Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=O.[NH2:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[C:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=O.C([N:30](CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:30]=[C:15]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]3[C:13](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CCC(=O)c1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCc1nc(-c2cccc(OC)c2)nc2ccccc12
Reaction time: 7 h

Procedure:
3-Methoxybenzoyl chloride (2.81 cc) is added at 5° C. to ethyl 3-(2-aminobenzoyl)propionate (2.21 g) and triethylamine (4.2 cc) in chloroform (25 cc). The mixture is left for 1 hour at room temperature (approximately 20° C.), water (25 cc) is added and the mixture decanted. The organic phase is evaporated under reduced pressure and the residue taken up with ammonium acetate (17 g). The mixture is brought to 100° C. for 7 hours and the acetic acid formed is then evaporated off under reduced pressure. The residue is poured into water (100 cc) and the aqueous phase extracted with ethyl acetate (3×50 cc). The aqueous phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure. The residual product is chromatographed in silica gel with a cyclohexane/ethyl acetate (1:1 by volume) mixture as eluant. After recrystallization in ethanol, ethyl 2-(3-methoxyphenyl)-4-quinazolinepropionate (1.5 g), m.p. 70° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH:13]([CH3:15])[CH3:14]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:5]=1)([O-:3])=[O:2]
Reactant: CC(C)CBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 55.1 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-2-methyl-propane (115 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-iso-butyl-1H-pyrazole (83 mg, 46%) as a white powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([CH:15]([C:21]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22]1)[CH2:16][CH2:17][CH2:18][S:19][CH3:20])[CH3:14]>ClCCl.Cl>[CH3:12][N:13]([CH:15]([C:21]1([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:24][CH2:23][CH2:22]1)[CH2:16][CH2:17][CH2:18][S:19]([CH3:20])=[O:9])[CH3:14]
Reactant: CSCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(CCCS(C)=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of m-chloroperbenzoic acid (1.75 g) in dichloromethane (50 ml) was added over 30 minutes to a stirred solution of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-4-methylthiobutylamine (2.4 g prepared in a similar manner to that described in Example 187) in dichloromethane (50 ml) at 0° C. The mixture was stirred at 0° C. for 11/2 hours and then kept at <5° C. overnight. The resulting solution was washed with 2N sodium hydroxide solution then brine and then dried and evaporated to give an oil which was treated with petroleum ether (b.p. 40°-60° C.). The resulting mixture was filtered and the filtrate evaporated to give a residue which was dissolved in 2N hydrochloric acid. The solution was washed with ether, basified and extracted with ether. The extracts were dried and evaporated to give N,N-dimethyl-1-[1-(4-chlorophenyl)-cyclobutyl]-4-methylsulphinylbutylamine as an oil the boiling point of which was not determined.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.Cl.C(O[C:14](=N)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)C>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCOC(=N)COc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-phenylene-diamine (19.2 g, 0.103 mol) and 2-(4-trifluoromethyl-phenoxy)-acetimidic acid ethyl ester hydrochloride (35.0 g, 0.123 mol) in EtOH (377 mL) was stirred at room temperature for 12 hours. The reaction was concentrated to give a brown solid, which was partitioned between EtOAc and water. The organic fraction(s) were washed with brine, dried over Na2SO4, and the filtrate was concentrated to afford the title compound as a brown solid (100%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.74 (s, 1H), 7.62 (d, 2H, J=8.0 Hz), 7.50 (d, 1H, J=8.8 Hz), 7.39 (dd, 1H, J=8.4 Hz, J=1.6 Hz), 7.23 (d, 2H, J=8.4 Hz), 5.41 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C15H11BrF3N2O: 372.2 (M+H), Found 372.9.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[CH2:12][CH2:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (E)-tert-butyl(2-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)ethyl)carbamate (step 3) (400 mg, 0.936 mmol) in DCM (5 ml) was added TFA (0.865 ml, 11.23 mmol) and the mixture was stirred at RT for 1 h. The solvent was removed under reduced pressure and the crude material was dissolved in MeOH and loaded on to an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with excess MeOH. The product was eluted using 2.0 M ammonia in MeOH and the solvent removed under reduced pressure to afford the title compound as a white solid;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[N:20][OH:21])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1

