Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13]([OH:20])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH3:14])[CH:3]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:12])[CH2:10][O:20][C:13]([CH3:14])([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: CC(O)(c1cccs1)c1cc(Br)ccc1NC(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of N-[4-bromo-2-(1-hydroxy-1-thien-2-ylethyl)phenyl]-2-chloroacetamide (1.29 g, 3.44 mmol) in anhydrous THF (20 mL) was added at 0 under nitrogen sodium hydride (60% in mineral oil, 0.38 g, 9.5 mmol). After addition, the reaction mixture was stirred for 3 h, treated with an aqueous saturated ammonium chloride solution (30 mL). Ethyl acetate (50 mL) was added and organic layer separated, dried (Mg2SO4), and concentrated to yield the title compound as a white solid (1.1 g, 96%). 1H-NMR (DMSO-d6) δ 10.13 (s, 1H), 7.57 (dd, J=5.0, 1.0 Hz, 1H), 7.47 (dd, J=8.6, 1.4 Hz, 1H), 7.39 (d, J=1.67 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.00 (m, 1H), 6.88 (dd, J=2.6, 0.9 Hz, 1H), 4.18 (d, J=15.8 Hz, 1H), 4.03 (d, J=16.3 Hz, 1H), 1.99 (s, 3H). MS (ES) m/z 338/340 ([M+H]+, 100%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[CH:19]([CH2:20][CH3:21])[CH2:18][CH:17]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:16]2[S:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1>ClCCl>[CH:8]([O:11][C:12]([N:14]1[CH:19]([CH2:20][CH3:21])[CH2:18][CH:17]([N:22]([C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:25]=2)[C:16]2[S:38][CH:39]=[CH:40][C:15]1=2)=[O:13])([CH3:9])[CH3:10]
Reactant: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2sccc2N1C(=O)OC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(C)=O)c2sccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
Inject acetic anhydride (0.250 ml, 2.65 mmol) dropwise to a solution of crude 7-(3,5-bis-trifluoromethyl-benzylamino)-5-ethyl-6,7-dihydro-5H-thieno[3,2-b]pyridine-4-carboxylic acid isopropyl ester (0.120 g, 0.243 mmol) and pyridine (0.250 ml, 3.10 mmol) in dichloromethane (1 ml) at room temperature. Stir the mixture at room temperature for 16 h. Evaporate the solvents and purify the resulting reside using silica gel column chromatography (gradient eluent, 0-35% ethyl acetate in hexane) to provide the title compound (0.0290 g, 22%). MS (ES+): 559 (M+Na); (ES−): 535 (M−H). cl Example 2
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[F:18][C:19]1[C:20]([N+:28]([O-:30])=[O:29])=[C:21]([O:26][CH3:27])[CH:22]=[C:23](F)[CH:24]=1>CN1C(=O)CCC1>[F:18][C:19]1[CH:24]=[C:23]([CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:22]=[C:21]([O:26][CH3:27])[C:20]=1[N+:28]([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Di-t-butyl malonate(18 g) was added dropwise to a stirred suspension of sodium hydride[60% dispersion in mineral oil](3.3 g) in N-methyl pyrrolidinone(100 mL) under an atmosphere of argon and the mixture was stirred until effervescence ceased. 3,5 Difluoro-2-nitro-anisole(6.4 g) was added and the mixture was stirred at 80° C. for 2 h. The mixture was cooled to room temperature then partitioned between water and ether and then the ether extract was dried and evaporated to dryness. The residue was subjected to flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product(5.5 g)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11](C2C=CC=CC=2N)=[CH:10][CH:9]=1)([O-:3])=[O:2].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].[N:33]1C=CC=CC=1>>[N+:24]([C:22]1[CH:21]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:33][C:28](=[O:29])[O:30][CH2:31][CH3:32])=[CH:12][CH:13]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1-c1ccc(Oc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1
