Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(O)C=CC=1F.[F:10][C:11]1[C:16]([F:17])=[CH:15][C:14](B2OC(=O)CN(C)CC(=O)O2)=[C:13]([O:29][C@H:30]([CH2:32][CH:33]=[CH2:34])[CH3:31])[CH:12]=1>>[F:17][C:16]1[CH:15]=[CH:14][C:13]([O:29][C@H:30]([CH2:32][CH:33]=[CH2:34])[CH3:31])=[CH:12][C:11]=1[F:10]
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B1OC(=O)CN(C)CC(=O)O1
Agent: Oc1ccc(F)c(F)c1
Product: C=CC[C@H](C)Oc1ccc(F)c(F)c1

Procedure:
Prepared in 69% from 3,4-difluorophenol following the procedure for (S)-2-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione. 1H NMR (400 MHz, CDCl3) δ 7.11-6.97 (m, 1H), 6.72 (ddd, J=12.1, 6.6, 2.9 Hz, 1H), 6.64-6.54 (m, 1H), 5.85 (ddt, J=17.2, 10.2, 7.0 Hz, 1H), 5.19-5.09 (m, 2H), 4.38-4.23 (m, 1H), 2.48 (qd, J=7.0, 5.9 Hz, 1H), 2.40-2.28 (m, 1H), 1.31 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −135.75 (d, J=20.8 Hz, 1F), −148.32 (d, J=22.5 Hz, 1F).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: Cc1ncoc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1ncoc1-c1cccc(N)c1

Procedure:
Pd/C (5 g) was transferred carefully to a solution of 4-methyl-5-(3-nitrophenyl)-1,3-oxazole (50 g) in MeOH (600 mL) in a Parr-shaker bottle and hydrogenated at 3.5 kg pressure for 20 h. The reaction mixture was filtered over a celite bed and the filtrate concentrated. The residue was purified by silica gel column chromatograph using 40% EtOAc in petroleum-ether to get a yellow solid. Yield 18 g (42%). 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.08 (t, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.71 (d, J=7.9 Hz, 1H), 6.52 (d, J=8.2 Hz, 1H), 5.24 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]2[F:28])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3ccccc3)cc2)[C@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: F[C@@H]1CNCC[C@@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of cis-tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (400 mg, 1.04 mmol) in CH2Cl2 (4 mL) was dropwise added TFA (1 mL, 13 mmol) at rt. The mixture was stirred at rt for 2 h and then concentrated. To the residue was added 50 mL of saturated aqueous sodium bicarbonate and the mixture was extracted with 3×60 mL of CH2Cl2. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness to yield 270 mg cis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (0.95 mmol, 91%). (M+H)+=286.25. 1H NMR (500 MHz, chloroform-d) δ 7.49-7.38 (m, 4H), 7.34 (t, J=7.5 Hz, 1H), 7.26-7.20 (m, J=8.5 Hz, 2H), 7.01-6.93 (m, 2H), 5.08 (s, 2H), 4.70 (d, J=49.0 Hz, 1H), 3.38 (t, J=12.5 Hz, 1H), 3.25 (dt, J=13.4, 2.0 Hz, 1H), 2.93 (d, J=14.3 Hz, 1H), 2.90-2.68 (m, 3H), 2.09 (qd, J=12.9, 4.1 Hz, 1H), 1.69 (d, J=14.3 Hz, 1H).
Reaction SMILES: [NH:1]([C:8](=[O:30])[CH2:9][N:10]([CH2:20][C:21](=[O:29])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:67][C:68]1[CH:69]=[C:70]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH:71]=[CH:72][C:73]=1[NH:74]C(=O)OC(C)(C)C>CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[NH2:74][C:73]1[CH:72]=[CH:71][C:70]([C:82]2[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=2)=[CH:69][C:68]=1[NH:67][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N:10]([CH2:20][C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[CH2:9][C:8](=[O:30])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: O=C(CN(CC(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1)Nc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N(CC(=O)Nc2ccccc2)CC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[bis(2-anilino-2-oxoethyl)amino]benzoic acid (40 mg, 0.099 mmol) in 2:1 CH2Cl2/DMF was added BOP (66 mg, 0.149 mmol), Hunigs base (26 μL, 0.149 mmol) and tert-butyl (3-aminobipheyl-4-yl)carbamate (56 mg, 0.199 mmol) and the reaction was allowed to stir at room temperature for 12 hours. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (30-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired N-(2-aminophenyl)-4-[bis(2-anilino-2-oxoethyl)amino]benzamide: 1H NMR (600 MHz, MeOH-d4) δ 7.93 (d, J=8.9 Hz, 2H), 7.66 (dt, J=8.6, 1.5 Hz, 4H), 7.52 (d, J=7.2 Hz, 2H), 7.44 (s, 1H), 7.30 (m, 8H), 7.10 (t, J=7.8 Hz, 2H), 6.96 (d, J=7.8 Hz, 1H), 6.74 (d, J=9.1 Hz, 2H), 6.53 (t, J=7.2 Hz, 1H), 4.79 (s, 2H), 4.42 (s, 4H); MS: cal'd 570.2 (MH+), exp 570.2 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:2]1.Br[C:23]1[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[N:27][CH:28]=1>CC(N(C)C)=O>[F:30][C:29]([F:32])([F:31])[C:26]1[N:27]=[CH:28][C:23]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C@@H:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]3[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:2]2)=[CH:24][N:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reactant: FC(F)(F)c1ncc(Br)cn1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2cnc(C(F)(F)F)nc2)C1
Temperature: 100 °C
Yield: 44.3 %

