Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.C(C1N=C(C2C=C(OC3CC4C(C(=O)N(C)CCCCC=CC5C(C(NS(C6CC6)(=O)=O)=O)(NC4=O)C5)C3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[CH:22]([C:23](=[O:43])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:53][S:50]([CH:47]6[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)O)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NCCCCCC=CC5CC5(C(=O)NS(=O)(=O)C5CC5)NC(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-3,14-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (80) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]Ctadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (47): m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-0.96 (m, 1H), 1.1-1.2 (m, 4H), 1.39 (d, J=6.9 Hz, 6H), 1.4-1.55 (m, 5H), 1.80-1.92 (m, 5H), 2.15-2.25 (m, 1H), 2.30-2.40 (m, 1H), 2.45-2.55 (m, 2H), 2.68 (s, 3H), 2.85-2.92 (m, 1H), 3.15-3.30 (m, 2H), 3.45-3.55 (m, 2H), 3.96 (s, 3H), 4.09 (dd, J=11.5 Hz, J=3.8 Hz, 1H), 4.61 (t, J=7.9 Hz, 1H), 4.99 (t, J=9.0 Hz, 1H), 5.51-5.53 (m, 1H), 5.71 (dd, J=18.6 Hz, J=8.2 Hz, 1H), 6.86 (s, 1H), 7.03 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.50 (s, 1H), 7.88 (d, J=9.2 Hz, 1H), 9.40 (br s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([OH:10])=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][CH:41]([NH:44][C:45]([N:47]4[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]4)=[O:46])[CH2:40][CH2:39]3)=[CH:34][CH:33]=2)=[O:31])[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([N:50]1[CH2:51][CH2:52][N:47]([C:45]([NH:44][CH:41]2[CH2:42][CH2:43][N:38]([C:35]3[CH:34]=[CH:33][C:32]([C:30](=[O:31])[NH:29][CH2:28][CH2:27][N:24]4[CH2:23][CH2:22][O:21][CH2:26][CH2:25]4)=[CH:37][CH:36]=3)[CH2:39][CH2:40]2)=[O:46])[CH2:48][CH2:49]1)=[O:10])[CH3:2]
Reactant: O=C(NCCN1CCOCC1)c1ccc(N2CCC(NC(=O)N3CCNCC3)CC2)cc1
Reactant: CCn1cccc1C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cccc1C(=O)N1CCN(C(=O)NC2CCN(c3ccc(C(=O)NCCN4CCOCC4)cc3)CC2)CC1
Temperature: 80 °C

Procedure:
1-ethylpyrrole-2-carboxylic acid (139 mg, 1.0 mmol) was dissolved in DMF (3.0 ml), and WSCD (230 mg, 1.2 mmol), HOBt (168 mg, 1.2 mmol), and N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (400 mg, 0.9 mmol) obtained in Example 15(5) was added thereto, followed by stirring under heat at 80° C. for 14 hours. After the reaction mixture was allowed to cool to room temperature, a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with chloroform. The extract was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium-pressure silica gel flash column chromatography (methanol:chloroform=1:30 to 1:10), thereby obtaining 4-((1-ethylpyrrol-2-yl)-carbonyl)-N-(1-(4-(2-morpholinoethylcarbamoyl)phenyl)-piperidin-4-yl)-1-piperazinecarboxamide (213 mg, 42%) as a milky-white solid.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[N:23]([CH:24]=1)[CH:22]=[CH:21][S:20]2>CN(C=O)C.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[I:8])[CH:22]=[CH:21][S:20]2
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3ccsc3n2)c(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3sccn3c2I)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
NIS (5.56 g, 24.7 mmol) was added to 6-(2,4-difluorophenyl)imidazo[2,1-b]thiazole (5.84 g, 24.72 mmol) in DMF (60 mL) then stirred at ambient temperature for about 30 min. The mixture was diluted with water (about 500 mL), filtered, and washed with ether to give the title compound (5.17 g, 58%): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 363.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1([C:10]([OH:12])=O)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)[CH3:3].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[CH2:42][NH2:43])([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][C:33]=1[CH2:42][NH:43][C:10]([C:4]1([CH:2]([OH:1])[CH3:3])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)=[O:12])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)Oc1ccc(C(F)(F)F)cc1CN
