Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([C:20]([F:23])([F:22])[F:21])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33]([N:17]2[CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:34])[CH:26]=[CH:25]1
Reactant: Fc1ccc(C2CCN(CC3CNCC3C(F)(F)F)CC2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccc(F)cc3)CC2)C(C(F)(F)F)C1

Procedure:
A solution of 0.12 g (0.36 mmol) of 3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(RS)-(trifluoromethyl)pyrrolidine, 0.069 g (0.43 mmol) of indole-7-carboxylic acid, 0.088 g (0.72 mmol) of DMAP and 0.097 g (0.5 mmol) of 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (Aldrich) in 10 mL of CH2Cl2 was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone:hexanes, 1:5) to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([N:14]3[CH2:18][C@H:17]([SH:19])[CH2:16][C@H:15]3[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[O:13])[C:5]=2[O:4][CH2:3][CH2:2]1.[C:32](Cl)(=[O:34])[CH3:33]>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:12]([N:14]3[CH2:18][C@H:17]([S:19][C:32](=[O:34])[CH3:33])[CH2:16][C@H:15]3[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[O:13])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: O=C(Oc1cccc2c1OCCO2)N1C[C@H](S)C[C@H]1COCc1cc(F)c(F)cc1F
Solvent: c1ccncc1
Product: CC(=O)S[C@@H]1C[C@@H](COCc2cc(F)c(F)cc2F)N(C(=O)Oc2cccc3c2OCCO3)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
A solution of 10 g (21.96 mmol) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo [1,4]dioxin-5-yl ester in 130 ml pyridine were treated at 0° C. with 3.12 ml (43.92 mmol) acetyl chloride and stirred for 6 h at RT. The reaction was poured on ice water and extracted wit Et2O (3×). The organic phases were washed with aqueous 1 N HCl and 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography on silica gel (CH2Cl2/Et2O 99.5:0.5 to 98:2) gave 9.94 g (91%) (2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester, MS: 498 (MH+).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[C:10]([NH:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])=O)(C)(C)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[NH2:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[C:10]([NH:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl [[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)propanoyl]amino]acetate (73.8 g) in ethyl acetate (150 ml) was added dropwise 4N hydrogen chloride in ethyl acetate (669 ml) at 10° C. over 30 minutes. The mixture was warmed to room temperature and stirred for 3 hours. The mixture was diluted with ethyl acetate (300 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate (700 ml), and dried in vacuo to give the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4].[CH3:22]I.O>CN(C)C=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][O:21][CH3:22])=[CH:18][CH:19]=2)[C:12]=1[CH3:13])=[O:7])[CH3:4]
Reactant: CI
Reactant: CCOC(=O)c1cnn(-c2ccc(CO)cc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(COC)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (129 mg) was added to a solution of 1-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg) in N,N-dimethylformamide (13 ml) at room temperature and stirred at the same temperature for 0.5 hour. Methyl iodide (0.3 ml) was added therein and stirred at 80° C. for two hours. Methyl iodide (0.2 ml) was further added and stirred at the same temperature for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added therein and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[4-(methoxymethyl)phenyl]-5-methyl-1H-pyrazol-4-carboxylic acid ethyl ester (401 mg) as a white solid.
Reaction SMILES: [Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:29])[CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[Si:1]([C:8]1[S:9][C:10]([C:13]2([OH:29])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:11][N:12]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCN(C(=O)OCc3ccccc3)CC2)s1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)c1ncc(C2(O)CCNCC2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of benzyl 4-(2-(tert-butyldimethylsilyl)thiazol-5-yl)-4-hydroxypiperidine-1-carboxylate (as prepared in the previous step) (3 g, 6.94 mmol, 1.00 equiv) in methanol (20 mL) and Palladium carbon (0.3 g). Hydrogen was introduced into the above mixture. Under H2 atmosphere, the resulting solution was stirred overnight at 50° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[N:9]=[CH:8][CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1.[OH-].[K+]>OS(O)(=O)=O>[Br:21][C:4]1[C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2cccnc2cc1C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: COc1c(C)cc2ncccc2c1Br
Temperature: 15 °C
Reaction time: 3.5 h
Yield: 171.2 %

