Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1.CC(C)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([N:14]2[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]2)=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3Cl)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (3.05 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jones oxidant in water (8.00 M, 2.54 mL) at 0 degrees celsius and the resulting solution was stirred at rt for 1 hour. The mixture was filtered through celite and the filtrate was concentrated. The resulting residue was dissolved in AcOEt, washed with water and brine successively, dried with MgSO4, and concentrated in-vacuo. The crude product was purified by Combiflash eluting with 40% AcOEt in hexanes.
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].C([N:19]([CH2:22][CH3:23])CC)C.C([O:26]C(Cl)=O)C.N1C=CC=CC=1.C[N:37](C)[CH:38]=[O:39]>CCOCC>[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1].[CH:8]1[C:16]([NH2:15])=[CH:11][C:10]2[C:38]([NH:37][NH:19][C:22](=[O:26])[C:23]=2[CH:7]=1)=[O:39]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Reactant: CN(C)C=O
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CCOCC
Solvent: c1ccncc1
Product: Nc1ccc2c(=O)[nH][nH]c(=O)c2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Biotin (0.29 g, 1.2 mmole) and 0.17 ml triethylamine were dissolved in 20 ml dry dimethylformamide under anhydrous conditions and cooled to -10° C. A solution of 0.141 ml ethylchloroformate in 2.86 ml ether was added slowly and the reaction was stirred for 30 min. A precipitate which formed was separated by filtration. A suspension consisting of 600 mg (2.4 mmole) of the intermediate from Part C, 20 ml dry dimethylformamide and 1 ml dry pyridine was added to the filtrate quickly. This mixture was stirred at -10° C. for 30 min and then at room temperature overnight. During this period a solution was obtained. The dimethylformamide was removed by distillation at 60° C. and 0.10 mm Hg pressure. The oily residue was stirred with 50 ml 0.1N hydrochloric acid for 1 hr. A white solid which formed was filtered and washed with 0.1N hydrochloric acid and then water. After drying under a vacuum at room temperature overnight, 0.55 g (97% yield) of the product was obtained, m.p. 170°-3° C. Calculated for C21H28N6O5S: C, 52.92; H, 5.92; N, 17.64. Found: C, 51.69; H, 5.90; N, 17.63.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.O>ClCCl>[Br:1][CH2:2][C:3]([N:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CCc2ccccc2C1
Reaction time: 0.75 h

Procedure:
Bromoacetyl chloride (0.25 mL) was added slowly to a cold (5° C.) solution of 1,2,3,4-tetrahydroisoquinoline (0.8 g) in dichloromethane (25 mL) and the mixture was stirred in an ice bath for 45 minutes, then at room temperature overnight. Water (20 mL) was added, the layers were separated and the organic layer was washed in turn with 0.5N hydrochloric acid and sodium bicarbonate solution. The dried extract (MgSO4) was evaporated to provide 0.762 g of 2-(2-bromo-1-oxoethyl)-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C:9]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[C:10]2[CH2:16][CH:15]3[NH:17][CH:12]([CH2:13][CH2:14]3)[CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.CC1C=CC=CC=1[CH:35]=[O:36]>>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:17]1[CH:12]2[CH2:13][CH2:14][CH:15]1[CH2:16][C:10](=[C:9]([C:5]1[CH:4]=[CH:3][C:8]([O:36][CH3:35])=[CH:7][CH:6]=1)[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[CH2:11]2
Reactant: COc1cccc(C(=C2CC3CCC(C2)N3)c2ccsc2)c1
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1ccccc1C=O
Product: COc1ccc(C(=C2CC3CCC(C2)N3Cc2ccccc2Cl)c2ccsc2)cc1

