Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[N:3]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C)nc(N)n1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1

Procedure:
To 37 g. of 2-amino-4,6-dimethylpyrimidine in 500 ml of anhydrous acetonitrile was added 67 g of 2-methoxycarbonylbenzenesulfonylisocyanate with stirring at ambient temperatures. The resulting mixture was thereafter stirred for sixteen hours and then filtered to remove the desired product which had precipitated as a white solid, m.p. 198°-202°. It showed infrared absorption peaks at 1750, 1700, 1600 and 1500 cm-1, consistent for the desired compound.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][NH:5]1.Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>O.CS(C)=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][CH2:16][CH2:15][N:5]1[N:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:3]
Reactant: BrCCOC1CCCCO1
Reactant: O=c1[nH]ncc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=c1c2ccccc2cnn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 41.5 g of potassium hydroxide in 53 ml of water is added at room temperature to a solution of 61 g of 1-oxophthalazine in 430 ml of dimethyl sulfoxide. After 30 minutes, 130 g of tetrahydro-2-pyranyl 2-bromoethyl ether are added to the suspension obtained. The mixture is left stirring for 30 hours at room temperature and then concentrated, the residue is taken up in 400 ml of water and the product is extracted with dichloromethane. The organic phase is concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:25])=[CH:4][CH:3]=1.[C:26](O)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[O:10][C:9]2=[O:25])=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(OCC2CN(c3ccc(N)cc3)C(=O)O2)cc1
Product: COC(=O)c1ccc(OCC2CN(c3ccc(NC(C)=O)cc3)C(=O)O2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
A 1.2 ml quantity of anhydrous acetic acid was added dropwise to an acetic acid (60 ml) solution of 3.0 g of methyl 4-[3-(4-aminophenyl)-2-oxooxazolidin-5-yl]methoxybenzoate obtained in Example 9 at room temperature, and the mixture was stirred at the same temperature for 1 hour. The crystals were collected by filtration and washed with ethanol to give 3.05 g of the title compound (compound 113) in a yield of 99%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([NH:12][C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>CN(C=O)C>[Cl:3][C:4]1[CH:11]=[C:10]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C@H:13]2[CH2:17][C:16](=[O:18])[N:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC(C)N1C[C@@H](Nc2ccc(C#N)c(Cl)c2)CC1=O
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C[C@@H](N(Cc2ccccc2F)c2ccc(C#N)c(Cl)c2)CC1=O
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 78.4 %

Procedure:
NaH (60% in mineral oil, 0.026 g, 0.65 mmol) was washed free of mineral oil and then suspended in DMF (3 mL) and cooled to −20° C. To this suspension was added a solution of 2-chloro-4-{[(3S)-1-(1-methylethyl)-5-oxo-3-pyrrolidinyl]amino}benzonitrile (0.120 g, 0.43 mmol). After stirring at −20° C. for 20 min, 1-(bromomethyl)-2-fluorobenzene (0.12 g, 0.65 mmol) in DMF (2 mL) was added and the reaction was stirred at −20° C. for 5 min and then at 0° C. for 5 min. The reaction was quenched with aqueous NH4Cl, diluted with H2O, and extracted with Et2O (2×). The organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography with 25% EtOAc in hexane grading to 100% EtOAc in hexane to afford the product (0.13 g, 79%) as a white solid. 1H-NMR (CDCl3) δ: 1.137 (6H, dd, J=16.8 Hz, 6.8 Hz), 2.547 (1H, m), 2.842 (1H, m), 3.349 (1H, m), 3.749 (1H, m), 4.465 (1H, m), 4.588 (2H, m), 4.755 (1H, m), 6.566 (1H, d, J=8.8 Hz), 6.747 (1H, s), 7.031 (1H, m), 7.130 (2H, m), 7.325 (1H, m), 7.455 (1H, d, J=8.8 Hz). LC-MS (ES) m/e 386.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[Br:12]CCC1C=CC=CC=1F>>[Br:12][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Fc1ccccc1CCBr
Reactant: O=C(O)Cc1cccc(F)c1
Product: Fc1cccc(CCBr)c1

