Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([O-])(O)=O.[Na+].[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CO.O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[CH3:15])[N:3]=1
Reactant: CC1CCCN1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCCN1c1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold solution containing 2,4,6-trichloropyrimidine (8 g, 44 mmol) in MeOH (80 mL) and NaHCO3 (10 g) add slowly and dropwise a methanolic solution (20 mL) of 2-methylpyrrolidine (46 mmol). Allow the mixture to warm to 25° C. and stir overnight. Dilute with water, vigorously stir for 1 hour, and filter to give white crystalline solid as a mixture of regioisomers. Chromatograph the mixture using flash column chromatography (ethyl acetate/hexanes eluent systems) to give 4,6-dichloro-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[C:14]([O:20][CH3:21])[C:13]=2[N+:22]([O-])=O)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]>C1(C)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([Cl:19])=[C:14]([O:20][CH3:21])[C:13]=2[NH2:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: COc1c(Cl)cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
4-Chloro-3-(4-chloro-6-fluoro-3-methoxy-2-nitrophenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole (0.48 g, 1.24 mmol) was dissolved in toluene (8 ml) and 0.05 g of 10% palladium on carbon was added. The solution was vigorously stirred under hydrogen atmosphere for 4 hr at ambient temperature and the catalyst was removed by filtration. Removal of the solvent afforded a residue which was chromatographed on silica gel. Elution of the column with hexanemethylene chloride (3:7) furnished the title compound (0.38 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]1[CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OC2CCC2)cn1
Temperature: 60 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
2-Bromo-5-hydroxypyridine (1.0 g, 5.75 mmol), bromocyclobutane (0.783 mL, 8.33 mmol), and potassium carbonate (1.59 g, 11.5 mmol) were mixed in DMF (11 mL) and stirred at 60° C. for 5 h, then at 80° C. for 14 h. The reaction mixture was diluted with EtOAc and washed with water, saturated NaHCO3, and brine. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by ISCO (40 g), eluting with a gradient of EtOAc/hexane 0-10% to provide to give 2-bromo-5-cyclobutoxypyridine (0.92 g, 4.0 mmol, 70% yield) as white solid. ESI (M+1) 229.9.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[N+:34]([O-])([OH:36])=[O:35]>CC(OC(C)=O)=O>[CH2:27]([O:26][C:12]1[CH:13]=[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([Cl:17])=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:10]=1[N+:34]([O-:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 72.5 %

Procedure:
A suspension of 5-(2,4-bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide (1 g, 2.2 mmol) in Ac2O (20 ml) was cooled to 0° C. and HNO3 (0.26 ml, 4.3 mmol) was added dropwise under stirring, the temperature being maintained between 0-5° C. After the addition was complete, the mixture was stirred for 70 h at 5-10° C. and then poured into ice and extracted with DCM (3×40 ml). The extract was dried and concentrated under vacuo. The yellow solid obtained was triturated with Et2O and filtered to give 5-[2,4-bis(benzyloxy)-5-chlorophenyl]-N-ethyl-4-nitroisoxazole-3-carboxamide (810 mg, 73%).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[F:9][C:10]1([F:39])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH:12]([C:23](=[O:38])[NH:24][C:25]2([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)[CH2:11]1>>[F:39][C:10]1([F:9])[CH2:15][CH2:14][NH:13][CH:12]([C:23]([NH:24][C:25]2([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH3:37])=[O:35])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:38])[CH2:11]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC(F)(F)CCN3)CC2)cc1
Yield: 94.6 %