Procedure:
Following the protocol for Example 15, and substituting 3-[(4-methoxy-phenyl)-thiophen-3-yl-methylene]-8-aza-bicyclo[3.2.1]octane for 3-[(3-methoxy-phenyl)-thiophen-3-yl-methylene]-8-aza-bicyclo[3.2.1]octane and 2-chlorobenzaldehyde for 2-methylbenzaldehyde the title compound was obtained; MS m/z (MH+) 437; 1H NMR 300 MHz (MeOD-d4) δ 6.80-7.67 (m, 11H), 3.76 (s, 3H), 3.71 (s, 2H), 3.21-3.30 (m, 2H), 2.01-2.48 (m, 6H), 1.61-1.68 (m, 2H).
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([SH:18])=[N:16][N:17]=3)[N:14]=2)[CH:6]=[N:5]1.Br[C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2>C(O)C.CO.ClCCl>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([S:18][C:20]4[C:21]([N+:30]([O-:32])=[O:31])=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)=[N:16][N:17]=3)[N:14]=2)[CH:6]=[N:5]1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Reactant: O=[N+]([O-])c1c(Br)ccc2ncccc12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4[N+](=O)[O-])n3n2)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
A solution of KOH (146 mg, 2.6 mmol) in ethanol (10 mL) was degassed by bubbling in nitrogen for 15 min. To the solution was added 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (500 mg, 2.15 mmol) and 6-bromo-5-nitro-quinoline (600 mg, 2.36 mmol). The reaction mixture was stirred at 70° C. for 4 h, then cooled to room temperature, diluted with 10% methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-7% methanol/dichloromethane afforded 659 mg of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-5-nitro-quinoline as a dark yellow solid (76% yield).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH:14]=[CH:15]C(OCC)=O)[O:12][C@@H:11]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>[Pd]>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[O:12][C@@H:11]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Product: CCOC(=O)CCC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a stirred solution of 3'-O-t-butyldimethylsilyl-5'-carbethoxymethylene-5'-deoxy-thymidine (4.24 g, 10 mmol) in ethyl acetate was added 200 mg of 10% Pd/C under nitrogen atmosphere. The nitrogen gas was removed by vacuum and hydrogen was introduced. This procedure was repeated twice, and stirring was continued under atmospheric pressure of hydrogen for 16 hours. The catalyst was filtered over a celite pad, and the solvent was removed in vacuo. The title compound was crystallized from hexane/ethyl acetate. The title compound was obtained in 95% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([CH2:34]O)[CH:30]=[CH:31][C:32]=1[F:33].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCOC(C)=O.C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[F:33])[CH2:34][O:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4ccc(F)c(F)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3,4-difluorophenyl)methanol (0.066 ml), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, and quenched with water. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from IPA-IPE to give the title compound (51.4 mg) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2].[OH-].[K+].Br[CH:20](C(OCC)=O)[C:21]([O:23]CC)=[O:22]>CCO.Cl.C(O)(=O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=2)[C:6](=[O:7])[O:8][C:20]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C(=O)O)oc(=O)c2cc(C(F)(F)F)ccc12
Temperature: 90 °C
Yield: 41.7 %

Procedure:
To a solution of 1.12 g (4.8 mol) 2-acetyl-5-(trifluoromethyl)benzoic acid in EtOH (30 ml) were succesively added 270 mg (4.8 mmol) KOH and 1.15 g (4.8 mmol) diethyl 2-bromo-malonate at RT. The resulting mixture was heated at 90° C. for 6 h. After cooling to RT, the RS was concentrated in vacuo. The residue was taken up with water (30 ml) and extracted with EtOAc. The organic layer was washed with water (40 ml) and brine (30 ml), dried over Na2SO4 and concentrated in vacuo. This residue obtained was diluted with hydrochloric acid (10 ml) and acetic acid (6 ml) and the RS was heated at 90° C. for 2 h. After cooling to RT, the RS was poured into ice-water and the precipitate was filtered off to yield 540 mg (2.0 mmol, 41%) 4-methyl-1-oxo-7-(trifluoromethyl)-1H-isochromene-3-carboxylic acid, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(C(C)C)CC)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][S:42]([CH3:41])(=[O:44])=[O:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)ccc1-c1nc(NCCNS(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 157 (250 mg, 0.58 mmol), di-isopropylethylamine (111 uL, 0.64 mmol) and CH2Cl2 (10 mL) was cooled to −5° and methanesulfonyl chloride (50 uL, 0.64 mmol) was added and the resulting soln was warmed to 23°, stirred 15 min, diluted with CH2Cl2 (75 mL) and washed with 10% aq NaOH (2×20 mL) and satd aq NaCl, dried (Na2SO4), and concentrated to afford a brown solid. Chromatotron chromatography (CH2Cl2/CH3OH) and crystallization from Et2O afforded a pink solid. mp=105-115° (dec); LC MS (m/e)=504.2 (MH+). Rt=1.94 min
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[C:10](O)([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=3)[CH:10]([C:18]3[C:19]([OH:27])=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cc(F)ccc2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCC3)c2ccc(F)cc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-6-fluoro-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 1-(diphenylmethyl)-6-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (99%): mp 121-123° C. (methanol); 1H NMR (300 MHz, CDCl3) 7.36-7.16 (m, 11H), 6.95 (s, 1H), 6.77-6.71 (m, 1H), 6.67 (s, 1H), 6.46 (s, 1H), 6.25-6.21 (m, 1H), 5.00 (s, 1H), 4.53 (t, J=9.0 Hz, 2H), 3.08-3.01 (m, 2H); MS (ES+) m/z 451.9 (M+1).
Reaction SMILES: [H-].[Na+].CCCCC.[C:8]([C:13]1[CH:27]=[CH:26][C:16]([CH2:17]P(=O)(OCC)OCC)=[CH:15][CH:14]=1)([O:10][CH2:11][CH3:12])=[O:9].[CH3:28][C:29]([C:31]1[CH:40]=[C:39]2[C:34]([C:35]([CH3:43])([CH3:42])[CH2:36][CH2:37][N:38]2[CH3:41])=[CH:33][CH:32]=1)=O>CN(C)C=O>[CH3:41][N:38]1[C:39]2[C:34](=[CH:33][CH:32]=[C:31]([C:29]([CH3:28])=[CH:17][C:16]3[CH:15]=[CH:14][C:13]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:27][CH:26]=3)[CH:40]=2)[C:35]([CH3:42])([CH3:43])[CH2:36][CH2:37]1
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CC(=O)c1ccc2c(c1)N(C)CCC2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)N(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
2.9 g of a 50% suspension of sodium hydride in mineral oil were suspended in 30 ml of dimethylformamide after two-fold washing with pentane and treated dropwise at room temperature with a solution of 17.3 g of diethyl (4-carbethoxybenzyl)phosphonate in 50 ml of dimethylformamide. After stirring at room temperature for 1 hour, a solution of 5 g of 1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl methyl ketone in 50 ml of dimethylformamide was added dropwise thereto. The reaction mixture was heated to 50° C. for 1 hour, poured on to ice/water and extracted with ethyl acetate. The brownish oil obtained after drying and evaporation of the organic phase was chromatographed (silica gel, eluting agent hexane/ethyl acetate=9:1) and gave 4.2 g of ethyl p-[2-(1,2,3,4-tetrahydro-1,4,4-trimethyl-7-quinolinyl)propenyl]benzoate as a slightly yellow, viscous oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O-:16])=[O:15])([OH:3])=[O:2].[CH3:17]O>>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CO
Product: COC(=O)Cc1ccc(N)cc1C(=O)O
Yield: 90 %