Procedure:
4,4′-Dimethoxybenzophenone (25 g, 103 mmol) is suspended in ethanol (150 mL) and pyridine (30 mL). Hydroxylamine hydrochloride (21.50 g, 310 mmol) is added and the reaction mixture is refluxed for 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer dried is over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained following crystallisation from ethylacetate/cyclohexane. 1H nmr (CDCl3, 400 MHz); 7.70 (s, 1H), 7.40 (d of d, 4H), 6.95 (d, 2H), 6.85 (d, 2H), 3.85 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:29])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][NH2:23])=[N:20][C:19]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[N:18]1.[Cl:30][CH2:31][C:32](Cl)=[O:33].CN(C)C=O.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:29])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]1[C:21]([CH2:22][NH:23][C:32](=[O:33])[CH2:31][Cl:30])=[N:20][C:19]([C:24](=[O:28])[N:25]([CH3:26])[CH3:27])=[N:18]1
Reactant: CN(C)C(=O)c1nc(CN)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Reactant: O=C(Cl)CCl
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1nc(CNC(=O)CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Yield: 1084.6 %

Procedure:
A mixture of 2',5-dichloro-2-(3-dimethylcarbamoyl-5-carbobenzoxyaminomethyl-1,2,4-triazol- 1-yl)benzophenone (3.6 g) and 30% hydrogen bromide-acetic acid (9 ml) is stirred at room temperature for 2 hours. The reaction mixture is mixed with ether, and the precipitate is isolated by decantation and washed thrice with ether, whereby 2',5-dichloro-2-(3-dimethylcarbamoyl-5-aminomethyl-1,2,4-triazol- 1-yl)-benzophenone hydrobromide is obtained. This hydrobromide (1.2 g) is added to a solution of chloroacetyl chloride (1.2 g) in benzene (40 ml) to give a solution, which is mixed with dimethylformamide (20 ml). The resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer is separated, washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is treated with ethanol/n-hexane to give 2',5-dichloro-2-[3-dimethylcarbamoyl-5-(2-chloroacetylamino)methyl-1,2,4-triazol- 1-yl]-benzophenone (12.9 g), which is recrystallized from ethyl acetate to give colorless needles melting at 80°-82° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[C:14]([OH:25])[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCCC1.C1C=CC=CC=1>[CH:1]1([NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[C:17]([C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][CH:15]=[C:14]([O:25][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOCC1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)C1=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid cyclohexylamide (141 mg, 0.41 mmol) obtained in Step 3 was dissolved in tetrahydropyran/benzene (3 mL/2 mL), and 4-(2-hydroxyethyl)morpholine (99 μl, 0.82 mmol) and triphenylphosphine (215 mg, 0.82 mmol) were added thereto. Then, diisopropyl azodicarboxilate (149 μl, 0.82 mmol) was added slowly thereto at 0° C., and stirred for 2 hrs at RT. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 165 mg of the titled compound (yield: 88.3%).
Reaction SMILES: [CH2:1]([N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH3:24])[CH:19]=[N:18][C:17]=2[N:16]([CH3:25])[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C[N+]1([O-])CC[O:30]CC1.[OH2:34].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O>[OH:34][CH:11]([CH2:12][OH:30])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:13]1[C:22](=[O:23])[C:21]2[N:20]([CH3:24])[CH:19]=[N:18][C:17]=2[N:16]([CH3:25])[C:14]1=[O:15]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCCCCCCCC(O)CO)c(=O)n2C
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 1-(11-Dodecenyl)-3,7-dimethylxanthine (4.70 g, 13.6 mmol), 4-methylmorpholine-N-oxide (4.79 g, 40.7 mmol) and potassium osmate dihydrate (52 mg, 0.14 mmol) in acetone/water 1:2 (75 mL) was stirred for 16 hours. Water (50 mL) and sodium sulfite (5 g) were added and the mixture stirred for 1 hour. The reaction mixture was extracted with dichloromethane (3×100 mL), dried using magnesium sulfate and evaporated to obtain a pale green solid. Recrystallization from hot ethyl acetate yields 4.32 g (84% yield) 1-(11,12-dihydroxydodecyl)-3,7-dimethylxanthine (inventive compound no. 2517) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH2:15][CH:16]2[CH2:21][CH2:20][C:19]([CH:23]([OH:25])[CH3:24])([OH:22])[CH2:18][CH:17]2[C:26]([O:28]CC2C=CC=CC=2)=O)[CH:4]=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.C1CCCCC=1>CN(C)C1C=CN=CC=1.[Pd].N1C=CC=CC=1>[OH:25][CH:23]([C:19]1([OH:22])[CH2:20][CH2:21][CH:16]2[CH:17]([C:26](=[O:28])[C:4]3[C:5]([CH2:15]2)=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=3[O:2][CH3:1])[CH2:18]1)[CH3:24]
Reactant: COc1cc(CC2CCC(O)(C(C)O)CC2C(=O)OCc2ccccc2)c(OC)c2ccccc12
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: C1=CCCCC1
Solvent: c1ccncc1
Product: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)O)CCC1C2
Yield: 66.1 %

