Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:8][N:9]=[C:10]([NH2:12])[NH2:11])[CH2:2][C@H:3]([NH2:7])[C:4]([OH:6])=[O:5].O.[CH2:14]([O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]1[O:17][CH2:16]1.[ClH:27]>C(O)C>[ClH:27].[OH:17][CH:15]([CH2:14][O:18][CH2:19][CH:20]([CH2:25][CH3:26])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][NH:7][C@H:3]([C:4]([OH:6])=[O:5])[CH2:2][CH2:1][CH2:8][NH:9][C:10](=[NH:12])[NH2:11]
Reactant: NC(N)=NCCC[C@H](N)C(=O)O
Reactant: CCCCC(CC)COCC1CO1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCC(CC)COCC(O)CN[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 78 °C
Reaction time: 4 h

Procedure:
In a four-necked 200-mL flask equipped with a reflux cooling tube, a dropping funnel, a thermometer and a stirring blade, 9.4 g (53.7 mmol) of L(+)-arginine, 50.0 g of water and 50.0 g of ethanol were placed, and the mixture was heated to 78° C. while being stirred under a nitrogen atmosphere. Subsequently, the inside of the reaction system was maintained at 78 to 80° C., 10.0 g (53.7 mmol) of 2-ethylhexyl glycidyl ether was added dropwise thereto. Thereafter, the mixture was aged for 4 hours at 78 to 80° C., and then was returned to room temperature. Subsequently, 9.8 g (53.7 mmol) of a 6 mol/L aqueous solution of hydrochloric acid was added thereto to neutralize the mixture. Water and ethanol were completely distilled off from the reaction solution under reduced pressure, and thus 21.6 g of N-[2-hydroxy-3-(2-ethylhexyl)oxypropyl]-L-arginine hydrochloride was obtained as a white solid. This compound corresponds to the compound 2 of Table 1.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([C:30]3[N:35]=[C:34]4[CH2:36][O:37]C(C5C=CC=CC=5)[O:39][C:33]4=[CH:32][CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>O.C(O)(=O)C>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([C:30]3[N:35]=[C:34]([CH2:36][OH:37])[C:33]([OH:39])=[CH:32][CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCNCC(O)c2ccc3c(n2)COC(c2ccccc2)O3)c1)C1CCCC1
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(c1cccc(CCCCOCCCCCCNCC(O)c2ccc(O)c(CO)n2)c1)C1CCCC1

Procedure:
A solution of 2-[(6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexyl)amino]-1-(2-phenyl-4H-[1,3]dioxino[5,4-b]pyridin-6-yl)ethanol (61 mg) in water (5 ml) and glacial acetic acid (5 ml) was heated under reflux for 0.5 h. The reaction mixture was concentrated in vacuo to afford the title compound. LCMS RT=2.63 min 548(M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CO.[S:13]([O-])([O-:16])(=[O:15])=[S:14].[Na+].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:13]([OH:16])(=[O:15])=[S:14]
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=S([O-])([O-])=S
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(N)c(S(=O)(O)=S)c1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
N′,N′-dimethyl-p-phenylene diamine (10 g, 0.0735 mols) was added to a round bottom flask. To this was added de-ionised water (160 ml) and methanol (40 ml) and the solution was then cooled to 5° C. Sodium thiosulfate (20 g, 0.0808 mols) in water (20 ml) was added to the solution in one aliquot. Sodium persulfate (17.5 g, 0.0735 mols) in water (40 ml) was added drop-wise over a 15 minute period. The reaction mixture was stirred for 3 hours at 5° C. and then warmed to 22° C. over a period of 1 hour. The dark solid which precipitated was collected via filtration. The black solid was washed with water (50 ml) then dried at 40° C. for 16 hours, 7.88 g (43%).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6]SC)[C:3]([OH:5])=[O:4].O[O:10][S:11]([O-:13])=O.[K+].[CH3:15]C(C)=O>O>[CH3:1][C@H:2]([CH2:6][S:11]([CH3:15])(=[O:13])=[O:10])[C:3]([OH:5])=[O:4]
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Reactant: CSC[C@@H](C)C(=O)O
Agent: [K+]
Solvent: O
Product: C[C@H](CS(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A solution of Example 149A (0.085 g, 0.63 mmol) in acetone (1.2 mL) and water (0.25 mL) at 0° C. was treated with oxone (1.17 g, 1.9 mmol) and the mixture was stirred at 25° C. for 3 h. The mixture was filtered, rinsed with acetone, and the solvents were evaporated. The residue was dissolved in ethyl acetate, dried over MgSO4, filtered and the solvents were evaporated to give the crude title compound (47 mg, 45%).
Reaction SMILES: [SH2:1].[Na].Cl[C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21]I>CN(C=O)C.O>[CH3:21][S:1][C:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][S:6][N:5]=1
Reactant: CI
Reactant: Clc1nsnc1-c1cccnc1
Reactant: S
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nsnc1-c1cccnc1
Reaction time: 0.5 h

