Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[N+:24]([C:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=2[CH:30]=[CH:29][C:28]=1[O:37][CH2:38][CH2:39][CH2:40]Br)([O-:26])=[O:25]>O>[N+:24]([C:27]1[C:36]2[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=2[CH:30]=[CH:29][C:28]=1[O:37][CH2:38][CH2:39][CH2:40][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)([O-:26])=[O:25]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1c(OCCCBr)ccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1c(OCCCN2CCN(c3ccccc3)CC2)ccc2c1CCCC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
1-Phenylpiperazine (2.77 g, 17.1 mmol), potassium carbonate (7.1 g, 51.4 mmol) and N,N-dimethylformamide (30 ml) were added to 5,6,7,8-tetrahydro-1-nitro-2-(3-bromopropoxy)naphthalene (4.8 g, 15.3 mmol) and the mixture was stirred at 60° C. for 8 hours. The reaction mixture was added with water (80 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 200 g, eluent: hexane/ethyl acetate=7/1 to 3/1) to give 5,6,7,8-tetrahydro-1-nitro-2-[3-(4-phenyl-1-piperazinyl) propoxy]naphthalene (5.5 g).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O.O1CCOCC1.O1CCOCC1>[C:25]1([S:31]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[C:3]([OH:5])=[O:4])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(CCCCCCCc1ccc2c(n1)NCCC2)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](CCCCCCCc1ccc2c(n1)NCCC2)NS(=O)(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 13-9 (0.27 g, 0.88 mmol) in H2O/dioxane (2:1, 4.4 mL) was cooled to 0° C. and then treated dropwise with 1N NaOH to attained a pH of 10.5. The reaction mixture was then treated with with PhSO2Cl (0.23 g, 1.3 mmol) in dioxane (750 μL) while maintaining a pH of 10.5 by adding 1N NaOH. After 15 min, the pH was adjusted to 7 with 1N HCl to effect a white precipitate. The precipitate was collected by filtration and triturated with EtOAc and then ether to give 13-10 as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:16][CH2:17][C:18](=O)[NH2:19])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)(Cl)(Cl)Cl>[CH2:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:16][CH2:17][C:18]#[N:19])[C:3]([O:2][CH3:1])=[O:21])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Temperature: 50 °C

Procedure:
A solution of N-benzyloxycarbonyl-L-glutamine methyl ester (25 g) in THF (500 ml) was added dropwise to a stirred solution of triphenylphosphine (44.5 g) in carbon tetrachloride (1 L). The mixture was heated to 50° C. for 2 hours. The mixture was evaporated. The resultant oil was triturated in ethyl acetate. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatogaphy using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained methyl (2S)-2-benzyloxycarbonylarnino-4-cyanobutyrate (19.38 g, 83%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[N:12][C:11]=2[Cl:17])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][CH2:28][C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:11]1[N:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]([NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])[CH2:3][CH2:4]1)=[O:18]
Reactant: COCC(=O)O
Reactant: N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
N-(cis-4-Aminocyclohexyl)-2-chloro-5-fluoronicotinamide (837 mg, 2.72 mmol) and triethylamine (1.14 ml, 8.15 mmol) were dissolved in dimethylformamide (20 ml) and 2-methoxy acetic acid (208 μl, 2.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 2.99 mmol) and 1-hydroxybenzotriazole (404 mg, 2.99 mmol) were added. The reaction was stirred under nitrogen at room temperature for 18 h then partitioned between water and ethyl acetate. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane:methanol (96:4 to 91:9) as eluant to give 2-chloro-5-fluoro-N-{cis-4-[(methoxyacetyl)amino]cyclohexyl}nicotinamide (550 mg).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N+:2]=[N-:3].[C:17]1([CH3:28])[CH:22]=[CH:21][C:20]([S:23]([C:26]#[N:27])(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[CH2:4][N:1]1[C:26]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:28])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[N:27][N:3]=[N:2]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN=[N+]=[N-]
Product: Cc1ccc(S(=O)(=O)c2nnnn2C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 48 h
Yield: 91.2 %

