Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]#[N:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O.O>C(#N)C>[Br:18][C:12]1[C:13]([F:14])=[C:8]([C:5]2[C:4]([C:16]#[N:17])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([F:15])=[CH:10][CH:11]=1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: N#Cc1cc(F)ccc1-c1c(F)cccc1F
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(F)ccc1-c1c(F)ccc(Br)c1F
Temperature: 70 °C
Reaction time: 7 h
Yield: 171.1 %

Procedure:
To a slurry of 4,2′,6′-trifluorobiphenyl-2-carbonitrile (5.0 g, 21.4 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (3.37 g, 11.8 mmol) in acetonitrile (45 ml) was added concentrated sulphuric acid (3.15 g, 32.2 mmol). The slurry was warmed to 70° C. and the resulting solution stirred for 7 h then stood at ambient temperature for 18 h. Water (45 ml) was added dropwise to the solution over 15 min. The layers were allowed to settle and the product rapidly crystallised. The slurry was left to stir for 0.5 h then filtered, washed with 1:1 acetonitrile/water (10 ml) and left to air-dry, which gave 3′-bromo-4,2′,6′-trifluorobiphenyl-2-carbonitrile (6.3 g, 94%) as a white solid: δH (360 I, CDCl3) 6.97-7.08 (1H, m), 7.38-7.54 (2H, m), 7.62-7.68 (1H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 82.7 %

Procedure:
A solution of 1-benzyl-4-piperidone (4.9 mL, 26.5 mmol) in anhydrous diethyl ether (50 mL) was cooled to −78° C. and treated with methyllithium (1.4 M, 21 mL, 29 mmol). This mixture was stirred for 2.5 hr at −78° C., then quenched with aqueous brine, and extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2→90:10:1 CH2Cl2/methanol/NH4OH) to yield 4.5 g (83%) of the title compound, ESI-MS m/z: 206 [M+1].
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:36][NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[C:10](=O)[CH2:11][C@H:12]1[N:15]([C:16](=O)[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:14](=[O:24])[C@@H:13]1[C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH3:26])=[O:6])[CH:2]=[CH2:3].P(OCC)(OCC)OCC.C1(C=CC(O)=CC=1)O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([C:10]1[CH2:11][C@H:12]2[N:15]([C:14](=[O:24])[C@@H:13]2[C@H:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29])[CH3:26])[C:16]=1[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:36][NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NCC(CNC(=O)OCC=C)C(=O)C[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N1C(=O)C(=O)OCC=C
Agent: CCOP(OCC)OCC
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NCC(CNC(=O)OCC=C)C1=C(C(=O)OCC=C)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2C1
Temperature: 130 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
A solution of 0.48 g of allyl 2-[(3S,4R)-4-(4-allyloxycarbonylamino-3-(N-allyloxycarbonylaminomethyl)-2-oxobutyl]-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-oxoazetidin-1-yl]-2-oxoacetate and 0.39 ml of triethyl phosphite in 2.4 ml of toluene was stirred at 90° C. for 10 hours. After ylid was identified by thin layer chromatography the temperature was raised to 130° C. and 42 mg of hydroquinone was added. After stirring for 4 hours at 130° C., the reaction mixture was cooled to room temperature and then ethyl acetate was added. The organic layer was washed in turn with 5% aqueous potassium carbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel to give 0.28 g of allyl (5R,6S)-3-[2-allyloxycarbonylamino-1-(N-allyloxycarbonylaminomethyl)ethyl]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:24])=[O:12])=[CH:5]2.C(OC(N[C@@H]1CC2C(=CC=CC=2)NC1=O)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]1=[O:24])=[O:12])=[CH:5]2
Reactant: O=C(N[C@@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2NC1=O
Product: O=C(N[C@H]1Cc2ccccc2NC1=O)c1cc2cc(Cl)ccc2[nH]1

Procedure:
The title compound was prepared from (S)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril (prepared in Example 5) by the procedures described for the preparation of (R)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 5) from (R)-3-t-butyloxycarbonylamino-3,4-dihydrocarbostyril. HPLC/MS [M+H]+, 340; [M+Na]+, 362.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>O1CCCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:32])[N:8]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepi n-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 271°-273° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][N:18]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:24][C:25]([OH:42])([CH3:41])[CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>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>[CH:19]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:12]1[N:13]=[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([C:30]4[CH:29]=[N:28][N:27]([CH2:26][C:25]([CH3:41])([OH:42])[CH3:24])[CH:31]=4)=[CH:3][C:4]=3[O:10][CH2:9][CH2:8][N:7]2[CH:11]=1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)n1ccnc1-c1cn2c(n1)-c1ccc(-c3cnn(CC(C)(C)O)c3)cc1OCC2
Temperature: 25 °C

