Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:13])=[O:12].O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[S:11]([Cl:14])(=[O:12])=[O:13]
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-3-chlorosulfonyl-benzoic acid (6.90 g, 23.04 mmol, 1.00 Eq) in SOCl2 (27.41 g, 230.40 mmol, 10.00 Eq) was stirred at 80° C. for 3 hr. Then the solvent was evaporated. The residue was diluted in TOLUENE (50 mL), and MeOH (959.66 mg, 29.95 mmol, 1.30 Eq) was added, the formed mixture was stirred at 110° C. for 2 hr. Solid was formed, and the solvent was evaporated, the solid was washed with PE, and filtered to afford product methyl 4-bromo-3-chlorosulfonyl-benzoate (7.22 g, 23.03 mmol, 99.94% yield) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.[CH2:13]([SH:16])[CH2:14][SH:15].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([S:16][CH2:13][CH2:14][S:15]1)[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(Br)ccc21
Reactant: SCCS
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Brc1ccc2c(c1)CCCC21SCCS1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88 %

Procedure:
A solution of 6-bromo-3,4-dihydro-2H-naphthalen-1-one (CAS[66361-67-9]) (0.9 g, 4.00 mmol) in dichloromethane (8 ml) was cooled to 0° C. and treated with 1,2-ethandithiol (769 mg, 686 μl, 8.00 mmol) and boron trifluoro etherate (284 mg, 247 μl, 2.00 mmol). The reaction mixture was left to warm to room temperature and stirred for 15 hours. For the workup, the reaction mixture was poured into a solution of sodium hydroxide (1N) followed by extraction with dichloromethane (40 ml). The organic layer was dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 70:30 as the eluent. The 6′-bromo-3′,4′-dihydro-2′H-spiro[[1,3]dithiolane-2,1′-naphthalene] (1.06 g, 88% yield) was obtained as a light red oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14]1([Si:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>N1C=CC=CC=1>[C:27]1([Si:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1ccn(CCCCO)c(=O)[nH]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: O=c1ccn(CCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1

Procedure:
1-(4′-Hydroxybutyl)uracil (0.048 g, 0.26 mmol) was dissolved in dry pyridine (1.5 mL) and cooled in an ice-salt bath. A solution of triphenylsilyl chloride (0.099 g, 0.34 mmol) in dry pyridine (1.5 mL) was added drop-wise. The reaction mixture was kept at 0° C. under nitrogen for 2 h30. CH3OH (15 μL) was added and after 10 min the solution was concentrated on the rotary evaporator. The resultant crude transparent oil was purified by silica gel chromatography using a gradient elution of 0→3% CH3OH in CHCl3. The title compound was obtained as a white solid (0.085 g, 74%) from the fractions with Rf=0.50 (10% CH3OH/CHCl3).
Reaction SMILES: C(OC([N:11]1[C@H:16]([C:17]2[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=2)[CH2:15][O:14][CH2:13][C@@H:12]1[C:26](=[O:28])[CH3:27])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:23][C:21]1[CH:22]=[C:17]([C@H:16]2[NH:11][C@@H:12]([C:26](=[O:28])[CH3:27])[CH2:13][O:14][CH2:15]2)[CH:18]=[C:19]([F:25])[C:20]=1[F:24]
Reactant: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
A suspension of (3R,5R)-3-acetyl-5-(3,4,5-trifluorophenyl)morpholine-4-carboxylic acid benzyl ester (800 mg) and 10% palladium-carbon (79.2 mg, 50% water content) in ethanol (15 mL) was stirred under a hydrogen atmosphere for 15 minutes. The catalyst was filtered off over Celite. The obtained filtrate was concentrated, to thereby obtain the titled compound (529 mg). The physical properties of the compound were as follows.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[N+:6]=1[O-:7].[H-].[Na+].[CH3:14]I.Cl>O.CN(C)C=O>[CH3:14][O:7][N:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: CI
Reactant: Cc1[nH]c2ccccc2[n+]1[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COn1c(C)nc2ccccc21
Reaction time: 0.25 h

