Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClC(Cl)C>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1
Reactant: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1N2C1CCNCC1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1N2C1CCN(Cc2ncc[nH]2)CC1
Temperature: 80 °C
Yield: 6.5 %

Procedure:
To a solution of the TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a (40.7 mg; 0.091 mmol) and 1H-imidazole-2-carboxaldehyde (35 mg; 0.36 mmol) in dichloroethane (5 mL) was added tetramethylammonium triacetoxyborohydride (36 mg; 0.14 mmol). The mixture was heated to 80° C. for 15 hr in a sealed tube. The mixture was allowed to cool to rt, and the solvent was removed via evaporation. The residue was purified via reverse phase HPLC (eluent gradient: 15 to 40% acetonitrile in water containing 0.1% TFA) to yield 3.1 mg (6.5%) of 10-[1-(1H-imidazol-2-ylmethyl)-piperidin-4-yl]-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 7a as a TFA salt. MS m/z (MH+) 414.9.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[S:13][C:14]([CH3:16])=[CH:15][C:8]=2[C:7]1=[O:17])C.Cl.O>O1CCCC1>[CH3:16][C:14]1[S:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH:4]=[O:3])[C:7](=[O:17])[C:8]=2[CH:15]=1
Reactant: CCOC(CN1CCCc2sc(C)cc2C1=O)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2c(s1)CCCN(CC=O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 5.0 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 70 ml of dimethylformamide was added 4.4 g of potassium t-butoxide with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. To the mixture was added 7.1 g of bromoacetaldehyde (2-bromo-1,1-diethoxyethane) dropwise under ice-cooling. The mixture was stirred at 60° C. for 5 hours and poured into chilled water and then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was chromatographed on a silica gel using chloroform as an eluent to give 2.5 g of 5-(2,2-diethoxyethyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]-azepin-4-one as a pale yellow oil. To the solution of 2.1 g of 5-(2,2-diethoxyethyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 30 ml of tetrahydrofuran was added 10 ml of 10% hydrochloric acid solution, and the mixture was stirred for 2 hours at room temperature, poured into water and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.39 g of 2-methyl-5,6,7,8-tetrahydro-4-oxo-4H-thieno[3,2-c]azepin-5-acetoaldehyde. To the solution of 1.39 g of 2-methyl-5,6,7,8-tetrahydro-4-oxo-4H-thieno[3,2-c]azepin-5-acetoaldehyde in 20 ml of ethanol were added 2.4 g of 4-[bis(4-fluorophenyl)methylene]piperidine and 0.39 g of sodium cyanoborohydride. The mixture was stirred for 2.5 hours at room temperature, poured into chilled water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting orange oil was chromatographed on a silica gel using chloroform as an eluent and the eluate was concentrated under reduced pressure. The resulting residue was dissolved in ethanol and to the solution of the residue was added ethanolic hydrochloric acid to produce its hydrochloride. The precipitated crystals were collected by filtration and recrystallized from methanol to give 5-[2-(4-(bis(4-fluorophenyl)methylene)piperidino)ethyl]-2-methyl-5,6,7,8-tetrahydro-4H -thieno[3,2-c]azepin-4-one hydrochloride as white crystals, melting at 228°-229° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:27](Cl)(=[O:36])[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1.ClCCl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:27](=[O:36])[CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:13]([O:18][CH3:19])[CH:12]=3)=[CH:9][N:8]([CH:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of 4-[4-amino-5-(4-amino-3-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (0.8 g, 2.3 mmol) in pyridine (13 mL) and dichloromethane (32 mL) at 0° C. was added hydrocinnamoylchloride (0.57 g, 3.4 mmol) in dichloromethane (5 mL) under nitrogen. The solution was stirred at 0° C. for 2 hr, warmed to room temperature and quenched by addition of saturated aqueous citric acid solution (50 mL). The organic layer was washed with saturated aqueous citric acid solution (2×50 mL), dried (sodium sulphate), filtered and evaporated to leave N1-{4-[4-amino-7-(4-oxocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-methoxyphenyl}-3-phenylpropanamide (1.0 g, 92% crude) as a brown foam. 1H NMR (d6 DMSO, 400 MHz):9.17(1H, s), 8.18(1H, s), 8.06(1H, d), 7.51(1H, s), 7.18-7.29(6H, m), 7.09(1H, m), 6.99(1H, d), 6.21(2H, bs), 5.18 (1H, m), 3.88(3H, s), 1.99-2.93(12H, m). HPLC: (5 to 95% CH3CN in 0.1 N aqueous ammonium acetate over 20 min.) tr=14.48 min, 92.2%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]#[N:30])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[OH-:35].[Na+]>O>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[O:27][CH2:28][C:29]([NH2:30])=[O:35])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: [OH-]
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc2CC1
Agent: [Na+]
Solvent: O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC(N)=O)n3)cc2CC1
Yield: 20.1 %

