Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO[Si](C)(C)C(C)(C)C)c1CCC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (0.837 mmol, 438 mg) in THF (12 mL) was added a solution of n-tetrabutyl ammonium fluoride (1.25 mmol, 1.25 mL, 1.0M) in THF at 0° C. Then, the resulting colorless solution was allowed to warm to room temperature in 2 h and the mixture was stirred for another 2 h at room temperature before being diluted with water (˜50 mL). The organic compound was extracted into ethyl acetate (2×50 mL) and the combined extracts were washed with brine solution (100 mL). The organic solution was dried over anhydrous magnesium sulfate and the filtrate was removed under vacuum after filtration of the drying agent. The crude residue was dried further under high vacuum and the desired 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (342 mg, 99%) was isolated as a colorless oil: ES(+)-HRMS m/e calculated for C23H36O6 (M+Na)+ 431.2404, found 431.2404.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])(=[O:17])=[O:16])=[CH:11][CH:10]=1.C[Mg]I.[CH2:32]1COC[CH2:33]1>O.C(OCC)(=O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:21]([C:22]3([OH:23])[CH2:33][CH2:32]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: C[Mg]I
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(Nc1cccc(C2(O)CC2)c1)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoate (500 mg, 1.03 mmol) and titanium isopropoxide (61 μL, 0.206 mmol) in anhydrous THF (10 mL) was cooled under nitrogen to −10° C. A solution of 3 Methylmagnesium iodide in THF (2.4 mL, 7.2 mmol) was added by syringe and the solution was stirred at 0° C. for 1 hour, then at room temperature overnight. The mixture was diluted with water (5 mL) and ethyl acetate (20 mL) and filtered through Celite. The layers were separated. The organic phase was washed with water (10 mL) and brine (10 mL) and dried over MgSO4. Evaporation of the solvents gave an orange gum which was purified by column chromatography on silica, eluting with acetone/hexane (1:4) and the title compound obtained as a light yellow foam (100 mg). 1H NMR (300 MHz, CDCl3): δ 0.95-1.05 (2H, m), 1.20-1.24 (2H, m), 6.90-7.10 (3H, m), 7.20-7.46 (3H, m), 7.47-7.48 (3H, m) and 7.83 (2H, d). MS, m/z: Calcd, 433.031. Found, 433.22 (M).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[N:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:14]([CH2:15][CH2:16][CH3:17])[C:12]1[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:38]=[N:37][CH:36]=[N:35][CH:34]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cncnc3)c1)=N2

Procedure:
The title compound was prepared from {5-(methyl-propyl-amino)-2-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M90) (0.40 g, 0.70 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (210 mg, 66%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-nitrobenzoic acid.
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22](Br)[CH:23]=[CH2:24].O>CN(C)C=O.C(O)(C)C>[CH2:24]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=1)[CH:23]=[CH2:22]
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reactant: C=CCBr
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: O
Product: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1

Procedure:
1-Phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine 5 g (0.015 mol) was dissolved in dimethylformamide (15 ml). To this was added allyl bromide 2.8 g (0.023 mol) and the mixture was heated at 95°-100° C. for about 1.5 hours. The reaction mixture was cooled and diluted with 30 ml of isopropanol and added slowly to about 900 ml of cold water. The precipitate was collected by filtration, washed with water and dried under reduced pressure to provide 1-allyl-1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine (m.p. 99°-101° C.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH:8]1[C:20]2[CH:19]([CH2:21]O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:8]1[C:20]2[CH:19]([CH2:21][O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCCBr)OCC1c2ccccc2-c2ccccc21
Reaction time: 18 h
Yield: 86.9 %