Reactant: CC(O)C1(C(=O)O)CCC(=O)C1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(O)C1(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)CCC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(1-hydroxyethyl)-3-oxocyclopentanecarboxylic acid (3.54 g, 20.6 mmol), 1-hydroxy-7-azabenzotriazole (4.14 g, 30.9 mmol), and EDC (5.92 g, 30.9 mmol) in 70 mL of DCM was stirred at rt for 10 min then 1-[2-tert-butoxy-5-(trifluoromethyl)phenyl]methanamine (5.08 g, 20.6 mmol) was added in 10 mL of DCM. The resulting mixture was stirred at rt for 50 min, then was diluted with DCM and washed with water followed by brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 85% ethyl acetate/hexanes) provided N-[2-tert-butoxy-5-(trifluoromethyl)benzyl]-1-(1-hydroxyethyl)-3-oxocyclopentanecarboxamide as a mixture of threo and erythro enantiomer pairs.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:24]([OH:26])=O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][C:24]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:26])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)NS(C)(=O)=O)c1ccccc1
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
To a solution of 100 mg of (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazolo[1,2-a]pyridin-3-yl]carbonyl}amino)-3-phenylpropanoic acid in 1 mL of DMF was added 43 mg of 1,1′-carbonyldiimidazole, followed by stirring for 30 minutes. To the reaction solution were added 24 mg of methanesulfonamide and 0.039 mL of 1,8-diazabicyclo[5.4.0]-7-undecene, followed by stirring for 5 hours. To the reaction mixture were added 1 M hydrochloric acid and ethyl acetate to carry out a layer separation operation. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. To the purified product were added ethyl acetate and hexane, and the resulting solid was collected by filtration and dried to obtain 41 mg of 8-(cyclohexylmethoxy)-2-methyl-N-{(1S)-3-[(methylsulfonyl)amino]-3-oxo-1-phenylpropyl}imidazolo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.C([Li])CCC.[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].O>O1CCCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([N:6]([Si:17]([CH3:19])([CH3:18])[CH3:16])[Si:17]([CH3:19])([CH3:18])[CH3:16])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1N([Si](C)(C)C)[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-2,6-dimethylaniline (commercially available) (40 g, 0.2 mol) in tetrahydrofuran (500 ml) under a nitrogen atmosphere was added a solution of n-butyl lithium in hexanes (1.6 M) (125 ml, 0.2 mol). During this operation, the internal temperature was kept between −70° C. and −78° C. After five minutes, trimethylsilyl chloride (25 ml, 0.2 mol) was added whilst the internal temperature was kept below −68° C. After five minutes, the cooling bath was replaced with a water bath and the internal temperature rose to 0° C. Then the cooling bath was put back and the reaction mixture was cooled to −78° C. To this solution, a solution of n-butyl lithium in hexanes (1.6 M) (125 ml, 0.2 mol) was added whilst keeping the internal temperature below −70° C., followed by addition of trimethylsilyl chloride (30 ml, 0.237 mol) whilst keeping the internal temperature below −68° C. The reaction mixture was gradually allowed to warm to 20° C. Hexanes (200 ml) and water (40 ml) were added and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, and concentrated. The residue was distilled under a high vacuum leading to the title compound as a colorless oil which crystallized on standing. M.p. 47-52° C. 1H-NMR (CDCl3, 400 MHz): 0.08 (s, 18H), 2.21 (s, 6H), 7.15 (s, 2H) ppm.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[O:21][C:20]=2[CH3:30])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2cc(-c3ccncc3)oc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccncc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methanol (407 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (274 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.7 mL) and 1,1′-(azodicarbonyl)dipiperidine (757 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (5% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give methyl 4-{cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methoxy}benzoate as an amorphous compound. The obtained methyl 4-{cyclohexyl[2-methyl-5-(pyridin-4-yl)furan-3-yl]methoxy}benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N sodium hydroxide (2.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (261 mg, 45%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([O-])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[NH4+:12].[CH:13]([O-])([O-])OC>C(O)CCC>[I:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:13][NH:12][C:7]2=[O:8]
Reactant: COC([O-])[O-]
Reactant: Nc1ccc(I)cc1C(=O)[O-]
Reactant: [NH4+]
Solvent: CCCCO
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
