 h and was then poured into water, made basic with 2N NaOH and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 0 to 3% methanol in methylene chloride to obtain 100 mg of title compound. NMR (CDCl3): δ 1.5 (br s, NH/H2O), 1.8-1.9 (m, 1H), 1.9-2.05 (m, 2H), 2.2-2.35 (m, 1H), 2.24 (m, 1H), 3.3-3.45 (m, 1H), 3.45-3.55 (m, 2H), 3.59 (s, 3H), 3.63 (s, 3H), 3.68 (d, 1H), 6.86 (d, 1H), 6.98 (t, 2H), 7.17 (m, 2H), 7.36 (d, 1H), 7.46 (dd, 1H), 8.85 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)=[O:23].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(c1ccc(NC(=O)C(O)(C(F)F)C(F)F)cc1)c1ccccn1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 39.3 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in dimethylacetamide (10 mL) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(2-Pyridylcarbonyl)aniline (0.58 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, sodium bicarbonate solution added to give a pH of 7 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (Na2SO4), decolorized (charcoal), and evaporated. The crude solid was dissolved in ether, clarified by filtration, and evaporated to give a yellow orange gum. Crystallization from methylene chloride/hexane gave the title compound (0.35 g, 35%) as a tan solid; mp 158°-161° C. 1H-NMR (300 MHz, d6-DMSO); 6.48(t, J=54.12 Hz, 2H, HCF2), 7.67(t, J=6.18 Hz, 1H, ArH), 7.91-8.10 (m, 7H, ArH, OH), 8.73 (d, J=7.35 Hz, 1H, ArH), 10.40 (s, 1H, NH). MS(CI),CH4 : 357(M+H, 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([CH2:21][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To methyl 1H-indole-7-carboxylate (1.5 g) was added DMF (15 mL), and potassium tert-butoxide (1.5 g) was added thereto under ice-cooling, followed by stirring for 10 minutes. 4-(Bromomethyl)biphenyl (2.8 g) was added thereto, followed by stirring at room temperature for 19 hours. The reaction mixture was again ice-cooled, and a 10% aqueous citric acid solution (20 mL) was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3-95/5) to obtain methyl 1-(biphenyl-4-ylmethyl)-1H-indole-7-carboxylate (2.5 g).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)/[CH:4]=[CH:5]\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C[C]1[C](C)[C](C)[C](C)[C]1C.C1CC=CCCC=C1.Cl[Ru]>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:3](/[CH:4]=[CH:5]/[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:2][O:1][CH:21]=2)=[CH:16][CH:15]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: ON=C(Cl)/C=C\c1ccccc1
Agent: Cl[Ru]
Agent: C1=C\CC/C=C\CC/1
Agent: C[C]1[C](C)[C](C)[C](C)[C]1C
Solvent: C1=CCCC=CCC1
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2conc2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A screw-top Schlenk flask (250 mL) purged with dry nitrogen was charged with compound 25B (7.31 g, 40 mmol) and 4-chlorophenylacetylene (5.0 g, 36.6 mmol). At room temperature, degassed 1,2-dichloroethane (100 mL) was added followed by [Cp*RuCl(cod)] (450 mg, 1.18 mmol) and triethylamine (6.38 mL, 45.8 mmol). The flask was purged with N2 and capped. After being stirred at room temperature for 7 h, the reaction mixture was passed through a plug of silica gel, and washed with DCM. The resulting solution was concentrated and the residue was purified by column chromatography on silica gel (pure hexanes to 10:1 hexanes/EtOAc) to provide the desired compound. MS (m/z) 282.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([N+]([O-])=O)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[CH2:9]3)=[CH:4][CH:3]=2)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)C1CCc2ccc(O)cc2C1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCc2ccc(Oc3ccnc(Cl)c3)cc2C1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A mixture of 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5.62 g, 29.2 mmol); 2-chloro-4-nitropyridine (5.10 g, 32.2 mmol) and cesium carbonate (28.6 g, 87.7 mmol) in DMF (150 mL) was heated at 50° C. for 5 hr. The reaction mixture was allowed to cool to rt and acidified to pH 3 by addition of 1N HCl. The mixture was extracted with EtOAc and the organic solutions were combined, washed with water, dried over Na2SO4 and evaporated. The residue was adsorbed onto silica and purified by filtration through a pad of silica. The product was then triturated with EtOAc to give 7-[(2-chloropyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.62 g, 52.0%). LCMS: (FA) ES+ 304.1, ES− 302.1.