Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([CH:43]2[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[CH:43]1([C:40]2[N:41]=[CH:42][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:38][N:39]=2)[CH2:45][CH2:44]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnc(C2CC2)nc1
Product: C[C@@H](c1ccc(-c2cnc(C3CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 5-bromo-2-cyclopropyl-pyrimidine (for preparation see WO 2006004532) following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=O)[CH2:11][S:12]([CH3:14])=[O:13].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:16]([N:20]=[C:10]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[OH:1])[CH2:11][S:12]([CH3:14])=[O:13])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: COc1cccc(C(=O)CS(C)=O)c1O
Product: CCCCN=C(CS(C)=O)c1cccc(OC)c1O
Yield: 97 %

Procedure:
A solution of 2'-hydroxy-3'-methoxy-2-(methylsulfinyl)acetophenone (5 g, 0.022 mole) in n-butylamine (25 ml) was stirred at room temperature for 24 hrs. The reaction mixture was poured into petroleum ether (200 ml) and the product, which precipitated, was filtered off. Recrystallization from ethylacetate gave yellow crystals (6.0 g, 97%), mp 125°-127°.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]2[O:17][CH2:16]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][C:25]=1[CH3:37]>>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=3)=[CH:26][C:25]=2[CH3:37])=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Reactant: CC(C)OCCOCc1ccc(OCC2CO2)cc1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(COCCOC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isopropoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH:19]=[CH2:20])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:22]C([N-]C(C)C)C.IC>CO>[CH3:22][C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:18]2[C:13]([CH:12]=1)=[C:14]([CH:19]=[CH2:20])[CH:15]=[CH:16][CH:17]=2
Reactant: CC(C)[N-]C(C)C
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Agent: [Li+]
Solvent: CI
Solvent: CO
Product: C=Cc1cccc2c1cc(C)n2S(=O)(=O)c1ccccc1
Yield: 30 %

Procedure:
1-(Phenylsulfonyl)-4-vinyl-1H-indole (190 mg, 0.7 mmol, Intermediate 45) was weight in to a pre dried reaction flask and purged with nitrogen gas for 1 h. Dry THF (50 mL) was added and the reaction flask was cooled to −78° C. before LDA (0.35 mL, 0.7 mmol, 2M) was added. The reaction was stirred for 15 minutes before iodomethane (95.2 mg, 0.7 mmol) was added. Allowed the reaction mixture to slowly reach RT ON. Added 1 mL MeOH and evaporated the reaction mixture on silica. Purified by flash chromatography using 20% DCM in hexanes. Got 61 mg of a white solid, 30% yield. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[N:15]=[C:14]([C:16](O)=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[CH:11][CH:12]=2)[C:7]1=[O:21].CN(C)C=O.S(Cl)([Cl:33])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[N:15]=[C:14]([C:16]([Cl:33])=[O:17])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[CH:11][CH:12]=2)[C:7]1=[O:21]
Reactant: COc1ccc2c(C(=O)O)nn(Cc3ccc(Cl)c(Cl)c3)c(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)Cl)nn(Cc3ccc(Cl)c(Cl)c3)c(=O)c2c1

Procedure:
A stirred mixture of 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid (1.9 g.) in thionyl chloride (10 ml.) containing dimethylformamide (0.1 ml.) was heated under reflux for 3 hours. The solution obtained was then evaporated. The residue was dissolved in dry toluene and the solution evaporated. This procedure was carried out three times to give 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid chloride in essentially quantitative yield as a solid, having a satisfactory IR spectrum.
Reaction SMILES: FC1C=CC(C[O:7][C:8](=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:11]([F:24])[CH:10]=2)=CC=1.[OH-].[K+].Cl>O.O1CCOCC1>[F:24][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:8]([OH:25])=[O:7]
Reactant: O=C(OCc1ccc(F)cc1)c1ccc(OCc2ccc(F)cc2)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)c(F)c1
Temperature: 100 °C
Yield: 84.3 %

