Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH:10]([C:12]([O:14]CC)=[O:13])[CH2:9][C:8]2[N:7]=[N:6][C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:4][C:3]1=2.Cl>O1CCOCC1>[OH:1][CH:2]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][C:8]2[N:7]=[N:6][C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)=[CH:4][C:3]1=2
Reactant: CCOC(=O)C1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1Cc2nnc(-c3cccc(C(F)(F)F)c3)cc2C(O)C1
Yield: 5.4 %

Procedure:
Ethyl 5-hydroxy-3-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydrocinnoline-7-carboxylate (60 mg, 0.164 mmol) obtained in Example 3 was dissolved in dioxane (1 mL), followed by adding 0.1 ml of a concentrated HCl solution and stirring over night. The reaction liquid was concentrated, followed by neutralization with an aqueous solution of sodium hydrogen carbonate, making weak acid using a 1N aqueous solution of sodium hydrogen sulfate, extraction with ethyl acetate, drying with sodium sulfate anhydride, filtration, concentration of thus obtained organic layer under reduced pressure and purification of residue using silica gel column chromatography (methylene chloride/methanol=10/1) to obtain an objective compound (3 mg, 5.4%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.C(O)(C)C>[O:21]1[C:2]2([CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)[CH2:1]1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC2(CO2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.1 %

Procedure:
To a 0° C. solution of tert-butyl 3-methyleneazetidine-1-carboxylate (3.50 g, 20.7 mmol) in 115 mL CHCl3 was added 77% mCPBA (13.9 g, 62.0 mmol) in 3 batches. Isopropyl alcohol (2 mL) was added. The reaction mixture was stirred for 10 minutes, then warmed to ambient temperature and stirred. After 19 hours, the milky reaction mixture was cooled to 0° C., 10 mL isopropyl alcohol was added (reaction mixture clarified), and another 1 equivalent of mCPBA was added. The reaction mixture was warmed to ambient temperature and stirred 2 hours, then another 1 equivalent mCPBA was added portionwise. After a total of 40 hours, the reaction mixture was cooled to 0° C., and 200 mL of 1:1 saturated Na2S2O3/saturated NaHCO3 was added slowly by pouring portionwise through ice (internal temperature was monitored; an initial 10° C. exotherm was observed). The mixture was stirred for 30 minutes, then extracted with CHCl3, and combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (5-50% ethyl acetate in hexanes gradient) to give the desired product (1.0 g, 26.1% yield) as a clear colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6].I[CH2:12][CH3:13]>CN(C=O)C.C1COCC1.O>[CH2:12]([O:3][C:4]([CH3:10])([CH3:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:13]
Reactant: COC(=O)C(C)(C)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(C)(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A 0° C. suspension of NaH (60% wt. in mineral oil, 1.4 g, 35.0 mmol) in DMF (11 mL) under Ar was treated drop-wise with a solution of methyl 2-hydroxyisobutyrate (2.0 g, 16.93 mmol) in THF (5 mL), stirred at 0° C. for 0.5 h, allowed to warm to RT, and stirred for 0.5 h. The mixture was re-cooled to 0° C., treated drop-wise with iodoethane (6.0 g, 35.3 mmol) and stirred overnight as the cooling bath expired. The mixture was diluted with water, extracted with Et2O (5×) and the combined organics were dried over MgSO4 and concentrated to dryness to afford methyl 2-ethoxy-2-methylpropanoate (1.6 g, 65%) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 3.63 (s, 3H), 3.31 (q, J=7.0 Hz, 2H), 1.30 (s, 6H), 1.06 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:33]4[CH:34]=[CH:35][O:31][CH:32]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccoc1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2c(-c3ccoc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (70 mg, 0.134 mmol) (Example 33), 3-furanylboronic acid (22.43 mg, 0.20 mmol), sodium carbonate (28.3 mg, 0.267 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.44 mg, 0.013 mmol) in acetonitrile (1 mL) and water (250 μl) was heated at 80° C. under nitrogen for 1.5 h. The reaction mixture was cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in isohexane, afforded the title compound (55 mg). LCMS (A) m/z: 511 [M+1]+, Rt 1.51 min (acidic), Rt 0.98 min (basic).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd]>[C:1]([NH:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)[CH2:15][CH2:14]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(NC(=O)c1ccccc1)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Product: Nc1cccc(CN2CCC(NC(=O)NC(=O)c3ccccc3)CC2)c1
Yield: 46.1 %

Procedure:
1-Benzoyl-3-[1-(3-nitrobenzyl)piperid-4-yl]urea 4.47 g (from Example 13) was hydrogenated with 5% Pd/C (0.5 g) at atmospheric pressure and room temperature until no more hydrogen was taken up. The catalyst was filtered and the filtrate evaporated. The residue was dissolved in water and basified with 0.880 ammonia. The precipitated solid was filtered, washed well with water, dried, treated with charcoal, and evaporated to give the title compound, (1.9 gms). This was recrystallised from ethanolic HCl to give the dihydrochloride salt, monohydrate, m.p. 194°-195° C.