Procedure:
9-bromo-2-(1-isopropyl-1H-imidazol-2-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (157 mg, 0.421 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (139.9 mg, 0.5258 mmol), and Tetrakis(triphenylphosphine)palladium(0) (68.05 mg, 0.05889 mmol) dissolved in Acetonitrile (2.66 mL, 50.9 mmol) and with dissolved 2.00 M of Potassium carbonate in Water (0.421 mL). The reaction mixture was degassed. The reaction was microwaved on 150 watts, 140° C. for 10 minutes. The reaction was cooled to r.t., extracted with ethyl acetate to give crude product purified by rHPLC to give 214. MS: (ESI+)=433.2. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.4 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.68 (s, 1H), 7.42-7.31 (m, 2H), 7.26 (d, J=1.7 Hz, 1H), 6.94 (s, 1H), 5.66 (dt, J=13.5, 6.7 Hz, 1H), 4.74 (s, 1H), 4.50 (s, 4H), 4.03 (s, 2H), 1.46 (d, J=6.7 Hz, 6H), 1.09 (s, 6H)
Reaction SMILES: C(O)C.[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6].[BH4-].[Na+]>O>[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC1CCC(C2CCC(CO)CC2)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.5 %

Procedure:
Ethanol (30 ml) was added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (2.3 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to 0° C., and sodium borohydride (0.22 g) was added slowly. After the mixture had been returned to room temperature and stirred for another 20 hours and water (30 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/2 by volume) to give (4-(3-propylcyclopentyl)cyclohexyl)methanol (2.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[C:12](O)(=O)[CH3:13]>>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: CC(=O)O
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 130 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
4-Amino-3-hydroxybenzoic acid (4.9 g) was added to acetic acid (250 ml) and stirred for 3 days at 130° C. The solution was concentrated under reduced pressure, and precipitates were collected by filtration. The precipitates were dissolved in methanol and chloroform. The solution was concentrated under reduced pressure, and precipitates were collected by filtration, washed with methanol and dried under reduced pressure to give the title compound (3.5 g, Y.:62%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([NH:10][CH:11]=[O:12])[CH:9]=1.[CH2:21]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:21][N:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:3][C@@H:2]([C:4]2[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([NH:10][CH:11]=[O:12])[CH:9]=2)[OH:1])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=CNc1cc([C@@H]2CO2)ccc1OCc1ccccc1
Product: O=CNc1cc([C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
A mixture of {5-[(2R)-2-oxiranyl]-2-[(phenylmethyl)oxy]phenyl}formamide (WO 0276933) (200 mg) and dibenzylamine (0.75 ml) were heated in a microwave oven at 150° for 30 min. The mixture was allowed to cool to 20° and was purified on a silica SPE bond elut cartridge (10 g) using a gradient of 0% to 50% EtOAc in cyclohexane (Gradmaster™). The appropriate fractions were evaporated in vacuo and the residue further purified by mass-directed autopreparative HPLC to give the title compound (123 mg). LCMS RT=2.75 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[CH:20]=[C:19]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=4[F:30])[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:2]1.CCN(C(C)C)C(C)C.[C:40](O)(C(F)(F)F)=[O:41]>CN(C=O)C>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][NH:21][C:19]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:4][N:1]([CH:40]=[O:41])[CH2:2]3)=[CH:6][CH:7]=2)[CH:20]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CNC3)cc2)cc1NCc1cccc(F)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnc(Nc2ccc(C3CN(C=O)C3)cc2)cc1NCc1cccc(F)c1F

