Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40](Cl)=[O:41])[CH:33]=2)=[CH:28][C:27]=1[F:43]>ClCCl>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([CH2:39][C:40]([NH:1][C:2]3([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]3)=[O:41])[CH:33]=2)=[CH:28][C:27]=1[F:43]
Reactant: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)Cl
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)c(F)c3)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20.50 g (80.32 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 8.13 g (80.32 mmol) of triethylamine were dissolved in 280 ml of dichloromethane. 21.70 g (73.02 mmol) of (4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)acetyl chloride (Example 4AA), dissolved in 280 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 37.05 g (98% of theory) of the title compound as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([CH3:20])=[C:10]([CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[C:9]([CH3:20])=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([Cl:25])=[O:18])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(CCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Product: Cc1c(CCCC(=O)Cl)cccc1C(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 8 g of 4-(3'-p-chlorobenzoyl-2'-methylphenyl)-butyric acid (Example V) and 80 ml of thionyl chloride was refluxed for 45 minutes and after removal of excess thionyl chloride under reduced pressure, 60 ml of benzene were added thereto. The traces of thionyl chloride were removed by entrainment with benzene. This operation was repeated 3 times. The residue was taken up in tetra-hydrofuran to obtain a solution of 4-(3'-p-chlorobenzoyl-2'-methyl-phenyl)-butyric acid chloride which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[N:7]=1.N[C:28](C)(C)CO.FC(F)(F)C(O)=O>>[F:1][C:2]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:8]([NH:17][C:18]([CH3:28])([CH3:21])[CH2:19][OH:20])[N:7]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cccc(CSc2nc(N[C@H](C)CO)cc(NS(C)(=O)=O)n2)c1F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CSc2nc(NC(C)(C)CO)cc(NS(C)(=O)=O)n2)c1F

Procedure:
The title compound was prepared as a white solid by the method of Example 115 using the subtitle product of Example 115 step (1.0 g), 2-amino-2-methyl-1 propanol (1.5 ml) and trifluoroacetic acid (2 ml). Yield: 0.19 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH:11]([S:19](Cl)(=[O:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][CH:11]([S:19]([N:28]1[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]1)(=[O:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=C(CC(Cc1ccccc1)S(=O)(=O)Cl)OCc1ccccc1
Solvent: ClCCl
Product: CC1CCN(S(=O)(=O)C(CC(=O)OCc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 40.7 %

Procedure:
The product from Step H (0.92 g, 2.6 mmol) was taken up in DCM (25 mL) with stirring and cooled to 0° C. TEA (362 μL, 2.6 mmol) and 4-methyl-piperidine (307 μL, 2.6 mmol) were added and the reaction warmed to room temperature and stiired overnight. The reaction was diluted with DCM and washed successively with water, 1 M HCl, water, brine, dried, filtered and concentrated in vacuo to give a yellow oil. This was purified by silica gel column chromatography eluting with hex /EtOAc 8:2 to give the titled compound as a yellow oil (440 mg, 41%). 1H-NMR δ (CDCl3) 7.40-7.18 (10H, m), 5.0 (1H, d, J=12.2 Hz), 4.95 (1H, d, J=12.2 Hz), 3.9 (1H, m), 3.68 (2H, m), 3.42-3.31 (1H, dd, J=4.4, 14.1 Hz), 2.91-2.80 (1H, dd, J=5.9, 17.1 Hz), 2.79-2.62 (3H, m), 2.58-2.47 (1H, dd, J=6.2, 17.1 Hz), 1.69-135 (2H, m), 1.30-1.10 (3H, m) and (3H, d, J=6.2 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][C:17](OC)=[O:18].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:23][Si:2]([CH3:1])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][CH2:17][OH:18]
Reactant: COC(=O)C=C[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C[C@H](C=CCO)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -95 °C
Reaction time: 1 h