Procedure:
(S)-2-(azidomethyl)-1-Boc-pyrrolidine (480 mg, 2.1 mmol) was added to a flask containing p-toluenesulfonyl cyanide (420 mg, 2.3 mmol) and a stir bar (no solvent). The flask was placed in a 80° C. bath and reaction proceeded for 48 hours. The reaction was concentrated in vacuo. The crude amber oil was purified by flash silica gel chromatography using a hexane/ethyl acetate gradient. The product (780 mg, 91% yield) was obtained as a colorless oil. 1H-NMR (500 MHz, CDCl3): δ 8.01 (broad d, J=18 Hz, 2H), 7.44 (m, 3H), 4.85-4.70 (m, 2H), 4.52-4.48 (m, 1H), 3.50-3.34 (m, 2H), 2.49 (s, 3H), 2.01-1.71 (m, 4H), 1.40 & 1.33 (2 s, 9H). ESI-MS (m/z) for C18H25N5O4S (exact mass 407.16): [M+H]+ calc. 408.2, obs. 408.2; [M+Na]+ calc. 430.2, obs. 430.2.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)C>C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Fc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncccc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
n-Butyl lithium (2.5M, 1 mL, 2.5 mmol) was added dropwise to a solution of 2-bromo-3-fluoro-pyridine (0.4 g, 2.27 mmol) in diethyl ether (8 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.51 g, 2.27 mmol) in diethyl ether (5 mL) was added dropwise at −78° C. and the reaction mixture stirred for 0.5 hours before warming to room temperature. The reaction mixture was poured onto ice, acidified with acetic acid and extracted into ethyl acetate. The remaining aqueous solution was basified with 1 M sodium hydroxide, extracted with DCM and the combined organics were dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. Methanol (10 mL) and sodium borohydride (0.14 g) were added to the residues and stirred for 2 hours to reduce any unreacted ketone. The solvent was removed by evaporation under vacuum, DCM added to the residues and the organics washed with water and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-10% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.25 g). LCMS m/z 323 [M+H]+. R.T.=4.67 min (Analytical Method 3).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([CH2:15][NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)=[O:29])[CH2:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a Parr shaker flask containing compound of step B (14.0 g, 34.5 mmol) dissolved in MeOH (50 mL) was added Palladium hydroxide (2.8 g, 20 wt %). The suspension was shaken at rt under hydrogen (55 psi) overnight. The mixture was filtered through celite and concentrated to give the title compound as a white solid; yield 10.5 g, 97%; 1H NMR (CDCl3) δ 9.06 (t, 1H), 8.20 (m, 3H), 7.94 (d, 1H), 7.75 (t, 1H), 4.23 (a, 1H), 3.89 (d, 2H), 3.00-3.22 (m, 4H), 2.82 (m, 1H), 2.05 (m, 1H), 1.73 (m, 1H); MS m/z=316.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:7](=O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[C:14]1([C@@H:20]2[CH2:22][C@H:21]2[NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]1([CH:7]([NH:23][C@@H:21]2[CH2:22][C@H:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)C1CCCCC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of 1-cyclohexylethanone (95 mg, 0.751 mmol) in 1,2-dichloroethane (DCE) (40 mL) and acetic acid (0.052 mL, 0.901 mmol) was added [(trans)-2-phenylcyclopropyl]amine (100 mg, 0.751 mmol). The reaction mixture was stirred for 2 hour at room temperature, then sodium triacetoxyborohydride (477 mg, 2.252 mmol) was added and the reaction mixture was stirred 3 hours at room temperature. The reaction mixture was quenched with saturated NH4Cl. Water (20 mL) followed by dichloromethane (40 mL) were added. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The solid was suspended in diethylether, sonicated and filtered. trans-N-(1-Cyclohexylethyl)-2-phenylcyclopropanamine (48 mg, 0.187 mmol, 24.95% yield) was isolated as white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.11-9.35 (m, 1H), 8.80-9.03 (m, 1H), 7.27-7.42 (m, 2H), 7.13-7.27 (m, 3H), 3.23 (br. s., 1H), 2.91 (d, J=2.78 Hz, 1H), 2.57 (ddd, J=3.54, 6.44, 9.98 Hz, 1H), 1.68-1.87 (m, 4H), 1.57-1.68 (m, 2H), 1.46-1.57 (m, 1H), 1.26-1.42 (m, 1H), 1.18-1.24 (m, 3H), 0.95-1.18 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 244.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]([OH:16])[CH3:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)=[O:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:33](=[O:34])([O:35][C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)[O:16][CH:14]([CH3:15])[C:13](=[C:11]1[CH2:12][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:10]1)[C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 420 mg (0.91 mmol) of 1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-1-(3,5-difluorophenyl)propan-2-ol (Example 35) and 222 mg (1.82 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was added 276 mg (1.37 mmol) of 4-nitrophenyl chloroformate, followed by stirring for 4 h at rt. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=12:1 to afford the title compound. Mass Spectrum: m/e=627 (M+1 35Cl, 35Cl) and 629 (M+1 35Cl, 37Cl).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][O:4][CH:5]1[O:9][CH:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[N:13]([CH2:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]2=[O:12])[CH2:7][CH:6]1[O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.O>[CH:2]([CH2:3][O:4][CH:5]1[O:9][CH:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[N:13]([CH2:19][C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]2=[O:12])[CH2:7][CH:6]1[O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:1]
Reactant: Cc1cn(C2CC(OC(=O)c3ccccc3)C(OCC(O)CO)O2)c(=O)n(CC(=O)c2ccccc2)c1=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(C2CC(OC(=O)c3ccccc3)C(OCC=O)O2)c(=O)n(CC(=O)c2ccccc2)c1=O
Yield: 93.3 %