Procedure:
Operation as described in Example 6, 0.44 g of 1-(1,4-dimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxyl-cyclohexane, prepared as described in Example 11, was treated with acetic anhydride in presence of 4-dimethylamino-pyridine and pyridine. The corresponding acetate was treated with cyclohexene in the presence of 10% by weight palladium-on-carbon in order to remove the benzyl group. The acid was cyclized by treatment with a mixture of trifluoroacetic anhydride and trifluoroacetic acid at 0° C. Finally the removal of the acetyl O-protecting groups by treatment with sodium methylate afforded. after purification by chromatography on a silica gel column, 0.225 g of the title compound (overall yield 66%); IR (film): 3450 cm-1 (OH), 1675 cm-1 (C=O, benzylic ketone). PMR (CDCl3): inter alia δ 1.3 (d, J=4 Hz, CH3 --CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH3), 3.90 (s, OCH3), 7.2-8.4 (m, four aromatic H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:25](=[O:26])[N:4]2[C:5]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7]S[C@H:3]12.OO.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+]>C(OCC)(=O)C.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[NH2:1][C@@H:2]1[C:25](=[O:26])[N:4]2[C:5]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:29](=[O:32])(=[O:30])[C@H:3]12
Reactant: COc1ccc(COC(=O)C2=C(CN=[N+]=[N-])CS[C@@H]3[C@H](N)C(=O)N23)cc1
Reactant: O=S([O-])[O-]
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)C2=C(CN=[N+]=[N-])CS(=O)(=O)[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
p-Methoxybenzyl 7β-amino-3-azidomethyl-3-cephem-4-carboxylate (17.15 g, 0.046 mol) in ethyl acetate was cooled to 15° C., sodium tungstate dihydrate (1.52 g, 0.0046 mol) was added followed by hydrogen peroxide (30%, 20.73 ml) in one portion and the stirring was continued at room temperature. After two hours an additional portion of hydrogen peroxide (5.18 ml) was added and the reaction mixture was stirred at room temperature for a total period of 18 h; the mixture was cooled to 10° C. and a solution of sodium sulphite (10%, 600 ml) was added while stirring. Organic layer was separated out, washed with aq. sodium bicarbonate solution, brine and dried (Na2SO4). Evaporation of the solvent in vacuo gave a foam (12 g) which was purified over a silica column using hexane-ethyl acetate (1:3) as eluant to give the pure product as a white foam (6.8 g, 36.5%). IR (Nujol) ν max 2083 cm-1.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:2]2.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([Cl:25])=[O:24])([O-:19])=[O:18]>>[ClH:25].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=3)=[CH:12][CH:11]=1)[CH2:3][CH2:2]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)nc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: Cl
Product: O=C(Nc1ccc(N2CCN3CCC2CC3)nc1)c1cccc([N+](=O)[O-])c1

Procedure:
Was prepared according to Method G from 6-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-pyridin-3-ylamine and 3-nitrobenzoyl chloride. Mp. >280° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][OH:19])[CH:11]=2)[CH:6]=1)=[O:4].CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C@@H:17]3[CH2:18][O:19][C:23]([CH3:25])([CH3:24])[O:20]3)[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: COC(=O)c1ccc2cc(OC[C@@H](O)CO)ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OC[C@@H]3COC(C)(C)O3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 6-((S)-2,3-dihydroxy-propoxy)-naphthalene-2-carboxylic acid methyl ester (0.9 g, 3.26 mmol) in anhydrous DMF (10 ml) is added 2,2-dimethoxypropane (2.0 ml, 16.3 mmol) and pyridinium p-toluenesulfonate (0.08 g, 0.32 mmol) and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc. The EtOAc layer is washed with 10% NaHCO3, water, and brine, dried over anhydrous Na2SO4 and the solvent is evaporated in vacuo to obtain 6-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-naphthalene-2-carboxylic acid methyl ester as solid; 1H NMR (DMSO-d6): 1.32 (3H, s), 1.37 (3H, s), 3.78-3.82 (1H, m), 3.88 (3H, s), 4.11-4.20 (3H, m), 4.45-4.50 (1H, m), 7.26 (1H, dd, J=9.0, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 7.88 (1H, d, J=9.0 Hz), 7.93 (1H, d, J=9.0 Hz), 8.04 (1H, d, J=9.0 Hz), 8.55 (1H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16](OC)=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1.O.[NH2:28][NH2:29]>CO.CN(C=O)C>[O:1]=[S:2]1(=[O:26])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([NH:28][NH2:29])=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:23][CH2:24][CH2:25][C:4]2=[N:3]1
Reactant: NN
Reactant: COC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1

