Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:14]2[CH:13]=[CH:12][N:11]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:10]3[C:9]=2[N:8]([C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)(=O)C.[Mn]([O-])(=O)(=O)=[O:30].[K+].S([O-])(O)=O.[Na+]>CC(C)=O.O>[C:20]([N:8]1[C:9]2[C:10]3=[N:17][C:16]([CH3:18])=[C:15]([CH3:19])[N:11]3[CH:12]=[CH:13][C:14]=2[C:5](=[O:4])[C@H:6]([OH:30])[C@H:7]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC1=C[C@@H](c2ccccc2)N(C(C)=O)c2c1ccn1c(C)c(C)nc21
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C(=O)[C@H](O)[C@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
2.0 g (5.4 mmol) of (9S)-7-acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2h][1,7]-naphthyridine are dissolved in 30 ml of acetone and 6 ml of water. 1.0 g (6.4 mmol) of potassium permanganate is then introduced in portions at 0° C. After 30 min, the brown suspension is admixed with 1 ml of saturated sodium hydrogensulphite solution, filtered through Celite and washed with methanol and dichloromethane. The filtrate is concentrated and the residue crystallized using ethanol. 0.3 g (16%) of the title compound is isolated as a yellow solid (m.p. 192° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][CH2:16][CH2:15][C:14]3[CH:13]=[C:12](C(=O)N(C4C=CC(Cl)=CC=4Cl)C)[S:11][C:10]=3[C:9]=2[CH:30]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.C(O)C>[S:11]1[C:10]2[C:9]3[CH:30]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12]1
Reactant: COC(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(Cl)cc3Cl)cc1CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)-c1sccc1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid methyl ester (700 mg) in THF (8 mL) and ethanol (4 mL) was added sodium hydroxide solution (121 mg in 4 mL of water) and the reaction stirred at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and the resulting solid was filtered and air-dried to give 2-(2,4-dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid.
Reaction SMILES: [Cl-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C@H:14]([CH3:18])[C:15](O)=[O:16])[CH:8]=[CH:7]2>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C@H:14]([CH3:18])[C:15]([Cl:1])=[O:16])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: [Cl-]
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reaction time: 2 h

Procedure:
2.85 ml, 32.5 mmol Oxaly chloride ((COCl)2) is added slowly to 3 g, 13 mmol (S)-2-(6-methoxy-2-naphthyl)propionic acid dissolved in 3 ml dichloromethane (CH2Cl2), and the resulting solution is heated under a first reflux temperature with stirring for 2 hours. The excess oxaly chloride is removed by evaporation under reduced pressure to obtain a crude product of (S)-2-(6-methoxy-2-naphthyl)propionic acid chloride. The crude (S)-2-(6-methoxy-2-naphthyl)propionic acid chloride is dissolved in 5 ml dichloromethane and then added to a solution of 3.36 ml, 32.5 mmol N,N′-diethylamine (HN(CH2CH3)2) and 5 ml triethylamine (TEA) in 10 ml dichloromethane with stirring under ice bath, i.e. under a temperature about 0° C. After some solids are produced, the mixture is stayed in a refrigerator overnight, i.e. stayed in a low temperature about−5° C. for a period of time about 12 hour. The mixture is evaporated to dryness under reduced pressure and the residue is purified by column chromatography over silica gel (70˜230 mesh ASTM) using dichloromethane/ethyl acetate (V:V=8:2) as the eluant. As a result, about 70 percent yield of white N,N′-diethyl (S)-2-(6-methoxy-2-naphthyl)propionate is obtained, which is the first intermediate (I) for synthesizing the chiral compound of the first preferred embodiment of the present invention.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:20]=1[N+:26]([O-])=O)[CH3:18])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C>[C:11]([O:15][C:16](=[O:29])[N:17]([C:19]1[CH:24]=[C:23]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:22]=[CH:21][C:20]=1[NH2:26])[CH3:18])([CH3:14])([CH3:12])[CH3:13]
Reactant: OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To anhydrous DMF were added benzyl alcohol (2.48 ml) and 55% NaH (1.05 g) and then N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (5.73 g) was added in small portions. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The resulting residue was stirred in a mixture of dioxane (100 ml), water (10 ml), sodium hydrosulfite (20.9 g) and sodium hydrogencarbonate (21.0 g) at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water and the extract was dried over anhydrous sodium sulfate and concentrated. The resulting residue was chromatographed on a silica gel column using ethyl acetate/n-hexane (1/2) as the eluant to afford the title compound (2.29 g). melting point: 86-89° C.
