Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[CH3:19][S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].C(N(CC)C(C)C)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH2:24][CH2:25]2)[CH:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1nc(Cl)cc(N2CCN(S(C)(=O)=O)CC2)n1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 68.9 %

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-chlorophenyl)ethyl]pyrimidine-2-amine and 119 mg of 1-methanesulfonyl piperazine were dissolved in 3 ml of 1-butanol, and 0.23 ml of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 60° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 196 mg of the objective compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1[CH:56]=[CH:55][C:45]([CH2:46][NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(F)=C([C@@H]2[C@](C3C=CC(Cl)=CC=3F)(C#N)[C@H](CC(C)(C)C)N[C@H]2C(O)=O)C=CC=1>ClCCl>[C:50]([O:49][C:48](=[O:54])[NH:47][CH2:46][C:45]1[CH:44]=[CH:43][C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[CH:56][CH:55]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CNC(=O)OC(C)(C)C)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 0.5 h
Yield: 288.1 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) in dichloromethane (5 ml) were added N,N-DIISOPROPYLETHYLAMINE (33 mg) and tert-butyl 4-aminobenzylcarbamate (57.0 mg, 0.256 mmol, Array) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (29 mg, Chem-Impex) and the reaction mixture was stirred for 30 min; Another portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg) was added and stirring was continued for 30 min before the addition of the last portion of N,N-DIISOPROPYLETHYLAMINE (33 mg), (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (20.0 mg) and HATU (29 mg). 1 hr later, the reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give rac-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzyl)-carbamic acid tert-butyl ester as off-white solid (82.8 mg, 96%). HRMS (ES+) m/z Calcd for C35H39Cl2F2N4O3 [(M+H)+]: 671.2362. found: 671.2360.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:18])=[O:11])=[CH:7][CH:8]=1
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)cc1

Procedure:
A solution of 25.3 g (152 ml) of (4-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of conc. sulfuric acid and heated under reflux for 16 h. The cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[CH:25]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:5][C:3]#[N:4])[CH:27]=[CH:28][C:29]=1[N+:30]([O-:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (2) (4.18 g, 25 mmol) was dissolved in anhydrous DMF (100 mL). To this solution was added benzyl bromide (3.27 mL, 27.5 mmol) and potassium carbonate (3.8 g, 27.5 mmol). The reaction mixture was stirred at room temperature for 18 h, filtered and evaporated. The residue was taken up into ethyl acetate (250 mL) and water (250 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated leaving 3-benzyloxy-4-nitro-benzaldehyde (3) as an orange solid (6.31 g, 98% yield): 1HNMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.45 (m, 5H), 5.40 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 192.4, 151.2, 143.5, 139.9, 135.9, 128.9, 128.6, 127.9, 125.9, 122.7, 115.5, 71.1. To a suspension of sodium hydride (0.29 g, 12 mmol) in anhydrous THF (25 mL) at 0° C. was added via dropping funnel diethyl cyanomethylphosphonate (4) (1.94 mL, 12 mmol) in anhydrous THF (5 mL) followed by 3-benzyloxy-4-nitro-benzaldehyde (3) (2.6 g, 10 mmol) in anhydrous THF (30 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solvent was evaporated and the residue was taken up into ethyl acetate (50 mL) and water (25 mL). The organic phase was washed with brine (25 mL), dried over MgSO4, filtered and evaporated leaving 3-(3-benzyloxy-4-nitro-phenyl)-acrylonitrile (5) as an orange-red solid (0.28 g, 100% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.04 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J=16.6 Hz, 1H), 7.45 (m, 6H), 6.72 (d, J=16.6 Hz, 1H), 5.33 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 151.4, 148.9, 140.8, 139.5, 136.0, 128.9, 128.6, 128.0, 126.0, 120.7, 118.5, 114.5, 101.3, 71.1; MS calculated for C16H12N2O3 (M)+: 280. found 280. 3-(3-Benzyloxy-4-nitro-phenyl)-(5) (0.28 g, 1.0 mmol) was dissolved in anhydrous methanol (20 mL). To this solution was added 10% palladium on carbon (56 mg, 20% wt) under a blanket of carbon dioxide. The hydrogenation was carried out under 60 psi of hydrogen at room temperature for 4 h, filtered through a pad of Celite and evaporated to yield an orange oil. This oil was stirred in hexane, decanted and vacuum dried leaving 3-(4-amino-3-hydroxy-phenyl)-propionitrile (1) as an orange solid (0.58 g, 100% yield): 1HNMR (400 MHz, DMSO-d6) δ 8.81 (bs, 1H), 6.31 (m, 3H), 4.30 (bs 2H), 3.18 (s, 2H), 2.35 (s, 2H); 13CNMR (400 MHz, DMSO-d6) δ 144.3, 135.5, 127.1, 120.8, 119.6, 114.9, 30.5, 19.2; MS calculated for C9H10N2O (M)+: 162. found 162.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 100 °C