Procedure:
A mixture of 3-fluoro-4-(4-fluoro-benzyloxy)-benzoic acid 4-fluoro-benzyl ester (8.1 g, 22 mmol) and potassium hydroxide (6.1 g, 109 mmol) in water:dioxane (4:1, 150 mL) was heated at 100° C. for 12 h. After cooling to room temperature the mixture was acidified to pH 3 with HCl and the mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts washed with brine (100 mL) and dried over sodium sulfate. Filtration and half evaporation gave a precipitate which was filtered off and crystallised from ethyl acetate:heptane to afford the title compound (4.9 g, 85%) as a white solid. MS: m/e=263.0 (M−H−).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=1.B([C:25]1[CH:36]=[CH:35][C:28]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])=[CH:27][CH:26]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[NH2:31][CH:30]([CH2:29][C:28]1[CH:35]=[CH:36][C:25]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=2)=[CH:26][CH:27]=1)[C:32]([OH:34])=[O:33]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Cc1ccc(C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(Oc2cc(-c3ccc(CC(N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
A microwave vial was charged with 4-chloro-2-amino-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1N) was added to above solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 14.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-methylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 7.94 (d, J=8.20 Hz, 2H), 7.47 (d, J=7.24 Hz, 4H), 7.27 (d, J=8.01 Hz, 2H) 6.80 (s, 1H), 6.75 (m, 1H), 4.30 (t, 1H), 3.21-3.44 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>O1CCCC1>[Br:11][CH2:12][CH2:13][CH2:14][C:15]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:16]
Reactant: O=C(Cl)CCCBr
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCCBr)OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
80% Sodium hydride dispersion in oil (0.18 g, 5.9 mmol) was added portionwise to a stirred solution of benzyl alcohol (0.64 g, 5.9 mmol) in anhydrous tetrahydrofuran (10 ml) under nitrogen. After a further 1 hour at room temperature, the reaction mixture was cooled to -70° C. and a solution of 4-bromobutanoyl chloride (1.0 g, 5.4 mmol) in anhydrous tetrahydrofuran (3 ml) added dropwise. After 0.5 hour, the cooling bath was removed and the reaction mixture quenched at room temperature with 5% aqueous ammonium chloride solution (20 ml) and then extracted with dichloromethane (3×20 ml). The combined extracts were washed with saturated brine, dried (Na2SO4) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, eluting with dichloromethane, to give the required ester as a gum. Rf 0.60 (SS 16).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[CH:20][N:19]=3)[CH:11]=2)[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=4[F:37])=[CH:20][N:19]=3)[CH:11]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2cnc(COc3cccc(C(CC(=O)O)C4CC4)c3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methoxy)phenyl)propanoate (128 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 4 hr. 1N Hydrochloric acid (2.0 mL) was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (121 mg) as a white amorphous solid.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][CH:4]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([N:35]=[C:36]=[O:37])[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>C(Cl)Cl>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([NH:35][C:36]([N:20]2[CH2:21][CH2:22][N:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:18][CH2:19]2)=[O:37])[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1ccc(N2CCNCC2)c(OCc2ccncc2)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazine dihydrochloride (0.3 mmol, 100 mg), DCM (5 ml), TEA (1 mmol, 139 ul), and 3,5-bis(trifluoromethyl)phenyl isocyanate (0.6 mmol, 104 ul) was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified on silica column using 80% EtOAc/hexanes to give N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-ylmethyl)oxy]phenyl}piperazine-1-carboxamide. 1H NMR (CDCl3) 8.599-8.586 (d, 2H), 7.855 (s, 2H), 7.559-7.452 (d, 2H), 7.390-7.377 (d, 2H), 7.021-6.888 (m, 4H), 5.146 (s, 2H), 3.728-3.704 (m, 4H), 3.149-3.125 (m, 4H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:22]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])=[CH:21][N:20]=[C:19]1[CH3:30].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:30][C:19]1[N:18]([CH3:17])[C:22]([C:23]2[CH:24]=[C:25]([NH:26][C:11]([C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:16]=[CH:15][CH:14]=3)=[O:13])[CH:27]=[CH:28][CH:29]=2)=[CH:21][N:20]=1
Reactant: Cc1ncc(-c2cccc(N)c2)n1C
Reactant: O=C(O)c1cccc(-c2ccc(F)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc(-c2cccc(NC(=O)c3cccc(-c4ccc(F)cc4)c3)c2)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
To a suspension of 3-(4-fluorophenyl)benzoic acid (151 mg) and 3-(1,2-dimethylimidazol-5-yl)aniline (131 mg) in dichloromethane (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg) and 4-dimethylaminopyridine (43 mg). The mixture was stirred at ambient temperature for 18 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-[3-(2,3 dimethyl-3H-imidazolyl)-phenyl]-4′-fluoro-biphenyl-3-carboxamide (240 mg, 88.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(F)cc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(-c2cccnc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