Procedure:
To the solution of 6-methoxy-7-methylquinoline (4.28 g, 24.6 mmol) in 50 mL of concentrated H2SO4 was added NBS (4.41 g, 14.6 mmol) at 15° C., and the reaction was stirred at 15° C. for 3.5 hours. The reaction mixture was poured into ice-water (600 mL). The aqueous mixture was adjusted with a 50% KOH solution to pH ˜10, and then extracted with DCM (3×). The combined extract was dried with sodium sulfate. Concentration under reduced pressure gave 5-bromo-6-methoxy-7-methylquinoline (6.3 g). LCMS-ESI+ (m/z): 252.1, 254.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=O)[CH2:9][F:10])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O.CCOC(C)=O>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=[N:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH2:9][F:10])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cc(Br)ccc1F
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[S@@](=O)N=C(CF)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone (14 g, 59.6 mmol, step 1) and (R)-2-methylpropane-2-sulfinamide (14.44 g, 119 mmol, AK Scientific) in THF (120 ml) was added tetraethoxytitanium (27.2 g, 119 mmol, Aldrich). The reaction was stirred at RT for 16 hours. The reaction was poured slowly into vigorously stirring water (700 ml) and the resulting suspension was stirred for 20 minutes. EtOAc (400 ml) was added and the suspension was stirred for an additional 20 minutes. The suspension was filtered through celite and the filter cake was washed with additional EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The material was purified via silica gel flash chromatography using a gradient of 0-25% EtOAc in Hexanes to afford the title compound as a yellow oil (15.35 g, 45.4 mmol, 76% yield). MS m/z=338.0 M+. Calculated for C12H14BrF2NOS: 338.211
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[O:6][CH:7]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1/[CH:9]=[CH:8]/[C:5]1[O:6][CH:7]=[C:3]([CH2:2][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:4]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2Cl)n1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3Cl)n2)cc1
Yield: 54.1 %

Procedure:
Using 4-(chloromethyl)-2-[(E)-2-(2,4-dichlorophenyl)ethenyl]-1,3-oxazole (257 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (35.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (246 mg) as a-colorless crystal powder.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:29])=[N:11][C:12]2[N:13]([N:23]=[C:24]([C:26]([O-:28])=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([CH2:8][C:9]1[C:10]([CH3:29])=[N:11][C:12]2[N:13]([N:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=2)[C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2nc(C(=O)[O-])nn2c(-c2ccc(Cl)cc2Cl)c1CC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(C(=O)O)nn2c(-c2ccc(Cl)cc2Cl)c1CC(=O)OC(C)(C)C
Temperature: 40 °C
Yield: 99.1 %

Procedure:
To a stirred solution of 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylate (13 mg, 0.03 mmol) in THF (1 mL) was added LiOH-H2O (9 mg, 0.21 mmol) in H2O (0.1 mL). After heating to 40° C. for 1 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure afforded 6-((tert-butoxycarbonyl)methyl)-7-(2,4-dichlorophenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxylic acid (13 mg, 100%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](=[N:8][OH:9])[NH2:7])([O-:3])=[O:2].Cl[C:15](OCC)=[O:16]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]1[NH:7][C:15](=[O:16])[O:9][N:8]=1)([O-:3])=[O:2]
Reactant: NC(=NO)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2ccccc2[N+](=O)[O-])no1

Procedure:
The reactions of Equation 41 above can be run by methods known in the art. Thus, in reaction 41a, 2-nitrobenzamidoxime LII is reacted with ethyl chloroformate in excess pyridine at 0° to 100° C. for about 1 hour to form a 3-(2-nitrophenyl)-1,2,4-oxadiazolin-5-one of Formula (LIV), according to the teachings of A. R. Katritzky et al., Tetrahedron, 21, 1681 (1965). In reaction 41b, LIV is reacted with excess phosphorus oxychloride or phosphorus oxybromide with pyridine catalyst at 25° to 100° C. for 1 to 15 hours to form Xl"', according to the teachings of T. Fujita et al., Yakugaku Zasshi, 84, 1061 (1964). And in reaction 41c, Xl"' is reacted with sodium methoxide or sodium ethoxide in a solvent such as methanol, ethanol or tetrahydrofuran at 20° to 50° C. for about 0.2 to 1 hour to form Xl" ", according to the teachings of F. Eloy et al., Bull. Soc. Chim. Belg., 78, 47 (1969).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].C(O[C:20](=O)/[CH:21]=[CH:22]/CC)C.C(O)(=O)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:20]([CH2:21][CH3:22])[CH2:3][C:2](=[O:4])[NH:5]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC/C=C/C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)NC(=O)CC1CC
Yield: 87.1 %