Procedure:
A 3.66 g amount of methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-pentenoate was placed in a 500 ml eggplant-shaped flask, and 100 ml of hexane and 40 ml of toluene were then added to dissolve it. The solution was cooled to −95° C., then 12.2 ml of diisobutylaluminum hydride was slowly added and the solution stirred at the same temperature for 1 hour. Next, a further 24 ml of diisobutylaluminum hydride was added, followed by stirring for 2 hours. The consumption of the material was confirmed by thin layer chromatography, then the excess reducing agent was broken down by methanol and a saturated aqueous solution of sodium sulfate and then 300 ml of ethyl acetate and 80 ml of a saturated aqueous solution of ammonia chloride were added for separation. Extraction was performed from the aqueous layer by 100 ml of ethyl acetate, then the organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate=19/1 to 4/1) to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y l]-2-penten-1-ol in an amount of 3.31 g (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21](=[O:24])(=[O:23])[NH2:22])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8].[CH3:30][N:31]=[C:32]=[S:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[C:7]([NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([S:21]([NH:22][C:32]([NH:31][CH3:30])=[S:33])(=[O:23])=[O:24])[CH:19]=2)[O:14][CH2:13][CH2:12]1)=[O:8]
Reactant: CN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NCC1CCOc2cc(OC)c(S(N)(=O)=O)cc21
Solvent: CN(C)C=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)c1cc(Cl)ccc1OC

Procedure:
(+)-4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonyl-aminosulfonyl)-7-methoxychroman ##STR59## (+)-4-(5-Chloro-2-methoxy-benzamidomethyl)-6-(methylaminothiocarbonylaminosulfonyl)-7-methoxychroman is prepared as described in Example 4 from optically active 4-(5-chloro-2-methoxy-benzamidomethyl)-6-sulfamoyl-7-methoxychroman and methyl isothiocyanate. Melting point: 201° C.; [α]D20 : +47.2° (c=1, DMF); HPLC: ee 88.1%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:7](=[O:8])[NH:6][NH:5][C:4]1=[O:9])[CH3:2].[C:19]([O:25][CH3:26])(=[O:24])[CH:20]=[CH:21][CH:22]=[CH2:23]>>[CH2:1]([C:3]1([CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:4](=[O:9])[N:5]2[CH2:23][CH:22]=[CH:21][CH:20]([C:19]([O:25][CH3:26])=[O:24])[N:6]2[C:7]1=[O:8])[CH3:2]
Reactant: CCC1(CCOC2CCCCO2)C(=O)NNC1=O
Reactant: C=CC=CC(=O)OC
Product: CCC1(CCOC2CCCCO2)C(=O)N2CC=CC(C(=O)OC)N2C1=O
Yield: 58.6 %

Procedure:
In a manner analogous to that described in Example 7(B) (b), from 7.75 g of 4-ethyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione and 3.7 g of methyl penta-2,4-dienoate there were obtained 6.49 g (59%) of methyl 2-ethyl-2,3,5,8-tetrahydro-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 96°-97° C. (from diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1.[H-].[Na+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([O:22][CH2:30][C:29]#[CH:28])[CH:20]=2)[CH:15]=[N:14]1
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1cc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxy-5-nitroindazole [Compound No. 31] (3 g) in N,N-dimethylformamide, 60% sodium hydride (0.5 g) was added, and the resultant mixture was stirred while cooling with ice. After 10 minutes, propargyl bromide (1.2 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitro-6-propargyloxyindazole (2.8 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH:14]([CH3:21])[CH2:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>ClCCl.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH:14]([CH3:21])[CH2:13][C:12]=3[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC2CCC3=C(C2)CC(C)C(=O)N3)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC1CC2=C(CCC(Cc3ccc(O)cc3)C2)NC1=O
Yield: 81.9 %

