Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])C(O)=O.C([N:25](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])[NH2:25]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)c(C(=O)c2ccnc(Cl)c2)cc1OC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N)c(C(=O)c2ccnc(Cl)c2)cc1OC
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)benzoic acid (70 g) in tetrahydrofuran (1800 ml) is added triethylamine (45.5 ml) at room temperature under nitrogen atmosphere, and thereto is added dropwise ethyl chloroformate (25 ml) at a temperature below -20° C., and the mixture is stirred at -20° C. for 10 minutes. To the reaction mixture is added a 1.38 M aqueous sodium azide solution (500 ml), and the mixture is stirred at room temperature for 1.5 hour, and extracted with ethyl acetate. The extract is washed, dried, and concentrated. The residue is dissolved in toluene (1300 ml), and the mixture is heated under reflux for one hour. To the reaction mixture is added conc. hydrochloric acid (450 ml) under ice-cooling, and the mixture is heated with stirring at 80° C. for one hour. To the reaction mixture is added ice-water, and the mixture is extracted with chloroform. The extract s washed, dried and concentrated. The residue is crystallized from ether to give 3,4-dimethoxy-6-(2-chloroisonicotinoyl)aniline (50.3 g).
Reaction SMILES: I[C:2]1[N:3](C)[CH2:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.[CH2:27]([Mg]Br)C.Br[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:27][C:4]1[NH:5][CH:6]=[C:2]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:3]=1
Reactant: CN1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C=C1I
Reactant: CC[Mg]Br
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2)c[nH]1
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a solution of 4-Iodo-3-methyl-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 3-bromopyridine (1.1 eq) were added to the reaction mixture. Subsequent reaction conditions were performed as in Example 91(b) to provide 3-(2-methyl-1H-imidazol-4-yl)-pyridine (88%) MH+(160).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>CO>[CH2:12]([NH:16][C:1](=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccccc1O
Reactant: CCCCN
Solvent: CO
Product: CCCCNC(=O)c1ccccc1O
Yield: 79 %

Procedure:
10.0 g (65.7 mmol) of methyl salicylate and 33 ml of n-butylamine were dissolved in 100 ml of methanol, followed by heating at reflux for 8 hours while stirring. Methanol was distilled off under reduced pressure, and the residue was acidified by adding an aqueous 2 N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed in turn with water and saturated sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The organic layer was filtered, and the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography (eluant hexane/ethyl acetate=10/1 to 5/1) to obtain 10.0 g (yield: 79%) of salicylic acid n-butylamide as an oily substance. 1H—NMR spectrum data of salicylic acid n-butylamide are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([OH:10])=[C:4]([CH2:11]C)[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([O:10][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: CCc1cc(Br)cc(CC)c1O
Reactant: FC(F)(F)Oc1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1OCCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 78.3 %

Procedure:
To a mixture of 10 g of 4-bromo-2,6-diethylphenol, 13.5 g of l-(3-bromopropyloxy)-4-trifluoromethoxybenzene and 100 ml of N,N-dimethylformamide was added 6.6 g of potassium carbonate, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water, and extracted twice with 200 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 14.8 g of 4-bromo-2-ethyl-6-methyl-1-[3-(4-trifluoromethoxyphenoxy)propyloxy]benzene (76% yield).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30](=[O:37])[CH2:29][CH2:28][C:27]1=[O:38]>>[ClH:21].[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[C:30](=[O:37])[CH2:29][CH2:28][C:27]3=[O:38])[CH2:19][CH2:20]2)[CH:8]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N2CCNCC2)nc(C(C)(C)C)n1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Product: CC(C)(C)c1cc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)nc(C(C)(C)C)n1
Product: Cl

