Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:8][C:7]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1)=[CH:6]2.Br>C(O)(=O)C>[CH3:25][C:23]1[NH:22][N:21]=[C:20]([NH:19][C:7]2[N:8]=[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[C:5]([CH:6]=2)=[CH:4][C:3]([OH:2])=[CH:12][CH:11]=3)[CH:24]=1
Reactant: COc1ccc2c(-c3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3cc(O)ccc3c(-c3ccccc3)n2)n[nH]1
Temperature: 180 °C
Yield: 73.1 %

Procedure:
The mixture of (6-methoxy-1-phenyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg), 40% aq. HBr (1 ml), acetic acid (2 ml) was heated at 180° C. for 30 minutes under microwave irradiation. After reaction finished, the mixture was evaporated to oil by reduced pressure and was dissolved in 50 ml ethyl acetate. The organic layer was washed with aq. NaHCO3 and evaporated to give 70 mg of crude 3-(5-methyl-1H-pyrazol-3-ylamino)-1-phenyl-isoquinolin-6-ol. LC-MS m/e 317(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[NH4+].[Cl-].Cl>[Fe].O>[NH2:19][C:18]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccc(N)c1OCc1ccccc1
Temperature: 85 °C
Reaction time: 5 h

Procedure:
Into a 500-mL 4-necked round-bottom flask, was placed methyl 2-(benzyloxy)-3-nitrobenzoate (20 g, 69.62 mmol, 1.00 equiv), ethanol (200 mL), water (100 mL) and NH4Cl (11.1 g, 207.52 mmol, 2.98 equiv). This was followed by the addition of Fe (19.5 g) in portions. To the mixture was added hydrogen chloride (5 mL). The resulting solution was stirred for 5 h at 85° C. in an oil bath. The solids were filtered out. The filter cake was washed with 3×50 mL of ethanol. The resulting mixture was concentrated under vacuum. The residue was dissolved in 1000 mL of ethyl acetate. The resulting mixture was washed with 3×800 mL of water. The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 17 g (95%) of methyl 3-amino-2-(benzyloxy)benzoate as yellow oil. MS (ESI) m/z 258 ([M+H]+).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:1][O:7][N:8]=[C:9]([C:15]([CH3:17])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C(=NOC)C(C)=O
Reaction time: 1 h

Procedure:
Pulverized potassium carbonate (160 g.) was added to a solution of ethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti isomers) (152 g.) in acetone (500 ml.). Dimethyl sulfate (130 g.) was dropwise added thereto with stirring over 1 hour at 45° to 50° C. and the mixture was stirred for 2 hours. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The filtered insoluble material was dissolved in water (500 ml.) and this solution was added to the residue. The mixture was extracted twice with ethyl acetate (300 ml.). The extract was washed twice with water (200 ml.) and with a saturated sodium chloride aqueous solution (200 ml.) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was distilled under reduced pressure to give colorless oil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (145.3 g.), bp 55° to 64° C./0.5 mm Hg.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1>CO.[OH-].[Na+]>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccn2)cc1