Procedure:
The title compound (D99) (500 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 4,4-difluoro-2-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)piperidine-1-carboxylate (D68) (685 mg)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:13])=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]([CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=O.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:15]=[C:16]([CH:18]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]4)[N:13]=3)[CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1nccnc1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)CBr)C1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cn3ccnc(N4CCOCC4)c3n2)C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of compound 1b (2.4 g, 13 mmol) in DMF (20 mL), Na2HPO4 (4.7 g, 33 mmol) was added followed by tert-butyl 3-(2-bromoacetyl)azetidine-1-carboxylate (6.0, 21 mmol). The resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was allowed to cool to rt and water (50 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL). The combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0:1-1:0 EtOAc/hexanes) to obtain compound 29a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C18H25N5O3: 360.2 (M+H). found: 360.3.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH2:26].O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][C:25]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=1[F:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Reactant: Nc1ccc(F)cc1F
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
35.3 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added dropwise, while cooling with ice. The mixture is stirred at room temperature for 1.5 hours, 120 ml of water are added, while cooling, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 40.5 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate are obtained, melting point: 84°-86° C.
Reaction SMILES: [C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[O:17]1CCOCC1>O.[Pd]>[C:1]1([C:13](=[O:17])[C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[C:1]1([CH2:13][C:14]([NH2:16])=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: C1COCCO1
Agent: [Pd]
Agent: NC(=O)Cc1cn2c3c(cccc13)CCC2
Solvent: O
Product: NC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Yield: 96 %

Procedure:
To a solution of (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide (0.30 g, 1.31 mmol) in dioxane (6 mL) and water (2 mL) was added 10% palladium on carbon (0.060 g), followed by the careful addition of NaH2PO2H2O (0.60 g, 5.67 mmol) and the reaction was brought to reflux under nitrogen. After 3 hours an additional 0.60 g of NaH2PO2.H2O was added and the reaction was heated at reflux for another 6 hrs. The mixture was cooled, filtered through a pad of Celite, and washed well with ethyl acetate (100 mL). The solution was concentrated under reduced pressure and the residue triturated with water (20 mL). The resulting suspension was filtered and the recovered solid dried under reduced pressure to provide 0.27 g (96%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1F>CN(C)C=O>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][CH:19]([CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[N:23]3)[O:18][N:17]=2)[CH:12]=[CH:13][C:14]=1[N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1-n1cccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
A slurry of sodium hydride (60% in oil, 44 mg, 1.1 mM) in anhydrous N,N-dimethylformamide (1 ml) was stirred under an atmosphere of nitrogen and treated dropwise with a solution of pyrazole (76 mg, 1.1 mM) in anhydrous N,N-dimethylformamide (1 ml) at 0°. The mixture was allowed to warm to ambient temperature over 20 minutes, then a solution of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-yl-methyl)-4,5-dihydroisoxazole (264 mg, 1 mM) in anhydrous N,N-dimethylformamide (2 ml) added, and the mixture stirred at 70° for 16 hours. After cooling, the mixture was partitioned between aqueous sodium bicarbonate solution (40 ml) and ethyl acetate (40 ml), and the organic extract washed with water (40 ml) and brine (40 ml). After drying (magnesium sulfate) and evaporation, the crude product was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with ethyl acetate. Relevant fractions were combined to give the desired product (141 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([Cl:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (4-nitrophenoxy)acetic acid (50 g) and thionyl chloride (150 ml) was heated under reflux for 3 h. The solution was concentrated and then coevaporated with benzene to give 4-nitrophenoxyacetyl chloride as a solid. A solution of this solid (9.4 g) in acetone (100 ml) was added dropwise to a stirred mixture of 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (10 g) and sodium hydrogen carbonate (9 g) in acetone (100 ml) at 0°. Stirring was continued at room temperature for 16 h, the mixture was then filtered, and the filtrate was concentrated. The residue was treated with water and extracted with dichloromethane. The organic layer was washed with water, dried and concentrated to give the title compound (6.6 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: O=C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCCN1c1ncc(Br)cn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (11.3 g), pyrrolidin-2-one (5 g), and K2CO3 (27.4 g) in 1-methylpyrrolidin-2-one (100 mL) was heated to 80° C. under nitrogen and stirred at this temperature overnight. After cooling to room temperature, the reaction mixture was concentrated to give an oil which was poured into water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined organic phase was concentrated to afford an oil, which was purified by column chromatography on silica gel to afford the title compound. Yield: 592 mg (4% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:26]([CH:29]1[CH2:31][CH:30]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:27]=[O:28].O>CN(C=O)C>[C:32]1([CH:30]2[CH2:31][CH:29]2[NH:26][C:27]([NH:1][C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]3)=[CH:4][CH:3]=2)=[O:28])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C=NC1CC1c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)NC1CC1c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (123 mg, 0.35 mmol) in DMF (20.0 mL) was added (2-isocyanatocyclopropyl)benzene (111 mg, 0.7 mmol). The mixture was stirred at 60° C. overnight. After cooling, the mixture was poured into water (120 mL). The white solid, which precipitated, was filtered off and dried in vacuum to give the title product (162 mg) as a white solid in 90% yield. 1H NMR (300 MHz, CDCl3) δ 8.01-7.97, 7.73, 7.60, 7.55, 7.32, 7.22-7.10, 7.06, 4.00-3.95, 3.87-3.86, 3.62-3.52, 3.43-3.41, 3.25-3.22, 2.85-2.82, 2.14-2.10, 0.91-0.86. MS (ES+) m/z 511.2 (M+1).
Reaction SMILES: N([O:3][C:4](C)(C)[CH3:5])=O.ON1C(=O)C2=CC=CC=C2C1=O.C1(=NO)CCCCC1.[N+](C1CCCCC1)([O-])=O.[C:37]1(=[O:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(O)(=O)C.C1CCCCC1>[C:4]([O:43][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)(=[O:3])[CH3:5]
Reactant: CC(C)(C)ON=O
Reactant: O=C1CCCCC1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=[N+]([O-])C1CCCCC1
Agent: ON=C1CCCCC1
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: CC(=O)OC1CCCCC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Cyclohexane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclohexanone oxime, nitrocyclohexane, cyclohexanone, and cyclohexyl acetate were formed in yields of 16%, 10%, 3%, and 2%, respectively.
Reaction SMILES: C(O)C.[H][H].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([O-])=O>[Pd].C1C=CC=CC=1>[NH2:6][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: *O[SiH2]*
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2ccc(N)cc2)cc1
Yield: 123.9 %