Procedure:
3,4,5,6,7,8-Hexahydro-6-((4-methoxyphenyl)methyl)-3-methylquinolin-2[1H]-one (2.85 g) prepared according to Example 1 (2.85 g) was suspended in dichloromethane (5 ml) and cooled with ice and boron tribromide (3.3 ml) was added. The mixture was left to stir until tlc (SiO2 /chloroform) showed no starting material remained and then the mixture was quenched by slow addition of water (10 ml). The reaction mixture was further diluted with water and the resulting solid was isolated by filtration. The solid was dissolved in methanol (100 ml) and concentrated HCl (1 ml) was added. The methanol was removed under reduced pressure and the procedure repeated three times. The solid was suspended in ethyl acetate, filtered and washed with ether to give the hemihydrate of the title compound (2.22 g), mp.230°-235° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]CC)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].O.[OH-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a solution of ethyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetate (for a preparation see Intermediate 22) (270 mg, 0.597 mmol) in methanol (6 mL) and water (2.0 mL) was added aqueous sodium hydroxide (2N, 0.597 mL, 1.193 mmol) at room temperature and the resulting mixture was stirred for 6 h. Aqueous sodium hydroxide (2N, 0.5 mL) was added and the mixture was left standing overnight. The bulk of methanol was removed in vacuo and the resulting residue was partitioned between water and Et2O and the layers were separated. The aqueous layer was acidified with hydrochloric acid (2N, 2 mL) and extracted twice with EtOAc. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}acetic acid (200 mg, 0.471 mmol, 79% yield) as a brown foam. This compound was used in the next step without further purification. LCMS (HpH, 2 min), Rt=0.65, MH+=425.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([NH:11]C(=O)C(F)(F)F)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N+:18]([O-:20])=[O:19])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])c(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1ccc([N+](=O)[O-])c(N)c1

Procedure:
The title compound was prepared as outlined in Example PP-1 from N-(5-tert-butyl-2-nitro-phenyl)-2,2,2-trifluoro-acetamide (prepared in Example OO-2; 248 g, 855 mmol), MeOH (500 mL), and 7% aqueous potassium carbonate solution. The crude product was used without any purification. MS(APCI): 195 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=2)=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[O:17])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc(Cl)nc(NCc2ccccc2)c1)c1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccnc(NCc2ccccc2)c1)c1ccc(O)cc1

Procedure:
Rf value: 0.58 (silica gel; methylene chloride/methanol=9:1) by hydrogenation of 4-[(2-benzylamino-6-chloro-4-pyridyl)aminocarbonyl]-1-benzyloxy-benzene at ambient temperature.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=O.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C([O-])(O)=O.[Na+]>Cl>[OH:10][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:19]=1
Reactant: COC(=O)CCCCCCO
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: OCCCCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
1.6 g of methyl 7-hydroxyheptanoate and 1.08 g of o-phenylenediamine were refluxed for 7 hours in 15 ml of 2:1 hydrochloric acid aqueous solution. The reaction mixture was cooled to room temperature, then adjusted to pH 8 with addition of aqueous NaHCO3 and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.9 g of the title compound (yield: 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][C:4]=1[O:9][CH2:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Nc1ncc(Br)cc1OCc1c(F)cccc1Cl
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: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)cccc1Cl
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
5-Bromo-3-(2-chloro-6-fluoro-benzyloxy)-pyridin-2-ylamine (Example I(e), 9.00 g, 27.0 mmol), 4-carboxybenzeneboronic acid (4.41 g, 27.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.9 mmol), potassium carbonate (13.1 g, 95.0 mmol), dimethylformamide (72 mL) and water (36 mL) were charged to a 250 mL three neck round bottom flask equipped with a thermometer, a reflux condenser and magnetic stirring. The mixture was purged with nitrogen and gradually heated from 81° C. to 98° C. over a period of 4 hr. Thin layer chromatography (ethyl acetate:hexane:acetic acid 4:6:0.5) showed a trace of starting material at Rf 0.7, product at Rf 0.4 and many small impurities. The mixture was cooled to 45° C. The solids were collected by vacuum filtration, washed with 30 mL of ethanol:water 1:1 and discarded. The filtrate was diluted with 432 mL of water and 8 mL of 9 N potassium hydroxide solution (to pH 12–13), cooled in an ice bath and stirred for 30 minutes. The solids were collected by vacuum filtration and washed with 5 mL of water. The filtrate was cooled in an ice bath and acidified to pH 7.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 2.5 g of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid and a second compound as a brown solid in a ratio of about 1:1 by 1H-NMR. This material was discarded. The filtrate was acidified to pH 6.5 with acetic acid using a pH meter. The solids were collected by vacuum filtration, washed with 10 mL of ethanol:water 1:1 and dried under vacuum to give 3.6 g (36% yield) of 4-[6-amino-5-(2-chloro-6-fluoro-benzyloxy)-pyridin-3-yl]-benzoic acid as a brown solid containing a 5–10% impurity by 1H-NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C@H:3]([OH:14])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6]1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:19].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[C:18](=[O:19])([O:14][C@H:3]([CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6]1)[C:2]([CH3:16])([CH3:15])[CH3:1])[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[C@H](O)Cn1ccc(C(F)(F)F)n1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)[C@@H](Cn1ccc(C(F)(F)F)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To 875.3 mg (3.71 mmol) of (2S)-3,3-dimethyl-1-[3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-butanol in 12 mL of 1,2-dichloroethane at room temperature was added 746.8 g (3.71 mmol) of 4-nitrophenyl chloroformate. Then, 359.6 μL (4.45 mmol) of pyridine was added and the solution was heated at reflux for 22 h. Upon cooling to room temperature, saturated aqueous sodium bicarbonate was added to the solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:4) to give 1.39 g (93%) of 4-nitrophenyl (1S)-2,2-dimethyl-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}propyl carbonate. Rf=0.29 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.28 (d, J=9 Hz, 2H), 8.07 (s, 1H), 7.31 (d, J=9 Hz, 2H), 6.74 (s, 1H), 4.87 (d, J=8 Hz, 1H), 4.69 (d, J=14 Hz, 1H), 4.42 (dd, J=15 Hz, J=10 Hz, 1H), 1.03 (s, 9H); ES-LCMS m/z 424 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CCN(CC)CC.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>C(O)C>[Cl:19][C:20]1[N:25]=[C:24]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccnc(Cl)n2)CC1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 87.2 %