Procedure:
DDC (6.00 g, 29 mmol) was added in one portion to a cooled solution (0° C.) of 4-bromobutyric acid (5.00 g, 29.9 mmol), 4-(dimethylamino)pyridine (353 mg, 2.9 mmol) and 9-fluorenemethanol (5.63 g, 25 mmol) in CH2Cl2 (150 mL). The mixture was allowed to stand at 4° C. for 18 h, and then filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in EtOAc and the solution washed sequentially with 1N NaHCO3, 1N HCl and H2O. The solution was dried (Na2 -SO4) and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography on silica gel (200 g) using hexane-EtOAc (15:1) as the eluant to give the pure title compound as an oil (7.5 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18]S([O-])(=O)=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[C:30]1([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(OC(=O)C)C>CN(C=O)C.O>[C:30]1([CH:36]2[CH2:37][CH2:38][N:39]([CH2:18][C:16]3[N:17]=[C:12]([C:4]4[S:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[C:2](=[O:1])[N:3]=4)[CH:13]=[CH:14][CH:15]=3)[CH2:40][CH2:41]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(CN3CCC(c4ccccc4)CC3)n2)sc2ccccc12
Temperature: 70 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (0.30 g, 0.86 mmol), triethylamine (0.20 ml, 1.42 mmol) and 4-phenylpiperidine (0.15 g, 0.95 mmol) were dissolved in DMF (30 ml), and the mixture was stirred at 70° C. for 18 hrs. The reaction mixture was combined with ethylacetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.16 g, 76%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([F:19])[CH:13]=[C:12](F)[C:11]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([F:19])[CH:13]=[C:12]([O:23][CH3:22])[C:11]=1[F:21]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 456.4 %

Procedure:
To a solution of 2-fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-iodobenzeneamine (2.55 g, 6.16 mmol) in THF (40 mL), was slowly added NaOMe solution (25% in MeOH, 1.4 mL, 0.62 mmol) at −78° C. The mixture becomes dark in color immediately. After the addition was complete, the reaction mixture was warmed to rt and stirred overnight. It was then diluted with ethyl acetate and washed with water, brine and then dried. After removal of volatiles, the crude product was purified by silica gel flash column using 2-10% ethyl acetate/hexanes as eluent to produce the desired product as yellow powder (1.2 g, 48%). Unreacted starting material 2-fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-iodobenzeneamine (1 g) was also recovered.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C1COCC1.N1C=CC=CC=1>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:22][CH2:21]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 107 mg (0.24 mmol) of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole in a mixture of 20 mL of THF and 20 mL of pyridine was cooled to 0° C. and 41 mg (0.36 mmol) of methanesulfonyl chloride was added. The mixture was allowed to warm to room temperature, and after 1 hr, water was added. The precipitate was collected, washed with water, and dried to give 95 mg (75% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[4-(methylsulfonyl)-1-piperazinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (MeOH) 311-314° C.; 1H NMR (CDCl3) δ 7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.43 (t, JHF=53.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.05 (s, 3H), 4.03 (m, 4H), 3.89 (m, 4H), 3.79 (m, 4H), 3.33 (m, 4H), 2.81 (s, 3H); Anal. Calcd. for C21H26F2N8O4S: C, 48.1; H, 5.0; N, 21.4. Found: C, 48.0; H, 4.9; N, 21.2%.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1>ClCCl>[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]2=[O:13])=[CH:38][CH:37]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.050 g, 0.169 mmol) and (4-fluorophenyl)methanamine (0.023 g, 0.186 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.20-7.30 (m, 9H), 7.06-7.12 (m, 2H), 6.93-6.99 (m, 2H), 6.24-6.27 (m, 1H), 4.26 (d, J=5.9 Hz, 2H), 4.04 (s, 3H), 3.49 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 401 (M−H)−.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[C:11]([O:24][CH3:25])=[CH:12][C:13]3[O:18][C:17](=[O:19])[C:16]4[CH2:20][CH2:21][CH2:22][C:15]=4[C:14]=3[CH:23]=2)[CH2:38][CH2:39]1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2cccc(C)c2C)CC1)CCC3
Yield: 84 %