Procedure:
Dimethylacetamide (5.25 mL) was added to a round bottom flask containing tert-butyl (1R,2R)-2-(piperidin-3-ylamino)cyclohexylcarbamate (0.47 gm, 1.58 mmol) and 5-bromo-2-(trifluoromethyl)pyrimidine (0.43 gm, 1.89 mmol). The reaction mixture was then heated at 100° C. After 48 h heating was stopped. The reaction mixture was partitioned between EtOAc and sat. NaHCO3. The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes holding at 100% EtOAc to give the diastereomeric product, tert-butyl (1R,2R)-2-(1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-3-ylamino)cyclohexylcarbamate, (0.31 gm, 0.70 mmol, 44% yield) as light yellow solid. Anal. Calcd. for C21H32F3N5O2 m/z 443.3, found: 444.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C=O)C>[N:18]1([CH2:17][CH2:16][CH2:15][O:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: ClCCCN1CCOCC1
Reactant: CCOC(=O)c1ccccc1O
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 2-hydroxybenzoate (2.4 ml, 16.38 mmol), K2 CO3 (4.98 g), and DMF (30 ml) was added N-(3-chloropropyl)morpholine hydrochloride (3.93 g). The mixture was stirred at room temperature for 30 minutes, then was warmed on a steam bath overnight. The reaction mixture was cooled, filtered and stripped to afford a liquid which was partitioned between EtOAc (350 ml) and water. The organic layer was separated, washed with water (2×200 ml), dried over MgSO4 and stripped to afford ethyl 2-[3-(4-morpholinyl)propoxy]benzoate.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH3:10])[NH:5][C:4](=O)[C:3]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:2]([CH3:1])[N:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1c(C)nc(COC)[nH]c1=O
Product: CCOC(=O)CCc1c(C)nc(COC)nc1Cl
Yield: 84 %

Procedure:
A mixture of ethyl 3-(6-methyl-2-methoxymethyl-3H-pyrimidin-4-on-5yl)propionate (4.00 g, 15.6 mmol) and phosphorus oxychloride (25 mL) was heated under reflux for 2 h. The mixture was concentrated, cooled, and poured onto ice. 1N NaOH was added to bring the pH to 6 and the mixture was extracted with EtOAc. The extracts were dried (MgSO4) and concentrated to give 3.6 g (84%) of product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](OS(C(F)(F)F)(=O)=O)=[C:10]([CH:22]=[O:23])[CH:9]=2)=[C:4]([F:24])[CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br-].[Na+]>O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:25]3[CH2:27][CH2:26]3)=[C:10]([CH:22]=[O:23])[CH:9]=2)=[C:4]([F:24])[CH:3]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2F)ccc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc(-c2ccc(Cl)cc2F)ccc1C1CC1
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a mixture of trifluoromethanesulfonic acid 4′-chloro-2′-fluoro-3-formylbiphenyl-4-yl ester (30.0 g, 0.078 mol), cyclopropyl boronic acid (8.80 g, 0.10 mol), potassium phosphate (58.40 g, 0.28 mol) and sodium bromide (8.0 g, 0.078 mol) is added toluene (300 ml) then distilled water (30 ml) under a nitrogen atmosphere. To this mixture is then added tetrakis(triphenylphosphine) palladium (9.60 g, 8.40 mmol) in one portion, and the mixture is then heated at 100° C. overnight. After cooling to room temperature the mixture is diluted with distilled water (500 ml) and ethyl acetate (500 ml), and the two layers are separated and the aqueous phase extracted again with ethyl acetate (2×500 ml). Organic fractions are combined, washed with distilled water (1 L) then brine (1 L), and then dried over magnesium sulphate. The suspension is filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography on silica gel, then additionally by flash column chromatography on basic alumina (10% ethyl acetate in hexane as eluant) to afford 4′-chloro-4-cyclopropyl-2′-fluoro-biphenyl-3-carbaldehyde (7.6 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1>O1CCOCC1.C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)=[O:20])[CH:8]=2)[N:3]=1
Reactant: Cn1cncc1C(O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cncc1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
Manganese (IV) oxide (1.17 g, 13.4 mmol) was added to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (1.03 g, 2.68 mmol, Intermediate 2: step a) in 1,4-dioxane (15 mL). The resulting black suspension was fitted with a reflux condenser and was refluxed for 3 hours. The reaction mixture was cooled to room temperature, diluted with DCM, and was filtered through Celite®, washing with DCM. The filtrate was concentrated and the residue was purified by flash column chromatography (silica gel, 1-3% MeOH-DCM, first column; 10-25% acetone-EtOAc, second column) to afford the title compound as a white solid.
Reaction SMILES: CC1CCP(=O)(C2C=CC=CC=2)C=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([N:26]=[C:27]=O)([CH3:25])[CH3:24])[CH:18]=1)=[CH2:16].[C:29]1([N:35]=C=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(N=C=NC2C=CC=CC=2)C=CC=CC=1>>[C:29]1([N:35]=[C:27]=[N:26][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]([CH3:14])=[CH2:16])[CH:18]=2)([CH3:25])[CH3:24])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: O=C=Nc1ccccc1
Agent: C(=Nc1ccccc1)=Nc1ccccc1
Agent: CC1=CP(=O)(c2ccccc2)CC1
Product: C=C(C)c1cccc(C(C)(C)N=C=Nc2ccccc2)c1