Procedure:
To a solution of ethyl piperidine-4-carboxylate (13.0 g, 82.69 mmol,) in ethanol (130 ml) were added Et3N (17.29 ml, 124 mmol) and 2,4-dichloropyrimidine (13.55 g, 90.96 mmol). After stirring for 8 minutes at 80° C., the solvent was removed under reduced pressure and purified by normal phase chromatography, eluting with Heptane with 50% ethyl acetate to give compound ethyl 1-(2-chloropyrimidin-4-yl)piperidine-4-carboxylate (19.45 g, 76%) as a colourless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11]
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCC1=C(C)[C@@H](O[Si](C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
1 To a solution of (S)-4-hydroxy-3-methyl-2(2-propynyl)-cyclopent-2-ene-1-one (12.88 g) and triethylamine (13.2 g) in tetrahydrofuran (200ml) was added dropwise chlorotrimethylsilane (10.4 g) for 5 minutes under ice-water cooling, then the solution was stirred for 2 hours under ice-water cooling, and 13 hours at room temperature. Then this solution was poured into ice-water and extracted twice with diethyl ether. The ether layers were combined and washed twice with brine. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resultant residue was subjected to column chromatography over florisil (eluent; n-hexane:ethyl acetate=20:1) to afford (S)-4-trimethylsilyloxy-3-methyl-2-(2-propynyl )-cyclopent-2-ene-1-one (18.0 g, yield 79.1% ) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([O:18][CH3:19])[CH:11]=2)[O:17][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COc1cc(C(C)=O)ccc1OCc1ccccc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)ccc1OCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzyloxy-3'-methoxyacetophenone (2.00 g, 7.81 mmol), lithium bis(trimethylsilyl)amide (1.96 g, 11.71 mmol), chlorotrimethylsilane (1.48 mL, 11.71 mmol), THF (80 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 114°-115° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.77 (t, 2 H), 2.98 (t, 2 H), 3.86 (s, 1 H), 6.75 (s, 1 H), 7.21 (m, 7 H), 7.40 (m, 6 H).