Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[F:26][C:27]([F:33])([F:32])[CH2:28][C:29](=O)[CH3:30].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:29]([CH2:28][C:27]([F:33])([F:32])[F:26])[CH3:30])[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: CC(=O)CC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(CC(F)(F)F)N1CCC(CNc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 70 °C

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.37 g, 1 mmol) in 11 mL of 95:5 methanol-acetic acid was treated with excess of 4,4,4-trifluorobutan-2-one (1 g, 7.9 mmol), followed by sodium cyanoborohydride (0.25 g, 4 mmol). The reaction mixture was heated at 70° C. overnight, after which a small trace of the desired product was detected by LC-MS analysis. The crude reaction mixture was directly submitted to silica gel chromatography; elution with 9:1 dichloromethane-2 M ammonia in methanol provided a small amount of impure product. Further purification by preparative thin layer chromatography afforded 10 mg of the title compound, identified by LC-MS (Method A).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20]([OH:22])=O)=[O:14])[N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NCC1CC1>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[C:20](=[O:22])[N:43]([CH:42]2[CH2:40][CH2:41]2)[CH3:38])=[O:14])[N:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)O)n(-c2ccccc2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)N(C)C2CC2)n(-c2ccccc2)n1

Procedure:
To a solution of 1.3 g 5-[2-((S)-2-carboxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester in 20 ml DMF were added 1.28 g HATU and 0.56 ml DIPEA. After 10 minutes 0.29 ml aminomethylcyclopropane were added. After 12 h the reaction mixture was diluted with dichloromethane and extracted with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 1.45 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8])([O-:3])=[O:2].[NH3:19]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[NH2:19])[C:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1cccnc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N
Solvent: CCO
Product: Nc1ccc(C(=O)c2cccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A suspension of 63 g. (0.24 mol) of 3-(3-nitro-4-chlorobenzoyl)pyridine in 3 liters of a saturated solution of ammonia in ethanol was autoclaved at 100° C. for 24 hours. The mixture was concentrated in vacuo and the resulting residue dissolved in 1.5 liters of warm 5N HCl. The solution was cooled to room temperature and neutralized with concentrated ammonium hydroxide. The resulting product was collected as yellow-orange prisms, mp. 229° -230° C. (dimethylformamide-2-propanol).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1CCN2C(=NCCC2)CC1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([CH3:16])[CH2:22]2)[C:11]=1[CH3:12]
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.00 g, 4.10 mmol) and (R)-tert-butyl 2-methylpiperazine-1-carboxylate and using DBU as a base to give (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: C[C@@H](N(C)C)[C@@H](O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:20]([C:23]1[C:28]([C:29](=[O:31])[CH3:30])=[C:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:26]([CH2:39][CH2:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:22])[CH3:21]>CCOCC>[CH:20]([C:23]1[C:28]([CH:29]([OH:31])[CH3:30])=[C:27]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:26]([CH2:39][CH2:40][CH3:41])=[C:25]([CH:42]([CH3:43])[CH3:44])[N:24]=1)([CH3:22])[CH3:21]
Reactant: CCCc1c(C(C)C)nc(C(C)C)c(C(C)=O)c1-c1ccc(F)cc1
Agent: C[C@H]([C@@H](O)c1ccccc1)N(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92241.4 %

Procedure:
To a solution of (1S,2R)-(+)-N-methylephedrine (31.1 g, 0.174 mol) in ether (208 mL) was added lithium aluminum hydride (1M/diethylether, 1.5 eq., 174 mL) dropwise at 0° C. under argon. The reaction was refluxed for 1.5 h. turning from a clear solution to a white milky solution. The reaction was cooled to room temperature and then −78° C. The intermediate obtained in Step A (39.53g, 0.116 mmol) was dissolved in 400 mL of dry diethyl ether and cooled to 0° C. for a dropwise addition to the reaction mixture (˜2 mL/min., the temperature should not rise above −60° C.). The reaction was kept at −78° C. for 4.0 hours and then allowed to warm overnight. The reaction was quenched at 0° C. with isopropanol (70 mL) and diluted with ether (700 mL), washed with water (4×500 mL), 10% HCl (2×500 mL), brine (2×500 mL) and dried with MgSO4. Filtration and concentration afforded a residue which was filtered through a pad of silica (600 g, 10% diethyl ether/hexane) to give the title compound (97% e.e.) as a white solid (36.67 g, 107 mmol, 92%). 