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].[NH2:9][C:10]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C:12](=[CH:13][C:14](Cl)=[CH:15][CH:16]=2)[CH:11]=1.O>CO>[NH2:9][C:10]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:17]2[C:12](=[CH:13][C:14]([S:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CC(C)CS
Reactant: Nc1cc2cc(Cl)ccc2cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CSc1ccc2cc([N+](=O)[O-])c(N)cc2c1
Reaction time: 0.17 h

Procedure:
To 1 mole of isobutylmercaptan in 500 ml of methanol stirring at room temperature is added 1.1 mol of sodium methoxide. The mixture is stirred for 10 minutes and the solvent is evaporated under vacuum. The residue is taken up in 500 ml of dimethylformamide. To this mixture, stirring at room temperature, is added 1 mole of 2-amino-7-chloro-3-nitronaphthalene. The mixture is refluxed for 2 hours, then cooled and poured into 2 liters of water. After stirring for 30 minutes the resulting precipitate is filtered off and recrystallized from methanol or ethanol to yield the title compound.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Se:10][C:9]=1[C:19]([O:21]CC)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[Se:10][C:9]=1[C:19]([NH2:2])=[O:21])[CH3:5]
Reactant: CCOC(=O)c1[se]c(-c2ccccc2)cc1N=NN(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1cc(-c2ccccc2)[se]c1C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (160 mL) was added a solution of ethyl 3-[(dimethylamino)diazenyl]-5-phenylselenophene-2-carboxylate (1.2 g) in THF (25 mL) for 5 min and a catalytic amount of PEG-400 was added and stirred at rt for 48 h. The solution was poured into ice cooled water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (94:6) as eluents to give the product as off-white solid, which was recrystallized from chloroform-hexane (270 mg, 31%), mp 222-224° C. IR (Neat) νmax 3346, 2927, 2850, 1645, 1594, 1221, 1113, 1019, 875, 850 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.25 (1H, s, —CONH2), 7.87 (1H, s, H-4), 7.57-7.60 (2H, m, Ar—H), 7.30-7.40 (3H, m, Ar—H), 6.18 (1H, br s, —CONH2), 3.58 (3H, s, —N—CH3), 3.19 (3H, s, —N—CH3); 13C NMR (100 MHz, DMSO-d6): δ 165.6, 152.1, 151.9, 136.1, 131.1, 128.9, 128.5, 126.2, 118.1, 43.7, 36.6; LC-MS (positive ion mode): m/z 343, 345 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([O:11]CC)=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[NH3:14]>>[N+:1]([C:4]1[C:5]([C:9]([NH2:14])=[O:11])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: N
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Product: NC(=O)c1n[nH]cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
Ethyl 4-nitro-1H-pyrazole-3-carboxylate (741 mg, 4 mmol) was heated at 90° C. with a concentrated solution of aqueous ammonia (28%, 20 ml) in a sealed vessel for 3 hours. The mixture was evaporated and the residue was triturated with diethyl ether to give 4-nitro-1H-pyrazole-3-carboxamide (0.54 g, 86% yield) as a white solid:
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[NH2:20]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 140 °C
Reaction time: 7 h
Yield: 51.2 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (90 mg) in 1-methyl-2-pyrrolidone (0.7 mL), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and the mixture was heated to 140° C. and stirred for 7 hrs. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→8/2). The object fraction was concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (90 mg) as pale-yellow needle crystals.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]([CH2:43][O:44]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:32][C@H:10]2[CH2:11][O:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>CC(C)=O>[C:1]1([CH2:7][O:8][C@H:9]2[C@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]([CH2:43][OH:44])[O:32][C@H:10]2[CH2:11][OH:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CO[C@H]2[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: OC[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A solution of 847 mg of 2,5-anhydro-3,4-bis-O-(phenylmethyl)-1,6-bis-O-(triphenylmethyl)-D-glucitol in 5 ml of acetone was treated with 16 ml of 80% aqueous acetic acid with stirring for 1 hour at 80° C., for 20 hours at room temperature and then evaporated in vacuo. The residue was taken up in ether, washed with brine, dried and evaporated to an oil. Chromatography of the oil, eluting with ether, gave 260 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:14]=[CH:15][CH:16]=1)#[CH:10]>C1COCC1.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([CH:10]=[CH:9][C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C#Cc1cccc(NC(=O)C(F)(F)F)c1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cccc(C=Cc2ccnc(Cl)n2)c1)C(F)(F)F