Reaction SMILES: [F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CC(OC)(C)C>[F:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[CH3:15])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2o1
Reactant: CC(Br)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: COC(C)(C)C
Product: CC(c1cccc([N+](=O)[O-])c1)n1c(=O)oc2cc(F)c(F)cc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
500 mg (2.9 mmol) of 5,6-difluoro-3H-benzoxazol-2-one, 672 mg (2.9 mmol) of (1-bromoethyl)-3-nitrobenzene and 1.58 g (11.4 mmol) of potassium carbonate are suspended in 6 ml of acetonitrile, and the mixture is stirred at 60° C. for 6 h. The mixture is subsequently diluted with 30 ml of MTBE, washed with 3×20 ml of H2O, dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography on silica gel.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.O>C1C=CC=CC=1>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A solution of 2.2 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8) and 2.6 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3) in 200 ml of benzene was heated under reflux for about 2 hours, whilst the water being formed during the reaction was continuously removed. At the end of this time, the reaction mixture was freed from the benzene used as solvent by distillation under reduced pressure, and the resulting residue was dissolved in 150 ml of absolute methanol. 1 g of sodium borohydride was added to this solution, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then mixed with ethyl acetate and with a saturated aqueous solution of sodium chloride. The organic layer was separated and was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 40:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the eluent, to give 2.3 g of the title compound having an Rf=0.44 (thin layer chromatography over silica gel, using a 40:1:1 by volume mixture of ethyl acetate, ethanol and triethylamine as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:5][CH:4]=1.[C:14](Br)(Br)([Br:16])[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:12][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:13])[CH:10]=[C:14]([Br:16])[Br:15]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C(C)(C)C=O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a stirred solution of Compound 45 (3.0 g, 17 mmol) and CBr4 (11 g, 34 mmol) in CH2Cl2 (100 ml) was added PPh3 (18 g, 67 mmol) at r.t., and stirred for 1.5 h. The mixture was quenched by the addition of H2O, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 53 (2.5 g, 45%) as a colorless oil.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:5])=[O:4])[CH3:2].[H-].[Na+].[CH3:20]I>C1COCC1>[CH2:1]([S:3]([N:6]([CH:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)[CH3:20])(=[O:5])=[O:4])[CH3:2]
Reactant: CI
Reactant: CCS(=O)(=O)NC1CCCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C)C1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[NH:23](/[N:24]=[C:17]1\[CH2:18][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][C:11]2[O:15][CH:14]=[C:13]([CH3:16])[C:12]\1=2)[C:20]([NH2:22])=[NH:21]
Reactant: COc1ccccc1C1CC(=O)c2c(C)coc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: COc1ccccc1C1C/C(=N\NC(=N)N)c2c(C)coc2C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a mixture of 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.19 g) and aminoguanidine hydrochloride (82 mg) were added ethanol (15 ml) and 6N hydrochloric acid (0.064 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-4-guanidinoimino-6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 46) (0.19 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][NH:17][NH2:18].O>CO>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[N:17]([CH3:16])[NH2:18]