Procedure:
Methyl 2-carboxy-4-nitrophenyl acetate was prepared from 2-carboxy-4-nitrophenylacetate and methanol by the procedure described above. Hydrogenation of this nitro compound gives methyl 4-amino-2-carboxyphenylacetate (yield 90%). The guanidination of the amino compound with 3,5-dimethylpyrazole-1-carboxamidine nitrate (ADMP) was performed by a standard method described previously (Tsunematsu & Makismi, J. Biochem. 88, pp 1773-1783, (1980)). 2.2 g of amino compound (10 mmole), 1.9 g of triethylamine (19 mmole) and 3.0 g of ADMP (15 mmole) was heated in 20 ml of THF and refluxed for 18 hrs. The white precipitate was filtered and washed with cold methanol to give 1.5 g of methyl 2-carboxy-4-guanidinophenylacetate, (yield 46%). One spot on TLC, Rf =0.6 (Butanol:acetic acid:pyridine:water=4:1:1:2), it shows an orange color when sprayed with Sakaguchi reagent. NMR spectrum (CF3COOH), δ 8.4, 7.7 (b, 4H), 6.6 (b, 4H) 4.4 (s, 2H), 4.1 (s, 3H). Anal. Calc. for C11H13N3O4.1/2H2O: C, 50.77; H, 5.42; N, 16.15. Found: C, 51.03; H, 5.38; N, 16.19. 0.9 g of methyl 2-carboxy-4-guanidinophenylacetate (3 mmole) was heated with 1.5 g of PCl5 (7.2 mmole) at 70°-80° C. for 2 hrs, white solid precipitated out during the heating. The solid was filtered off and purified by silica gel column chromatography with methylene chloride and methanol (5:1) as an eluent to give 0.5 g of 7-guanidino-3-methoxyisocoumarin (yield 59%). One spot on TLC, Rf =0.7 (Butanol:acetic acid: pyridine:water=4:1:1:2); m.p. 185°-186° C. (dec);, NMR spectrum (d6 -DMSO): δ 7.9, 7.6 (b, 3H), 7.7 (b, 4H), 6.1 (s, 1H), 3.9 (s, 3H); mass spectrum (FAB+), m/e=234 (M+ -Cl). Anal. Calc. for C11H12N3O3Cl1.1/2H2O: C, 47.40; H, 4.67; N, 15.08; Cl, 12.75. Found: C, 47.42; H, 4.74; N, 15.05; Cl, 12.68.
Reaction SMILES: [OH-:1].[K+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:12]=O)[C:6]=2[CH:5]=[CH:4]1.O[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C([N+](CC)(CC)CC1C=CC=CC=1)C>C(O)C.O>[OH:1][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[O:17])[CH:15]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][NH:3]2
Reactant: [OH-]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: O=C(CO)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1O
Temperature: 30 °C
Reaction time: 23 h