Procedure:
To a solution of 7.8 g (0.53 mole) of 2-methylbenzimidazole N-oxide [Chem. Pharm. Bull., 11, 1375 (1963)]in 50 ml of dimethylformamide was added 2.53 g (0.053 mole) of 50% sodium hydride in oil over a period of 5 minutes. After stirring 15 minutes, 3.33 ml (0.053 mole) of methyl iodide was added over a 15-minute period and the reaction mixture allowed to stir at room temperature for 3 hours. The reaction was poured into water, the pH adjusted to 2 with 12N hydrochloric acid and the impurities extracted with ethyl acetate. The pH was adjusted to 12 with 6N sodium hydroxide solution and the product extracted with ethyl acetate (3×100 ml). The extracts were combined, dried over magnesium sulfate and evaporated under a nitrogen stream.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][C@H:8]([CH2:23][NH:24][C@@H:25]([C:29]1[N:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37](=[O:46])[C:36]2[C:31](=[CH:32][C:33]([Cl:47])=[CH:34][CH:35]=2)[N:30]=1)[CH:26]([CH3:28])[CH3:27])[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:56]1([CH3:65])[CH:61]=[CH:60][C:59]([C:62](Cl)=[O:63])=[CH:58][CH:57]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:48])[NH:7][CH:8]([CH2:23][N:24]([CH:25]([C:29]1[N:38]([CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:37](=[O:46])[C:36]2[C:31](=[CH:32][C:33]([Cl:47])=[CH:34][CH:35]=2)[N:30]=1)[CH:26]([CH3:28])[CH3:27])[C:62]([C:59]1[CH:60]=[CH:61][C:56]([CH3:65])=[CH:57][CH:58]=1)=[O:63])[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)[C@@H](NC[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)N(CC(CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of ((S)-1-{[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-methyl}-4-benzyloxycarbonylamino-butyl)-carbamic acid tert-butyl ester (250 mg, 0.37 mmol) in toluene (4 mL) was added triethylamine (0.10 mL, 0.74 mmol) followed by dropwise addition of p-toluoyl chloride (0.049 mL, 0.37 mmol). The reaction mixture was heated to 80° C. for 18 h, then reflux for 4 h. The reaction mixture was allowed to cool to room temperature, quenched with saturated aqueous NaHCO3 (10 mL) and diluted with CH2Cl2 (10 mL). The extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexanes:ethyl acetate) to provide 235 mg (79%) of the title compound as a pale yellow powder. MS(ES+) m/e 794.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([NH:16][S:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:6]=3[C:7]=2[CH3:14])(=[O:12])=[O:11])[CH:18]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Reactant: COC(=O)c1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 56.1 %

Procedure:
The intermediate methyl 3-{[(5-bromo-3-methyl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate was prepared according to General Procedure 1, described in Example 1, starting from 5-bromo-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 10) (870 mg, 2.67 mmol) and methyl 3-aminobenzoate (367 mg, 2.43 mmol). The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 1M HCl (30 mL). The organic phase was dried (Na2SO4). Evaporation of the solvents afforded 600 mg of crude methyl-3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2/[CH:19]=[CH:20]/[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=2)=[O:22])=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:1]([N:3]([CH2:4][CH3:5])[C:31](=[O:32])[CH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:14]2[CH:15]=[N:16][N:17]([CH3:18])[C:13]=2[C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1)[CH3:2]
Reactant: CCNCC
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 59.9 %

Procedure:
A mixture of diethylamine (0.17 g), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ((2E)-N-{4-[2-(diethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.48 g, yield 62%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 175-176° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18]>C1(C)C=CC=CC=1>[Cl:19][C:17]([O:16][CH2:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: OCCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
N-[9H-(Fluorenyl-9-ethoxycarbonyl)]amino-4-benzoic acid was prepared from a solution of 2-(9-fluorenyl) ethanol (1.5 g, 7.1 mmol) in 10 ml of toluene to which was added dropwise with stirring a solution of phosgene in toluene (12.4 ml, 1.93M). After 0.5 hours, the solution was put under vacuum to remove excess phosgene, and concentrated to yield 2-(9-fluorenyl)ethyl chloroformate. This was then dissolved in 10 ml of dioxane and add to a solution of 4-aminobenzoic acid (1.0 g, 7.3 mmol) in 15 ml water. After 5 hours, the dioxane was evaporated, the solution diluted with an equal amount of water, rendered basic with sodium carbonate solution, and filtered to remove insoluble materials. Acidification with 10% HCl yielded a white precipitate, which was filtered and dried. Crystallization from aqueous DMF gave a white solid (1.22 g, 46%), mp 202° C. IR(KBr) 3342, 2964, 2666, 2543, 2363, 1699, 1676, 1609, 1594, 1524, 1509, 1477, 1414, 1313, 1293, 1266, 1177, 1069, 1049, 938, 853, 768, 750, 735 cm-1. 1H NMR (300 MHz, DMSO) δ 2.3(q, 2H, J=7.0), 400(t, 2H, J=7.0), 4.12(t, 1H, J=6.0), 7.29-7.88(m, 13H, 9.97(s, 1H). Anal. calcd for C23H19NO4 0.25H2O: C, 73:10; H, 5.20; N, 3.71. Found: C, 73.32; H, 5.23; H, 3.70.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH3:16])[CH:3]=1.[NH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=2)[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH3:16])[CH:3]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: Cc1cc(Br)ccc1C(Cl)C1CCCCC1
Product: COC(=O)c1ccc(NC(c2ccc(Br)cc2C)C2CCCCC2)nc1