Procedure:
12.85 g (60.2 mmol) of 4-(pyridin-2-yl)-benzoic acid methyl ester in 125 ml of methanol and 67 ml of 1N sodium hydroxide solution are stirred at room temperature for 6 hours. The resulting solution is partially concentrated by evaporation; the aqueous residue is extracted with ethyl acetate and acidified to pH-1.5 with 2N HCl solution. The title compound precipitates out and can be filtered off and washed with water: TLC (ethyl acetate): Rf =0.35; FAB MS (M+H)+ =200.
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][C:13]([F:17])=[CH:14][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][C:13]([F:17])=[CH:14][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)c2ccc(F)cc2C1(O)c1cc2c(cc1O)OCC2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCC3)c2cc(F)ccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 1-(diphenylmethyl)-5-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)-5-fluoro-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one was obtained (94%): mp 179-181° C. (methanol); 1H NMR (300 MHz, CDCl3) δ7.36-7.19 (m, 11H), 7.02-6.97 (m, 2H), 6.77-6.69 (m, 2H), 6.45-6.39 (m, 2H), 5.04 (s, 1H), 4.53 (t, J=9.0 Hz, 2H), 3.10-3.02 (m, 2H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1([CH3:15])[CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>C(#N)C.CCOCC.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]([CH3:15])([OH:13])[CH3:14])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc(Br)ccc1OCC(C)(C)O
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (8 g, 39.4 mmol), 2,2-dimethyloxirane (14 mL, 158 mmol), potassium carbonate (4.3 g, 35.5 mmol), and sodium phosphate, monobasic (4.25 g, 35.5 mmol) in acetonitrile and water (85:15, 100 mL) was stirred in a steel bomb at 150-165° C. for 8 h. The reaction was cooled to RT, diluted with ether and EtOAc (1:1), washed with 1N NaOH, dried (Na2SO4), and concentrated. The crude was passed through a pad of silica gel using EtOAc for elution to afford the desired product 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol 7A (10 g, 36.3 mmol, 92% yield) as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ6.95-7.08 (2H, m), 6.77 (1H, d, J=8.28 Hz), 3.85 (3H, s), 3.79 (2H, s), 1.34 (6H, s).
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:27])[NH:16][C:17]34[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]5)[CH2:18]3)[CH2:24]4)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[C:17]12([NH:16][C:15]([N:13]3[CH2:14][C:11]4([N:8]([S:35]([C:32]5[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=5)(=[O:37])=[O:36])[CH2:9][CH2:10]4)[CH2:12]3)=[O:27])[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NC13CC4CC(CC(C4)C1)C3)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CC2(CCN2S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(Adamantan-1-ylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as an off-white sticky solid (29 mg, 35%). MS m/e: 450 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.CC(C)([O-])C.[K+].[F:22][C:23]([F:38])([F:37])[C:24](=[O:36])[CH2:25][C:26]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>C(OCC)C>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH2:1][C:24]([OH:36])([CH2:25][C:26]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)([CH3:28])[CH3:27])[C:23]([F:22])([F:38])[F:37]
Reactant: CC(C)(CC(=O)C(F)(F)F)c1ccc(F)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(CC(O)(Cc1cc2ccccc2[nH]1)C(F)(F)F)c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a diethyl ether solution of 53 mg of 2-methylindole was added 3 equivalents of n-butyl lithium followed by 90 mg of potassium tert-butoxide (t-BuOK) (solid) at room temperature. The mixture was allowed to stir for 30 minutes. 1,1,1-Trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one (100 mg) in diethyl ether was then added to the above mixture. The reaction was stirred at room for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, and extracted three times with EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to yield 40 mg of the title compound as a foam. Resolution to the (+)- and (−) enantiomers was accomplished by chiral HPLC on a CHIRALCEL® OD™ column, eluting with 10% isopropanol-hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH2:13][CH2:12][C:11]([CH3:14])=[CH:10][CH2:9][CH2:8][C:7]([CH3:15])=[CH:6][CH2:5][CH2:4][CH:3]=1.[CH3:16][OH:17]>>[CH3:16][O:17][C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][CH2:13]1
Reactant: CO
Reactant: CC1=CCCC=C(C)CCC(C)=CCC1
Product: COC1(C)CCCC=C(C)CCC=C(C)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
340 g (1.67 M) of 2,5,9-trimethyl-cyclododeca-1,5,9-triene and 110 g of acidic diatomaceous earth in 5000 ml of methanol (containing less than 0.05% of water) were refluxed during 40 h. After cooling at room temperature and filtration, the mixture was concentrated at reduced pressure to yield, after a distillation, 366 g of a product having b.p. 79°-110°/0.01 Torr. After fractional distillation, 212 g of starting 2,5,9-trimethylcyclododeca-1,5,9-triene (b.p.43°-52°/0.1 Torr) and 140 g of the desired product, b.p. 78°-82°/0.01 Torr (yield 95% based on the converted starting material).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:12]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][N:15]=3)[C:20](=[O:21])[C:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=3)=[CH:12]2)=[CH:27][CH:26]=1
Reactant: CC(=O)c1ccc(Cc2cn(-c3ccc(F)cc3)c3ncccc3c2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(Cc2cn(-c3ccc(F)cc3)c3ncccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
A solution of 49 mg (0.13 mmol) of the compound of Example 7 in 7 mL of methanol was cooled to 0° C. and treated with 5.0 mg (0.13 mmol) of sodium borohydride. After stirring for 1 hour at 0° C. and 2 hours at room temperature, the mixture was quenched by the addition of 2 mL of water. The mixture was concentrated to remove methanol and the residue was partitioned between 50 mL of ethyl acetate and 50 mL of water. The separated organic layer was washed with brine (1×50 mL), dried (MgSO4), and evaporated to give 22 mg of the title compound as a white solid, mp 197-198° C. Anal. Calcd for C23H19N2O2F: C, 73.78; H, 5.11; N, 7.48. Found: C, 73.41; H, 5.20; N, 7.41.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:19][CH2:20][CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CN(C=O)C.C(Cl)Cl.CCOCC.O>[Cl:19][CH2:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C1CCCc2cc(OCCCl)ccc21
Temperature: 25 °C
Reaction time: 58 h
Yield: 95.9 %