Temperature: 50 °C

Procedure:
To a mixture of 2,4-dichloropyrimidine (14.5 g, 97.5 mmol), dichlorobis(triphenyl-phosphine)palladium(II) (1.3 g, 2.6 mmol), and copper(I) iodide (25 mg, 0.13 mmol) in degassed THF was added TEA (34 mL, 263 mmol), and the mixture was heated to 50° C. A solution of N-(3-ethynyl-phenyl)-2,2,2-trifluoro-acetamide (14 g, 65 mmol) in THF was added to the mixture over 45 minutes. After several h, the reaction was cooled to rt and diluted with DCM. The organic mixture was washed with water and brine, dried over MgSO4 and concentrated. The crude material was purified through silica to give the title compound as an off-white solid. 1H NMR (400 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.76 (m, 1H), 7.54-7.52 (m, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F>C1COCC1.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-n2ccc3ccccc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
A slurry of 334 mg (374 mg of 60% in oil, 9.35 mmol) of sodium hydride in 5 mL THF was treated with a solution of 1.0 g (8.5 mmol) of indole in 5 mL THF, followed by stirring at ambient temperature for 15 min. The solution was then treated with 1.35 g (8.5 mmol) of 3,4-difluoronitrobenzene. The solution was stirred at ambient temperature for 48 h, followed by concentration in vacuo to afford brown oil which was dissolved in ethyl acetate and washed with water. Drying (Na2SO4) and concentration in vacuo afforded an oil which was chromatographed over 100 g of 230-400 mesh silica gel, eluting with 20% (v/v) ethyl acetate in hexane. These procedures afforded 1.1 g (51%) of the title compound as a yellow solid. 1H NMR (CDCl3): δ 8.23, 7.74, 7.40, 7.35, 7.30, 6.80.
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17](C(O)=O)[C:18]=3[CH3:19])[CH:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.O=O.C(=O)=O>C(OCC)(=O)C.CCCCCC>[CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[CH:17][C:18]=3[CH3:19])[CH:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCn2c(C(=O)c3ccc4n3CCC4)c(C)c(C(=O)O)c21
Agent: O=C=O
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1CCn2c1cc(C)c2C(=O)c1ccc2n1CCC2

Procedure:
A stirred portion (0.63 g, 0.0007 m) of the acid from Step D above in an oxygen-free atmosphere is set in an oil-bath set at 210° C. (and rising to 230° C.) and kept there until carbon dioxide evolution ceases. Chromatography of the residue obtained, using a silica gel column and 25% ethyl acetate/hexane as eluant yields pure ethyl 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:20]=[CH:19][C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])#[N:9]>ClCCl>[C:8]([C:10]1[CH:22]=[C:21]([O:23][CH:24]([CH3:26])[CH3:25])[CH:20]=[CH:19][C:11]=1[C:12]([OH:14])=[O:13])#[N:9]
Reactant: CC(C)Oc1ccc(C(=O)OC(C)(C)C)c(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)O)c(C#N)c1
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (0.6 mL, 7.8 mmol) was added drop-wise to a solution of tert-butyl 2-cyano-4-isopropoxybenzoate (82 mg, 0.31 mmol) in dichloromethane (0.6 mL) at 0° C. under N2 atmosphere. After the addition was complete, the cooling bath was removed and stirring was continued for an additional 2 h at 25° C. The solvent was removed under reduced pressure to yield 2-cyano-4-isopropoxybenzoic acid that was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[C:13]1([NH:19][CH2:20]C(O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([N:19]2[CH2:20][CH2:3][CH:2]3[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CNc1ccccc1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CCN(c3ccccc3)C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate and 7.6 50 mmol) of phenylglycine are heated under reflux overnight in 200 ml of toluene. The mixture is decanted from resinous material and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][S:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:4][CH2:3]1.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>>[CH2:20]([N:15]1[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[N:12]=[C:11]1[S:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(CCSc2nc3ccccc3n2Cc2ccccc2)CC1