Procedure:
Sodium hydrogen sulfide (0.5 g, 6.8 mmol) was added to a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.5 g, 2.5 mmol) in DMF (20 ml) at room temperature and the reaction mixture was stirred for 30 min. Potassium carbonate (2 g, 14.5 mmol) and methyl iodide (1 ml, 15 mmol) were added and the reaction mixture was stirred for additionally 10 min. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated to give the title compound. Yield: 0.5 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([OH:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C@H:10]([O:21][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of trans-N-t-butoxycarbonyl-4-(3-methylphenyl)-3 hydroxy piperidine (131 mg, 0.449 mmol), in DMF (2 ml) at 0° C. was added sodium hydride (27 mg of a 60% dispersion in mineral oil, 0.890 mmol). After 10 min, benzyl bromide (0.107 ml, 0.890 mmol) was added and the reaction allowed to warm to room temperature over 16 hrs. The reaction was quenched by the addition of saturated NH4Cl solution (5 ml) and extraction with EtOAc. The organic extracts were washed with brine and dried (MgSO4) and the solvent evaporated in vacuo. Chromatography of the residue (SiO2, gradient elution, 10-15% EtOAc in hexanes) afforded the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([NH:12][NH2:13])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:3]([C:10]([NH:12][NH:13][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Cl)c(C(=O)NN)n1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CSc1ncc(Cl)c(C(=O)NNC(=O)Cc2ccccc2)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carbohydrazide (1.0 g, 4.6 mmol) and 2-phenylacetyl chloride (0.61 mL, 4.6 mmol) were dissolved in 20 mL pyridine. The solution was stirred at 60° C. for 3 h. Upon cooling to room temperature, the reaction mixture was diluted with excess H2O. The aqueous layer was extracted with EtOAc 3 times. The combined organic layers were washed with 2 N HCl and H2O, dried over magnesium sulfate and concentrated under vacuum. Flash chromatography was required to obtain 0.442 g (26% yield) of product as a white solid. MS (M+H)+ 337.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:54])[CH2:21][C:22]1([CH2:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH2:34][CH2:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.CN1C(=O)CCC1>C(#N)C>[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:33][C:31]2[CH:30]=[CH:29][C:28]([CH2:34][CH2:35][C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])=[C:27]([C:24]3[CH2:23][C:22]([CH2:46][C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])([CH2:21][C:20](=[O:54])[O:19][C:15]([CH3:18])([CH3:16])[CH3:17])[O:26][N:25]=3)[CH:32]=2)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(O)ccc2CCC(=O)OCc2ccccc2)=NO1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2CCC(=O)OCc2ccccc2)=NO1
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (96 mg) was added to a mixture of benzyl 3-(2-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoate (227 mg), pyridine (0.2 mL), and NMP (0.2 mL) at 50 C, and the obtained mixture was stirred at 50 C for 30 minutes. 4-Carbamimidamidobenzoyl chloride hydrochloride (96 mg) was further added thereto, and the obtained mixture was stirred overnight at 50 C. To the reaction mixture, acetonitrile was added. The precipitate was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) to obtain the title compound (163 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[CH3:15][N:4]([CH2:3][CH2:2][NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: CN(CCN)CCNC(=O)OC(C)(C)C
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)OC(C)(C)C)CCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (400 mg, 1.84 mmol) was taken up in CH3CN (10 mL) along with nicotinic acid (227 mg, 1.84 mmol) and EDCI (353 mg, 2.02 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (5% MeOH—CH2Cl2) to afford tert-butyl 2-(methyl(2-(nicotinamido)ethyl)amino)ethylcarbamate (180 mg, 30%). MS calculated for C16H26N4O3: 322.2; found: [M+H]+323.
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:10]OC(OC)N(C)C.Cl.[F:19][C:20]1[CH:21]=[C:22]([NH:27][NH2:28])[CH:23]=[C:24]([F:26])[CH:25]=1>C(O)C>[F:19][C:20]1[CH:21]=[C:22]([N:27]2[CH:10]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([CH2:8][CH3:9])=[N:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: COC(OC)N(C)C
Reactant: NNc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCO
Product: CCc1nn(-c2cc(F)cc(F)c2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of methyl 3-oxopentanoate (5.2 g) and dimethylformamide dimethylacetal (5.6 mL) was stirred at 100° C. overnight, and the mixture was allowed to cool to room temperature. Ethanol (100 mL) and 3,5-difluorophenylhydrazine hydrochloride (7.9 g) were added to the reaction mixture, and the mixture was further stirred at 100° C. for 15 hr. After allowing to cool, ethanol was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10, volume ratio) to give the title object compound (6.5 g, 62%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]2=[C:13]3[C:18](=[N:19][C:3]=12)[CH:17]=[CH:16][CH:15]=[CH:14]3.[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][CH2:28][CH2:29][N:30]([CH2:32][CH2:33][CH2:34][NH2:35])[CH3:31])([CH3:23])([CH3:22])[CH3:21]>C(OCCO)C>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][CH2:28][CH2:29][N:30]([CH3:31])[CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]2=[C:13]3[C:18](=[N:19][C:3]=12)[CH:17]=[CH:16][CH:15]=[CH:14]3)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2ccccc21
Reactant: CN(CCCN)CCCNC(=O)OC(C)(C)C
Solvent: CCOCCO
Product: CN(CCCNC(=O)OC(C)(C)C)CCCNc1c2nc3ccccc3c-2n(C)c2ccccc12
Temperature: 120 °C
Yield: 490 %

