Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.N[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH:8]([CH:4]1[O:3][C:2]([NH:1][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][C:5]1=[O:7])([CH3:10])[CH3:9]
Reactant: CC(C)C1OC(N)=NC1=O
Reactant: NCCN1CCOCC1
Product: CC(C)C1OC(NCCN2CCOCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and N-(2-aminoethyl)morpholine according to Method G+H.
Reaction SMILES: [CH:1]1([N:5]([CH3:27])[C:6]2[C:7]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:16]([O:18]C)=[O:17])=[CH:11][CH:10]=3)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH:1]1([N:5]([CH3:27])[C:6]2[C:7]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:8][C:9]3[C:14]([N:15]=2)=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][CH:10]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of methyl 3-(cyclobutyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (70.0 mg, crude) in MeOH (15 mL) was added sodium hydroxide (18.0 mg, 0.45 mmol) and water (0.5 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (10 mL) and adjusted to pH 3 with hydrochloric acid (1N). The solids were collected by filtration to afford 3-(cyclobutyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (30 mg).
Reaction SMILES: Br[C@@H:2]1[C@H:6]2[O:7][CH2:8][CH2:9][C@@:5]2([CH2:10][OH:11])[CH2:4][C@@H:3]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CCOC(C)=O.[Pd]>[OH:11][CH2:10][C@:5]12[CH2:4][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:2][C@H:6]1[O:7][CH2:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1Br
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(CO)C1

Procedure:
A solution of the product of Step G (83 g, 0.245 mol), 10% Pd on C (12.5 g), triethylamine (69 mL, 0.49 mol, 2 eq.) in EtOAc (830 mL) was shaken on a PAAR hydrogenator at 40 psi for 3.5 h until the pressure remained constant. The reaction was filtered with celite, the filter cake was washed with EtOAc, and the collected filtrate was washed with aqueous HCl (1N), brine, dried (Na2SO4) and concentrated under reduced pressure to give the product of Step H. 1H NMR (400 MHz, CHLOROFORM-d) d=4.60-4.73 (m, 1H), 4.06-4.24 (m, 3H), 3.84-3.93 (m, 1H), 3.52-3.67 (m, 4H), 2.12-2.21 (m, 1H), 1.98-2.04 (m, 1H), 1.90 (br. s., 3H), 1.70-1.78 (m, 1H), 1.46-1.56 (m, 3H), 1.44 (s, 11H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][C:7]1[CH:8]=[C:9]([NH2:25])[CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[N:16][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:18][CH:19]=1>FC(F)(F)C(O)=O>[F:6][C:7]1[C:12]([O:13][C:14]2[CH:15]=[N:16][C:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:11][C:10]([N+:1]([O-:4])=[O:2])=[C:9]([NH2:25])[CH:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(N)cc2F)cn1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.8 g of potassium nitrate was added to a trifluoroacetic acid (100 ml) solution of 10.5 g of 3-fluoro-4-(6-ethanesulfonyl-pyridin-3-yloxy)-phenylamine, and the reaction liquid was stirred for 1 hour at room temperature, and the solvent was evaporated away under reduced pressure. The residue was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/2) to obtain the entitled compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[ClH:17].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[ClH:18].[ClH:17].[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:19][CH2:20][CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:9][CH:10]=4)[C:5](=[O:16])[C:4]=3[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C1c2cc(O)ccc2-c2ccc(O)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc(OCCCN3CCCCC3)ccc2-c2ccc(OCCCN3CCCCC3)cc21
Reaction time: 20 h

Procedure:
A mixture of 63.6 g (0.30 mole) of 2,7-dihydroxy-fluoren-9-one, 188 g (0.95 mole) of 1-(3-chloropropyl) piperidine hydrochloride, 132 g (2.0 mole) of 85% potassium hydroxide in 900 ml of toluene and 300 ml of water is refluxed with vigorous stirring for 20 hours. The layers are separated upon cooling and the organic layer is washed 3 times with water, once with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent removed in vacuo. The residue is taken up in isopropyl alcohol and acidified to Congo Red with ethereal hydrogen chloride. The solid which precipitates is filtered, recrystallized from a mixture of 3 parts isopropyl alcohol to 1 part methanol, and the 2,7-bis (3-piperidinopropoxy)fluoren-9-one dihydrochloride so prepared is dried at 100° C. for 24 hours under vacuum, m.p. 279.5°-80.5° C., λmaxH2O 270, and E1cm1% 1370.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][CH:40]=[CH:41][N:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ncccn2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2ncccn2)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 8.3 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoate (0.072 g) in ethyl acetate (4 mL) and methanol (4 mL), 10% palladium-carbon (36 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 45 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 75-60% hexane/ethyl acetate] to obtain 5 mg of tert-butyl 2-(2-hydroxy-5-(pyrimidin-2-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:11])[CH:4]=[CH:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(O[CH3:22])(=O)=O>CC(=O)CC>[CH3:12][O:1][C:2]1[C:3](=[O:11])[CH:4]=[CH:5][CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:22][O:11][C:3]1[C:2](=[O:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: COc1cccc(=O)c(O)c1
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc(=O)c(OC)c1
Product: COc1cccc(OC)c(=O)c1