3-Fluoro-5-(pyrid-3-yl)aniline (1.05 g, 0.0050 mole) in dry dichloromethane was treated under argon with triethylamine (1.12 ml, 0.0080 mole) followed dropwise by phenyl chloroformate (0.97 ml, 0.0077 mole) and stirred at ambient temperature for 18 hours. The reaction mixture was washed (x2) with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.1 g, 71%) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[N:44]=[C:43]([CH3:55])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[C:45]([CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[N:44]=[C:43]([CH3:55])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and (RS)-3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionic acid tert-butyl ester (Example K64) (426 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (500 mg, 69%).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:32])=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3[O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:21]=O)[CH:16]=2)[C:11]([CH3:34])([CH3:33])[CH2:10][C:9]1=[O:35])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH3:32])=[C:15]([C:18]3[CH:19]=[C:20]([CH:21]=[CH2:1])[CH:23]=[CH:24][C:25]=3[O:26][CH2:27][C:28]([F:30])([F:31])[F:29])[CH:16]=2)[C:11]([CH3:34])([CH3:33])[CH2:10][C:9]1=[O:35])[CH3:7]
Reactant: [Li]CCCC
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OCC(F)(F)F)cc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCC(F)(F)F)c(-c2cc3c(cc2C)C(C)(C)CC(=O)N3CC)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In accordance with Scheme 16, to a suspension of methyltriphenylphosphonium bromide (3.27 mmol, 1.17 g) in 7.5 mL THF was added a solution of n-butyllithium in hexanes (1.6 M, 3.27 mmol, 2.04 mL) at −40° C. The reaction was warmed to −10° C. and stirred for 30 min. The reaction mixture was cooled to −60° C. and then Compound 1D (0.14 mmol, 0.06 g), in 7.5 mL THF, was added dropwise. The yellow suspension was allowed to stir at r.t. overnight and then quenched by adding 1 mL H2O. It was extracted with EtOAc and was washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. The yellow oil thus obtained was then purified by column chromatography (3.5:1 hexanes/EtOAc) to obtain 1-ethyl-4,4,6-trimethyl-7-[2-(2,2,2-trifluoro-ethoxy)-5-vinyl-phenyl]-3,4-dihydro-1H-quinolin-2-one as a colorless thick gum (0.61 g, 94% yield).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1COCC1>[C:1]1([S:7]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzenesulfonyl chloride (1 g, 5.66 mmol) in THF (20 mL) were sequentially added triethylamine (1.97 mL, 14.15 mmol) and piperazine (2.92 g, 33.9 mmol). The reaction was stirred at room temperature for 1 hour before it was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate to 10/1 dichloromethane/methanol) to give 22 as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[C:11]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].Cl>O1CCCC1>[OH:20][C:17]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
4-Bromoanisole (22.4 g, 0.12 mol) in tetrahydrofuran (180 ml) was slowly added to magnesium (2.9 g, 0.12 mol) in tetrahydrofuran (20 ml) and the mixture stirred for one hour at room temperature. The solution formed was slowly added to a solution of 1-acetyl-4-piperidone (16.9 g, 0.12 mol) in tetrahydrofuran (200 ml) at -78° C., and the suspension produced was stirred to room temperature for 2 hours. Hydrochloric acid (120 ml, 1M) was added and the organic phase was separated and concentrated in vacuo. The residue was taken up in dichloromethane (300 ml), washed with water (300 ml) and dried (MgSO4). Concentration in vacuo and trituration with diethyl ether gave 1-[4-hydroxy-4-(4-methoxyphenyl)-piperidin-1-yl]ethanone (14.75 g, 50% yield) as a white solid; δH (CDCl3) 1.7-2.1 (4H, m, 2× piperidinyl CH2), 2.1 (3H, s, COCH3), 3.1 (1H, m, piperidinyl H), 3.6-3.8 (3H, m, piperidinyl H), 3.8 (3H, s, ArOCH3), 4.6 (1H, m, OH), 6.9 (2H, d, J 10 Hz, ArH), and 7.4 (2H, d, J 10 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C[O:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N:28]2[CH:32]=[C:31]([C:33]3[CH:34]=[N:35][N:36]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:37]=3[CH2:38][CH3:39])[N:30]=[CH:29]2)[CH:22]=1>>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([CH3:17])=[C:2]([NH:1][C:20](=[O:19])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([N:28]3[CH:32]=[C:31]([C:33]4[CH:34]=[N:35][N:36]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:37]=4[CH2:38][CH3:39])[N:30]=[CH:29]3)[CH:22]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: Cc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4C)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 157 was prepared from N-(3-amino-5-tert-butyl-2-methyl-phenyl)-methanesulfonamide and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 611 [C34H38N6O3S+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(N)ccc1O
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(N=Cc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 68.7 %

Procedure:
Methyl 2-hydroxy-5-aminobenzoate (43.6 g, 0.261 mole) was dissolved in benzaldehyde (26.6 ml, 0.26 mole) by heating to 100° C. for 10 minutes and cooled with ice-water after which 95% ethanol (40 ml) was added, and the resulting crystalline material was isolated by filtration. The product was recrystallized from 96% ethanol to give the title compound (45.6 g, 69%), m.p. 58°-59° C. Found (Calc. for C15H13NO3) C 70.60 (70.58), H 5.06 (5.10), N 5.50 (5.49).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2ccccc2)CC1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4-phenylpiperidine, [Chem. Abs., 75, 5728b (1971] (16.30 g) was added portionwise over 1 hour to stirred chlorosulphonic acid (53.3 ml) at 0°. The solution was stirred at 0° for 1 hour, then at room temperature for 2 hours, and then finally poured cautiously onto an excess of ice. When the ice had melted the mixture was extracted several times with dichloromethane. The combined organic extracts were washed with water, dried (Na2SO4) and evaporated to give the title compound, (23.0 g), m.p. 133°-134°, used directly in the next step.