Procedure:
Using 4-bromo-1-(chloro(cyclohexyl)methyl)-2-methylbenzene obtained in Example 16, step B and methyl 6-aminonicotinate, and in the same manner as in Example 1, step D, the title compound was obtained.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([C@@H:14]1[C@H:19]([CH3:20])[CH2:18][CH2:17][NH:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[NH:11][CH:12]=[N:13][C:6]=12.[C:21]([CH2:23][C:24](O)=[O:25])#[N:22].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O>[N:13]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:3])[C@@H:14]2[C@H:19]([CH3:20])[CH2:18][CH2:17][N:16]([C:24](=[O:25])[CH2:23][C:21]#[N:22])[CH2:15]2)[NH:11][CH:12]=1
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]cnc12
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ccnc2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of N-methyl-N-[(3R,4R)-4-methyl-3-piperidinyl]-3H-imidazo[4,5-b]pyridin-7-amine dihydrochloride (40 mg) in N,N-dimethylformamide (0.6 mL) were added cyanoacetic acid (16 mg), 1-hydroxybenzotriazole (25.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.033 mL). The mixture was stirred at ambient temperature overnight, then extracted with EtOAc and washed with brine. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform and methanol (100:0 to 90:10) to give 3-{(3R,4R)-3-[3H-imidazo[4,5-b]pyridin-7-yl(methyl)amino]-4-methyl-1-piperidinyl}-3-oxopropanenitrile (25 mg) as a white powder.
Reaction SMILES: Br[CH:2]([CH2:18][CH3:19])[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O>[O:23]1[CH2:24][CH2:25][N:20]([CH:2]([CH2:18][CH3:19])[C:3]([C:5]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:17])[NH:10]3)=[O:4])[CH2:21][CH2:22]1
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1

Procedure:
g of 5-(α-bromobutyl)-8-hydroxy-3,4-dihydrocarbostyril (IV) was suspended in 30 ml of benzene, and 4.2 ml of morpholine (III) was added to the suspension followed by allowing the mixture to react for 4 hours while heating under refluxing. The reaction mixture was filtered and the filtrate was washed with water followed by concentration under reduced pressure to remove any remaining water. The resulting residue was dissolved in 50 ml of isopropanol, and the solution was adjusted to a pH of 2-3 with concentrated hydrochloric acid. The viscous precipitate formed upon ice-cooling was separated and dissolved in acetone by heating. After allowing the solution to cool, the precipitate formed was dissolved in 30 ml of water and adjusted to a pH of 7.5-8 with sodium bicarbonate. The precipitate formed upon ice-cooling was filtered and dissolved in 10 ml of a 47% aqueous hydrobromic acid followed by concentration under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to obtain 2.8 g of white amorphous 5-(α-morpholinobutyryl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide monohydrate. The structure of the material thus obtained was confirmed by NMR and IR spectra and elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([O:22][CH3:23])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:36](=[O:37])[C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:41]([O:42][CH3:43])=[C:40]([O:44][CH3:45])[CH:39]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH:21]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCNCC1)=C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)CC1)=C2
Temperature: 0 °C
Yield: 67.1 %

Procedure:
To a mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)piperazine (1.2 g), triethylamine (0.5 g) and methylene chloride (20 ml) is added dropwise, with stirring under ice-cooling, a solution of 3,4,5-trimethoxybenzoyl chloride (1.0 g) in methylene chloride (25 ml). The reaction mixture is stirred for one hour at room temperature. The reaction mixture is pourd into ice-water (100 ml), and extracted with methylene chloride. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is crystallized from ethyl acetatehexane to give 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine (1.3 g), as obtained in Example 62, as colorless prisms, m.p. 164°-165° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(OC([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([NH:17][C:18](=[O:19])[C:13]=12)=[O:16])=O)C.Cl.N[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[OH:32]>O>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[CH2:25][N:17]1[C:18](=[O:19])[C:13]2[C:14](=[CH:20][CH:21]=[CH:22][CH:12]=2)[C:15]1=[O:16]
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Reactant: NCC1CCCCC1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CCCC[C@@H]1O
Reaction time: 3 h
Yield: 74.5 %