1H NMR (300 MHz, CDCl3): δ 7.11 (m, 4H), 4.67 (dq, J=3.3, 6.6 Hz, 1H), 3.74 (septet, J=6.6 Hz, 1H), 3.20 (septet, J=6.6 Hz, 1H), 2.17 (m, 2 H), 1.61 (d, J=2.9 Hz, 1H), 1.40 (d, J=7.0 Hz, 3H), 1.30 (m, 14H), 0.741 (t, J=7.4 Hz, 3H). FAB-MS: calcd for (C22H30NOF) 343, found 344 (M+H). mp 102-104° C. Rf=0.2 (60% CH2Cl2/hexane).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[F:31][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH:21]3[CH2:26][CH2:25][N:24]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1
Reactant: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(NC2CCNCC2)n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N1CCC(Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.7 %

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (18 mg) and N,N-dimethylformamide (0.36 mL) were added N,N-dimethylglycine (4.8 mg), 1-hydroxybenzotriazole (6.2 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (8.8 mg), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate, and subsequently chloroform:methanol=96:4). Desired fractions were combined and concentrated under reduced pressure. The residue was solidified by the addition of a small amount of diisopropyl ether to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{1-[(dimethylamino)acetyl]piperidin-4-yl}-6-morpholin-4-ylpyrimidin-2-amine (9 mg) as a white powder.
Reaction SMILES: [OH:1][C@H:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].N1C=CN=C1.O>CN(C=O)C>[Si:32]([O:1][C@H:2]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:12][C@H:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:23])[CH:19]=2)[O:14]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C[C@H]1CCc2cc(I)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@@H](COc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 27 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A reaction mixture containing tert-butyl (2S)-2-hydroxy-3-phenoxypropyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 81, 8.625 mmol, 1.0 eq.), tert-butyldimethylsilyl chloride (10.35 mmol, 1.2 eq.), and imidazole (21.5625 mmol, 2.5 eq.) in anhydrous DMF (18 mL) was stirred at 27° C. overnight. The resulting mixture was then cooled to room temperature, poured into water, and extracted with diethyl ether. The organic extract was washed with water, brine, dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=100:5). The product was obtained as a colorless oil in 97% yield. MH+=654.0, retention time (LC-MS)=5.29 min.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][CH2:13][NH:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:16])=[CH:7][CH:6]=1.[OH-].[Na+]>O1CCCC1.CO>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[C:15]([NH:14][CH2:13][C:12]#[C:11][C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)=[O:16]
Reactant: COC(=O)C(=O)c1ccc(C#CCNC(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(C#CCNC(=O)c2ccc3ccccc3c2)cc1
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
A solution of 4-[3-[[(2-naphthalenyl)carbonyl]amino]-1-propynyl]-alpha-oxobenzeneacetic acid methyl ester (0.225 g) in tetrahydrofuran (2 mL) and methanol (1 mL) was treated with 1N sodium hydroxide (1 mL). After five minutes, the reaction mixture was concentrated and the resulting white suspension partitioned between dichloromethane (10 mL) and 1N hydrochloric acid (2 mL). The aqueous layer was diluted with saturated sodium chloride and was extracted with tetrahydrofuran (2×10 mL). The combined extracts were dried (MgSO4) and concentrated to give 0.2 g of a white solid, mp 153°-155° C. Crystallization from dichloromethane-ethyl acetate-hexane gave 0.15 g of 4-[[(2-naphthalenyl)carbonyl]amino]-1-propynyl]-alpha-oxobenzeneacetic acid, mp 156-°158° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13](OC)=[O:14])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].Cl>O1CCCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CO