Procedure:
1-(2-Bromoethyl)-3-fluorobenzene was prepared from 3-fluorophenylacetic acid as described above for 1-(2-bromoethyl)-2-fluorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:31][CH2:32][CH2:33][OH:34])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(C(F)(F)F)nc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridine-2-carboxylic acid (132 mg, 0.30 mmol) obtained in Example 26 in methylene chloride (5 ml), 2-aminoethanol (0.020 ml, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (0.036 ml, 0.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.33 mmol) were added at room temperature. After stirring for 6 hours at room temperature, the reaction mixture was washed with 0.5 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain the title compound (143 mg, 0.30 mmol, 99%) as a colorless oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:16]([OH:18])=[O:17].C(N(C(C)C)CC)(C)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].[OH-].[Na+].Cl>O1CCCC1>[C:28]([NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][C:5]=1[C:16]([OH:18])=[O:17])(=[O:30])[CH3:29]
Reactant: COc1cc2c(CCN)c(C(=O)O)[nH]c2cc1F
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(CCNC(C)=O)c(C(=O)O)[nH]c2cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-aminoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (1.90 g) and tetrahydrofuran (38.0 mL) were added diisopropylethylamine (6.45 mL) and acetic anhydride (1.42 mL), followed by stirring at room temperature overnight. To the reaction mixture was added a 1 M aqueous sodium hydroxide solution (50.0 mL), followed by stirring for 1 hour and acidifying by the addition of 1 M hydrochloric acid (90.0 mL). This mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration and the filtrate was concentrated under reduced pressure to obtain 3-(2-acetamidoethyl)-6-fluoro-5-methoxy-1H-indole-2-carboxylic acid (2.21 g) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8]/[C:9](/[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[N:10]\[O:11][CH3:12])=[CH:5][CH:4]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[C:26]([O:36][CH3:37])[CH:25]=1>>[C:17]([C:16]1[CH:15]=[CH:14][C:13](/[C:9](=[N:10]/[O:11][CH3:12])/[CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([O:36][CH3:37])[CH:25]=3)=[CH:22][CH:21]=2)=[CH:20][CH:19]=1)#[N:18]
Reactant: COC(=O)CCc1ccc(O)cc1OC
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(C#N)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OC)c2)cc1)c1ccc(C#N)cc1
Yield: 71.5 %

Procedure:
Compound 43 was synthesized from 4-{(1Z)-2-[4-(hydroxymethyl)-phenoxy]-N-methoxyethanimidoyl}benzonitrile (0.563 g, 1.9 mmol) and methyl 3-(4-hydroxy-2-methoxyphenyl)propanoate (0.4 g, 1.9 mmol) by following the procedure described in scheme 18 (0.27 g, yield: 71.5%); Purity: 94.96%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:6])([C@H:7]1[CH2:8][CH2:9][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:11][CH2:12]1)[CH3:5]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.400 g trans-2-(4-hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester (residue HH) are dissolved in 10 ml of dichloromethane. Triethylamine (0.42 ml) and 4-dimethylamino pyridine (0.012 g) are added and the solution is cooled to 0° C. 0.419 g of para-toluenesulfonyl chloride are added portionwise and the reaction mixture is then stirred at room temperature for 16 hours. The reaction mixture is poured onto saturated aqueous sodium hydrogencarbonate solution and the layers are separated. The aqueous layer is extracted with dichloromethane and the combined organics are dried over sodium sulphate and concentrated. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1.00 g) in N,N-dimethylformamide (20 ml) were added potassium carbonate (0.96 g) and ethyl bromoacetate (0.62 ml). The mixture was stirred at 70° C. for 9 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (1.31 g, yield quantitative) as a yellow oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([OH:20])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]([N:23]([O:24][CH3:25])[CH3:22])=[O:20])[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNOC
Reactant: COc1ccc(-c2c(C(=O)O)cnn2C(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(C(=O)N(C)OC)cnn2C(C)(C)C)cc1
Yield: 92.5 %

Procedure:
A solution of the compound (300 mg, 1.09 mmol) obtained in step 2, N,O-dimethylhydroxylamine monohydrochloride (160 mg, 1.64 mmol), HOBt (222 mg, 1.64 mmol), WSC (314 mg, 1.64 mmol) and TEA (0.228 mL, 1.64 mmol) in DMF (5 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution and dried, and the solvent was evaporated under reduced pressure to give a crude product 1-tert-butyl-N-methoxy-5-(4-methoxyphenyl)-N-methyl-1H-pyrazole-4-carboxamide (320 mg, 1.008 mmol, 92%) as a pale-yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:30]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]([F:30])=[O:11])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C#N)C(=O)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(2-cyano-phenyl)-propionic acid (2.5 g, 8.6 mmol) and pyridine (0.68 g, 8.6 mmol) were dissolved in dichloromethane (50 mL) at 0° C. Cyanuric fluoride (1.74 mL, 12.9 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour and then ice-water was added. The mixture was extracted with dichloromethane (2×). The organic extracts were washed with water, brine, and dried over sodium sulfate. Evaporation of the solvents gave crude [(S)-2-(2-cyano-phenyl)-1-fluorocarbonyl-ethyl]-carbamic acid tert-butyl ester as a yellow solid which was used without further purification in the next step (2.4 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:18][C:19]([N:21]([N:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1)[CH3:22])=[O:20])[C:7]1[C:15]([CH3:16])=[CH:14][C:13]2[C:9](=[CH:10][N:11]([CH3:17])[N:12]=2)[CH:8]=1)C.[OH-:33].[Na+].Cl>CO.O1CCCC1>[CH2:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][N:23]1[N:21]([CH3:22])[C:19](=[O:20])[CH2:18][N:6]([C:7]1[CH:8]=[C:9]2[C:10](=[CH:14][C:15]=1[CH3:16])[N:11]([CH3:17])[N:12]=[CH:13]2)[CH2:5][C:4]([OH:3])=[O:33]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn(C)nc2cc1C
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cnn2C)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 88 %