Procedure:
Under a nitrogen atmosphere, potassium carbonate (375 mg, 2.72 mmol) and ethoxycarbonylphthalimide (364 mg, 1.66 mmol) were added to an aqueous solution (4 ml) of 2-aminomethylcyclohexanol hydrochloride (250 mg, 1.51 mmol) at room temperature. After 3 hours, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain cis-2-[(2-hydroxycyclohexyl)methyl]-1H-isoindole-1,3(2H)-dione (291.6 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[OH:18])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].Cl>CC(C)=O>[C:34]([O:33][C:31](=[O:32])[CH2:30][O:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[C:8](=[O:19])[NH:7][CH2:6][C:5]1[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][C:4]=1[F:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NCc1ccc(Br)cc1F)c1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([N+](=O)[O-])cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 96.3 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-5-nitro-benzamide (0.95 g, 2.6 mmol) in acetone (15 mL, 0.2 M) was treated with aq K2CO3 (2 M, 1.9 mL, 3.8 mmol) and t-butyl bromoacetate (2.2 mL, 8.4 mmol). After heating to 50° C. for 30 h, the reaction was acidified to pH 1–2 with 2 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed With saturated aq NaCl, dried over Na2SO4, filtered and concentrated. The crude oil was crystallized from heptane and ethyl acetate to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-4-nitro-phenoxy]-acetic acid tert-butyl ester as a white crystalline solid (1.21 g, 97%): 1H NMR (DMSO-d6, 300 MHz) δ 9.01 (br t, J=5.7 Hz, 1 H), 8.58 (d, J=3.0 Hz, 1 H), 8.33 (dd, J1=9.0 Hz, J2=3.0 Hz, 1 H), 7.51 (br d, J=9.6 Hz, 1 H), 7.42–7.34 (m, 2 H)., 7.32 (d, J=9.3 Hz, 1 H), 4.99 (s, 2 H), 4.52 (d, J=5.7 Hz, 2 H), 1.40 (s, 9 H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3[CH:27]=CO[C:23]=3[CH2:22]2)=[O:20])=[CH:17][CH:16]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[C:7]([C:15]1[CH:31]=[CH:30][C:18]([C:19]([N:21]2[CH2:26][CH2:25][C:24]3[CH:27]=[C:2]([CH:1]=[O:5])[O:3][C:23]=3[CH2:22]2)=[O:20])=[CH:17][CH:16]=1)(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 30 ml of N,N-dimethylformamide, 0.20 ml (2.3 mmol) of oxalyl chloride was added at -78° C., followed by stirring at room temperature for 15 minutes. To this mixture, a solution of 0.684 g (2.064 mmol) of 6-(4-benzoylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of N,N-dimethylformamide was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (hexane/ethyl acetate=1/1 to 1/3) to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[O:8][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(F)ccc1[N+](=O)[O-]
Yield: 89.6 %

Procedure:
To a mixture consisting of 5-fluoro-2-nitrophenol (47.1 g), acetonitrile (300 ml) and potassium carbonate (46 g) was added ethyl bromoacetate (60.1 g) dropwise at a temperature from 50° to 60° C., followed by a five-hour refluxing under heating and then filtration under cooling. The resulting filtrate was subjected to distillation under reduced pressure, and then dissolved in toluene (350 ml). The resulting toluene solution was washed with water, a 5% aqueous solution of potassium hydroxide, and water, in that order, followed by drying with magnesium sulfate and the toluene was distilled off therefrom under reduced pressure. The residue was distilled under reduced pressure to collect a fraction boiling at from 154° to 156° C., so as to obtain ethyl 5-fluoro-2-nitrophenoxyacetate (65.3 g). The whole quantity of the reaction product was dissolved in ethanol (8.1 l), followed by addition thereto of a solution of ammonium chloride (60 g) and water (400 ml). To the resulting mixture was added zinc dust (60.5 g) portionwise at a temperature of from 20° to 30° C.