Yield: 108 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-hydoxy-2-methoxycarbonylpyrrolidine (10 g) in tetrahydrofuran (20 ml) and ethanol (30 ml) was added by portions sodium borohydride (3.30 g) with stirring at 25°-30° C., and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture was added dropwise conc. hydrochloric acid (7.27 ml) with stirring at 0°-2° C. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of tetrahydrofuran (20 ml), ethanol (20 ml) and saturated aqueous sodium chloride (50 ml). The organic layer was evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-hydroxymethylpyrrolidine (9.48 g).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1>C1COCC1.C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:15][C:13]2[CH:12]=[CH:11][C:8]3[N:9]([CH3:10])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:14]=2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)Nc1nc2cc(N)ccc2n1C
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Nc1nc2cc(Nc3ccnc(Cl)n3)ccc2n1C
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a solution of N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine (1.46 g, 7.2 mmol) in THF (7 ml) and ethanol (21 ml) was added NaHCO3 (1.81 g, 21.6 mmol) and 2,4-dichloropyrimidine (2.68 g, 18 mmol) and the reaction was heated to 75° C. After 5 h, the reaction was filtered hot and concentrated to a gray foam. Ether was added and the solid was filtered and dried to give N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine as an off-white solid. N5-(2-chloro-pyrimidin-4-yl)-N2-isopropyl-1-methyl-1H-benzimidazole-2,5-diamine was dissolved in DMF (21 ml) and cesium carbonate (6.84 g, 21 mmol) was added After 15 min, iodomethane (0.70 ml, 11.2 mmol) was added, and the reaction was stirred at rt. After TLC showed the starting material to be consumed, the reaction was diluted with water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried over MgSO4 and concentrated to a red foam. The crude material was purified with silica gel to give the title compound as a white solid (1.10 g, 46% over two steps). 1H NMR (300 MHz, d6-DMSO) δ 7.87 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.11 (1.8 Hz, 1H), 6.82 (dd, J=8.1 and 1.8 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 6.09 (d, J=6.0 Hz, 1H), 4.04 (m, 1H), 3.51 (s, 3H), 3.37 (s, 3H), 1.23 (d, J=6.6 Hz, 6H). MS (ESI) m/z=331 [M+H]+.
Reaction SMILES: C([O:5]OC(C)(C)C)(C)(C)C.[Se](=O)=O.[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH3:35])[CH:29]=[CH:28]3)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.C(Cl)(Cl)Cl>[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[C:30]([CH:35]=[O:5])[CH:29]=[CH:28]3)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: O=[Se]=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)ccc3c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Di-tert-butyl peroxide (1.93 mL, 10.5 mmol) was added to a suspension of Selenium dioxide (2.68 g, 24.1 mmol) in 1,4-Dioxane (24.00 mL, 307.5 mmol). The mixture was stirred for 30 minutes, then 6-(trans-4-tert-Butyl-cyclohexyloxy)-2-methyl-quinoline (3.12 g, 10.5 mmol) was added as a solution in 1,4-Dioxane and the mixture was heated overnight at 50° C. The reaction mixture was then cooled to room temperature, diluted in chloroform and filtered through a pad of celite. The filtrate was washed with water. The layers were separated and the combined organic phase was dried over MgSO4, filtered, concentrated under reduced pressure, adsorbed onto silica gel and purified by flash chromatography (0-30% EtOAc in hexanes) to give the title compound as a pale yellow solid in 20% yield. ESI-MS (M+H+): 312.27.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.C(OCC)C>O1CCCC1.O.ClCCl>[C:13]([O:17][C:18](=[O:19])[NH:20][CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Brc1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCCCC(=O)c1cncnc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Cool a solution of 5-bromopyrimidine (7.63 g, 48.0 mmol) in tetrahydrofuran (375 mL) to −100° C., and add slowly n-butyllithium (2.5 M in hexanes, 17.8 mL, 44.5 mmol), keeping the temperature below −90° C. Stir the reaction for 30 min at −100° C. Cool a solution of 1-(tert-butoxycarbonyl)-2-pyrrolidinone (8.08 g, 43.6 mmol) in tetrahydrofuran (100 mL) to −78° C. and add to the reaction mixture with a cannula. Stir the reaction at −100° C. for 30 min, then add a 2 M solution of hydrogen chloride in diethyl ether (25 mL, 50 mmol). Allow the reaction to warm to room temperature and add dichloromethane (500 mL) and water (500 mL). Separate the layers and