Procedure:
Grams 2 2-[2-(4-methylpiperazin-1-yl)ethylthio] benzimidazole, 0.86 ml benzyl chloride, a 3.5 g aqueous solution containing 1.16 g NaOH and 7.5 ml N,N-dimethylformanide were refluxed for 6 hours, then the solid precipitate was filtered off, and the limpid solution was evaporated almost to dryness. The obtained residue was dissolved in chloroform and water and the extraction was carried out three times; the organic phase was washed, made anhydrous and then evaporated to dryness. The obtained residue was chromatographed on a column eluting with chloroform, methyl alcohol, cyclohexane, ammonium hydroxide (65:15:15:0.1). The fractions, which contained the compound, were evaporated to dryness and the residue which was taken up with boiling petroleum ether (80°-φ° C.) and separated from the insoluble oil, gave, on cooling 0.3 g 1-benzyl-2-[2-4- methylpiperazin-1-ethylthio]benzimidazole melting at 122°-125° C.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15](=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[C:5](OCC)=[O:6])(=O)[CH3:2].[ClH:32].[NH2:33][C:34]1[N:35]=[CH:36][NH:37][C:38]=1[C:39](=[O:41])[NH2:40]>>[ClH:32].[C:39]([C:38]1[N:37]=[CH:36][N:35]2[C:5]([OH:6])=[C:4]([CH2:10][CH2:11][N:12]3[CH2:13][CH2:14][C:15](=[C:18]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][CH2:17]3)[C:1]([CH3:2])=[N:33][C:34]=12)(=[O:41])[NH2:40]
Reactant: CCOC(=O)C(CCN1CCC(=C(c2ccccc2)c2ccc(C)cc2)CC1)C(C)=O
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Product: Cc1ccc(C(=C2CCN(CCc3c(C)nc4c(C(N)=O)ncn4c3O)CC2)c2ccccc2)cc1

Procedure:
This compound was prepared from ethyl 2-acetyl-4-{4-[(4-methylphenyl)phenylmethylene]-1-piperidyl}-butyrate and 4-amino-5-carbamoyl imidazole hydrochloride according to the process described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([C@H:18]3[CH2:30][CH2:29][O:28][C@H:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Yield: 97.7 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.335 g) was added to a solution of methyl cis-(3aRS,9bRS)-7-amino-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 19, 0.255 g) in DCM (4 mL) and pyridine (2 mL) and the resultant mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl cis-(3aRS,9bRS)-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (0.486 g) as a yellow gum.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH:7][C:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[CH:26][CH:25]=1)([C:13]([F:23])([F:22])[C:14](=[O:21])[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([F:12])([F:11])[F:10])=[O:6])([CH3:4])[CH3:3].[H-].[Na+].[CH:40]1[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH2:46]([N:7]([C:8]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:35])[F:36])=[CH:26][CH:25]=1)([C:13]([F:22])([F:23])[C:14](=[O:21])[N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([F:10])([F:11])[F:12])[S:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[O:6])[C:43]1[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)S(=O)NC(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N(Cc1ccccc1)C(c1ccc(OCCCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
A solution of Intermediate 103D (461 mg, 0.814 mmol) in anhydrous DMF (0.5 mL) was added to a suspension of NaH (65 mg, 1.627 mmol) (60% in mineral oil) at 0° C. After stirring for 5 min, BnBr (0.484 mL, 4.07 mmol) was added. The reaction mixture was warmed to rt and stirred for 1 h. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (4 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (260 mg, 44%) as a yellow gum. 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J=8.5 Hz, 2H), 7.33-7.27 (m, 3H), 7.14 (dd, J=7.3, 2.1 Hz, 2H), 6.80 (d, J=9.1 Hz, 2H), 4.46-4.38 (m, 2H), 4.00-3.95 (m, 2H), 3.72 (br. s., 1H), 3.51 (br. s., 1H), 3.35-3.10 (m, 2H), 2.37-2.25 (m, 2H), 2.09-1.99 (m, 2H), 1.70-1.39 (m, 6H), 1.34-1.29 (m, 9H).
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC(C)C[C@@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of 2.62 g of D-leucine in 30 ml of 1N sulfuric acid at 0° C. was added a solution of sodium nitrite (2.07 g) in water (15 ml). The resulting solution was stirred at 0° C. for 3 hours, and then at room temperature for 2 hours. The reaction mixture was extracted with ethyl ether (10 ml×3), and the combined organic layers were washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield the title compound as a light-yellow solid (2.08 g).