Procedure:
Compound 6-(4-(azetidin-3-yl)phenylamino)-4-(2,3-difluorobenzylamino)nicotinamide (Example 212) (35 mg, 0.08 mmol) was stirred in 4 mL DMF with DIEA (300 μL) at 120° C. in a sealed tube for three days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (11 mg). MS found for C23H21F2N5O2 as (M+H)+ 438.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.02 (1H, s), 7.44 (2H, dt, J=8.0; 1.6 Hz), 7.24 (1H, m), 7.17 (2H, dt, J=8.4; 1.6 Hz), 7.14 (1H, m), 7.11 (1H, m), 5.82 (1H, s), 4.68 (1H, t, J=8.0 Hz), 4.56 (2H, s), 4.46 (1H, m), 4.27 (1H, m), 4.05 (2H, m) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](C=O)[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:31])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:31])[CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To the solution of 4-(2-fluoro-4-formyl-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (97 mmol) in CH2Cl2 (600 ml), m-chloroperbenzoic acid (194 mmol) is added at 0° C. for 5 min and NaHCO3 (243 mmol) is added at 0° C. The mixture is stirred at 0° C. for 20 min and at room temperature for 1 h. To the mixture, m-chloroperbenzoic acid (48.5 mmol) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h, slowly quenched with saturated NaHCO3 at 0° C. and extracted with AcOEt. The combined extracts are washed with saturated NaHCO3, brine and dried over magnesium sulfate. The solvent is evaporated. To the residue, 10% KOH/EtOH is added at 0° C. and the reaction mixture is stirred at room temperature for 1 h. After the mixture is extracted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtered. The solvent is evaporated and the residue is chromatographed on silica gel using n-hexane, n-hexane:AcOEt=5:1, n-hexane:AcOEt=4:1, n-hexane AcOEt=3:1 to give the desired 4-(2-fluoro-4-hydroxy-phenyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[H-].[Na+].F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>O1CCOCC1.C(OCC)(=O)C>[CH:1]1([O:4][C:8]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(F)cc1F
Reactant: OC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1ccc(F)cc1OC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution cyclopropanol (1.9 g, 29 mmol) in 20 mL dioxane was added dropwise to a 0° C. solution of Sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL dioxane. The reaction mixture was allowed to warm to room temperature, 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added portionwise, and reaction temperature raised to 95° C. The reaction solution was cooled to room temperature after stirring for 18 hours, diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgSO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0-10% EtOAc/hexanes) afforded 2-cyclopropoxy-4-fluorobenzonitrile. 1H-NMR (400 MHz, Chloroform-d) δ 7.52 (dd, J=8.6, 6.2 Hz, 1H), 7.05 (dd, J=10.5, 2.3 Hz, 1H), 6.73 (td, J=8.2, 2.3 Hz, 1H), 3.87-3.76 (m, 1H), 0.87 (m, 4H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>CCO.O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:14]/[OH:15])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=Cc1ccc2cnccc2c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O/N=C/c1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of isoquinoline-6-carbaldehyde (2.48 g, 15.8 mmol) (prepared as shown in Example 6) in 160 mL of 1:2 EtOH:H2O was added hydroxylamine hydrochloride (1.21 g, 17.4 mmol). The mixture was cooled to 0° C., and 50 wt % NaOH in H2O (3.2 mL, 0.2 mL per mmol of aldehyde) was added dropwise. The mixture was then stirred at 0° C. for 2 hours, at which time the pH was adjusted to about 6 with 10% aqueous HCl. The resulting biphasic mixture was then transferred to a separatory funnel and extracted five times with 150 mL of DCM. The combined organic layers were dried over MgSO4. Concentration under reduced pressure afforded (E)-isoquinoline-6-carbaldehyde oxime (2.14 g, 78.8% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 9.20 (s, 1H), 8.44 (d, J=5.9 Hz, 1H), 8.28 (s, 1H), 8.06 (s, 2H), 7.99 (s, 1H), 7.83 (s, 5.9 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][C:9]([C:11]([C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:35])=[N-].C(OCC)C.CN(N=O)C(N)=O>C(OCC)C.C1(C)C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([C:11]([C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH:12][CH3:35])=[O:10])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=[N+]=[N-]
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc(C(=O)OCC)c(F)c1F
Agent: CN(N=O)C(N)=O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc(C(=O)OCC)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.2 %

Procedure:
In 30 ml of diethyl ether was dissolved 3.08 g of ethyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5-trifluorobenzoate. To the resulting solution was added, with ice-cooling, a diazomethane-diethyl ether solution prepared from 2.00 g of N-methyl-N-nitrosourea. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of toluene. The resulting solution was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene) to obtain 2.90 g (yield: 91.2%) of ethyl 4-(1-diphenylmethoxycarbonyl-2-methylvinyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([C:12]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[C:37](=[O:42])[C:38](=[O:41])[C:39]=3[OH:40])=[CH:26][CH:25]=2)[C:15]2=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]2[N:13]=1)[CH3:11].[I-].[K+].C(OCC)C>CN(C)C(=O)C>[C:1]([O:7][CH2:8][O:42][C:37]1[C:38](=[O:41])[C:39](=[O:40])[C:36]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:22]2[C:15]3=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]3[N:13]=[C:12]2[CH2:10][CH3:11])=[CH:25][CH:26]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(O)c(=O)c2=O)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2c(OCOC(=O)C(C)(C)C)c(=O)c2=O)cc1
Reaction time: 48 h