Procedure:
We combined 0.3182 g 3-methyl-1-phenyl-2-phospholene-1-oxide (MPPO), m-TMI [2-(3-isopropenylphenyl)-2-propylisocyanate], and 19.31 g phenyl isocyanate. After heating at 140°-150° C. for 14 hours, IR showed nearly complete conversion of isocyanates to carbodiimides. GC-MS integrated ionization current shows a response of 265944 units for the title mixed product, 3558 units for the diphenyl carbodiimide, and 3602 units for the ditertiarycarbodiimide. Assuming that the detector sensitivity for the mixed product is the same, the selectivity for the mixed product is the average of the two other products, the reaction selectivity for the mixed product is 265944/(265944+3602+3558) or 97%, so the maximum yield of either mixed product is 3%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([O:11][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)C1
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A solution of 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (prepared as described in PCT Int. Appl. 2008131946, 3.180 g, 20.1 mmol) in dichloromethane (100 mL) was subsequently treated with 2,6-lutidine (4.7 mL, 40.2 mmol) and triisopropylsilyl trifluoromethanesulfonate (8.1 mL, 30.15 mmol). After stirring for 3.5 h, the reaction was quenched with pH 4 buffer. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/diethyl ether 1:0 to 9:1 to afford the title compound (6.15 g, 97%) as a light yellow oil and as a 3.5:1 mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3): δ 1.04-1.08 (m, 27H), 1.27 (t, J=7.1 Hz, 4H), 1.70-2.00 (m, 5.2H), 2.04-2.21 (m, 2.6H), 2.66-2.79 (m, 1H), 2.97-3.10 (m, 0.3H), 4.14 (q, J=7.1 Hz, 2.6H), 4.29-4.39 (m, 1H), 4.43-4.50 (m, 0.3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[Br:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][S:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)(=[O:22])=[O:21])=[CH:3][CH:4]=2)[CH:9]=[N:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2c(Br)cncc2c1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2c(Br)cncc2c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
In 1.5 ml of pyridine was dissolved 20 mg (0.09 mmol) of 7-amino-4-bromoisoquinoline (Preparation Example 20), 23 mg of 4-chlorobenzenesulfonyl chloride was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extracting with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. Then, the resulting residue was purified by silica gel thin layer chromatography, to give 13 mg of the title compound. Melting point: gradually decomposed from 229 degrees.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH:14]([OH:15])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])=[C:4]([F:18])[CH:3]=1.[CH3:19][N:20]=[C:21]=[O:22]>C(#N)C.N12CCC(CC1)CN2>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH:14]([O:15][C:21](=[O:22])[NH:20][CH3:19])[CH2:13][N:12]([CH3:16])[C:11]2=[O:17])=[C:4]([F:18])[CH:3]=1
Reactant: COc1cc(N2C(=O)N(C)CC2O)c(F)cc1Cl
Reactant: CN=C=O
Agent: C1CN2CCC1CN2
Solvent: CC#N
Product: CNC(=O)OC1CN(C)C(=O)N1c1cc(OC)c(Cl)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
27.5 g (0.10 mol) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-4-hydroxy-1-methylimidazolidin-2-one (Example 1) are dissolved in 200 ml of acetonitrile, 50 mg of diazabicyclo[2.2.2]octane are added, and 6.84 g (0.12 mol) of methyl isocyanate are added dropwise at 20° C. The mixture is stirred for 5 hours at 50° C. and the solvent is removed by distillation. The solid residue which remains is boiled up in 200 ml of ether and cooled in an ice-bath. The precipitate is filtered off under suction and dried. 31.0 g (93% of theory) of 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-4-(N-methylcarbamoyloxy)imidazolidin2-one are obtained in the form of colorless crystals having the melting point 128°-131° C.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:37])[CH2:19][CH2:20][NH:21][C:22]([C:24]3[N:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[O:27][C:28]=3[CH3:29])=[O:23])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.O>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:26]1[O:27][C:28]([CH3:29])=[C:24]([C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([CH2:4][C:3]([OH:38])=[O:2])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)=[O:37])=[O:23])[N:25]=1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2Cl)nc1C(=O)NCCC(=O)Nc1ccc([C@H]2CC[C@H](CC(=O)O)CC2)cc1
Reaction time: 24 h