Procedure:
270 mg of 5%-Pd/C was suspended in 14 mL of a 1:1 mixed solvent of ethanol and benzene. While passing hydrogen through the system, a solution was added that consisted of 3.21 g of the 4,4'-dinitrobiphenyl-containing polysiloxane (average value of n: 14.4) synthesized in Reference Example 2 dissolved in 14 mL of the same mixed solvent. Hydrogen was injected into the system for 3 hours while stirring. The catalyst was then filtered off and the solvent was distilled under reduced pressure to give 3.00 g of the 4,4'-diaminobiphenyl-terminated polysiloxane as a viscous yellow liquid.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:15])[C:13]=1[Cl:14])[C:7](OC)=[O:8]>CO>[Br:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[C:12]([Br:15])[C:13]=1[Cl:14]
Reactant: COC(=O)c1cc(Br)c(Cl)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)c(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH4 (1.53 g, 40.65 mmol) was added portionwise to a stirred solution of methyl 3,5-dibromo-4-chlorobenzoate (4.45 g, 13.6 mmol) in MeOH (50 mL) at 0° C. The reaction mixture was then stirred at ambient temperature for 8 h. The volatiles were evaporated and the residue was diluted with CH2Cl2 and washed with brine followed by water. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as an off white solid (3.3 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ 7.71 (s, 2H), 5.49 (bs, 1H), 4.48 (d, J=4.5 Hz, 2H); ESIMS m/z 297.9 ([M]+); IR (thin film) 3460, 747, 534 cm−1.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=4[CH:29]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:52]1[CH2:71][O:70][C:54]2([CH2:59][CH2:58][CH:57]([N:60]([CH2:62][C:63]3[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=3)[CH3:61])[CH2:56][CH2:55]2)[O:53]1>CN(C=O)C.C(N(CC)CC)C>[CH2:71]1[CH2:52][O:53][C:54]2([CH2:55][CH2:56][CH:57]([N:60]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([NH:67][C:26]([C:20]4[CH2:21][CH2:22][S:23](=[O:24])(=[O:25])[C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([N:5]7[CH2:6][CH2:7][O:2][CH2:3][CH2:4]7)=[CH:9][CH:10]=6)=[CH:29][C:18]=5[CH:19]=4)=[O:28])=[CH:68][CH:69]=3)[CH3:61])[CH2:58][CH2:59]2)[O:70]1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Reactant: CN(Cc1ccc(N)cc1)C1CCC2(CC1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a solution of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (200 mg) and 1-hydroxybenzotriazole (0.12 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]aniline (0.19 g) and triethylamine (0.2 ml) in DMF (3 ml), and the mixture was stirred for 64 hours. The mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:1) to give yellow crystals of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 15) (119 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[N:15]([CH3:20])[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.C(Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([N:15]1[C:14](=[O:21])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:22])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH2:19][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(C)c2=O)cn1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(Cc3ccccc3)n(Cc3ccccc3)c2=O)cn1
Yield: 69 %