Reactant: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
[4-(3,5-Dinitrophenoxy)phenyl]benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(3,5-dinitrophenoxy)phenyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH:26]([CH3:28])[CH3:25])[CH2:15][CH2:14]3)[N:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n(-c3ccccc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 5 (30 mg, 0.089 mmol) in DCM (0.5 mL) were added acetone (0.026 mL, 0.355 mmol), triacetoxyborohydride (75 mg, 0.355 mmol) and acetic acid (10.7 mg, 0.178 mmol). The mixture was stirred at room temperature overnight, quenched with 1 N NaOH, and extracted with EtOAc. The organic layer was washed with water, dried (MgSO4) and concentrated. The residue was purified by preparative TLC (4% MeOH/DCM) to give the title compound. LC-MS m/z 380.16 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[CH3:16].[O-:17][C:18]#[N:19].[K+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:9]2[C:18](=[O:17])[NH:19][C:13](=[O:15])[C:10]32[CH2:11][CH2:12]3)=[CH:6][C:7]=1[CH3:8]
Reactant: N#C[O-]
Reactant: Cc1cc(NC2(C(=O)O)CC2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)NC(=O)C23CC3)cc(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a mixture of 1-((4-bromo-3,5-dimethylphenyl)amino)cyclopropane carboxylic acid (198 mg, 0.697 mmol) in acetic acid (3 mL) and dichloromethane (1.5 mL), potassium cyanate (424 mg, 5.23 mmol) was added at room temperature. The mixture was stirred at room temperature for one hour, and then stirred at 60° C. for two hours. A saturated aqueous sodium hydrogen carbonate solution was added to adjust pH to 8, and this mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 4-(4-bromo-3,5-dimethylphenyl)-4,6-diazaspiro[2.4]heptane-5,7-dione (49 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[SH:15][CH2:16][CH2:17][C:18]([OH:20])=O.C(=O)([O-])[O-].[NH4+:25].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:5]([CH:6]2[S:15][CH2:16][CH2:17][C:18](=[O:20])[NH:25]2)[CH:4]=1
Reactant: [NH4+]
Reactant: O=C(O)CCS
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1cc(C2NC(=O)CCS2)cc(OC)c1OC
Temperature: 80 °C
Yield: 77 %

Procedure:
A mixture of 19.6 g of 3,4,5-trimethoxybenzaldehyde, 10.6 g of 3-mercaptopropionic acid and 6 g of ammonium carbonate in 250 ml of benzene was refluxed for 5 hours at 80° C. in a flask provided with a Dean-Stark apparatus and the thus distilled water was removed. The crystals which separated out from the reaction mixture after reaction was over and on cooling the reaction mixture, were collected by filtration and recrystallized from benzene to give 21.8 g of colourless aciculates melting at 181° to 182° C. in a yield of 77%.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(#N)C>[F:12][C:11]1[C:2]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:3]2[C:8]3=[C:9]([C:13](=[O:19])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[N:6]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:5][CH2:4]2)[CH:10]=1
Reactant: C1CCNC1
Reactant: O=C(O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2Cc1ccccc1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
50 mg of compound (182) obtained in Example 59, 26 mg of pyrrolidine and 10 mg of triethylamine were added to 3 ml of acetonitrile, and the solution was heated at 80° C. for 3 hours. The solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with ethanol and ether in this order to obtain 33 mg of the subject compound (183).