Procedure:
To a 500 mL round-bottom flask was added tert-butyl 4′-methylbiphenyl-2-carboxylate (7.04 g, 26.23 mmol), NBS (5.14 g, 28.85 mmol), AIBN (0.43 g, 2.62 mmol) and CCl4 (200 mL). The reaction mixture was refluxed for 2 h at 100° C. The completion of the reaction was monitored by analytical HPLC. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0→30%) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[Br:16].[N:17]([O-])=O.[Na+]>Cl.O>[Br:16][C:3]1[CH:4]=[C:5]([C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][NH2:17]
Reactant: O=N[O-]
Reactant: CCOC(=O)C(C)(C)c1ccc(N)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C)(C)c1ccc(NN)c(Br)c1
Reaction time: 0.5 h

Procedure:
A solution of 0.091 g of ethyl 2-(4-amino-3-bromophenyl)-2-methylpropionate in 0.32 mL of concentrated hydrochloric acid was stirred at -10 to -5° C. in an ice-acetone bath as a solution of 0.023 g of sodium nitrite in 0.20 mL of water was added dropwise over about 15 minutes. Stirring was continued at this temperature for an additional 30 minutes. Next, the supernatant was removed by syringe and added dropwise over 10 minutes to a solution of 0.36 g of stannous chloride dihydrate in 0.25 mL of concentrated hydrochloric acid stirred under nitrogen in an ice-acetone bath. The addition was carried out at such a rate that the internal temperature remained at about -5° C. A gummy material separated during the addition. After completion of the addition, stirring was continued at -10 to -5° C. for 1 hour. The mixture was then diluted with 60 mL ethyl acetate and washed with sodium carbonate. The organic layer was washed with water and brine then dried over magnesium sulfate. Concentration in vacuo gave the crude title compound.
Reaction SMILES: [O:1]([C@H:19]1[CH2:53][C@H:52]([O:54][C:55]([O:57][CH3:58])=[O:56])[C@@:51]2([CH3:59])[C:21](=[CH:22][CH:23]=[C:24]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:60])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C@H:29]([CH3:46])[CH:30]=[CH:31][C@@H:32]2[CH2:36][CH2:35][CH2:34][C:33]2([O:38][Si](CC)(CC)CC)[CH3:37])[CH2:20]1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:58][O:57][C:55]([O:54][C@@H:52]1[C@@:51]2([CH3:59])[C:21](=[CH:22][CH:23]=[C:24]3[C@@H:50]2[CH2:49][CH2:48][C@@:47]2([CH3:60])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C@H:29]([CH3:46])[CH:30]=[CH:31][C@@H:32]2[CH2:36][CH2:35][CH2:34][C:33]2([OH:38])[CH3:37])[CH2:20][C@@H:19]([OH:1])[CH2:53]1)=[O:56]
Reactant: CC[Si](CC)(CC)OC1(C)CCC[C@H]1C=C[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C[C@H](OC(=O)OC)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)O[C@H]1C[C@H](O)CC2=CC=C3[C@@H]4CC[C@H]([C@H](C)C=C[C@@H]5CCCC5(C)O)[C@@]4(C)CC[C@@H]3[C@]21C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
To a solution 13a (719 mg, 0.845 mmol) in THF (15 mL) was added a solution of tetra-n-butylammonium fluoride (1.0M in THF, 2.5 mL), and the mixture was stirred at ambient temperature for 1.5 h. A solution of tetra-n-butylammonium fluoride (1.0M in THF, 2.5 mL) was added twice to the mixture, and the mixture was stirred at ambient temperature overnight. The mixture was poured into cold NaHCO3 solution, and the mixture was extracted with EtOAc. The combined organic layers were washed with NaCl solution, and dried over Na2SO4. Filtration and concentration gave 0.97 g of a crude product, which was purified by column chromatography (SiO2 gel 30 g, EtOAc in n-hexane 20-50%), to give 373 mg (88.5%) of 14a, as white solids.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:25]4)=[C:20]([F:35])[CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C@H:24]4[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29]4)=[C:20]([F:35])[CH:19]=3)=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=Cc4ccc(OCC)cc4)cc3)cc2F)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(CCc4ccc(OCC)cc4)cc3)cc2F)CC1