Reactant: CNN
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Solvent: O
Solvent: CO
Product: CN(N)c1cnn(-c2ccccc2)c(=O)c1Cl

Procedure:
To a solution consisting of 22.9 grams of 4,5-dichloro-2-phenylpyridazin-3(2H)-one in 120 grams of methanol is added 20 grams of methylhydrazine. The reactants are heated to reflux for two hours, cooled and poured into one kilogram of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene and methanol to yield 4-chloro-2-phenyl-5-(1-methylhydrazino)-pyridazine-3(2H)-one (m.p. 128° to 130° C with decomposition).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[CH:3]=[N:2]1.[Cl:10][C:11]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[C:19]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:7]1[CH2:8][CH2:9][C:4]2[CH:3]=[N:2][NH:1][C:5]=2[CH2:6]1)=[O:14]
Reactant: c1n[nH]c2c1CCNC2
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2cn[nH]c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (1.01 g, 5.15 mmol) in DMF (17 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (2.31 g, 10.30 mmol), Hunig's base (3.55 mL, 20.60 mmol) and HATU (2.31 g, 10.30 mmol). The solution was allowed to stir for 30 min at rt then poured into ice water (300 mL). The resulting solid was collected by suction filtration and allowed to air dry. The solid was purified by chromatography on silica gel (0-100% ethyl acetatehexanes). The product fractions were concentrated to a white solid which was dissolved in ethanol (20 mL) and 1M NaOH (20 mL) and stirred at 80° C. for 1 h. Water (50 mL) and CH2Cl2 (50 mL) were added. The layers were separated and the water layer was extracted two times with CH2Cl2. The organic layers were combined, dried over anhydrous MgSO4, filtered and concentrated to an oil (1.37 g, 81%). MS (ESI) mass calcd. C14H11ClF3N3O, 329.1. m/z found, 330.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.79-7.73 (m, 1H), 7.52-7.41 (m, 2H), 7.37 (br s, 1H), 5.11 (d, J=16.6 Hz, 0.5H), 4.85 (d, J=16.6 Hz, 0.5H), 4.46 (d, J=15.9 Hz, 0.5H), 4.36 (d, J=15.9 Hz, 0.5H), 4.22-4.18 (m, 0.5H), 3.94-3.88 (m, 0.5H), 3.49-3.44 (m, 1H), 2.85-2.80 (m, 1H), 2.75-2.65 (m, 1H), 2.62-2.54 (m, 1H).
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:7]([N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[C:20](=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCNCCC(C)C
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a stirred solution of diisopentylamine (5.0 ML, 24.7 mmol) and triethylamine (9.4 mL, 67.4 mmol) in dichloromethane (23 mL) at 0° C. was added slowly isonicotinoyl chloride hydrochloride (4 g, 22.5 mmol). The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was diluted with saturated sodium bicarbonate and the separated aqueous layer was extracted with methylene chloride (3×25 mL). The combined organics were washed with water (10 mL), brine, dried (anh. sodium sulfate), filtered and evaporated. The residue solidified upon standing to afford 4.7 g of an orange solid. LCMS m/z 263.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:28])[C:10]=1[NH:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[CH:16]=[CH:15][C:14]=1[CH3:26])[C:5]([OH:7])=[O:6].[BH4-].[Na+]>CO>[OH:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]2[CH:16]=[CH:15][C:14]([CH3:26])=[C:13]([CH:18]=2)[C:12]([NH:11][C:10]2[C:9]([CH3:28])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[CH3:1])=[O:27])[CH2:24][CH2:23]1
Reactant: Cc1ccc(N2CCC(=O)CC2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N2CCC(O)CC2)cc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
To a solution of 3,5-dimethyl-4-[[2-methyl-5-(4-oxo-1-piperidyl)-benzoyl]amino]benzoic acid (69.5 mg, 182.68 μmoles) in methanol (1.83 ml) is added sodium tetrahydroborate (13.82 mg, 365.36 μmoles) and the resulting mixture is stirred at ambient temperature. After 1 hour, the mixture is quenched with saturated solution of NH4Cl (0.2 ml) and extracted with CHCl3 (3 ml):IPA (1 ml). The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid is triturated with H2O (5 ml), filtered, and washed with H2O (5 ml). The residue is purified by reverse phase chromatography (C18) using 20% acetonitrile in H2O with 0.1% formic acid to afford the title compound as a white powder (0.01 g, 15.7%). Mass spectrum (m/z): 383.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1>>[CH2:25]([CH:24]([N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=3)=[CH:6][CH:7]=2)[CH2:19][CH2:20]1)[CH2:27][CH3:28])[CH3:26]
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Reactant: CCC(CC)N1CCC(N)CC1
Product: CCC(CC)N1CCC(Nc2ccc(-c3ccc(OC)c(F)c3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(4-methoxy-3-fluorophenyl)pyridazine and 4-amino-1-(1-ethylpropyl)piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:27])([CH2:8][CH2:9][C@H:10]3[C@H:19]2[CH2:18][CH:17]=[C:16]2[C@:11]3([CH3:26])[CH2:12][CH2:13][C@H:14]([O:22][C:23](=[O:25])[CH3:24])[CH2:15]2)[C:3]=1[C:4](=O)[CH3:5].Cl.[NH2:29][OH:30].O>C(O)C.N1C=CC=CC=1>[CH3:1][C:2]1[CH2:21][C@@H:20]2[C@:7]([CH3:27])([CH2:8][CH2:9][C@H:10]3[C@H:19]2[CH2:18][CH:17]=[C:16]2[C@:11]3([CH3:26])[CH2:12][CH2:13][CH:14]([O:22][C:23](=[O:25])[CH3:24])[CH2:15]2)[C:3]=1[C:4](=[N:29][OH:30])[CH3:5]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=C(C)C[C@@H]32)C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=NO)=C(C)C[C@@H]32)C1

Procedure:
A solution of 16-methyl-3β-acetoxy-5,16-pregnadien-20-one (3.70 g, 10 mmoles) was refluxed in a mixture of ethanol (100 ml) and pyridine (10 ml) containing 3.50 g (50 mmoles) of hydroxylamine hydrochloride for one hour. The reaction mixture was added to water and the crude product was filtered and washed with water. Solution in methylene chloride, filtration through anhydrous sodium sulfate, and concentration to dryness in vacuo gave the crude oxime.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:23]=2)[CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(Oc3ccccc3)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3-phenoxyaniline (74.0 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid. (96 mg, 68 %). 1H NMR (CDCl3): 8.62 (d, J 4.2 Hz, 1H), 8.25 (d, J=8.1 Hz, 1H), 7.65 (t, J=1.5 Hz, 1H), 7.21 (m, 5H), 6.94 (m, 5H), 6.64 (d, J=8.1 Hz, 1H), 6.49 (s, 1H), 2.33 (s, 3H),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH2:12])=[O:11])=[CH:4][C:3]=1[F:13].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:18]=[C:16]([CH2:15][Cl:14])[N:12]=2)=[CH:4][C:3]=1[F:13]
Reactant: NC(=O)/C=C/c1ccc(Cl)c(F)c1
Reactant: O=C(CCl)CCl
Product: Fc1cc(/C=C/c2nc(CCl)co2)ccc1Cl
Yield: 41.9 %

Procedure:
Using (E)-3-(4-chloro-3-fluorophenyl)-2-propenamide (8.67 g) and 1,3-dichloroacetone (11.0 g), the same reaction as Reference Example 1-(ii) was carried out to yield the titled compound (4.95 g) as colorless flaky crystals.