Reaction SMILES: IC.[CH3:3][O:4][C:5](=[O:23])[C@@H:6]1[CH2:10][C@@H:9]([O:11]C(=O)C2C(C)=CC(C)=CC=2C)[CH2:8][NH:7]1.C(N(CC)CC)C.C(Cl)[Cl:32]>[Cl-].[Na+].O>[ClH:32].[CH3:3][O:4][C:5](=[O:23])[C@@H:6]1[CH2:10][CH:9]([OH:11])[CH2:8][NH:7]1
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)c2c(C)cc(C)cc2C)CN1
Reactant: ClCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CC(O)CN1
Product: Cl
Yield: 32 %

Procedure:
Iodomethane (573.0 mL, 9.20 mmol) was slowly added through a condenser at 0° C. To a suspension of trans-4-(2,4,6-trimethylbenzoyloxy) proline methyl ester (21 b, 1.35 g, 4.60 mmol) and triethylamine (1.29 mL, 9.20 mmol)in anhydrous methylene chloride (5 mL). The mixture was then refluxed overnight. Brine (20 mL) was then added to the mixture and the mixture was extracted with chloroform (30 mL 4X). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1:1) to give 543.0 mg (32% yield from 4-hydroxyproline methyl ester hydrochloride salt) of the title compound (21c) as an oil. TLC Rf =0.65 (ethyl acetate:hexane=2:l). MS (DCl/NH3) m/e 306 (M+H)+. 1H NMR (CDCl3) δ: 6.85 (s, 2H, 2ArH), 5.44-5.52 (m, 1H, OCH), 3.77 (s, 3H, OCH3), 2.26-2.64 (m, 4H, 2CH2), 2.47 (s, 3H, NCH3), 2.30 (s, 6H, 2ARCH3), 2.28 (s, 3H, ARCH3).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[CH3:11][N:12]1[CH2:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH2:14][CH2:13]1.Cl>C(OCC)C.C1(C)C=CC=CC=1>[CH3:21][O:20][C:18]([C@H:16]1[C@@H:15]([C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=2)[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17]1)=[O:19].[CH3:21][O:20][C:18]([C@H:16]1[C@H:15]([C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=2)[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17]1)=[O:19]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: COC(=O)C1=CCCN(C)C1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CN(C)CC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: COC(=O)[C@@H]1CN(C)CC[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 6 h
Yield: 10 %
Yield: 25 %

Procedure:
A stirred suspension of magnesium turnings (3.4 g, 142 mmol) in diethyl ether (20 ml) was added a solution of 1-bromo-3,4-dichlorobenzene (29 g, 130 mmol) in diethyl ether (150 ml). The mixture was heated at reflux for 20 minutes and then cooled at −40° C. A solution of arecoline (10 g, 65 mmol) in toluene (100 ml) was added slowly while keeping the internal temperature between −40° C. and −30° C. The reaction mixture was stirred at −20° C. for 6 hours and then added 4 N HCl (50 ml). The phases were then separated and the aqueous phase was added ammonia (aq) until basic pH and extracted with dichloromethane (4×100 ml), dried with magnesium sulfate and evaporated to an oil. The isomers (1) and (2) were separated by column chromatography (petroleum ether, ether, triethylamine 70:25:5) to give 5.0 g (25%) of (1) (mp. 70-75° C.) and 2.0 g (10%) of (2) (oil).
Reaction SMILES: [CH2:1]([P:5](=[O:14])([O:10][CH:11]([CH3:13])[CH3:12])[O:6][CH:7]([CH3:9])[CH3:8])[C:2]([CH3:4])=O.[NH2:15]/[C:16](/[CH3:22])=[CH:17]\[C:18]([O:20][CH3:21])=[O:19].[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O)([O-:25])=[O:24].C(O)(=O)C.N1CCCCC1>C(O)(C)C>[CH3:22][C:16]1[NH:15][C:2]([CH3:4])=[C:1]([P:5]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])=[O:14])[CH:29]([C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)CP(=O)(OC(C)C)OC(C)C
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(P(=O)(OC(C)C)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 34.7 %

Procedure:
A mixture of 2.44 grams of diisopropyl acetonylphosphonate, 1.15 grams of methyl 3-aminocrotonate, and 1.51 grams of m-nitrobenzaldehyde was dissolved in 10 ml of isopropanol, then 290 mg of piperidine acetate was added thereto, and the mixture was heated to reflux for sixteen hours with stirring. The reaction solution was concentrated in vacuo, to the residue was added ether, the resulting crystals were collected by filtration, washed with ether and then with water, dried, and recrystallized from ethyl acetate to afford 1.57 grams (yield 34%) of methyl 2,6-dimethyl-4-(3-nitrophenyl)-5-diisopropoxyphosphinyl-1,4-dihydropyridine-3-carboxylate, melting point 205°-7° C.