Procedure:
A solution of 11-chloro-5-methyl-5H-indolo[3,2-b]quinoline (cf. Bierer et al., J. Med. Chem. 1998, vol. 41, pp. 2754) (61 mg, 0.23 mmol) and [[3-[(3-amino-propyl)methylamino]propyl]carbamic acid tert-butyl ester previously prepared (Spicer at el., Bioorg. Med. Chem. 2002, vol. 10, p. 19) (84_l, 0.34 mmol) in 2-ethoxyethanol (10 ml) was heated at 120° C. for 10 min. Removal of the solvent and purification by chromatography on alumina (CHCl3: MeOH 2%) yielded [3-[methyl-[3-(5-methyl-5H-indolo[3,2-b]quinolin-11-yl-amino)propyl]-amino]propyl]carbamic acid tert-butyl ester (49 mg, 490%) as a foam. 1H NMR [CDCl3—, ppm]: 8.16 (d, J=8.5 Hz, 1H), 7.81 (m, 4H), 7.55-7.48 (m, 2H), 7.21 (m, 1H), 4.51 (s, 3H, NCH3), 4.27 (m, 2H, CH2NO), 3.12 (m, 2H, CH2NHBOC), 2.76 (m, 2H, CH2N(CH3)), 2.63 (m, 2H, CH2N(CH3)), 2.39 (s, 3H, N(CH3)), 2.34 (m, 2H, CH2CN(CH3)), 1.73 (m, 2H, CH2CN(CH3)), 1.37 (s, 9H, C(CH3)3).
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2ccoc12
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c1OCC2
Yield: 99 %

Procedure:
Methyl benzofuran-7-carboxylate (12 g, 68 mmol) was hydrogenated at 60 psi over 10% Pd/C (2 g) in acetic acid (60 ml) for 18 hr. The mixture was filtered, and the filtrate was concentrated in vacuo to give a pale green oil (12 g, 100%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[C:29]#[N:30].O[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][C:17]=1[C:29]#[N:30]
Reactant: CN1CCN(CCCO)CC1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of diisopropyl azodicarboxylate (12.1 ml) in methylene chloride (50 ml) was added dropwise during 30 minutes to a stirred mixture of 4-chloro-3-cyano-7-hydroxy-6-methoxyquinoline (12 g), 1-(3-hydroxypropyl)-4-methylpiperazine (9.7 g), triphenylphosphine (16.1 g) and methylene chloride (200 ml) that had been cooled to 5° C. The resultant mixture was allowed to warm to ambient temperature and was then stirred for 1 hour. Further portions of diisopropyl azodicarboxylate (1.2 ml) and triphenylphosphine (1.6 g) were added and the mixture was stirred at ambient temperature for a further 1 hour. The mixture was poured into water and the organic layer was separated, washed with a saturated brine solution, dried over magnesium sulphate and evaporated. The material so obtained was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the required starting material as a solid (14.5 g); NMR Spectrum: (DMSOd6) 1.95 (m, 2H), 2.13 (s, 3H), 2.24–2.5 (m, 10H), 4.0 (s, 3H), 4.25 (t, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 8.95 (s, 1H); Mass Spectrum: M+H+ 375 and 377.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C#N.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:21]([N:23](CC)CC)C>C(Cl)Cl>[C:12]([O:1]/[N:2]=[CH:3]/[C:6]1([C:21]#[N:23])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:11]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC(=NO)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: N#CC1(/C=N/OC(=O)c2ccccc2)C=CC=CC1
Yield: 75.3 %