Procedure:
0.5 ml of 38% potassium hydroxide solution was added with stirring under an inert atmosphere at 30° C. to a mixture of 0.132 g of indole-4-carboxaldehyde, 0.1 ml of 2-hydroxy-acetophenone and 0.189 g of triethylbenzylammonium in 2 ml of ethanol and after stirring at 30° C. for 23 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with methylene chloride to obtain 159 mg of 1-(2-hydroxyphenyl)-3-(1H-indol-4-yl)-2-propen-1-one melting 164° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:14]([F:24])[CH:13]=[CH:12][CH:11]=2)=[O:7])(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].ClCCl>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[F:24][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[C:8]([C:6]([OH:7])=[O:5])[NH:9]2
Reactant: CC(C)(C)OC(=O)c1[nH]c2cccc(F)c2c1Nc1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1[nH]c2cccc(F)c2c1Nc1ccncc1
Temperature: 25 °C
Yield: 88 %

Procedure:
Stir at ambient temperature for 3 h a solution of 4-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic tert-butyl ester (Example 17, 0.15 g, 0.458 mmol) in 35% trifluoroacetic acid/dichloromethane. Concentrate the reaction under vacuum to obtain a gray solid. Dry the solid at 40° C. under vacuum and then triturate with hot ethyl acetate. Allow to cool to ambient temperature and collect a light gray powder. Dry the powder at 45° C. under vacuum for 2 h and obtain 0.15 g (88%) of the title compound: MS 272(M+H), m.p. 231–234° C. (dec.)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[O:25]=[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]1[CH2:32][C:33](O)=[O:34]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33](=[O:34])[CH2:32][N:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=[O:25])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(O)Cn1ccccc1=O
Product: Cl
Product: O=C(Cn1ccccc1=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and (2-oxopyridin-1(2H)-yl)acetic acid, and by a method similar to that of Example 39, the title compound was obtained.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]2[CH:14]([CH3:23])[CH2:15][CH2:16][C:17](=[CH:18][N+](Cl)(C)C)[C:10]2=[N:9][CH:8]=1)=[O:6])[CH3:3].[C:24]([O-])(=[O:26])[CH3:25].[Na+].C([OH:31])C>>[CH2:2]([O:4][C:5]([C:7]1[C:12](=[O:13])[N:11]2[CH:14]([CH3:23])[CH2:15][CH2:16][C:17]([C:18]([O:26][CH2:24][CH3:25])=[O:31])=[C:10]2[NH:9][CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=C[N+](C)(C)Cl
Reactant: CC(=O)[O-]
Reactant: CCO
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(=O)C1=CNC2=C(C(=O)OCC)CCC(C)N2C1=O
Reaction time: 24 h
Yield: 60 %

Procedure:
A solution of 1.8 g. of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethylammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine chloride and 5 mmoles of sodium acetate in 5 ml. of anhydrous ethanol is allowed to stand for 24 hours at room temperature and the precipitated sodium chloride is filtered and the filtrate is evaporated. The residue is dissolved in water and the pH of the solution is adjusted to 7 by adding sodium hydrogen carbonate. The precipitated crystals are filtered, washed with water and dried. 0.92 g. (60%) of 3,9-diethoxycarbonyl-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine is obtained, melting point: 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17](O)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:4][CH:3]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH2:31])[CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([NH:31][CH2:30][CH2:29][NH+:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[O:18])[CH:13]=3)[C:8]2=[O:20])=[CH:21][CH:22]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Reactant: NCCN1CCOCC1
Product: O=C(NCC[NH+]1CCOCC1)c1ccc2c(c1)C(=O)N(Cc1ccc(Cl)cc1)C2=O
Product: [Cl-]

Procedure:
2-(4-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-morpholinoethane amine (103 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 122 mg (83%) was obtained by following the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[O:18]CC(C)(C)[N:21]=2)=[CH:14][CH:13]=1.S(=O)(=O)(O)[O-].[Na+].CN1CCCC1=O>O.C1(C)C(C)=CC=CC=1>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:16]([C:15]3[CH:24]=[CH:25][C:12]([Cl:11])=[CH:13][CH:14]=3)[C:17](=[O:18])[NH:21]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC1(C)COC(Cc2ccc(Cl)cc2)=N1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccc(Cl)cc1

Procedure:
17.5 g of 2,4-dichlorobenzaldehyde, 22.4 g of 2-(4-chlorobenzyl)-4,4-dimethyl-2-oxazoline, 1 g of sodium bisulphate, 50 ml of 1-methyl-2-pyrrolidinone and 30 ml of xylene are heated at a bath temperature of 170° to 220° C., using a water separator, until 3.2 ml of water and 20 ml of xylene have been separated off. After cooling the reaction mixture, methanol is added and the title compound (m.>300° C.) is collected by filtration (yield: 24.8 g).