Reaction SMILES: [CH:1]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.[F:38][C:39]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42].C(N(CC)C(C)C)(C)C>ClCCCl>[CH:4]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:35]([NH:42][CH2:41][C:40]4[CH:43]=[CH:44][C:45]([F:47])=[CH:46][C:39]=4[F:38])=[O:36])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: NCc1ccc(F)cc1F
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1C2CCC1CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)NCc2ccc(F)cc2F)ccc1OCCN1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture stirred at room temperature for 1 hour. To the resulting precipitate mixture was added 2,4-difluorobenzylamine (0.030 mL, 0.25 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), and the mixture stirred an additional 1 hour. The mixture was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (62 mg, 87%). LCMS m/z (%)=560 (M+H 79Br, 100), 562 (M+H 81Br, 91). 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (bs, 1H), 7.58 (bs, 1H), 7.48-7.38 (m, 2H), 7.29 (bs, 1H), 7.24-7.18 (m, 1H), 7.10-7.04 (ma, 2H), 6.60-5.59 (m, 1H), 4.29 (d, J=4.0 Hz, 2H), 4.06-3.96 (m, 2H), 3.64 (s, 3H), 3.11 (bs, 2H), 2.58-2.54 (m, 2H), 1.54-1.52 (m, 4H), 1.15-1.13 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1B(O)O.[CH2:25](N(CC)CC)C>C(Cl)Cl>[CH3:25][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([I:11])=[C:2]([O:1][C:13]2[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: OB(O)c1ccc2ccccc2c1
Solvent: ClCCl
Product: COC(=O)c1ccc(I)c(Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-hydroxy-4-iodo-benzoic acid acid methyl ester (0.505 g, 1.82 mmol), cupric acetate (0.330 g, 1.82 mmol), 2-naphthylboronic acid (0.625 g, 3.63 mmol) and powdered 4A molecular sieves (0.3 g) in CH2Cl2 (21 mL) was treated with triethylamine (1.27 mL, 9.08 mmol) and stirred at ambient temperature for 18 hr. The reaction mixture was filtered through celite, concentrated to dryness and chromatographed (SiO2, 5-40% EtOAc: hexane) to give the title compound. FAB mass spectrum (M+1) 405.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][C:8]2[C:12]3[C:13](=[O:27])[N:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[NH:10][N:9]=2)=[CH:5][CH:4]=1)#N.S(=O)(=O)(O)[OH:31].[OH2:35]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:12]3[C:13](=[O:27])[N:14]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]=3[NH:10][N:9]=2)=[CH:28][CH:29]=1)([OH:31])=[O:35]
Reactant: O
Reactant: N#Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reactant: O=S(=O)(O)O
Solvent: CS(C)=O
Product: O=C(O)c1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Temperature: 140 °C
Yield: 56 %

Procedure:
To a solution of 3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (180 mg, 0.48 mmol, prepared in Example 31) in DMSO (18 ml) was added 50% sulfuric acid (10 ml), and the mixture was stirred at 140° C. After water (5 ml) was added, the mixture was heated under reflux, admixed with additional water (5 ml), and heated under reflux for totally 3 hours. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-carboxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (106 mg, 56%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20]>CCOCC.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cccc(Cl)c2)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