Procedure:
(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-phenoxy)-acetonitrile (0.100 g, 0.2 mmol) and NaOH (1 mL, 0.05 mol) (50% solution) and water (1 mL) were heated at 100° C. for 16 h. The resulting ppt was filtered from the reaction mixture. Product was isolated as a white solid (20 mg, 19%), MP=123-125. LCMS 497.22 (M+H), HPLC purity 99+%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.66 (m, 1H), 9.38 (s 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.90 d, 1H), 7.50 (m, 2H), 7.46 (s, 1H), 7.31 (d, 1H), 7.16 (m, 1H), 7.02 (m, 3H), 4.55 (s, 2H), 3.73 (m, 2H), 3.64 (m, 2H), 3.38 (m, 2H), 3.34 (s, 3H), 3.15-2.88 (m, 5H), 2.68 (m, 1H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.[CH3:13][C:14]([CH3:24])([C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:15]>O1CCCC1.CCCCCC>[CH3:15][C:14]([CH3:24])([C:16]([OH:23])([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH3:13]
Reactant: C#CCCCCC
Reactant: CC(C)(C)C(=O)Cn1cncn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a solution of hept-1-yne (3.9 g, 0.041 mol) in dry tetrahydrofuran (30 mls) at -70° C. under nitrogen was added n-butyl lithium (30 mls of a 1.55M solution in hexane) and the resulting mixture stirred for 1 hour. To this mixture was added a solution of 2,2-dimethyl-4-(1,2,-4-triazol-1-yl)-butane-3-one (6.8 g, 0.041 mol) in dry tetrahydrofuran (50 mls), and the resulting mixture was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous HCl (1.0M). The aqueous was further extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate solution and brine, dried (anhydrous MgSO4) and then concentrated in-vacuo to give a yellow oil. Chromatography on silica using gradient elution (diethyl ether 20-80% in petrol) gave the title compound (2.87 g) as a yellow crystalline solid melting point 76°-78° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([NH:18]C(C)(C)C)=O)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]#[N:18])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncccc1CCc1cccc(Cl)c1