Procedure:
A mixture of 2-hydroxy-4-methoxy-2,4,6-cycloheptatrien-1-one (described above, 13 g), potassium carbonate (23.6 g), dimethyl sulfate (21.6 g) and 2-butanone (130 ml) is heated at reflux for 3 hours. The mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on silica gel using acetone-ethyl acetate (1:1) and evaporation of the eluates gives 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one and 2,6-dimethoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]1(C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1(C2CCCCC=2)CCCC1.[OH2:30]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]2=[O:30])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cc1ccccc1
Reactant: O
Agent: C1=C(N2CCCC2)CCCC1
Product: O=C(CC1CCCCC1=O)c1ccc(Br)cc1

Procedure:
A suspension of 50 g (0.18 mole) of p-bromophenacyl bromide in 215 ml. of toluene is added in small portions to a stirred boiling solution of 27.2 g (0.18 mole) of 1-pyrrolidino-1-cyclohexene in 90 ml. of toluene. The mixture is heated under reflux for 2 hours, diluted with 90 ml. of water and refluxed for 3 hours. The layers are separated and the aqueous phase is extracted with ether. The organic solution is dried over sodium sulfate and concentrated to an oil which solidifies. The solid is recrystallized from a cyclohexane-ethanol mixture to give 2-(p-bromophenacyl)-cyclohexanone as colorless crystals, m.p. 78°-80° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[CH3:21][O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2nc(NCc3ccc(C)o3)ccc2c1

Procedure:
The title compound, MS: m/e=374.0 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 2-methoxybenzylamine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:42])(=O)=O)=CC=1>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:42])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g, 2.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (1.2 mL, 3.0 mmol, 2.5 M) at -78° C. After 20 minutes, N-fluorobenzenesulfonimide (0-8 g, 3.2 mmol) is added to the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and 1N hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:9][CH:10]=1)[CH3:4].[N:18]#[C:19][NH2:20].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[F:16][C:11]([F:17])([C:8]1[N:9]=[CH:10][C:5]([CH:3]([S:2]([CH3:1])=[N:20][C:19]#[N:18])[CH3:4])=[CH:6][CH:7]=1)[C:12]([F:13])([F:14])[F:15]
Reactant: CSC(C)c1ccc(C(F)(F)C(F)(F)F)nc1
Reactant: N#CN
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Product: CC(c1ccc(C(F)(F)C(F)(F)F)nc1)S(C)=NC#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a stirred solution of the 5-(1-methylthioethyl)-2-pentafluoro-ethylpyridine (A) (0.16 g, 0.6 mmol) and cyanamide (0.025 g, 0.6 mmol) in THF (3 mL) cooled to 0° C. was added iodobenzene diacetate (0.19 g, 0.6 mmol) in one portion and the resulting mixture was stirred at 0° C. for 2 h and then at room temperature overnight. The solvent was removed in vacuo and the resulting mixture was suspended in brine-saturated NaHCO3 (9:1), which was then extracted with CH2Cl2-EtOAc (1:1, v/v) two times. The combined organic layer was dried over Na2SO4, filtered, concentrated, and dried to give 0.16 g of (1-{6-[pentafluoroethyl]pyridin-3-yl}ethyl)(methyl)-λ4-sulfanylidenecyanamide (B) as a brownish oil in 85 percent yield. LC-MS: mass calcd for C11H10F5N3S [M]+ 311.28. Found [M−1]+ 309.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:15]([O-])=O)C(OCC)=O.[CH3:18][NH:19][NH2:20].C[CH:22]([OH:24])C>>[CH3:18][N:19]1[C:22]([OH:24])=[CH:15][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[F:1])=[N:20]1
Reactant: CCOC(=O)C(C(=O)[O-])c1ccc(Cl)cc1F
Reactant: CNN
Reactant: CC(C)O
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1O