Procedure:
Method B (20 h at 60° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 1-(2,3-dimethylphenyl)-piperazine; yield 84%; fusion point 164°-166° C. (from ethanol). Fumarate: method E; yield 94%; fusion point 235°-237° C. (from acetone).
Reaction SMILES: [OH-].[K+:2].[C:3]([CH2:5][CH2:6][N:7]([C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][C:9]([OH:11])=[O:10])#[N:4]>>[C:3]([CH2:5][CH2:6][N:7]([C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:8][C:9]([O-:11])=[O:10])#[N:4].[K+:2]
Reactant: CCCCCCCCCCCC(=O)N(CCC#N)CC(=O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)N(CCC#N)CC(=O)[O-]

Procedure:
A 30% aqueous solution of KOH was gradually added to the N-cyanoethyl-N-dodecanoylglycine obtained in Example 2 to thereby adjust the pH of the system to 6.0. Thus, an aqueous solution of potassium N-cyanoethyl-N-dodecanoylglycinate was obtained. 1H-NMR spectrum (200 MHz, D2O) 4.02 (s,1 H), 3.94 (s,1 H), 3.76 (t,1 H), 3.65 (t,1 H), 2.80 (t,1 H), 2.71 (t,1 H), 2.50 (t,1 H), 2.30 (t,1 H), 1.60 (m,2 H), 1.31 (b,16 H), 0.89 (t,3 H) ppm
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH:13]1(C#N)C[CH2:14]1>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([CH:11]1[CH2:14][CH2:13]1)=[O:12]
Reactant: CC(=O)c1cc(C)cc(C)c1N
Reactant: N#CC1CC1
Product: Cc1cc(C)c(N)c(C(=O)C2CC2)c1

Procedure:
Cyclopropyl 2-amino-3,5-dimethylphenyl ketone was synthesized in the same fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) except that cyclopropyl cyanide was used instead of acetonitrile.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH2:1]([C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(O)CC2)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1cnc(N2CCC(=O)CC2)cn1

Procedure:
The title compound is prepared from 1-(5-ethyl-pyrazin-2-yl)-piperidin-4-ol by oxidation with Dess-Martin periodinane in dichloromethane at room temperature. LC (method 7): tR=0.73 min; Mass spectrum (ESI+): m/z=206 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24](O)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1([CH3:36])[O:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[O:29]1.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24]([CH:31]1[C:32](=[O:34])[O:33][C:28]([CH3:36])([CH3:27])[O:29][C:30]1=[O:35])=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)COC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxymethyloxymethyl-4-methanesulfonyloxypyrrolidine (79.4 g), 2,2-dimethyl-1,3-dioxane-4,6-dione (29.55 g) and 4-(dimethylamino)pyridine (25.05 g) in dichloromethane (635 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (39.3 g) at 5°-10° C. The solution was stirred at the same temperature for one hour and at ambient temperature for 18 hours. The mixture was washed with water (650 ml), 1N hydrochloric acid (650 ml), saturated aqueous sodium hydrogen carbonate (650 ml), and brine (650 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (800 g) and eluted with a mixture of methanol and dichloromethane (2:98 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[2-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxoethyl]oxymethyl-4-methanesulfonyloxypyrrolidine (80.98 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:19]3[C:11](=[CH:12][C:13]4[CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]7[O:35]C(C)=[N:37][N:38]=7)=[CH:30][C:29]=6[CH3:40])=[CH:24][CH:23]=5)=[O:21])[C:17]=4[CH:18]=3)[O:10][CH2:9]2)[CH2:5][CH2:4]1)[CH3:2].Cl.CCOCC>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2([C:19]3[C:11](=[CH:12][C:13]4[CH2:14][CH2:15][N:16]([C:20]([C:22]5[CH:23]=[CH:24][C:25]([C:28]6[CH:33]=[CH:32][C:31]([C:34]([NH:38][NH2:37])=[O:35])=[CH:30][C:29]=6[CH3:40])=[CH:26][CH:27]=5)=[O:21])[C:17]=4[CH:18]=3)[O:10][CH2:9]2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2C)cc1)CC3
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(C(=O)NN)cc2C)cc1)CC3
Reaction time: 20 h
Yield: 39.2 %