0.2 mol of butyl-lithium (a suspension in ether, containing 1.8 mol/liter) is placed in a 500 cm3 flask; it is cooled to -20° C. and 37.4 g (0.2 mol) of meta-bromoanisole diluted with 50 cm3 of anhydrous ether are added dropwise; when the addition has ended, the mixture is stirred for 10 to 15 minutes at the same temperature and 15.7 g (0.1 mol) of meta-chlorobenzoic acid dissolved in the minimum amount of THF are added dropwise; the temperature is allowed to return to ambient temperature and the reaction mixture is stirred for 2 hours under these conditions; it is then poured onto water, the ether is decanted and the aqueous phase is extracted with ether; the combined ether phases are washed with sodium bicarbonate and then with water, dried, decolorised and concentrated in vacuo. 26 g of a solid melting at 52° C. are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1Br)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19](Br)=[C:18]([N+:23]([O-])=O)[CH:17]=2)[CH:10]=1)=[O:8])([O-])=O.[H][H].N>[Pd].C(O)(C)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[CH:17]=2)[CH:10]=1)=[O:8]
Reactant: O=C(c1cccc(C(=O)c2ccc(Br)c([N+](=O)[O-])c2)c1)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: N
Solvent: CC(C)O
Product: Nc1cccc(C(=O)c2cccc(C(=O)c3cccc(N)c3)c2)c1
Yield: 30 %

Procedure:
To a sealed glass reaction vessel equipped with a thermometer, stirrer and reflux condenser, 10.7 g (0.02 mole) of 1,3-bis(3-nitro-4-bromobenzoyl)benzene, 0.43 g of a 5% palladium/activated carbon catalyst (a product of M.E. Chemcat Co.) and 50 ml of isopropyl alcohol were charged. Hydrogen was introduced with stirring at 30°~35C. Absorbed hydrogen was 2.20 l (0.098 mole) over 9 hours. Successively, 3.6 g (0.06 mole) of a 28% aqueous ammonia solution was added and introduction of hydrogen was continued at 30°~35° C. for 6 hours and additionally at 60° C. for 4 hours with stirring. Further absorbed hydrogen was 0.401 g (0.018 mole). The catalyst was removed by filtration at the same temperature, 4.5 g of a 36% aqueous hydrochloric acid solution was added to the filtrate, and the mixture was allowed to cool. The precipitated crystals of 1,3-bis(3-aminobenzoyl)benzene hydrochloride were filtered, dissolved in 200 ml of water, and neutralized with a 28% aqueous ammonia solution. The precipitated crystals were was filtered, washed and dried to obtain 1.9 g of 1,3-bis(3-aminobenzoyl)benzene. The yield was 30%.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14]CC)=O)[CH:3]=1.[F:17][C:18]1[CH:28]=[C:27](F)[CH:26]=[CH:25][C:19]=1[C:20]([N:22]([CH3:24])[CH3:23])=[O:21].[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1>>[CH3:23][N:22]([CH3:24])[C:20]([C:19]1[CH:25]=[CH:26][C:27]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([NH:36][C:33]3[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=3)=[O:14])[CH:3]=2)=[CH:28][C:18]=1[F:17])=[O:21]
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CN(C)C(=O)c1ccc(F)cc1F
Product: Cc1cc2c(Oc3ccc(C(=O)N(C)C)c(F)c3)cc(C(=O)Nc3ccn(C)n3)cc2o1

Procedure:
The title compound was prepared in a similar manner as described for Example 271, from ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (0.275 g, 1.25 mmol), 2,4-difluoro-N,N-dimethylbenzamide (0.289 g, 1.56 mmol) and 1-methyl-1H-pyrazol-3-amine (0.21 g, 2.12 mmol) in two steps to give a solid (5 mg, 1% yield) as expected product. 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1 H) 8.12 (s, 1H) 7.61-7.62 (m, 2 H) 7.38-7.42 (t, 1 H) 7.03-7.06 (m, 1 H) 6.88-6.91 (m, 1 H) 6.58-6.59 (m, 1 H) 6.50 (m, 1H) 3.78 (s, 3 H) 3.00 (s, 3 H) 2.88 (m, 3 H) 2.47-2.48 (m, 3 H). LCMS for C23H21FN4O4 m/z 437.20 (M+H)+.