In a 2-mL volume glass vessel equipped with a reflux condenser were placed 530 mg (1.9 mmol) of ammonium 5-iodoanthranilate (prepared in the same manner as in Reference Example 4), 403 mg (3.8 mmol) of methyl orthoformate, and 1.5 mL of n-butyl alcohol. The reaction was carried out at 120° C. for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and analyzed (according to absolute quantitative analysis) by high performance liquid chromatography. There was produced 350 mg (reaction yield: 67%) of 6-iodoquinazolin-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].[N:26]([CH:29]1[CH2:31][CH2:30]1)=[C:27]=[S:28].[CH3:32][O:33][C:34](=[O:40])[C:35](=O)[CH:36](Br)[CH3:37].O>O1CCCC1>[CH:29]1([NH:26][C:27]2[S:28][C:36]([CH3:37])=[C:35]([C:34]([O:33][CH3:32])=[O:40])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH2:31][CH2:30]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)C(C)Br
Reactant: S=C=NC1CC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(NC2CC2)sc(C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
To a solution of (triphenylphosphoranylidene)-acetic acid ethyl ester (15 g) in anhydrous tetrahydrofuran (100 ml) was added isothiocyanato-cyclopropane (4.4 g) and the mixture was refluxed under a nitrogen atmosphere for 20 hr. After allowing to cool to ambient temperature the reaction mixture was cooled to −78° C. and then a solution of 3-bromo-2-oxo-butanoic acid methyl ester (8.7 g) in anhydrous tetrahydrofuran (10 ml) was added. The resulting mixture was allowed to warm to ambient temperature and then refluxed for 20 hr., then ambient temperature for 2 days. The reaction was poured into water and extracted with diethyl ether. The collected organic extract was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (95:5) then triturated with i-hexane/diethyl ether (8:2) to give the sub-title compound as a solid (7.5 g).
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[Br:14][C:15]1[C:16](Cl)=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1.OC1C=CC([N+]([O-])=O)=CN=1>C(OCC)C>[Br:14][C:15]1[C:16]([CH3:1])=[N:17][CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=[N+]([O-])c1ccc(O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ncc([N+](=O)[O-])cc1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of diethyl malonate (17.6 mL, 0.116 mol) in diethyl ether (250 mL) at ambient temperature was treated with sodium hydride (80% in mineral oil, 3.5 g, 0.116 mol), and the mixture was stirred for 1 hour. Then 3-bromo-2-chloro-5-nitropyridine (25 g, 105 mmol; prepared from 2-hydroxy-5-nitropyridine according to the procedure of V. Koch and S. Schnatterer, Synthesis 1990, 499-501) was added in portions over 5 minutes. After the mixture had stirred for 1 hour, the solvent was evaporated, and the residue was heated at 100° C. for 1 hour. After the mixture had cooled, 12 N H2SO4 was added, and the mixture was heated at reflux for about 16 hours. The mixture was allowed to cool to ambient temperature, then further cooled as it was treated with 50% NaOH to give an alkaline pH. The resulting solution was extracted with CHCl3 (3×), and the organic extracts were washed with H2O, dried (MgSO4) and evaporated to afford 17.1 g of the title compound as a red oil: 1H NMR (CDCl3, 300 MHz) δ 2.81 (s, 3H), 8.61 (d, J=2 Hz, 1H), 9.26 (d, J=2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]3[N:17]=[C:18]([CH3:21])[S:19][CH:20]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:22][C:23]1[N:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=1[C:25]([OH:27])=O.CC1(N2CCC(N(C3C=CC=CC=3)C3C=NC=CC=3)CC2)CCNCC1.[Cl:59][C:60]1[CH:65]=[CH:64][C:63](N)=[CH:62][CH:61]=1.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.ClCC1N=C(C)SC=1>>[Cl:59][C:60]1[CH:65]=[CH:64][C:63]([N:14]([CH2:15][C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)[CH:11]2[CH2:10][CH2:9][N:8]([C:2]3([CH3:1])[CH2:3][CH2:4][N:5]([C:25]([C:24]4[C:23]([CH3:22])=[N:31][CH:30]=[CH:29][C:28]=4[CH3:32])=[O:27])[CH2:6][CH2:7]3)[CH2:13][CH2:12]2)=[CH:62][CH:61]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: Cc1nc(CNC2CCN(C3(C)CCNCC3)CC2)cs1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC1(N2CCC(N(c3ccccc3)c3cccnc3)CC2)CCNCC1
Agent: Cc1nc(CCl)cs1
Product: Cc1nc(CN(c2ccc(Cl)cc2)C2CCN(C3(C)CCN(C(=O)c4c(C)ccnc4C)CC3)CC2)cs1

Procedure:
It is prepared from (chloro-phenyl)-(4′-methyl-[1,4′]bipiperidinyl-4-yl-(2-methyl-thiazol-4-ylmethyl)-amine and 2,4-dimethyl-nicotinic acid using a procedure as described in Example 1 of PCT/EP02/03871. MS-ESI 552 [M+H]+. (4′-Methyl-[1,4′]bipiperidinyl-4-yl)-phenyl-pyridin-3-yl-amine used as starting material can be prepared from 4-chloro-phenylamine, 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 4-chloromethyl-2-methyl-thiazole using procedures as described in Example 51e, 52, 1b, 1c and 1d of PCT/EP02/03871. MS/ESI 419 [M+H]+
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([O:25][Si](C(C)(C)C)(C)C)[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][C:13](=[O:16])[N:12]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([OH:25])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][C:13](=[O:16])[N:12]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCCCCC#N)Cc1cccc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.9 %

Procedure:
Following the procedure described for Example 5, Step B, 7-{2-[4-biphenyl-3-yl-3-(tert-butyl-dimethyl-silanyloxy)-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (187 mg, 0.351 mmol) was deprotected with TBAF (1M in THF, 0.53 mL, 0.53 mmol). The addition was performed at 0° C. and the reaction mixture was stirred at room temperature for 24 h. Purification by medium pressure chromatography (CH2Cl2 to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 6% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2) provided 7-[2-(4-biphenyl-3-yl-3-hydroxy-butyl)-5-oxo-pyrrolidin-1-yl]-heptanenitrile (85 mg). 1H NMR (CDCl3) δ7.58 (m, 1H), 7.51-7.33 (m, 4H), 7.21-7.12 (m, 4H), 3.85 (m, 1H), 3.60 (m, 2H), 2.90 (m, 1H), 2.83-2.60 (m, 2H), 2.45-2.30 (m, 4H), 2.14 (m, 1H), 1.73-1.25 (m, 14H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:12]([CH2:16][C:17](=[O:28])[N:18]2[CH2:27][CH2:26][C:21]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)[C:13]([O-:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1>O.O1CCCC1.CO>[CH:3]1([CH:12]([CH2:16][C:17](=[O:28])[N:18]2[CH2:19][CH2:20][C:21]3([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:26][CH2:27]2)[C:13]([OH:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=C([O-])C(CC(=O)N1CCC2(CCCC2)CC1)C1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC(=O)N1CCC2(CCCC2)CC1)C1CCc2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 6.8 g (0.17 mol) of sodium hydroxide in 60 ml of water is added to a solution of 20 g (0.0522 mol) of ethyl [R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoate in a mixture of 150 ml of tetrahydrofuran and 150 ml of methanol, and the mixture is stirred for 3 h at 60° C. The mixture is concentrated, 200 ml of water are added, the solution obtained is washed with twice 150 ml of diethyl ether and then acidified at 0° C. with 6 M hydrochloric acid to pH 2 and it is extracted with twice 250 ml of dichloromethane; the organic phases are washed with brine, dried with sodium sulphate and evaporated to dryness. 16 g of [R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoic acid are obtained in the form of a colourless oil; the (R*,S*) diastereoisomeric ratio=6/4. Yield 86%; 14 g (0.0295 mol) of this acid are dissolved in 320 ml of ethyl acetate, the solution is cooled to 0° C. and then a solution of 3.57 g (0.0295 mol) of (R) (+)-α-methylbenzylamine in 25 ml of ethyl acetate is added; the mixture is stirred at room temperature for 16 h, the precipitate formed is filtered, it is stirred in 30 ml of ethyl acetate, it is filtered and then it is dried; 7 g of a white solid of melting point 155-156° C. are obtained; 75 ml of water are added to a suspension of 7 g of the preceding solid, the solution is cooled to 0° C. and acidified with 6 M hydrochloric acid to pH 2; the mixture is stirred for 15 min with 170 ml of diisopropyl ether, the organic phase is decanted off and the aqueous phase is extracted with 170 ml of diisopropyl ether; the organic phases are washed with brine, dried over sodium sulphate and then evaporated to dryness. 4.9 g of [R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoic acid are obtained in the form of a white solid; (R*,S*) diastereomeric ratio >99%. The product melts at 137° C. with decomposition. [α]D=−26° (c=5%, ethanol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCC1CCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCCC4)cc3)c2cc1OC
Yield: 58.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopentylmethanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (42 mg, yield 54%).