Procedure:
A stirred solution of 1'-ethyl-5-[2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E26, 2.5 g, 4.7 mmole) in methanol (600 ml) was treated with 1M hydrogen chloride in ether (30 ml, 30 mmole) and kept at room temp. for 20 hours, then concentrated in vacuo. The residue was treated with 10% Na2CO3 solution (200 ml) and chloroform (500 ml), stirred well for 20 minutes, then the chloroform layer separated, dried and concentrated in vacuo. The residue was crystallised from ethyl acetate to afford the title compound as a beige solid (0.94 g, 39%) m.p. 222-225° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].Br[CH2:10][CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1>C(#N)C>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][CH2:10][S:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: BrCCC1OCCO1
Reactant: OCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OCCCCSCCC1OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-mercaptobutanol (4.936 g) in dry acetonitrile under argon was cooled to 0° C. and sodium hydride (60% in mineral oil, 2.044 g) was added portionwise. The mixture was stirred for 1 hour at 0° C. then 2-(2-bromoethyl)-1,3-dioxolane (9.26 g) was added and the resultant grey suspension was warmed to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous sodium bicarbonate solution (150 mL) and then extracted with ethyl acetate (3×150 mL). The organics were combined and washed with brine (150 mL), dried over sodium sulfate, filtered and dried to afford the crude product. Purification was by silica gel chromatography eluting with 0-50% ethyl acetate in cyclohexane to afford the subtitled compound as a yellow oil. Yield 7.3 g.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:8]=[N:9][C:10]([O:16][CH2:17][CH3:18])=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)(=O)=O.[NH3:19]>CO>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([CH2:6][NH2:19])[N:8]=[N:9][C:10]=1[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: CCOc1cc(COS(C)(=O)=O)nnc1OCC
Reactant: N
Solvent: CO
Product: CCOc1cc(CN)nnc1OCC
Reaction time: 6 h

Procedure:
5,6-Diethoxypyridazin-3-ylmethyl methanesulfonate (620 mg) was dissolved in methanol (10 ml) and added dropwise while cooling with ice to an ammonia solution (16 ml; 7N in methanol). After being stirred for 6 h and left to stand overnight, the solvent was drawn off and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile and freeze-dried. 305 mg of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]2[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[C:6](=[O:18])[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=1.[C:25]12([C:35](=[O:38])[CH2:36]Br)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C>[C:25]12([C:35](=[O:38])[CH2:36][N:22]3[CH2:23][CH2:24][N:19]([C:4]4[N:3]=[C:2]([CH3:1])[N:7]([CH2:8][C:9]5[S:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=5)[C:6](=[O:18])[N:5]=4)[CH2:20][CH2:21]3)[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: Cc1nc(N2CCNCC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1nc(N2CCN(CC(=O)C34CC5CC(CC(C5)C3)C4)CC2)nc(=O)n1Cc1ccc(C(F)(F)F)s1
Yield: 48.5 %

Procedure:
To an acetonitrile solution (4.0 mL) of 6-methyl-4-(piperazin-1-yl)-1-{[5-(trifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one (28.7 mg, 80.0 μmol) synthesized in Reference Synthesis Example 351, 1-(adamantan-1-yl)-2-bromoethanone (23.1 mg, 90.0 μmol), potassium carbonate (13.8 mg, 100 μmol), and sodium iodide (15.0 mg, 100 μmol) were added and the resultant mixture was stirred at room temperature for 1 day. After the completion of the reaction, to the reaction solution, saturated sodium bicarbonate aqueous solution was added and extraction with ethyl acetate from the reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (chloroform/methanol=10/0→9/1) to obtain the title compound (20.8 mg, yield: 49%).