Procedure:
Trans-{4-[4-(3-{[2-(2-chlorophenyl)-5-methyloxazole-4-carbonyl]amino}propionylamino)phenyl]cyclohexyl}acetic acid methyl ester (80 mg, 0.149 mmol) was put into THF/water (20 mL, 3:1) solvent, and NaOH (44.61 mg, 1.115 mmol) was added thereto. The mixture was stirred for 24 hours, THF was removed, and pH of the mixture was adjusted to be 2-3 with 1N hydrochloric acid. The reaction mixture was extracted with EtOAC (3×100 mL), washed with brine and dried with anhydrous sodium sulfate, and the solvent was removed. The obtained crude material was crystallized with acetonitrile to obtain a compound (77 mg, 98%) as a white solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[N:8]=1)=O.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:33]=[C:34]([NH:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.C(O)(C(F)(F)F)=O>C(O)C>[CH3:15][O:14][C:11]1[C:12](=[O:13])[C:7]([C:5]2[N:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:40])([F:41])[F:30])[CH:33]=3)[N:39]=[CH:3][CH:4]=2)=[N:8][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH:10]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)C=CN(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(-c2ccnn2-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (136 mg) in ethanol (1.5 mL) was added dropwise a solution of 3-(trifluoromethyl)phenylhydrazine (0.049 mL) and TFA (0.15 mL) in ethanol (1.5 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate), and recrystallized from ethanol/water to give the title compound (123 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[CH3:17]C([N-]C(C)C)C.IC.O>O1CCCC1.C(OCC)(=O)C>[CH3:17][C:9]1([C:12]([OH:14])=[O:13])[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:15]
Reactant: O=C(O)C1CCN(c2ccccc2)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCN(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79.5 %

Procedure:
To a stirred solution of 1-phenyl-2-oxo-3-pyrrolidinecarboxylic acid (205) (200 mg, 0.975 mmol) in dry tetrahydrofuran (5 mL) at −78° C. was added LDA (1.5M solution in cyclohexane, 1.63 mL, 2.44 mmol) and the mixture was stirred for 40 min. Iodomethane (152 μL, 2.44 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. Water and ethyl acetate were added. The aqueous layer was collected, acidified to pH 4 with a 1N HCl solution and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 2:98) to afford title compound 313 (170 mg, 80% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.67 (dd, J=8.8, 1.2 Hz, 2H), 7.39 (dd, J=8.8, 7.2 Hz, 2H), 7.16 (tt, J=7.2, 1.2 Hz, 1H), 3.92-3.80 (m, 2H), 2.54-2.46 (m, 1H), 2.08-1.98 (m, 1H), 1.34 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17](=[N:22][OH:23])[NH2:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: NO
Reactant: N#Cc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzonitrile (730 mg, Example 65), hydroxylamine hydrochloride (0.4 g), sodium carbonate (0.8 g) and ethanol (30 ml) was boiled under reflux for about 16 hours. The solvent was removed under reduced pressure at about 50° C. and the residue stirred with water (70 ml). The mixture was extracted with ethyl acetate and the combined organic phases dried, filtered and evaporated to give a solid. The solid was purified by flash column chromatography on silica using ethyl acetate as eluant to give a solid which was washed with diethyl ether and dried to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide oxime, m.p.>300° C.