Procedure:
To a solution of 6-hydroxy tetralone (2.0 g, 12.3 mmol) in DMF (50 mL) was added dry cesium carbonate (8.02 g, 24.6 mmol). Neat 2-chloroethyl-p-toluensulfonate (3.49 g, 14.9 mmol) was added to this mixture and the reaction stirred at room temperature for 58 hours. The reaction was poured into 200 mL of water and to this mixture was added 10 mL of 1N NaOH followed by 200 mL of Et2O. The mixture stirred at room temperature for 2 hours. The aqueous portion was separated and extracted with Et2O (3×200 mL). The combined organic portions were washed successively with 1N NaOH (2×100 mL), water (2×100 mL), and brine, dried, filtered, and concentrated under vacuum to give 5.07 g of a faintly orange solid. The solid was dissolved in minimal DCM and chromatographed (silica gel, 190 g, DCM). The appropriate fractions were pooled and concentrated under vacuum to afford 2.65 g (96%) of a white crystalline solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24]C)=[O:23])[CH:10]([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([CH3:21])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]([OH:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a solution of 4-benzyl 1-methyl N-(tert-butoxycarbonyl)-3-methyl-L-aspartate (Preparation 68, 0.5 g, 1.52 mmol) in THF/water (50 mL/10 mL) was added lithium hydroxide (34 mg, 1.42 mmol) at 0° C. and the reaction stirred warming slowly to room temperature for 18 hours. The reaction was extracted with heptane and the aqueous was acidified with 10% aqueous KHSO4 solution. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-60% MeCN in 0.1% formic acid in water to afford the title compound (182 mg, 38%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[N+]=[N-])[CH:16]=[CH:17][CH:18]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]2[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8]2)[CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=Cc1cccc(Cl)c1
Reactant: O=Cc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CSC
Product: Clc1cccc(C2OC2c2ccccc2)c1
Yield: 53 %

Procedure:
To a slurry of rhodium (II) acetate (0.001 g) and dichloromethane (4 ml) were added benzaldehyde (0.025 ml) and dimethylsulphide (0.009 ml). The solution of 3-chlorophenyldiazomethane (produced above) was added to this mixture over 24 hours. The solvent was removed in vacuo and the residue chromatographed on silica (Merck grade 60, 230-400 mesh) eluting with dichloromethane:hexane 2:3 to give the title compound as a colourless oil (0.0305 g, 53% yield) δH (CDCl3): 7.55(8H); 7.45(1H), 4.0(2H)ppm.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:16])=[CH:5][CH2:6][CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=O.[C:17](O)(=[O:19])[CH3:18].C(=O)C(C)=O>O.C(Cl)Cl>[OH:12][CH:10]([CH2:9][C:8](=[O:15])[CH2:7][CH2:6][CH:5]=[C:4]([CH3:3])[CH3:16])[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)CCC=C(C)C
Agent: CC(=O)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(O)CC(=O)CCC=C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
97 ml of 10 N sodium hydroxide solution were added over one hour at less than 33° C. to a suspension of 175 g of ethyl 7-methyl-3-oxo-6-octenoate in 875 ml of water and the mixture was stirred at room temperature for 20 hours and 25 ml of acetic acid were added thereto to obtain a pH of 7. An aqueous solution containing 396 g of pyruvaldehyde (16.8% by weight) was added to the mixture at 20° to 25° C. while maintaining a pH of 7 and the mixture was stirred for 20 hours at room temperature during which 30 ml of acetic acid were added to keep the pH at 7. 1000 ml of methylene chloride were added thereto and the mixture was stirred for 10 minutes. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 175 g of 3-hydroxy-9-methyl-8-decene-2,5-dione.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[CH:21]12[O:28][CH:25]([CH2:26][CH2:27]1)[CH2:24][N:23]([CH:29]([C:35](OCC)=[O:36])[C:30](OCC)=[O:31])[CH2:22]2>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:30]([OH:31])[C:29]([N:23]3[CH2:24][CH:25]4[O:28][CH:21]([CH2:27][CH2:26]4)[CH2:22]3)=[C:35]([OH:36])[N:16]=2)=[N:6]1
Reactant: CCOC(=O)C(C(=O)OCC)N1CC2CCC(C1)O2
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Solvent: Cc1ccccc1
Product: Oc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1N1CC2CCC(C1)O2
Temperature: 140 °C
Reaction time: 8 h