Procedure:
To 150 mg of sodium dissolved in 150 mL of absolute ethanol was added diethyl acetamidomalonate (5.3 g, 25 mmol) and ethyl-(2E)-pent-2-enoate (3.5 g, 27.3 mmol). The reaction mixture was then refluxed for 20 h. After this period of time, 2 mL of glacial acetic acid was added, volatiles were removed under pressure with the aid of a water aspirator and heating bath. On cooling the residue solidified. The residue was dissolved in 50 mL of toluene and to this was added 20 mL of petroleum ether. The product precipitated when the mixture was cooled. The crystals were collected and washed with water and further dried in vacuo to obtain a white solid (5.6 g, 79.77%). Mass Spectrum (+ESI): 258 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18](O)[CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(OC(=O)C1C=CC(CC#N)=CC=1)C>C(OCC)(=O)C>[N:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH2:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: CC(O)c1ccccc1N1CCCCC1
Agent: CCOC(=O)c1ccc(CC#N)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=Cc1ccccc1N1CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
An amount of 1.6 ml of conc. sulfuric acid was added in small drops to a mixture of 2 gm (9.74 m mol) of 1-(2-piperidino-phenyl)-ethanol and 4 gm (21.1 m mol) of 4-cyanomethylbenzoic acid ethyl ester under stirring and cooling with ice by keeping the internal temperature at 35° to 40° C. Subsequently, the mixture was heated for 2.5 hours in a bath of 80° C., a further 2 gm (10.5 m mol) of 4-cyanomethyl benzoic acid ethyl ester and 0.8 ml of conc. sulfuric acid were added, and heating was continued for one hour at 80° C. and for three hours at 100° C. After that time no starting alcohol could be detected in a thin layer chromatogram. After cooling to 20° C. the mixture was layered with ethyl acetate, and under stirring and cooling ice water was added. After extraction several times with ethyl acetate, the organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone=10:1). From the pre-fractions 0.5 gm of 2-piperidino-styrol was isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:61])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:61])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(=O)OC

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-methoxycarbonylaminopropane IIIe3 is allowed to react and worked up by the same procedure as described in (5). m.p. 79°-81° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[C:3]1[C:19]([O-:21])=[O:20].[K+].Cl.[H][H]>[Pd]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:4]1[C:5]([CH3:8])=[C:6]([CH3:7])[N:2]([CH3:1])[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: Cc1c(Nc2ccccc2[N+](=O)[O-])c(C(=O)[O-])n(C)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [K+]
Product: Cc1c(Nc2ccccc2N)c(C(=O)O)n(C)c1C

Procedure:
The solution of 61 g (0.19 mole) of potassium 1,4,5-trimethyl-3-[(2-nitrophenyl)amino]-1H-pyrrole-2-carboxylate obtained in Example 3 is adjusted to pH 2 with concentrated hydrochloric acid in a circulatory hydrogenation apparatus, and 0.5 g of palladium-on-charcoal (10%) is added. When the internal temperature reaches 40° C., hydrogenation is started. Sufficient hydrogen is metered to keep the internal temperature at about 100° C. When a sudden drop in the absorption of hydrogen is observed, the solution is allowed to cool; it is filtered under nitrogen, and the residue on the filter is washed 6 times with 5 ml of 1-methyl-2-pyrrolidone each time. The combined filtrates are concentrated to half their volume on a rotary evaporator. The resulting solution is subsequently processed in Example 5 without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:31](OCC)(=O)[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:15]2[S:16][C:17]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:31][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccc([N+](=O)[O-])cc3s2)C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)C1)c1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 34 %