Procedure:
A suspension of 500 mg (1.34 mmol) of the product obtained in Step A and 978 μl (20.13 mmol) of hydrazine monohydrate in a mixture of MeOH (30 ml) and DMF (6 ml) is refluxed for 24 hours. The MeOH is evaporated off, water is added to the reaction mixture and the precipitate, which corresponds to the title product, is filtered off.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:25]1[CH2:26][CH2:27][N:22]([CH2:2][CH2:3][CH2:4][O:5][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:23][CH2:24]1
Reactant: ClCCCOC(CCCc1ccccc1)c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CCCC(OCCCN2CCOCC2)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 1.5 g of 1-(3-chloropropoxy)-1,4-diphenylbutane, 7 ml of morpholine, 1,5 g of potassium carbonate and 15 ml of dimethylformamide was heated at 100° C. for 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel to give 1-(3-morpholinopropoxy)-1,4-diphenylbutane. M.P., 138°-139° C. (oxalate).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.Br[CH2:9][CH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:11][CH2:10][CH2:9][N:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1
Reactant: O=Cc1cn[nH]c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cnn(CCO)c1
Temperature: 150 °C
Yield: 97 %

Procedure:
Combine 1H-pyrazole-4-carbaldehyde (0.110 g, 1.14 mmol), 2-bromoethanol (0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150° C. for 20 min. Cool to room temperature and filter, washing with acetonitrile. Concentrate filtrate to give 1-(2-hydroxy-ethyl)-1H-pyrazole-4-carbaldehyde (0.155 g, 97%). GC-MS: m/z=140 [M+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:12][C:11](=[N:13][N+:14]([O-:16])=[O:15])[NH:10][C@H:9]2[CH3:17])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:12][C:11](=[N:13][N+:14]([O-:16])=[O:15])[N:10]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[N:22][CH:23]=3)[C@H:9]2[CH3:17])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: C[C@@H]1NC(=N[N+](=O)[O-])O[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](c2ccc(Cl)cc2)OC(=N[N+](=O)[O-])N1Cc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
1.0 g of trans-5-(4-chlorophenyl)-4-methyl-2-nitroiminooxazolidine obtained in Example 1 and 0.2 g of 60% sodium hydride were added into 20 ml of DMF. 0.7 g of 2-chloro-5-chloromethylpyridine was added gradually to the mixture with stirring on cooling. Then, the mixture was further stirred for 6 hours at 70° C., followed by pouring the reaction mixture into ice water. The solution was extracted with ethyl acetate, and the organic layer was dried and then condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 0.5 g of the title compound.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([O:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[NH:27][C@@H:28]1[CH2:33][CH2:32][NH:31][C@@H:30]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29]1)[CH3:14]>C(Cl)Cl>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:31]1[CH2:32][CH2:33][C@@H:28]([NH:27][C:19]2[N:18]([CH2:17][CH2:16][O:15][CH2:13][CH3:14])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)[CH2:29][C@@H:30]1[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOCCn1c(N[C@@H]2CCN[C@@H](Cc3ccccc3)C2)nc2ccccc21
Solvent: ClCCl
Product: CCOCCn1c(N[C@@H]2CCN(C(=O)c3ccccc3N)[C@@H](Cc3ccccc3)C2)nc2ccccc21
Reaction time: 3 h
Yield: 33.5 %

Procedure:
Isatoic anhydride (0.49 g) was added to a mixture of (±)-trans-1-(2-ethoxyethyl)-N-[2-(phenylmethyl)-4-piperidinyl]-1H-benzimidazol-2-amine (1.14 g) in CH2Cl2 (150 ml), the mixture was stirred for 3 hours and then refluxed for 3 hours. The solvent was evaporated, 2-propanol (100 ml) was added to the residue and the mixture was refluxed for 18 hours. Isatoic anhydride (0.2 g) was added again and the mixture was refluxed for 4 hours. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and evaporated. The residue was crystallized from DIPE, yielding 0.5 g (33.4%) of (±)-trans-1-[2-aminobenzoyl]-4-[[1-(2-ethoxyethyl)-1H-benzimidazol-2-yl]amino]-2-(phenylmethyl)piperidine (comp 123; mp. 197.4° C.).