Procedure:
A stirred solution of 44.0 grams (0.18 mole) of ethyl (2-fluoro-4-chloro-phenyl)malonate and 9.6 grams (0.24 mole) of methylhydrazine in 150 mL of 2-propanol was heated at reflux for about 48 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was slurred in 80 mL of methylene chloride and filtered to collect 27.0 grams of 1-methyl-2-hydroxy-3-(2-fluoro-4-chlorophenyl)pyrazole.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.C(OCC)(=O)C.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>O>[CH:25]([O:24][C:22]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 91.5 %

Procedure:
To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq), triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g) was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at a rate sufficiently slow to maintain the reaction mixture temperature at 10°-17° C. with reactor jacket cooling. After the addition had been completed, the reaction mixture was stirred at 20° C. for 18 hours. Then water (100 g) was added, and the resulting mixture was stirred for 15 minutes before the phases were separated. The organic phase was washed with two 100-gram-portions of 20 wt % aqueous NaCl by stirring for 15 min at 150 rpm before separating the aqueous wash. After a final wash with water (100 g), the organic phase was concentrated by distillation on a rotary evaporator at reduced pressure to provide product (2) (91.1 g, 92.0% yield) as light amber oil of 96.8% purity by GC. Distillation of this crude product at 117-120° C., 0.3-1.0 torr gave a 95.7% recovery of product (2) as a colorless oil collected at 112°-119° C.
Reaction SMILES: [Sm].II.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>CC#N>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:16])[CH2:14][CH3:15])=[C:8]([CH3:12])[CH:7]=1
Reactant: COc1cccc(C)c1
Reactant: CCC(=O)Cl
Agent: II
Agent: [Sm]
Solvent: CC#N
Product: CCC(=O)c1ccc(OC)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of samarium (598 mg, 3.97 mmol) in CH3CN is added iodine (3.0 g, 11.9 mmol, 3 eq.) and the mixture is stirred at RT for 2 hrs. 1-Methoxy-3-methylbenzene (500 μL, 3.97 mmol, 1 eq) is added followed by the dropwise addition of propionyl chloride (3472 μL, 39.7 mmol). After stirring at RT for 1 hr, the reaction is quenched with water (5 ml) and extracted with EtOAc (2×50 ml). The combined organic extracts are washed with Na2CO3 (2M, 50 ml), sat Na2S2O4 (4×50 ml), water and brine, dried over MgSO4 and concentrated under reduced pressure. The resulting crude residue is purified by column chromatography on silica gel eluting with 10% EtOAc/iso-hexane to yield 1-(4-methoxy-2-methyl-phenyl)-propan-1-one as a clear oil; m/z 179.16 [M+H]+. Alternatively, intermediate C can be made by an analogous process to that for intermediate DA below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([O:31]CC)=O)[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:36][CH3:35])=[O:31])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine (8 M in ethanol) employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.04 (m, 1 H), 8.55 (s, 1 H), 7.41 (s, 1 H), 7.17 (dd, J=8.5, 5.3 Hz, 2 H), 7.02 (t, J=8.6 Hz, 2 H), 4.16-4.11 (m, 4 H), 3.41-3.37 (m, 4 H), 3.01 (d, J=4.9 Hz, 3 H), 2.39 (t, J=8.0 Hz, 2 H), 2.05 (m, 2 H), 1.83 (m, 2 H); HRMS C24H25FN4O4 (M+H)+ calcd 453.1938, found 453.1945.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26]([OH:28])=O)=[CH:21][CH:20]=[CH:19]2.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([NH2:37])[CH:31]=1>>[NH2:37][C:32]1[CH:31]=[C:30]([Br:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:26]([C:22]1[C:23]2[C:24](=[CH:25][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[CH:19]=[CH:20][CH:21]=1)=[O:28]
Reactant: Nc1ccc(Br)cc1N
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)Nc5ccc(Br)cc5N)cccc4c3)c2cc1OC
Yield: 77 %