Procedure:
Prepared as in Example 10-65 from 4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,2-dimethyl-1,2,4-triazolidine-3,5-dione (example 10-69) and benzyl bromide. Yield: 69%. 1H NMR (CDCl3, 400 MHz): δ2.14 (s, 3H), 2.36 (s, 3H), 4.65 (s, 4H), 4.99 (s, 2H), 7.06-7.08 (m, 4H), 7.19-7.25 (m, 6H), 7.86 (s, 1H), 8.02 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.8 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[F:19])[CH:5]=[CH:4][N:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([F:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Yield: 78.3 %

Procedure:
A solution of 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (11.68 g, 40.8 mmol) in MeOH (200 mL) was treated with Raney Ni (50% wet, 0.955 g, 8.15 mmol) and hydrogenated (10-20 psi) for 4 h. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to dryness to provide 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (8.2 g, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (d, J=5.9 Hz, 1H), 7.25 (dd, J=11.2, 7.5 Hz, 1H), 7.02 (dd, J=2.2 Hz, 1H), 6.95 (dd, J=5.8, 2.0 Hz, 1H), 6.74 (dd, J=12.3, 8.3 Hz, 1H), 5.57 (s, 2H); MS (ESI): m/z 257.0 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:22])=[CH:3]1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C(O)(C)(C)C>[O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH:5]=[CH:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:31])([F:32])[F:33])=[O:22])=[CH:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CC(C)(C)O
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Nc1ccccc1C(F)(F)F

Procedure:
A mixture of (17β)-3-oxo-N-[2-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide (2-1) (3.74 g, 8.14 mmol) and p-chloranil (2.40 g, 9.77 mmol) in t-butanol (40 mL) under N2 was heated to reflux for 90 min. The reaction was concentrated and the residue dissolved in EtOAc and washed with 0.5 N NaOH solution (2×60 mL), 10% KHSO4 solution, and brine. Upon removal of the solvent, the residue was purified by flash chromatography on silica gel (0 to 35% EtOAc-hexanes) to afford 5-2 as a brownish foam.
Reaction SMILES: [C:1]([C:5]1[N:6]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1)(OC)=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:2][CH2:1][C:5]1[N:6]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:8][N:9]=1
Reactant: COC(=O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of XXIX (1.1 g, 0.003 mol) in dry THF (10 mL) was added dropwise with stirring at 0°-4° C. to a suspension of LAH (0.14 g, 0.0036 mol) in dry THF (10 mL). The mixture was stirred at room temperature, further cooled, H2O (0.13 mL) added, followed by 10% NaOH (0.2 mL) and finally H2O (0.33 mL). The mixture was stirred at room temperature for 30 minutes, then at 0° C. for 1 hour, filtered and the collected solid, washed with THF, hot EtOH (2x) and CHCl3. The combined filtrates were concentrated to dryness. The residue was triturated with hot absolute EtOH to yield 0.7 g (69%) of XXX; m.p. 243°-4°.