Procedure:
Heat a solution of the title compound of Preparative Example 1B, 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide (175 g, 0.554 mole) in phosphorous oxychloride (525 mL, 863 g, 5.63 mole) and reflux for 3 hours. Determine completion of the reaction by thin layer chromatography. Remove any excess phosphorous oxychloride by distillation at reduced pressure and quench the reaction in a mixture of water and isopropanol. Bring to pH 5-7 by adding 50% aqueous NaOH solution while maintaining the temperature below 30° C. Filter the crystalline slurry of crude product and wash with water. Purify the crude product by slurrying the wet cake in hot isopropanol, and cool to 0°-5° C. Filter the product, wash with hexane and dry at a temperature below 50° C. to yield the title compound. (Yield: 118 g (HPLC purity 95.7%), m.p. 72° C.-73° C., 89.4% of theory).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.O>[CH2:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:22][C:21]3[CH:23]=[CH:24][C:18]([O:17][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:20][C:19]=1[C:25]([F:26])([F:27])[F:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Solvent: CO
Solvent: O
Product: Fc1cnc(Nc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)nc1Nc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 4-benzyloxy-3-trifluoromethylaniline (481 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 9:1) to give N2,N4-bis(4-benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.51 (s, 1H), 8.05 (s, 1H), 7.38-7.64 (m, 5H), 6.94-7.14 (m, 11H), 6.44-6.73 (m, 4H), 4.84 (s, 2H), 4.79 (s, 2H); LCMS purity: 94.7%; MS (m/e): 628.93 (M+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:19]O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:13][CH3:19])=[O:12])([O-:3])=[O:2]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
A mixture of 2-nitrophenylacetic acid (300 g, 1.66 mol) and sulfuric acid (d=1.84 g/ml, 6 ml) in methanol (61) was heated under reflux for 21 h. The solvent was removed in vacuo and the residue dissolved in dichloromethane (21). The dichloromethane solution was then washed with saturated aqueous sodium carbonate solution (600 ml), brine (500 ml), dried (MgSO4), filtered and then evaporated in vacuo.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:24]=[CH:23][C:14]([C:15]([CH:17]([CH3:22])[CH2:18][C:19](O)=[O:20])=O)=[CH:13][CH:12]=2)[CH:7]=[CH:6]1>O>[CH3:22][CH:17]1[C:15]([C:14]2[CH:23]=[CH:24][C:11]([N:8]3[CH:9]=[CH:10][C:5](=[O:4])[CH:6]=[CH:7]3)=[CH:12][CH:13]=2)=[N:3][NH:2][C:19](=[O:20])[CH2:18]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2ccc(=O)cc2)cc1
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccc(=O)cc2)cc1

Procedure:
Hydrazine hydrate (1.8 g) was added to a suspension of 3-[4-(4-oxo-1,4-dihydropyridin-1-yl)benzoyl]-butanoic acid (5 g) in water (60 ml). The resulting solution was stirred under reflux for 2 hours and cooled to afford the title compound as a pale yellow solid, 4.45 g. m.p. 255-258° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:40](O)(=[O:43])[CH2:41][OH:42].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:41](=[O:42])[CH2:40][OH:43])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)CO
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CO)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Temperature: 23 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
To the solution of the product of Example 345 (0.0226 g, 0.048 mmol) in N,N-dimethylformamide (0.5 mL) was added triethylamine (0.020 mL, 0.145 mmol), 4-(dimethylamino)pyridine (0.018 g, 0.145 mmol), glycolic acid (0.011 g, 0.145 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.028 g, 0.145 mmol). The mixture was stirred at 23° C. for 15 hours and then was heated to 60° C. and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with dichloromethane, cooled to 0° C., and hydrochloric acid (4 M in dioxane) was added (0.037 mL, 0.145 mmol). The mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile in 0.1% trifluoroacetic acid/water to 95% acetonitrile in 0.1% trifluoracetic acid/water to give the title compound (10.8 mg, 42%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 2 H) 4.44 (d, J=5.88 Hz, 2 H) 5.61 (bs, 2 H) 7.14 (s, 1 H) 7.29 (m, 5 H) 7.41 (t, J=7.35 Hz, 1 H) 7.52 (d, J=9.19 Hz, 1 H) 7.75 (t, 1 H) 8.21 (dd, 1 H) 8.35 (t, 1 H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[N:8]=1)=[O:6].[H-].[Na+].Br[CH2:29][CH2:30][F:31]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH2:30][CH2:29][S:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[N:8]=1)=[O:6]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCCS)c1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NCCSCCF)c1
Reaction time: 1 h

Procedure:
1.0 g (0.0027 mol) of N-(2-mercaptoethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide (compound No. I-91) was dissolved in DMF, and the obtained solution was mixed with 0.12 g (ca. 60% in mineral oil; 0.0027×1.1 mol) of NaH and then with 0.68 g (0.0027×2.0 mol) of 1-bromo-2-fluoroethane, followed by stirring the solution for about one hour. The reaction solution was distributed in ethyl acetate-saturated sodium bicarbonate water and then washed with saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.[Br:12]N1C(=O)CCC1=O>>[Br:12][C:6]1[NH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c[nH]cc1C
Product: CCOC(=O)c1c[nH]c(Br)c1C
Yield: 76.7 %