Procedure:
The title compound (42.0 mg, 77% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-bromo-o-phenylenediamine (22.4 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.01 (s, 6H, 2×OCH3), 5.31 (s, 2H, benzene-NH2), 6.77 (d, J=8.3 Hz, 1H, Ar—H), 7.01 (s, 1H, Ar—H), 7.41 (s, 1H, Ar—H), 7.58-7.65 (m, 5H, Ar—H), 7.89 (d, J=7.0 Hz, 1H, Ar—H), 8.00 (s, 1H, Ar—H), 8.14 (d, J=10.2 Hz, 1H, Ar—H), 8.37 (d, J=9.1 Hz, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). LC-MS (m/z) 545 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([O-])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[Cl:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].[NH2:32][C@H:33]([CH:38]([CH3:40])[CH3:39])[CH2:34][C:35]([OH:37])=[O:36]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:32][C@H:33]([CH:38]([CH3:40])[CH3:39])[CH2:34][C:35]([OH:37])=[O:36])=[O:15])[CH:11]=[CH:10][C:9]=2[C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[Cl:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30]
Reactant: CC(C)[C@@H](N)CC(=O)O
Reactant: Cc1ccc(Cl)c(-c2ccc(C(=O)[O-])nc2-c2ccc(Cl)c(OCCCN(C)C)c2)c1
Product: Cc1ccc(Cl)c(-c2ccc(C(=O)N[C@@H](CC(=O)O)C(C)C)nc2-c2ccc(Cl)c(OCCCN(C)C)c2)c1
Product: Cl
Yield: 130.2 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 9 respectively, starting from 385 mg (0.84 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate and 130 mg (1 mmol) of (3S)-3-amino-4-methylpentanoic acid (J. Org. Chem., 1999, 6411-6417), we obtain 333 mg of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride in the form of white powder.
Reaction SMILES: [C:1]([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:25]([O-:28])([O-])=O.[Cs+].[Cs+].[C:31]([O:34][CH2:35]Br)(=O)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:8][N:9]1[C:15](=[O:16])[CH:14]([C:25](=[O:28])[CH2:31][O:34][CH3:35])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Reactant: CC(=O)OCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCC(=O)C1C(=O)N(NC(=O)OC(C)(C)C)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.03, 3.08 mmol) (Example 3-E) in DMF was treated with Cs2CO3 (1.10 g, 3.39 mmol) and warmed to 60° C. To the reaction mixture was added bromomethyl acetate (0.321 mL, 3.39 mmol) (Aldrich) and stirring continued for 17 hours. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3).
Reaction SMILES: [OH-].[K+:2].[SH2:3].Cl[C:5]1[N:10]=[N:9][C:8](Cl)=[C:7]2[CH:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:6]=12.[SH-:22].[K+]>C(O)(=O)C.CO>[SH-:3].[K+:2].[SH:3][C:5]1[N:10]=[N:9][C:8]([SH:22])=[C:7]2[CH:12]=[N:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:6]=12
Reactant: S
Reactant: Clc1nnc(Cl)c2cc(-c3ccccc3)ncc12
Agent: [K+]
Agent: [OH-]
Agent: [SH-]
Solvent: CO
Solvent: CC(=O)O
Product: Sc1nnc(S)c2cc(-c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium hydrosulfide methanolic solution is prepared by reacting 7 parts by weight of potassium hydroxide, 150 parts by volume of methanol and hydrogen sulfide gas in accordance with the known method. 4.2 parts by weight of 1,4-dichloro-7-phenyl-pyrido (3,4-d) pyridazine is added to the potassium hydrosulfide solution, and the resulting mixture is stirred at room temperature for three hours. Methanol is evaporated under reduced pressure, and the residue is added to 50 parts by volume of water to obtain a solution. The solution is acidified by the addition of acetic acid to precipitate yellow crystals. The crystals are collected by filtration, washed with water and dried to obtain 1,4-dimercapto-7-phenyl-pyrido (3,4-d) pyridazine melting at 212° to 215° C (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH:11]2[CH2:13][CH2:12]2)=[N:9]/[OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[C:19]([F:32])=[C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([F:25])=[CH:22][C:23]=1[F:24].CN(C)C=O>C1(C)C=CC=CC=1>[F:32][C:19]1[C:18]([CH2:17][O:10]/[N:9]=[C:8](/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)\[CH:11]2[CH2:12][CH2:13]2)=[C:23]([F:24])[CH:22]=[C:21]([F:25])[C:20]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O/N=C(/c1ccc(Cl)cc1)C1CC1
Reactant: Fc1cc(F)c(-c2ccccc2)c(F)c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2ccccc2)c(F)c1CO/N=C(/c1ccc(Cl)cc1)C1CC1
Yield: 40.1 %

Procedure:
In a manner similar to Example 6 of U.S. Pat. No. 4,079,149, the reaction of 0.59 g (0.003 mole) of (E)-(4-chlorophenyl)(cyclopropyl)methanone oxime with 0.072 g (0.003 mole) of sodium hydride and 0.77 g (0.003 mole) of 3-chloromethyl-2,4,6-trifluoro[1,1'-biphenyl] in 25 ml of a 20% solution of N,N-dimethylformamide in toluene produced 0.5 g of (E)-(4-chlorophenyl)(cyclopropyl)methanone O-[(2,4,6-trifluoro[1,1'-biphenyl]-3-yl)methyl]oxime as an oil.