Procedure:
Dissolve 3-[(6-nitro-benzothiazol-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (5.55 g, 14.7 mmol) in DMF (30 mL) and cool to 5° C. Add 60% NaH in mineral oil (1.12 g, 16.13 mmol) and stir for 5 min. Add iodomethane (6.0 mL, 74 mmol) and stir at 5° C. for 30 min. Quench the reaction with water and dilute with ethyl acetate. Wash the organic layer with water (5×20 mL), then wash with brine. Collect the organic layer, dry over Na2SO4, filter, and concentrate in vacuo. Chromatograph (silica gel, eluting with 20-60% Ethyl acetate:Hexane) to yield 1.96 g (34%) of the title compound. mass spectrum (ion-spray): (m/z)=393.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:29][CH2:28][C:23](=[O:24])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.2 %

Procedure:
To 3-[(1,4-Dioxa-spiro[4.5]dec-8-yl)-(trans 4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (401 mg, 0.806 mmol) in tetrahydrofuran (4 ml) was added 3N HCl solution (4 ml) and the reaction was stirred at room temperature for 20 hours. It was then diluted with ethyl acetate (10 ml), the organic layer was separated, and the aqueous phase was washed twice with ethyl acetate (2×10 mL). The combined ethyl acetate layer was washed with brine (10 ml) and dried on Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0% to 40% EtOAc/Hexane) to obtain 315 mg (86%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[CH2:16])[C:6]=2[CH:17]=1.C12BC(CCC1)CCC2.[O:27]1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][OH:27])[C:6]=2[CH:17]=1
Reactant: C=C1c2ccccc2C=Cc2ccc(Br)cc21
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-bromo-5-methylene-dibenzo[a,d]cycloheptene (3.8 g) in dry tetrahydrofuran (20 ml). under an inert atmosphere. was added 9-borabicyclo [3.3,1 ]nonane (30 ml of a 0.5 molar solution in tetrahydrofuran) at ambient temperature and the reaction mixture was refluxed for 3 h. After cooling in an ice bath the reaction was quenched by the slow addition of 2N sodium hydroxide solution (100 ml) and 30% hydrogen peroxide (20 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2 hour period then extracted with diethyl ether (3×200 ml). The combined organic layers were washed with brine (1×100 ml), dried (Na2SO4) filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 30% ethyl acetate in hexane as eluent to give the title compound (2.3 g) as a colourless oil. δ (CDCl3, 360 MHz) 3.83 (2H, d, J=7.9 Hz, CH2OH), 4.13 (1H, t, J=7.9 Hz, CH--CH2OH), 6.78 (1H, d, J=12 Hz, CHA =CHB), 6.87 (1H, d, J=12 Hz, CHA =CHB), 7.17-7.50 (7H, m, ArH). m/e 302 and 300 (M+).
Reaction SMILES: [ClH:1].C([N:5]1[CH2:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[NH:29])=[CH:24][C:22]=4[CH:23]=3)=[CH:13][C:12]=2[OH:31])[CH2:6]1)(=O)C>Cl>[ClH:1].[ClH:1].[OH:31][C:12]1[CH:13]=[C:14]([CH2:17][CH2:18][C:19]2[O:20][C:21]3[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[NH:29])=[CH:24][C:22]=3[CH:23]=2)[CH:15]=[CH:16][C:11]=1[O:10][C@H:7]1[CH2:8][CH2:9][NH:5][CH2:6]1
Reactant: CC(=O)N1CC[C@H](Oc2ccc(CCc3cc4cc(C(=N)N)ccc4o3)cc2O)C1
Agent: Cl
Product: N=C(N)c1ccc2oc(CCc3ccc(O[C@H]4CCNC4)c(O)c3)cc2c1
Yield: 64.8 %

Procedure:
1.0 g of 2-[2-[4-[((3S)-1-acetyl-3-pyrrolidinyl)oxy]-3-hydroxyphenyl]ethyl]-5-benzofurancarboxamidine hydrochloride was dissolved in 30 ml of 6N hydrochloric acid, and the solution was refluxed under heating for 4 hours. After distilling off the solvent, the resulting residue was subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. In this way, 320 mg of the title compound was obtained in a solid form.