Procedure:
Using ethyl 4-methyl-1H-pyrrole-3-carboxylate (4.50 g) and N-bromosuccinimide (5.2 g), a procedure as in Reference Example 40 was performed to give the title compound as a pale-yellow solid (yield 5.20 g, 76%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:20][C:19]4[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Reactant: Fc1cccc(CCl)c1
Product: Fc1cccc(CSc2nnc(-c3ccc4occc4c3)o2)c1
Yield: 84 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-fluorobenzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 84%) was obtained as colorless crystals.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:15][CH2:16][C:17]1([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[CH2:21][CH2:20][NH:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:15][CH2:16][C:17]1([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=2)[CH2:21][CH2:20][N:19]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:3][CH2:4]2)[CH2:18]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCNC1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCN(C2CCC(O)(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.8 %

Procedure:
100 mg (0.53 mmol) of 4-hydroxy-4-phenylcyclohexanone and 184 mg (0.53 mmol) of N-(2-{[3-(fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide were dissolved in 10 mL of methylene chloride. To the solution was added 221 mg (1.06 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 2 h. Direct chromatography on silica gel gave the final desired product 41 mg (top spot on TLC and first peak on HPLC, yield: 16.7%, MS: 522 (M+1)+) and the other isomer 51 mg (second peak on HPLC, yield: 20%, MS: 522 (M+1)+).
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1O>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[O:16][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:14][CH2:13]1)=[O:17]
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: CC1(C)CCC(C)(C)C1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1OC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 96 h

Procedure:
To a stirred solution of N-Cbz-1aminocyclopropane carboxylic acid in dry (CH2)2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethylcyclopentanol dissolved in CH2Cl2. After stirring for 4 days, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (1×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:18][CH2:19][C:20](Cl)=[O:21]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([Cl:9])[C:2]([NH:1][C:20](=[O:21])[CH:19]=[CH2:18])=[CH:7][N:6]=1
Reactant: O=C(Cl)CCCl
Reactant: Nc1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-Amino-2,4-dichloropyrimidine (Chempacific; 100 mg, 0.610 mmol) in THF (2 mL) was added triethylamine (170 μL, 1.22 mmol) followed by 3-Chloropropionyl Chloride (Aldrich; 64 mL, 0.671 mmol) The reaction was stirred at room temperature for 18 hrs.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[C:5]([F:25])=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:18][C@@:8]([C:6]1[C:5]([F:25])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:14])[F:16]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 150 mL round-bottomed flask was added (R)-N-((2S,4S)-2-(6-bromo-3-fluoropyridin-2-yl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (2.01 g, 4.43 mmol), 1,4-dioxane (30 mL) and finally HCl in 1,4-dioxane (Aldrich; 4.43 mL, 17.7 mmol, 4 M). The solution was stirred at rt for 45 min and then poured into sat NaHCO3 (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were dried (Na2SO4) and concentrated to afford (2S,4S)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5-tetrafluoropentan-2-ol which was carried on directly. MS m/z=351.0 [M+H]+. Calculated for C10H10BrF5N2O: 350.0.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([O:20][CH2:21][O:22][CH3:23])[CH:11]=1.CN([CH:27]=[O:28])C>C1COCC1>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[C:12]([O:20][CH2:21][O:22][CH3:23])[C:11]=1[CH:27]=[O:28]
Reactant: COCOc1cc(Cl)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOc1cc(C(F)(F)F)cc(Cl)c1C=O
Temperature: 0 °C

Procedure:
A 1.6M LDA solution (12.6 mL, 20.1 mmol) was added to a −78° C. THF solution (50 mL) of 1-chloro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene (from above). After 30 min neat DMF (3.9 mL, 50.0 mmol) was added, and the resulting solution was allowed to warm to 0° C. gradually, quenched with NH4Cl solution, and extracted with diethyl ether. The combined extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.