Procedure:
Chloromethyl pivalate (3.22 g) was added, dropwise, at ambient temperature, to a stirring suspension of 3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl -2-yl]-4-hydroxycyclobut-3-ene-1,2-dione (4.21 g; preparable as in Example 4) in dry N,N-dimethylacetamide (40 ml). Potassium iodide (2.5 g) was added to the resulting mixture and stirring was continued am ambient temperature for 2 days. More chloromethyl pivalate (3.7 g) was added and stirring was continued for an additional 2 days. The mixture obtained was poured into diethyl ether (500 ml) to give a gum which was separated and then dissolved in a mixture of acetone (100 ml) and ethyl acetate (300 ml). The resulting solution was washed with saturated aqueous sodium bicarbonate solution (2×400 ml) then water (2×400 ml) and dried over magnesium sulphate. The solvents were evaporated under reduced pressure and the residue obtained was purified by flash chromatography on silica gel (eluting with ethyl acetate) to give 2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxymethyl pivalate, an active compound of the present invention, as a fellow foam (0.54 g) which melted slowly at 60°-80° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[S:10])=[S:9].C([O-])(=O)C.[Zn+2:15].C([O-])(=O)C.[CH3:20][CH:21]1[O:25][CH:24]([C:26]([Cl:29])([Cl:28])[Cl:27])[NH:23][CH2:22]1.[Zn]>O>[CH3:20][CH:21]1[O:25][CH:24]([C:26]([Cl:29])([Cl:28])[Cl:27])[N:23]([C:8]([S-:10])=[S:9])[CH2:22]1.[CH3:20][CH:21]1[O:25][CH:24]([C:26]([Cl:29])([Cl:28])[Cl:27])[N:23]([C:8]([S-:10])=[S:9])[CH2:22]1.[Zn+2:15]
Reactant: S=C=S
Reactant: CC1CNC(C(Cl)(Cl)Cl)O1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CN(C(=S)[S-])C(C(Cl)(Cl)Cl)O1
Reaction time: 8 h

Procedure:
A mixture of 412.0 g. (4.0 moles) triethylamine, 60.8 g. (0.8 mole) carbon disulfide, 73.2 g. (0.4 mole) anhydrous zinc acetate and 163.6 g. (0.8 mole) 5-methyl-2-trichloromethyloxazolidine was stirred at 40° C. for 1 hour. After standing overnight at room temperature, the reaction mixture was diluted with water and filtered to give 417.8 g. of the desired crude product sintering at 89° C. and melting with decomposition at 128°-150° C. Extraction with chloroform and repeated crystallization from benzene gave an analytical sample melting at 170°-176° C. with decomposition. It had the following analysis: Found: N, 4.30; Zn, 10.16. Calc. for C12H14Cl6N2O2S4Zn: N, 4.48; Zn, 10.47.
Reaction SMILES: C[O:2][C:3]([P:5]([O:11][O:12][CH2:13][CH3:14])([O:7][O:8][CH2:9][CH3:10])=[O:6])=O.O.[NH2:16][NH2:17]>C(O)C>[CH2:9]([O:8][O:7][P:5]([C:3]([NH:16][NH2:17])=[O:2])([O:11][O:12][CH2:13][CH3:14])=[O:6])[CH3:10]
Reactant: NN
Reactant: CCOOP(=O)(OOCC)C(=O)OC
Solvent: CCO
Solvent: O
Product: CCOOP(=O)(OOCC)C(=O)NN
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
19.6 parts by weight of diethoxyphosphonoformic acid methyl ester are diluted with 10 parts by volume of ethanol, and a solution of 5.0 parts by weight of hydrazine hydrate in 10 parts by volume of ethanol is added at +10 to +20° C. The mixture is stirred at room temperature for 8 hours, the solvent is moved in vacuo and 19.4 parts by weight (yield 99%) of crude diethoxyphosphonoformic acid hydrazide, which is further processed without purification, are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH2:37]Cl)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(C)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.