Procedure:
The compound (631 mg, 1.45 mmol) of step C was dissolved in a methanol (5 ml)-tetrahydrofuran (2 ml) mixed solvent, 1N sodium hydroxide (5 ml) was added at room temperature, and the mixture was stirred at room temperature for 70 min. To the reaction mixture was added 1N hydrochloric acid (5 ml), and the solution was concentrated under reduced pressure. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (517 mg, yield 88%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:8]([O:15][C:16]([NH:18][C:19](=[NH:22])OC)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:16]([NH:18][C:19]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][OH:1])[CH2:4]1)=[NH:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=N)NC(=O)OCc1ccccc1
Reactant: OCC1CCNC1
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CO)C1
Temperature: 60 °C
Yield: 25.2 %

Procedure:
1.01 g (0.01 mole) (3RS)-3-hydroxymethylpyrrolidine and 2.29 g (0.011 mole) N-benzyloxycarbonyl-O-methylisourea was dissolved (the amine not very soluble) in toluene and heated to 60° C. for three hours followed by stirring at room temperature over night. The mixture was evaporated and the 1H-NMR showed that the reaction was not completed. The mixture was therefore dissolved in 15 ml acetonitrile and heated to 60° C. for three hours followed by stirring at room temperature over night. The solvebt was evaporated and the mixture was dissolved in CH2Cl2, washed once with water, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2/MeOH 95/5 as eluent to yield 0.70 g (25%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O-:11].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:11][CH3:10]
Reactant: BrCc1ccccc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1ccccc1Br
Yield: 87 %

Procedure:
685 g (2.74 mol) of o-bromobenzyl bromide are refluxed together with 2.74 mol of a 30% strength sodium methylate solution in methanol for 15 hours. The mixture is cooled and then concentrated, the residue is taken up in ethyl acetate, and the solution is washed with water. The organic phase is dried over sodium sulfate and then concentrated. 478.2 g (87%) of product are obtained as a colorless liquid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([F:23])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[S:18]1[C:14]([C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[F:23])[NH:10][N:9]=2)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: COC(=O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]nc(-c3cc4ccccc4s3)c2c1F
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 71.5 %

Procedure:
To a solution of 152 mg of 3-benzo[b]thiophen-2-yl-4-fluoro-1H-5-indazolecarboxylic acid methyl ester obtained in Production Example II-13-f in a mixture of 2 ml of tetrahydrofuran and 2 ml of methanol was added 1 ml of 5 N aqueous sodium hydroxide solution, and the mixture was stirred at 55° C. for 2.5 hours. After standing to cool, 5.5 ml of 1 N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was recrystallized from tetrahydrofuran-ethyl acetate, to give 104 mg of the title compound as pale red crystals.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([O:19][CH3:20])[CH:18]=1)[O:15][CH2:14][CH2:13][C:12]2=O>Cl.O.[Zn]>[Br:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([O:19][CH3:20])[CH:18]=1)[O:15][CH2:14][CH2:13][CH2:12]2
Reactant: COc1cc(Br)cc2c1OCCC2=O
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Br)cc2c1OCCC2
Yield: 47 %

Procedure:
According to the process of preparation I, from the amalgam of zinc prepared from 915 g (14 gram-atoms) of zinc, 91 g (3.8×10-1M) of mercurous chloride in 46 cm3 of concentrated hydrochloric acid and 1350 cm3 of water, after addition of 700 cm3 of water, 1100 cm3 of concentrated hydrochloric acid, 2500 cm3 of toluene and 450 g (1.8 M) of 6-bromo-8-methoxy-4-chromanon (III1), 200 g (yield=47%) of the expected product are obtained. M.p.=67° C.
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:28]([S:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([S:47](Cl)(=[O:49])=[O:48])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH:29]=[CH2:30]>>[CH2:28]([S:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([S:47](=[O:49])(=[O:48])[NH2:8])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH:29]=[CH2:30]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: C=CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: C=CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 3-allylthio-5-chlorosulfonyl-4-phenylbenzoic acid, and following the procedure described, 3-allylthio-4-phenyl-5-sulfamylbenzoic acid is obtained as a hydrate with a melting point of 78°-81° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C=O)C>[C:11]1([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: ClCCCCCCCCOc1cccc2ccccc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1cccc2ccccc12

Procedure:
9.5 g of 1-chloro-8-(1-naphthyloxy)octane and 8.4 g of potassium phthalimide were taken up in 50 ml DMF and the resulting solution was heated at 140° for 3 hours. The reaction solution was then poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated and the residue was crystallized from acetone/hexane to afford the intermediate N-[8-(1-naphthyloxy)octyl]phthalimide mp 63°-64°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:26])[C:15]([C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)=[CH:32][N:33]([CH3:35])[CH3:34])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)Cc2ccc3c(c2)CCCC3)cc1OC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
2.65 g (7.50 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, 3.92 g (22.5 mmol) of t-butoxybis (dimethylamino)methane and 30 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 3.30 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.