Procedure:
A solution of compound 168 (4.5 g, 2.85 mmol) and NaIO4 (0.78 g, 3.66 mmol) in 1:1 THF/H2O (120 mL) was stirred at RT for 2 hrs. The solvent was evaporated under vacuum and the residue was purified by silica gel chromatography (CHCl3 /MeOH, 20:1→10:1) to give 1.31 g of the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[N:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CCC(CC)CC(C(=O)Nc1ccn(CCO[Si](C)(C)C(C)(C)C)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 49 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid (Intermediate 31) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as light yellow solid (472.6 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.07 (s, 6H), 0.71-0.88 (m, 6H), 0.80 (s, 9H), 0.92-1.51 (m, 5H), 1.74-1.99 (m, 1H), 2.03-2.23 (m, 1H), 3.85 (t, J=5.1 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 5.52 (dd, J=10.7, 4.4 Hz, 1H), 6.03 (d, J=2.7 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.31-7.51 (m, 3H), 7.53 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1)[CH2:22][CH3:23].[Cl-].[NH4+]>CS(C)=O>[CH2:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[CH:29][CH:30]=1)[CH2:22][CH3:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCCOc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCOc1ccc(CN2CCC(C(=O)OCC)CC2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 47.5 grams (0.30 mole) of ethyl piperidin-4-ylcarboxylate in 70 mL (0.40 mole) of N, N-diisopropylethylamine was added dropwise a solution of 52.5 grams (0.29 mole) of 4-propoxyphenylmethyl chloride in 50 mL of dimethyl sulfoxide. The reaction caused the reaction mixture temperature to rise to about 35° C. Upon completion of the addition the reaction mixture was stirred for 30 minutes, warmed to 40° C., and then allowed to cool to ambient temperature. After this time the reaction mixture was poured into 500 mL of aqueous 10% ammonium chloride. The mixture was extracted with three 250 mL portions of diethyl ether, and the combined extracts were washed with two 250 mL portions of an aqueous solution saturated with ammonium chloride, one 250 mL portion of water, and one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 80.0 grams of ethyl N-(4-propoxyphenylmethyl)piperidin-4-ylcarboxylate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)\[CH3:16])[CH:7]=1)C.C(O)C>[OH-].[Na+].Cl.C(OCC)(=O)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17](/[C:15](/[CH3:16])=[CH:14]/[CH2:13][O:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:11]=[CH:10][CH:9]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1cccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C/C(=C\COc1cccc(CC(=O)O)c1)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 98.6 %