Procedure:
After dissolving 2-hydroxyimino-2-phenylacetonitrile (1.0 g, 6.84 mmol) in CH2Cl2 (30 ml), benzoylchloride (1.02 ml, 8.89 mmol) was slowly added at 0° C. under the presence of triethylamine (1.24 ml, 8.89 mmol). After stirring reaction solution for 1 hour, the reaction was quenched by 1 N hydrochloric acid and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-cyano-benzaldehyde O-benzoyloxime (14) (1.30 g, 81%) was obtained by separating the residue with silica gel column chromatography.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[N:11]1([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 53.4 %

Procedure:
To a stirred solution of 4-bromoacetophenone (10 g, 50 mmol) in DMF (100 mL), were added 1,2,4-triazole (5 g, 75 mmol), Cs2CO3 (32.6 g, 100.5 mmol) and CuI (1.4 g, 10.1 mmol) and the resultant reaction mixture was refluxed for 48 h. After completion of the reaction (by TLC), the reaction mixture was cooled to ambient temperature and diluted with water (200 mL) and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. Purification by washing with diethyl ether afforded the title compound as a solid (5 g, 96%): 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.16, (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 2.66 (s, 3H); ESIMS m/z 186.02 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:50])[C:34]2[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[C:36]([N:44]3[CH2:45][CH2:46][O:47][CH2:48][CH2:49]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(NC(=O)c2cc(N3CCOCC3)cc(C(F)(F)F)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 77 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 50, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholino-5-trifluoromethylbenzamide to give N-[2-methyl-5-(3-morpholino-5-trifluoromethylbenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 77% yield; NMR Spectrum: (DMSOd6) 1.37 (s, 9H), 1.55 (m, 2H), 1.95 (m, 2H), 2.19 (s, 3H), 3.2 (m, 2H), 3.25 (t, 4H), 3.63 (m, 2H), 3.77 (t, 4H), 4.63 (m, 1H), 7.18 (m, 1H), 7.22 (d, 1H), 7.37 (s, 1H), 7.41 (t, 1H), 7.5 (s, 2H), 7.57 (m, 1H), 7.62 (s, 1H), 7.7 (s, 1H), 7.78 (d, 1H), 9.83 (s, 1H), 10.31 (m, 1H); Mass Spectrum: M+H+683.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:16][C:13]([NH:17]C(=O)OC(C)(C)C)([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:16][C:13]([NH2:17])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)NC12CCCC(C#Cc3ccccn3)(CC1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC12CCCC(C#Cc3ccccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-ylcarbamate (1.1 g, 3.37 mmol) in DCM (5.0 mL) was added 2,2,2-trifluoroacetic acid (2.0 mL). After stirring at room temperature for two hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl ether (10 mL) to remove non-amine organic impurity. The aqueous layer was basified with NaOH to pH=12 and then extracted with DCM (3×10 mL). The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 600 mg (78%) of the title compound, 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]oct-1-ylamine. 1HNMR (500 MHz, CDCl3): δ 8.51 (d, J=5.0 Hz, 1H), 7.59-7.56 (m, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.16-7.13 (dd, J=7.0, 5.0 Hz, 1H), 2.42 (s, 2H), 2.15-1.54 (m, 12H); ESI-MS m/z: 227 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[C:16]([CH3:24])([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1.Cl.[SH2:27]>CN1CCCC1=O.O>[SH:27][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[C:16]([CH3:24])([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: S
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)c1ccc(S)cc1)N1CCOCC1

Procedure:
451 g of hydrated sodium sulfide (Na2S content 32-38%≈2 mols) are suspended in 800 ml of N-methyl-2-pyrrolidone and 400 ml of toluene and the mixture is warmed to 130°. Approx. 290 ml of water are removed in a water separator, and the toluene is then removed by distillation. 100 g (0.37 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholinopropan-1-one are introduced into the warm solution in portions, and the suspension is heated at 140° for 12 hours. After cooling, the pH of the reaction mixture is adjusted to 6 by adding 6N HCl, and the solution is freed from H2S. The solution is then diluted with 1 liter of water and extracted with diethyl ether. The ether extracts are extracted by shaking several times with 20% sodium hydroxide solution, and the combined aqueous alkaline extracts are neutralised with 6N HCl and extracted by shaking with diethyl ether. The ether extracts are dried over MgSO4 and concentrated. The oil which remains is crystallised from cyclohexane. Melting point 68°-69° C. (Compound No. 22).