Procedure:
Analogously to Example 3b, reaction of 2,4-di-tert-butyl-6-piperazin-1-ylpyrimidine (1.26 mmol, 0.35 g) with 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione afforded 0.04 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:20]([CH:23]=O)=[CH:21][N:22]=2)[C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2.C(C=O)=O.N.[NH:30]1[CH:34]=[CH:33][N:32]=C1>CO>[NH:30]1[CH:34]=[CH:33][N:32]=[C:23]1[C:20]1[N:8]2[C:9]3[C:14]([N:15]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]2=[N:22][CH:21]=1)=[CH:13][C:12]([C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=3
Reactant: c1c[nH]cn1
Reactant: O=Cc1cnc2c(NCCCO)nc3cc(C(F)(F)F)ccc3n12
Agent: N
Agent: O=CC=O
Solvent: CO
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3ncc[nH]3)cnc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-1-carbaldehyde (35 mg, 0.10 mmol) in methanol (1.2 mL) was added glyoxal (40% in water, 15 μL, 0.10 mmol). The mixture was cooled at 0° C. and NH3 (2M in ethanol, 150 μL, 0.30 mmol) was added. The reaction was stirred at 25° C. under argon overnight. The reaction was followed by TLC that showed small conversion of the starting material in imidazole. The addition of reactants was repeated 4 times in 4 days, until the TLC indicated completion of the reaction. The reaction was concentrated. The crude product was purified twice by preparative TLC (dichloromethane/methanol 9/1) to give the title compound (7 mg, 18%) as a beige powder.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].[C:22]([CH2:24][C:25](OCC)=[O:26])#[N:23].C(=O)([O-])[O-].[K+].[K+].Cl>CCO>[C:22]([C:24]1[C:17]([C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)=[N:9][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:10][C:25]=1[OH:26])#[N:23]
Reactant: CCOC(=O)CC#N
Reactant: N=C(N)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1c(O)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A mixture of benzamidine hydrochloride (16.4 g), 3-nitrobenzaldehyde (15.1 g), ethyl cyanoacetate (11.2 ml) and potassium carbonate (16.6 g) in abs. EtOH (250 ml) was stirred at 60° C. for 8 h. The reaction mixture was cooled to 0° C. in an ice bath. The resulting precipitate was filtered off, washed with abs. EtOH and heated in water (100° C.) until a clear solution was obtained. The solution was cooled to 50° C., acidified to pH 2 by adding 2N aq. HCl and cooled to 0° C. in an ice bath. The resulting precipitate was filtered off and washed with ice water. Residual water was removed by coevaporation with 1,4-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([NH2:8])[CH:7]=1.[CH3:10][N:11]([CH2:13][C:14](O)=[O:15])[CH3:12].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:8][C:6]1[CH:5]=[C:4]([NH:9][C:14](=[O:15])[CH2:13][N:11]([CH3:12])[CH3:10])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1cc(N)cc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-benzene-1,3-diamine (3 g, 21 mmol) and dimethylamino-acetic acid (2.2 g, 21 mmol) in CH2Cl2 (300 mL) was added EDC (5 g, 25 mmol), HOBt (2.9 g, 21 mmol), and DIEA (5 mL). The reaction mixture was stirred at RT for overnight. Solvent was removed in vacuum and the residue was purified through flash chromatography on silica gel (0-8% MeOH in EtOAc) to give the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:42])[C@:10]3([C@@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@H:13]([C:23]([NH:25][C:26]4[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=4)=[O:24])[NH:12][C@H:11]3[CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:5]2=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH4+:76].[Cl-:77]>CN(C=O)C.CCOC(C)=O>[C:32]([CH2:31][O:30][C:29]1[CH:35]=[CH:36][C:26]([NH:25][C:23]([CH:13]2[NH:12][CH:11]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:10]3([C:5]4[C:6](=[CH:7][C:2]([Cl:77])=[CH:3][CH:4]=4)[NH:8][C:9]3=[O:42])[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])=[O:24])=[CH:27][CH:28]=1)(=[O:33])[NH2:76]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(OCC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Reactant: [NH4+]
Reactant: [Cl-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCC(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A mixture of rac-(4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenoxy)-acetic acid prepared in Example 206 (23 mg, 0.037 mmol), N,N-diisopropylethylamine (33 mg, 0.258 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (Chem-Impex, 24 mg, 0.062 mmol) in DMF (4 mL) was stirred for 20 min before NH4Cl (6 mg, 0.099 mmol) was added. The mixture was stirred for 0.5 h and diluted with EtOAc (70 mL), washed with water (10 mL), brine (15 mL) and concentrated. The crude product was purified by flash chromatography (EtOAc/hexane, 25/75 to 95/5) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoylmethoxy-phenyl)-amide as a white solid (9 mg, 40%). MS (ES+) m/z [(M+H)+]: 613
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[NH:5]C(=O)OCC1C=CC=CC=1.C(N(CC)CC)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl.[Pd]>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:5][C@@H:3]2[CH2:4][C@H:2]2[CH3:1])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C[C@@H]1C[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H]1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of benzyl ((1R,2R)-2-methylcyclopropyl)carbamate (1.68 g, 8.2 mmol) in DCM (55 mL) was charged with 10 wt % Pd/C, then degassed and charged with hydrogen (50 PSI). The reaction was complete after 30 min and so was filtered over celite, rinsing with DCM (15 mL). The liquor was cooled to 0° C., and treated with triethylamine (3.43 mL, 24.6 mmol) and 4-bromobenzene-1-sulfonyl chloride (2.20 g, 8.61 mmol). The cold bath was removed and the reaction was stirred for 1 h. At completion, the reaction was washed with 0.5 M aq. HCl (2×20 mL) and brine (20 mL), dried over MgSO4 and concentrated to provide 4-bromo-N-((1R,2R)-2-methylcyclopropyl)benzenesulfonamide (2.06 g, 87% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.74-7.80 (m, 1H), 7.66-7.72 (m, 1H), 4.90 (br. s., 1H), 1.94 (dt, J=3.5, 1.8 Hz, 1H), 1.41 (t, J=7.3 Hz, 1H), 0.89-1.01 (m, 3H), 0.70-0.81 (m, 1H), 0.35-0.45 (m, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]([CH3:26])[C:17]3[CH:23]=[C:22]([CH:24]=O)[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:12]=[CH:13][CH:14]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][NH2:34].C([BH3-])#N.[Na+].[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO.C(O)(=O)C>[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44][N:34]([CH2:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[N:16]([CH3:26])[C:17]=2[CH:23]=1)[CH2:33][C:29]1[N:28]([CH3:27])[CH:32]=[CH:31][N:30]=1
Reactant: CCCN(CCC)Cc1cccc(-c2nc3ccc(C=O)cc3n2C)c1
Reactant: Cn1ccnc1CN
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cccc(-c2nc3ccc(CN(Cc4ncc[nH]4)Cc4nccn4C)cc3n2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
The compound (31.2 mg) obtained in Example 18-6 was dissolved in methanol (1.0 ml) and added with acetic acid (30 μl) and 1-methyl-2-aminomethylimidazole (15.4 mg), and the whole was stirred at room temperature for 2 hours. Sodium cyanoborohydride (22.7 mg) was added thereto and the whole was stirred at room temperature for 15 hours. Furthermore, 2-imidazole carboxaldehyde (18.0 mg) was added thereto and the whole was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining a hydrochloride (25.6 mg) of the subject compound as a white solid.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][N+:17]([O-])=O)=[CH:11][C:10]=1[F:20].CO>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][C:10]=1[F:20]
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
Lithium borohydride (2.16 g, 99 mmol) was suspended in THF (50 ml). Trimethylchlorosilane (21.6 g, 198 mmol) was added dropwise. A solution of 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (5.0 g, 24.8 mmol) in THF (20 ml) was added dropwise. Strong gas evolution and foam formation was observed. The white suspension was stirred at RT for 3 days. Carefully MeOH (80 ml) was added. The solvents were removed in vacuo and the residue was purified by flash column chromatography (CH2Cl2/MeOH+5% aq. NH4OH 4:1) to yield 2-(4-chloro-3-fluoro-phenyl)-ethylamine (3.1 g, 73%) as a white solid. MS (ISP) 174.1 (M+H)+. 1HNMR (DMSO-d, 300 MHz): δ 2.92 (t, J=4.8 Hz, 2H), 3.02 (t, J=6.3 Hz, 2H), 7.15 (dd, J=6.0 and 1.2 Hz, 1H), 7.38 (dd, J=1.2 and 7.8 Hz), 7.53 (t, J=6.3 Hz, 1H), 7.93 (br, 2H).
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH:14]([O:19]C(=O)NC(C2C=CC=CC=2)C)[C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C=CC=CC=1.[NH4+].[Cl-]>[O:1]([C:8]1[N:13]=[C:12]([C@@H:14]([C:15]([F:18])([F:16])[F:17])[OH:19])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(NC(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F)c1ccccc1
Agent: Cl[SiH](Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O[C@@H](c1cccc(Oc2ccccc2)n1)C(F)(F)F
Yield: 81 %

Procedure:
A stirred solution of 1.28 g (3.08 mmol) of the [S-(R*,S*)] carbamate from Step A, 0.52 ml (380 mg, 3.7 mmol) of triethylamine, and 0.34 ml (460 mg, 3.4 mmol) of trichlorosilane in 12 ml of toluene under a nitrogen atmosphere was heated at 60° C. for 2 hours. The reaction mixture was then diluted with 50 ml of saturated aqueous NH4Cl and extracted with ether (3×25 ml). After being dried (MgSO4), the combined organic extracts were concentrated under reduced pressure and chromatography of the residue on 20 g of silica gel with 1:15 ethyl acetate/hexane afforded 667 mg (81%) of the title compound as a white solid melting at 51.5°-53.5° C.: [α]D22 =+2.0° (CHCl3, c 1.00) and [α]36522 =+4.8° (CHCl3, c 1.00). The spectral and chromatographic properties of this material were identical to those of racemic material prepared in Example 1 (Step C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:17][Si](CC)(CC)CC)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C.[C:37]1([CH2:43][CH2:44][C:45](Cl)=[O:46])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:9]([F:11])([F:12])[F:10])[C:13]([F:14])([F:15])[F:16])[CH:5]=[CH:4][C:3]=1[N:25]([CH2:26][CH3:27])[C:45](=[O:46])[CH2:44][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(=O)CCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 67.1 %

Procedure:
A solution of 100 mg (0.23 mmol) of [2-chloro-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-amine in CH2Cl2 was treated with 0.08 mL (0.46 mmol) of DIPEA and 0.07 mL (0.46 mmol) of 3-phenylpropionylchloride. The mixture was stirred at RT for 10 hours and treated with 0.4 mL of a 1 M TBAF-solution in THF. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 4:1 yielded 70 mg (67%) of N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamide, light yellow oil, MS: 454 (MH+, 1Cl).
Reaction SMILES: [Cl:1][CH:2]([CH2:13]Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.O>[Cl:1][C:2](=[CH2:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(Cl)cc1)C(Cl)CCl
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=C(Cl)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 51.1 %

Procedure:
To a stirred solution of 17.0 grams (0.067 mole) of 2,3-dichloro-N-(4-chlorophenyl)propanamide (Step A product) in 300 ml of toluene was added dropwise 11.3 grams (0.074 mole) of 1,8-diazabicyclo[5.4.0]-undec-7-ene in 100 ml of toluene. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was diluted with distilled water and transferred to a separatory funnel. The organic layer was separated and washed twice with water and twice with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from methylcyclohexane using silica gel as a decolorant to give 7.4 grams of 2-chloro-N-(4-chlorophenyl)-2-propenamide; mp 105°-106.5°.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][C:6]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[CH3:7])C.[OH-].[Na+].O>CO>[SH:3][CH2:4][CH2:5][C:6]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CC(=O)SCCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CCS)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of S-3-(benzyloxycarbonylamino)-3-methylbutyl ethanethioate (10.60 g, 35.88 mmol, prepared as described in WO 2008/083347) in methanol (100 ml) was added 5.0 M NaOH in H2O (15 ml, 75 mmol). The solution was stirred for 2 hour, concentrated in vacuo, and the residue suspended in ethyl acetate (300 ml), washed with 3×100 ml 5% NaHSO4, 1×100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The reaction product was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.C(OCC)C.[NH3:30]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[S:6][C:5]=1[C:3]([NH2:30])=[O:2])[CH3:12]
Reactant: COC(=O)c1sc(-n2ccnc2)cc1OC(C)c1ccccc1Cl
Reactant: N
Solvent: CCOCC
Solvent: CO
Product: CC(Oc1cc(-n2ccnc2)sc1C(N)=O)c1ccccc1Cl
Temperature: 80 °C
Yield: 64 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-imidazol-1-yl-thiophene-2-carboxylic acid methyl ester (265 mg, 0.73 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 80° C. in a pressure tube for 3 days. The solvent was removed in vacuo and the product isolated by column chromatography (2% to 5% MeOH/EtOAc) followed by trituration from diethyl ether to give the title compound as cream powder (163 mg, 0.47 mmol, 64%); 1H NMR (400 MHz, d-6 DMSO) δ 1.71 (3H, d), 5.89 (1H, q), 7.03 (1H, br s), 7.11 (1H, s), 7.23 (1H, s), 7.36-7.42 (2H, m), 7.49 (1H, dd), 7.63 (1H d), 7.66 (1H, dd), 7.78 (1H, br s), 8.17 (1H, s)