Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:18]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]([CH:31]([NH2:41])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[CH2:25][CH2:24]1)=[O:22])[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]([CH:31]([NH:41][C:1]([C:4]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:30])[CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1cc(C(=O)O)nc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c2cc(C(=O)OC)c3ccccc3n2)CC1
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a mixture of 2,4-dicarboxyquinoline (1.085 g, 5 mmol) in methanol (40 mL) was added chlorotrimethylsilane (TMSCl) (1.41 mL), and the reaction mixture was stirred overnight. The reaction mixture turned into a clear solution. The solvents were evaporated to yield a crude product, 2-carboxy-4-methoxycarbonylquinoline. To a solution of 2-carboxy-4-methoxycarbonylquinoline (151 mg, 0.65 mmol) in THF (10 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (181 mg, 1.05 eq.), EDCI (161 mg, 1.2 eq. ), and HOBt (75 mg, 1.1 eq.), and the resulting reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (146 mg) which was treated with trifluoroacetic acid (TFA) and CH2Cl2 (TFA/CH2Cl2, 1:1, 1.5 mL) and the resulting reaction mixture was stirred at ambient temperture for 1 hour. Evaporation of the solvents gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (74 mg). To this was added a mixture of THF:H2O (2:1, 2 mL) and LiOH (4 eq.). The resulting mixture was stirred at ambient temperature for 1.5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Extraction of the organic layers with ethyl acetate was followed by evaporation of the solvents to yield 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-carboxyquinoline (39 mg); NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.5 (m, 2), 3.4–3.9 (m, 8), 4.16 (q, 2), 5.25 (m, 1), 7.75 (m, 1), 7.86 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.ClC[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:24]([C:33]([F:36])([F:35])[F:34])[CH:23]=1.[C:37](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:28]1([CH:25]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)[C:26]2[CH:27]=[CH:22][CH:23]=[C:24]([C:33]([F:34])([F:35])[F:36])[CH:37]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC(c3cccc(C(F)(F)F)c3)C3CCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a solution of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (50.0 mg, 0.193 mmol) and 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (152.0 mg, 0.578 mmol) in DMF (3 mL) was added cesium carbonate (75.0 mg, 0.231 mmol). The mixture was stirred at room temperature overnight, filtered through Celite®, and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound as a light pink oil (38.7 mg). LCMS m/z=486.5 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[NH:25][N:26]=[CH:27][C:20]=12.C(N(C(C)C)CC)(C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH:9]=[CH:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([NH:17][C:19]3[N:24]=[CH:23][N:22]=[C:21]4[NH:25][N:26]=[CH:27][C:20]=34)[CH2:15][CH2:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@H]1CC[C@H](C=CCCc2ccccc2)CC1
Reactant: Clc1ncnc2[nH]ncc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C(=C[C@H]1CC[C@H](Nc2ncnc3[nH]ncc23)CC1)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.330 g of trans-4-(4-phenyl-but-1-enyl)-cyclohexyl-amine, 0.222 g of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (R. K. Robins, J. Amer. Chem. Soc., 78, 784-790 (1956)), 0.376 mL of di-isopropyl-ethylamine and 1.0 mL of dimethyl-formamide were combined and allowed to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate. The ethyl acetate extract was dried over sodium sulfate, filtered, concentrated to an oil and chromatographed on silica using ethyl acetate to 5% methanol/ethyl acetate to give a crude product as a foam, (350 mg, 70%). Purification of the crude material (60 mg) using C-18 reversed phase chromatography (1% trifluroacetic acid in acetonitrile/water) gave 0.025 g of pure product as a foam: HRMS=348.2173.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(O)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C)c([N+](=O)[O-])c1C
Yield: 88.9 %

Procedure:
A mixture of 32.12 grams of 2,4-dimethyl-3-nitrophenol, 35.78 grams of methyltosylate and 28.5 grams of anhydrous K2CO3 in 200 ml of acetone is heated to reflux for 12 hours. The reaction mixture is filtered leaving a tan solid. The filtrate is concentrated in vacuo. The concentrated filtrate is taken up in ethyl acetate and washed with 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride. The remaining ethyl acetate layer is dried, filtered and concentrated in vacuo to give a dark oil which is distilled (T=80°-87° C./50μ) to give 30.95 grams of a yellow solid which is recrystallized from absolute ethanol, M.P. 53°-55° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:31])[C@@H:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)[CH2:10][NH:11]C(=O)OCC2C=CC=CC=2)=[CH:4][C:3]=1[C:32]1[N:36]([CH3:37])[N:35]=[CH:34][C:33]=1[Cl:38]>C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:11][CH2:10][C@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)[C:8]([NH:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:32]2[N:36]([CH3:37])[N:35]=[CH:34][C:33]=2[Cl:38])[CH:4]=1)=[O:31]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CNC(=O)OCc2ccccc2)Cc2ccc(F)c(F)c2)sc1Cl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)[C@H](CN)Cc2ccc(F)c(F)c2)sc1Cl
Reaction time: 4 h

Procedure:
Phenylmethyl {(2S)-3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-2-[(3,4-difluorophenyl)methyl]-3-oxopropyl}carbamate (91 mg, 0.157 mmol) was dissolved in a solution of thioanisole (0.286 ml) in trifluoroacetic acid (2.855 ml). After 4 h at 25° C., the reaction mixture was dry loaded onto silica and neutralized/purified through silica chromatography (0-15% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[C:8]([O:47][CH3:48])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:46])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30](=[O:45])[CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl.C(O)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:49][S:50]([CH3:53])(=[O:51])=[O:52])[C:8]([O:47][CH3:48])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:46])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:30](=[O:45])[CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)CN5CCN(C(=O)OC(C)(C)C)CC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)CN5CCNCC5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
160 mg tert-butyl 4-(2-{4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazin-1-yl}-2-oxo-ethyl)-piperazine-1-carboxylate are dissolved in 5 ml dichloromethane, combined with 1 ml of a 5 M solution of hydrogen chloride in isopropanol and stirred for 12 hours at ambient temperature. Then the solvents are eliminated in vacuo and the residue is divided between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution and then dried on magnesium sulphate. The solvent is eliminated in vacuo and the residue is chromatographed on aluminium oxide (dichloromethane/methanol 100:0 to 95:5).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[N:6]=1.[CH2:9](O)[CH2:10][OH:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[N:6]=1
Reactant: O=Cc1csc(Br)n1
Reactant: OCCO
Solvent: Cc1ccccc1
Product: Brc1nc(C2OCCO2)cs1
Yield: 74.7 %

Procedure:
2-Bromothiazole-4-carbaldehyde (6.56 g, 34.17 mmol) [A. T. Ung, S. G. Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407] and ethylene glycol (5.72 ml, 102.5 mmol) were heated under reflux in toluene (50 ml), with a Dean and Stark trap fitted, for 18 hr. The product was concentrated and purified by column chromatography (15% ethyl acetate/hexane) to give the product as a yellow solid (6.03 g); m/z 236, 238.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:25])([Cl:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][C:20]([Cl:25])([Cl:24])[C:21]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)=[O:22]
Reactant: Cc1ccc(N)c2cn[nH]c12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)C(Cl)(Cl)Cl)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Methyl-1H-indazol-4-amine (J. Chem. Soc. 1955, 2412; 550 mg, 3.74 mmol) and triethylamine (1.6 mL, 11.5 mmol) were combined in CH2Cl2 (22 mL) and treated with trichloroacetyl chloride (0.54 mL, 4.84 mmol) dropwise at 0° C. The mixture was allowed to gradually warm to ambient temperature and stir overnight. The mixture was concentrated and the residue was purified by flash chromatography (98:2, CH2C12:CH3OH), to provide the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11](CO)=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.I[CH3:17].[O:18]1CCC[CH2:19]1>>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([O:18][CH3:19])=[C:10]([CH3:17])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2cc(CO)oc12
Reactant: C1CCOC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1oc2c(OC)cccc2c1C
Reaction time: 8 h

Procedure:
Sodium hydride (3.82 g, 60% in mineral oil) was added to a solution of 7-methoxy-benzofuran-2-ylmethanol (11.21 g) in dry tetrahydrofuran (300 ml) under an atmosphere of dry nitrogen at room temperature. After 10 minutes iodomethane (15.67 ml) was added and the reaction was left to stir overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (50 ml). The organic extract was washed with water (50 ml), followed by brine (50 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (13.32 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6]C=1C#N.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][C:23]=1[C:22]([OH:20])=[O:24]
Reactant: CCO
Reactant: N#Cc1ccc(OCCCN2CCCCC2)cc1Cl
Reactant: [OH-]
Agent: [Na+]
Product: Cl
Product: O=C(O)c1ccc(OCCCN2CCCCC2)cc1Cl
Temperature: 120 °C

Procedure:
2-Chloro-4-(3-piperidin-1-ylpropoxy)benzonitrile (D26) (6.29 g) with aqueous 1M sodium hydroxide (45.2 ml) in ethanol (60 ml) was heated at reflux for 72 h. The reaction mixture was then evaporated to remove ethanol and the aqueous solution treated with excess conc. hydrochloric acid and heated at 120° C. for 2 h. The reaction mixture was then cooled to 5° C. and filtered. The filter cake was washed with a small volume of water and then acetone followed by drying at 65° C. under high vacuum overnight to give the title compound (D27) as a pale brown powder (6.48 g). MS electrospray (+ion) 298/230 (MH+). 1H NMR δ (DMSO-d6): 13.05 (1H, s), 10.85 (1H, s), 7.89 (1H, d, J=8.7 Hz), 7.10 (1H, s), 7.02 (1H, d, J=8.7 Hz), 4.16 (2H, t, J=6.0 Hz), 3.40 (2H, m), 3.13 (2H, m), 2.88 (2H, m), 2.23 (2H, m), 1.94-1.35 (6H, m).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][OH:5].CC(C)([O-])C.[K+].[F:19][C:20]([F:34])([F:33])[C:21]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:24](Cl)[O:23][N:22]=1.C(Cl)Cl>C1COCC1>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:6])[CH2:4][O:5][C:24]1[O:23][N:22]=[C:21]([C:20]([F:34])([F:33])[F:19])[C:25]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN(C(=O)CO)c1ccccc1
Reactant: FC(F)(F)c1noc(Cl)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)COc1onc(C(F)(F)F)c1-c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
0.99 g (6.0 mmole) of N-methyl-N-phenyl-2-hydroxyacetamide was dissolved in THF (6 ml) and the solution was mixed with 0.75 g (6.0 mmole) of 90% potassium t-butoxide with ice cooling. The mixture was stirred for 30 minutes and then 1.24 g (5.0 mmole) of 3-trifluoromethyl-4-phenyl-5-chloroisoxazole was added dropwise to the mixture. After being stirred for 30 minutes, the mixture was refluxed for 24 hours. After cooling the reaction mixture, 60 ml of methylene chloride was added and the mixture was washed with a 5% solution of HCl and water. The methylene chloride phase was evaporated under reduced pressure and the residue was purified by chromatography on silica gel to give 1.15 g of colorless crystals. These were recrystallized from n-hexane to give 950 mg of the titled compound, yield 50.5%, m.p. 93.0°-94.0° C.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:13]([NH:15][C@H:16]([C:19]([O:21]C)=[O:20])[CH2:17][OH:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CC1C(C2(C3C(C)=CC(O)=C(C(C)C)C=3)OC(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1.[OH-].[Na+]>O1CCOCC1.O>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@H:2]([C:13]([NH:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][OH:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Agent: Cc1cc(O)c(C(C)C)cc1C1(c2cc(C(C)C)c(O)cc2C)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)O)OCc1ccccc1

Procedure:
4.4 g (10 mmols) of Z-Trp-Ser-OMe were dissolved in 30 ml of dioxane/water (4:1) and mixed with a spatula tip of thymolphthaleine. The mixture was titrated, while stirring, with 1N NaOH until a constant blue color was obtained. 10 ml were consumed. 10 ml of 1N hydrochloric acid were added and the reaction mixture was evaporated. The residue was distributed between ethyl acetate and water. The ethyl acetate phase was dried with Na2SO4 and concentrated. The residue was triturated with petroleum ether. Yield: 3.2 g (75%). It was recrystallized from ethyl acetate/petroleum ether. Yield: 3 g (70%), melting point: 148° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][N:15]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:16]=2[CH:17]=[CH:18][CH:19]=1)=O.O>O1CCCC1>[OH:8][CH2:9][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][N:15]2[S:20]([C:23]1[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=1)(=[O:22])=[O:21]
Reactant: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.4 %

Procedure:
The suspension of 1.9 g of lithium-aluminum hydride in 165 ml of tetrahydrofuran cooled to 0° C. is proportionately mixed with 16.45 g of 1-tosylindole-4-carboxylic-acid-methylester. After 30 minutes 1.9 ml of water, 1.9 ml of 15% soda lye and 5.7 ml of water are carefully and sequentially dripped in. After 20 minutes, the precipitate is filtered off, washed out with acetic-acid-ethylester and the filtrates are concentrated. The raw product (15.97 g) is crystallized out of diisopropylether. 13.15 g of 4-hydroxymethyl-1-tosylindole with a m.p. of 125°-126° C. is obtained.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3[C:19](=[O:21])[CH3:20])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+:23]>C(Cl)Cl.CO.O>[C:19]([N:15]1[CH2:14][C@@H:13]2[CH2:18][C@H:16]1[CH2:17][N:12]2[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O-:4])=[CH:10][CH:9]=1)(=[O:21])[CH3:20].[Na+:23]
Reactant: CC(=O)Oc1ccc(CN2C[C@@H]3C[C@H]2CN3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc([O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 4-{[(1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenyl acetate (2.33 g, 8.08 mmol, 1 equiv.) in CH2Cl2 (12.1 mL) and MeOH (8.1 mL) was added a solution of NaOH (0.323 g, 8.08 mmol, 1 equiv.) in water (4.1 mL). The solution was stirred at rt for 3 h. The reaction mixture was concentrated to afford product as an off-white solid (100%). 1H NMR (500 MHz, CD3OD): 7.01 (dd, J=8.8, 2.7, 2H), 6.61 (d, J=8.2, 2H), 4.63 (s, 0.5H), 4.41 (s, 0.5H), 3.63-3.53 (m, 4H), 3.35 (s, 3H), 3.28 (m, 0.5H), 3.19 (d, J=11.5, 0.5H), 2.91 (dd, J=10.3, 2.1, 0.5H), 2.82 (dd, J=10.2, 2.2, 0.5H), 2.67 (m, 1H), 1.94 (m, 1H), 1.76 (d, J=9.9, 0.5H), 1.66 (d, J=9.9, 0.5H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[CH:4][CH:3]=1.[CH2:30]([NH2:32])[CH3:31].CO>>[ClH:1].[CH2:30]([NH:32][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[CH:6][N:7]=1)[CH3:31]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(Cl)nc1
Reactant: CCN
Solvent: CO
Product: CCNc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)cn1
Product: Cl
Temperature: 120 °C

Procedure:
(2S)-1-[(6-Chloro-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 26) (67 mg, 0.15 mmol) was weighed into a microwave vial, and treated with ethylamine, 2.0M in methanol (1.5 ml, 3.0 mmol). The clear solution was heated in the microwave to 120° C. for 18 h with stirring. LCMS analysis showed complete conversion. The reaction mixture was concentrated to give the crude material as a yellow gum (76 mg). This was purified by MDAP to give the free base of the title compound as a colourless gum (59 mg).
Reaction SMILES: [F-:1].C([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])CCCC)CCC.Cl.[C:20](#N)[CH3:21]>>[CH2:18]1[C:17]2[C:16](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2([CH2:21][CH2:20][F:1])[NH:6][CH:11]1[C:12]1[C:13]2=[CH:14][CH:17]=[CH:16][CH:15]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC#N
Reactant: [F-]
Agent: Cl
Product: FCCC12NC(Cc3ccccc31)c1ccccc12
Yield: 48 %

Procedure:
A 154 mg (0.31 mmol) sample of product from Step B was heated at 65° C. for 20 minutes in 3.0 mL of a 0.21M solution of tetra-n-butylammonium fluoride in acetonitrile, followed by treatment with 4.0 mL of 3.0M HCl at 65° C. for 15 minutes. The reaction mixture was washed with two portions of CHCl3, basified to pH 12 with 2.0M NaOH and extracted with two portions of CHCl3. The combined extracts were washed with water, dried over Na2SO4, and evaporated at reduced pressure to provide an oil which was chromatographed on silica gel using 98:2:0.2 CHCl3 --CH3OH--NH4OH and crystallized from hexanes to give 38 mg (48%) of the title compound as colorless crystals. 1H NMR,
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:11](=O)[CH3:12])[CH2:10][CH2:9][CH2:8]2)[CH:2]=1.[CH3:14][C:15]1[N:16]=[C:17]([C:23]2S[CH:25]=[CH:26][CH:27]=2)S[C:19]=1[C:20](=O)[CH3:21].[NH3:28]>>[CH3:14][C@@H:15]1[CH2:19][CH2:20][CH2:21][N:16]1[CH2:17][CH2:23][C:27]1[CH:2]=[C:3]2[C:7](=[CH:25][CH:26]=1)[N:28]=[C:11]([C:7]1([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:10][CH2:9][CH2:8]1)[CH:12]=[CH:4]2
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Reactant: CC(=O)C1(c2cccnc2)CCC1
Reactant: N
Product: C[C@@H]1CCCN1CCc1ccc2nc(C3(c4cccnc4)CCC3)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G using 1-(1-pyridin-3-yl-cyclobutyl)-ethanone for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CDCl3) δ 1.12 (d, J=6.10 Hz, 3H), 1.46 (m, 1H), 1.75 (m, 2H), 1.92 (m, 1H), 2.05 (m, 2H), 2.23 (q, J=8.82 Hz, 1H), 2.37 (m, 2H), 2.77 (m, 2H), 2.94-3.22 (m, 5H), 3.28 (m, 1H), 7.17 (m, 1H), 7.19 (m, 1H), 7.56 (s, 1H), 7.58 (dd, J=8.48, 2.03 Hz, 1H), 7.65 (ddd, J=8.05, 2.46, 1.70 Hz, 1H), 7.95 (d, J=8.81 Hz, 1H), 8.04 (d, J=8.48 Hz, 1H), 8.41 (dd, J=4.75, 1.70 Hz, 1H), 8.70 (dd, J=2.37, 0.68 Hz, 1H); MS (DCI-NH3) [M+H]+ at 372.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][C:36](Cl)=[O:37].CCOCC>ClCCl>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]([C:36](=[O:37])[CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)[C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccs1)C1C(=O)N(Cc2ccccc2)C(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 70.8 %

Procedure:
To a solution of 1,3-dibenzylbarbituric acid 154 mg (0.500 mmol) in dry dichloromethane 2.0 mL under a nitrogen atmosphere, added was pyridine 1.0 mL (12 mmol) and stirred at 0° C. Added was 2-thienylacetyl chloride 80 mg (0.50 mmol, 1.00 equivalent) in dichloromethane 1.0 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 3 hours. Added was ether 50 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 216 mg after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-dibenzyl-5-(2-thienylacetyl)barbituric acid 153 mg as yellow viscous oil (56.9% yield).