Procedure:
A solution of 1.9 g of 1-(p-ethoxyphenyl)-2-[4'-(trans-4-n-pentylcyclohexyl)-3'-fluorobiphenyl-4-yl]ethene [obtained by Heck coupling of 4-ethoxystyrene with 4'-(trans-4-n-pentylcyclohexyl)-3'-fluoro-4-bromobiphenyl] in 50 ml of tetrahydrofuran is hydrogenated in the presence of Pd/C. Customary work-up gives 1-(p-ethoxyphenyl)-2-[4'-(trans-4-n-pentylcyclohexyl)-3'-fluorobiphenyl-4-yl)ethane.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cccc1CBr
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of methyl 2-chloro-6-methylbenzoate (3.0 g, 16.2 mmol), N-bromosuccinimide (3.0 g, 17.0 mmol), and benzoyl peroxide (catalytic) in anhydrous carbon tetrachloride (50 mL) was stirred at reflux overnight. Dichloromethane (50 mL) was added after cooling to room temperature. The mixture was extracted with 1 N NaOH (2×100 mL). The organic layer was recovered, dried over MgSO4, filtered, and evaporated, and the residue was dried in vacuo, affording methyl 2-(bromomethyl)-6-chlorobenzoate (4.06 g, 95% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[N:5]=[C:4]([NH:20][CH3:21])[N:3]=1>C(O)(=O)C.ClCCl.[Fe]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([NH:20][CH3:21])[N:5]=2)(=[O:9])=[O:10])=[CH:12][CH:13]=1
Reactant: CNc1nc(Br)cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)n1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNc1nc(Br)cc(S(=O)(=O)c2ccc(N)cc2)n1
Temperature: 60 °C
Yield: 66.2 %

Procedure:
0.40 g (0.0011 mol) of [4-bromo-6-(4-nitrobenzenesulphonyl)-pyrimidin-2-yl]-methylamine was suspended in 20 ml of acetic acid, treated with 0.40 g of iron powder and heated to 60° C. for about 4 hrs. Thereafter, the solvent was removed, the residue was digested in water and the precipitate which thereby separated was isolated. This was dissolved in dichloromethane and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:2 and subsequently dried in a high vacuum. There was obtained 0.25 g (68%) of [4-(4-amino-benzenesulphonyl)-6-bromopyrimidin-2-yl]-methylamine as a yellow solid; m.p.: >250° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH:26]([C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:32]2)=[CH:38][CH:37]=1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)nn1-c1ccccc1

Procedure:
128 mg (71%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (95 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)([O:15][CH:16]([F:22])[C:17]([O:19]CC)=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].[Li+].[OH-]>C1COCC1.O.CO>[C:1]([C:3]1[CH:36]=[CH:35][C:6]2[NH:7][C:8]([C:10]([C:23]3[C:31]([O:32][CH3:33])=[CH:30][C:29]([CH3:34])=[C:28]4[C:24]=3[CH:25]=[CH:26][NH:27]4)([O:15][CH:16]([F:22])[C:17]([OH:19])=[O:18])[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C(F)OC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(OC(F)C(=O)O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (±)-ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)-2-fluoroacetate (Example 35-F) (60 mg, 0.119 mmol) in THF (1.0 mL), water (1.0 mL) and MeOH (0.20 mL) was added LiOH (25 mg, 0.595 mmol) and this mixture was stirred for 16 hr at room temperature. The reaction was partitioned between EtOAc and cold 1N HCl solution and the layers separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was purified with FCC eluting with dichloromethane/MeOH (0-10%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.03 (br.s., 1H) 10.96 (br.s, 1H), 8.17-8.34 (br.s., 1H) 7.78-7.97 (br.s., 1H) 7.53-7.59 (m, 1H) 7.19-7.29 (m, 1H) 7.00-7.02 (br.s, 1H) 6.74-6.79 (br.s., 1H), 6.65 (s., 1H), 4.87-5.37 (m, 1H) 3.01 (s, 3H) 2.46 (s, 3H). HRMS calcd. for C22H16F4N4O4 (M+H)+ 477.1141. found 477.1154.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: FCCCCBr
Reactant: FC(F)(F)Oc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: FCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1

Procedure:
3.1 g (20 mmol) of fluorobutyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.4 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-4-trifluoromethoxybiphenyl to obtain 4'-(trans-4-(4-fluorobutyl)-4-silacyclohexyl)-4-trifluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 5.8 g of the trans isomers (yield 71%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl>N1C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][CH:14]=[C:5]([S:2](=[O:4])(=[O:3])[NH:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:6]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 3-(chlorosulfonyl)benzoate (5.0 g, 21.31 mmol) in pyridine (50 ml), was added dropwise a solution of tert-butyl 3-aminopropanoate hydrochloride (5.11 g, 23.44 mmol) in pyridine (10 ml) at 0° C. The resulting solution was allowed to warm to RT and stirred for 4 h. 1N HCl (50 ml) was added to the reaction mixture and the aqueous phase was separated and extracted with DCM (3×20 ml). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to afford a viscous amber oil. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, s), 8.27 (1H, d), 8.08 (1H, d), 7.63 (1H, t) 5.38 (1H, t), 3.97 (3H, s), 3.20 (2H, m), 2.48 (2H, t), 1.43 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20](OCC1C=CC=CC=1)(=[O:22])[CH3:21]>C1COCC1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([CH2:1][C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OCc1ccccc1
Reactant: CSc1nccc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of 4-Methyl-2-(methylthio)pyrimidine (1) (3 g, 21.40 mmol) in THF (35.7 mL) at −10° C. was added LHMDS (32.1 mL, 32.1 mmol, 1M in THF). The resulting reaction was warmed to rt and stirred for 15 minutes, after which time the reaction was cooled back to −10° C. and Benzyl Acetate (3.21 mL, 23.54 mmol) was added. The reaction was then warmed to rt and stirred for 1 hour, after which time complete conversion to product was observed by LCMS. TLC after 1 hour still showed the presence of some starting material and the reaction was continued stifling for an additional hour. After this time there was no change in TLC and the reaction was worked up. The reaction was quenched by slow addition of saturated ammonium chloride and the volatile solvent evaporated. The mixture was then diluted with EtOAc and water. The organic layer was then washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 8-66% EtOAc in Heptane to give the desired product as a yellow liquid (1.93 g, 50%). MS (ES+): m/z=183.1 (100) [MH+]. HPLC: tR=0.91 minute over 3 minutes. Purity: 76% [HPLC (LC/MS) at 220 nm].