Procedure:
0.50 g (1.11 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide (example I, step 5) are suspended in 40 ml of toluene. Then 1.40 g (5.16 mmol) of diethyl 2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)malonate from step 5 are added. The mixture is stirred at 140° C. overnight. The solid is then filtered off with suction, washed with diethyl ether dried in vacuo.
Reaction SMILES: O[C:2]([CH2:4][C:5]1([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1>CN(C)C=O>[CH3:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:2]([CH2:4][C:5]2([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]2=[O:14])=[O:3])=[CH:53][CH:54]=1
Reactant: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reactant: Cc1ccc(N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)Nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
To a solution of 0.150 g of (RS)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one and 0.103 g of dicyclohexylcarbodiimide in 10 ml of N,N-dimethylformamide were added successively 0.074 g of 1-hydroxybenzotriazole and 0.052 g of p-toluidine. The resulting mixture was stirred at room temperature for 18 hours, followed by concentration. The residue was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 0.083 g (44%) of the title compound as a white powder.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]4[CH:21]=[C:22]([CH2:26]O)[CH:23]=[CH:24][CH:25]=4)=[N:18][CH:19]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:28]([C:31]1[CH:32]=[CH:33][C:34](=[O:37])[NH:35][N:36]=1)([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:28]([C:31]1[CH:32]=[CH:33][C:34](=[O:37])[N:35]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:17]3[N:16]=[CH:15][C:14]([C:12]4[CH:11]=[N:10][N:9]([CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:13]=4)=[CH:19][N:18]=3)[CH:21]=2)[N:36]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1ccc(=O)[nH]n1
Reactant: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(=O)n(Cc2cccc(-c3ncc(-c4cnn(CCN5CCOCC5)c4)cn3)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.3 A solution, kept under nitrogen, of 324 mg (0.70 mmol) of (3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}phenyl)methanol, 131 mg (0.91 mmol) of 6-isopropyl-2H-pyridazin-3-one and 278 mg (1.05 mmol) of triphenylphosphine in 1.4 ml of THF is cooled in an ice bath, and 217 μl (1.056 mmol) of diisopropyl azodicarboxylate are added dropwise. After the reaction mixture has been stirred at room temperature for 2 hours, it is evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent, giving 6-isopropyl-2-(3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}benzyl)-2H-pyridazin-3-one (“A13”) as yellowish crystals; ESI 486;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)([Cl:12])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:12])=[O:9])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Cl)cs1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)cs1

Procedure:
1.63 g (10.0 mmoles) of 4-chloro-2-thiophenecarboxylic acid (prepared according to Iriarte, J., et al., J. Het. Chem. 13:393 (1976)) was dissolved in 10 ml of thionyl chloride and heated to reflux. After refluxing for 1.5 hours excess thionyl chloride was evaporated, leaving 1.88 g of crude 4-chloro-2-thiophenecarbonyl chloride as a dark brown oil. This acid chloride was dissolved in 10 ml of N,N-dimethylformamide and slowly added to a cooled (ice-water) 40 ml N,N-dimethylformamide solution of 1.75 g (8.33 mmoles) 5-chloro-2-oxindole-1-carboxamide and 3.05 g (25.0 mmoles) of 4-(N,N-dimethylamino)pyridine. The reaction was complete in 1 hour. The mixture was poured into 100 ml of 1N hydrochloric acid causing a precipitate to form. The crude solid was filtered, dried and recrystallized to give 1.89 g (5.3 mmoles, 64% yield) of title compound as yellow needles, m.p. 212°-214° C. (2-butanone).