extract the aqueous layer with dichloromethane (2×250 mL). Combine the organic portions and wash with brine (400 mL), dry over magnesium sulfate, filter, and evaporate under reduced pressure to afford a crude mixture (10.98 g). Purify by flash chromatography (two stacked 120 g RediSep silica gel columns, 0:100 to 30:70 gradient of [90:10:1 dichloromethane:methanol:concentrated ammonium hydroxide]:dichloromethane) to provide an impure mixture containing the product (5.35 g, ˜35%) which is used without further purification. MS (APCI+): 148 [C13H19N3O3—C5H8O2—H2O+H]+; 1H NMR (300 MHz, CDCl3): δ 9.36 (s, 1H), 9.22 (s, 2H), 4.63 (br s, 1H), 3.19-3.29 (m, 2H), 3.04 (t, J=7.0 Hz, 2H), 1.97 (quintet, J=6.8 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:22]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[NH:25][C:24]([C:34]3[S:35][CH:36]=[CH:37][N:38]=3)=[N:23]2)=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:7]=1.C1C(=O)N([Br:46])C(=O)C1>>[Br:46][CH2:33][C:26]1[NH:25][C:24]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[N:23][CH:22]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:11]=[C:10]([C:18]([F:19])([F:21])[F:20])[CH:9]=2)[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 55 %

Procedure:
Ethyl 4-(5-fluoro-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5.69 g, 10.2 mmol) was reacted with NBS (2.2 g, 12.2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.57 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:4]1)[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[C:21]([NH:23][NH:24][CH:25]([CH3:27])[CH3:26])=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:13]/[C:14]([N:24]([CH:25]([CH3:27])[CH3:26])[NH:23][C:21](=[O:22])[C:20]2[CH:28]=[CH:29][CH:30]=[C:18]([F:17])[CH:19]=2)=[O:16])=[CH:4]1)[CH3:2]
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Reactant: CCn1cc(/C=C/C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(/C=C/C(=O)N(NC(=O)c2cccc(F)c2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-ethyl-1H-indol-3-yl)acrylic acid (180.0 mg, 0.83 mmol), 3-fluoro-N′-isopropylbenzohydrazide (245.3 mg, 1.25 mmol) and HATU (475.3 mg, 1.25 mmol) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.22 ml, 1.25 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) and dried so that white (E)-N′-(3-(1-ethyl-1H-indol-3-yl)acryloyl)-3-fluoro-N′-isopropylbenzohydrazide was obtained (203.0 mg, 62.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[O:38][CH3:39])#[N:28]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:32]5[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[C:30]([O:38][CH3:39])[CH:31]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1cc(B(O)O)ccc1C#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(C#N)c(OC)c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-cyano-3-methoxy-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 6): tR=1.18 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C[O:31][C:32]([CH:34]1[CH2:36][CH2:35]1)=O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:32]([CH:34]3[CH2:36][CH2:35]3)([OH:31])[O:22][N:21]=2)=[CH:9][CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C1CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=NOC(O)(C3CC3)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a mixture consisting of Example 1, Compound B (3.0 g) in anhydrous tetrahydrofuran (14 mL) at −5° C. under a nitrogen atmosphere is added a solution consisting of 1.6 M n-butyllithium in hexanes (12 mL.) The mixture is stirred between −5 and 0° C. for 30 minutes. To the stirring mixture at 0° C. is added a mixture consisting of cyclopropanecarboxylic acid methyl ester (1.3 g) in tetrahydrofuran (7 mL) and the resultant mixture is stirred for two hours. The mixture is raised to room temperature and is stirred for 18 hours. The mixture is then treated with saturated aqueous ammonium chloride (50 mL) and diluted with ethyl acetate (300 mL.) The organic layer is separated and is washed sequentially with an additional portion of saturated aqueous ammonium chloride (50 mL) and brine solution (50 mL.) The organic layer is separated and is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate is purified by flash silica gel column chromatography. Elution with dichloromethane then with a mixture of hexanes-ethyl acetate (4:1 v/v) afforded the synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-cyclopropyl-4-phenyl-4,5-dihydro-isoxazol-5-ol (1.15 g.)