Procedure:
(E)-{3-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl ester (example 22) (150 mg, 0.32 mmol) was suspended in 1N NaOH (0.82 mL) and ethanol (5 mL) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (0.82 mL) and ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (20 mL) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 138 mg (98%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cc1
Yield: 106.1 %

Procedure:
0.5 g (0.00216 mol) of 1-benzyl-4-hydroxypiperidine and 0.64 ml (0.0046 mol) of triethylamine were dissolved in 20 ml of toluene, treated with 0.5 g (0.0027 mol) of 4-nitro-benzoyl chloride and boiled at reflux for 6 hrs. The suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetatelhexane (1:3) as the eluent. 0.78 g (85%) of 1-benzyl-piperidin-4-yl 4-nitro-benzoate was obtained as yellow crystals; m.p. 87°-89°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[N:10][OH:11])[CH2:2]1.[H-].[Na+].S(OC)(O[CH3:18])(=O)=O>O>[CH3:18][O:11][N:10]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: ON=C1COc2ccccc21
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CON=C1COc2ccccc21
Yield: 42 %

Procedure:
3.7 g of benzofuran-3-one oxime are dissolved in 15 ml of dimethylfornamide. At 20° C., 1 g of sodium hydride (60%) is added and the mixture is stirred until the evolution of gas ceases. 3.15 g of dimethyl sulphate are then added dropwise and the mixture is stirred at 20° C. for 24 hours. The reaction mixture is poured into water, extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is chromatographed over silica gel using n-hexane/acetone (4:1). 1.7 g (42% of theory) of benzofuran-3-one O-methyl-oxime are obtained as an oil.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25]O>>[C:1]1([S:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: O=C1CCc2cc(OCCCCCSc3ccccc3)ccc2N1
Product: O=C1CCc2cc(OCCCCCS(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 2 from 6-(5-phenylmercapto-pentoxy)-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[O:5])[CH2:3][CH2:2]1.S(Cl)([Cl:21])=O.CN(C)C=O>CCOCC>[CH:1]1([C:4]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCOC(=O)C2CC2)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)c1ccc(OCCOC(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3.2 g (12.8 mmol) of 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid, 80 ml of ether and 1.5 ml (20.5 mmol) of thionyl chloride, at RT, is added 0.3 ml (3.8 mmol) of dimethylformamide. This mixture is stirred, at RT, for 1 day. The top phase is decanted (the residue is discarded), and solvent and other volatiles are removed from it by rotoevaporation to give 4-(2-cyclopropylcarbonyloxyethoxy)benzoic acid chloride.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:18][C@H:19]1[O:24][C@@H:23]([CH3:25])[CH2:22][N:21]([CH2:26][CH2:27][NH:28][C:29]([NH:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([SH:41])[CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:30])[CH2:20]1.[BH4-].[Na+]>C(N(CC)CC)C>[CH3:25][C@H:23]1[O:24][C@@H:19]([CH3:18])[CH2:20][N:21]([CH2:26][CH2:27][NH:28][C:29]([NH:31][C:32]2[S:33][C:34]3[CH:40]=[C:39]([S:41][C:2]4[N:6]5[N:7]=[C:8]([C:11]6[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=6)[CH:9]=[CH:10][C:5]5=[N:4][N:3]=4)[CH:38]=[CH:37][C:35]=3[N:36]=2)=[O:30])[CH2:22]1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Reactant: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(S)cc3s2)C[C@H](C)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(Sc4nnc5ccc(-c6ccc(F)cc6)nn45)cc3s2)C[C@H](C)O1
Yield: 16.9 %

Procedure:
The 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)urea was prepared according to the method described in Example 1a, but using 186 mg of 3-chloro-6-(4-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine, 366 mg of 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea, 0.14 cm3 of triethylamine and 38 mg of sodium borohydride. 73 mg of 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a beige powder, the characteristics of which are as follows: