Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH2:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:18]([N:29]3[C:33](=[O:34])[CH:32]=[CH:31][C:30]3=[O:35])=[CH:17][N:16]=2)[CH:8]=[CH:7][C:6]=1[N+:36]([O-:38])=[O:37]>>[NH2:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:18]([N:29]3[C:33](=[O:34])[CH2:32][CH:31]([N:2]([CH3:3])[CH3:1])[C:30]3=[O:35])=[CH:17][N:16]=2)[CH:8]=[CH:7][C:6]=1[N+:36]([O-:38])=[O:37]
Reactant: Nc1nc(NCCNc2ncc(N3C(=O)C=CC3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: CNC
Product: CN(C)C1CC(=O)N(c2cnc(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc2-c2ccc(Cl)cc2Cl)C1=O

Procedure:
A large excess of dimethylamine was added to clean fractions of 1-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)4-(2,4-dichlorophenyl)pyrimidin-5-yl]-3-pyrroline-2,5-dione concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH:32]([CH3:34])[CH3:33])[C:22]=1[O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH:18]=O)([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:18][C:17]1[CH:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:21]([CH:32]([CH3:34])[CH3:33])[CH:20]=1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc(C(C)C)c1OCCN1CCOCC1

Procedure:
5-Chloro-2-oxindole was condensed with 3,5-diisopropyl-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde using method B to give 5-chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a brownish-orange solid which was reduced using method E to give 1.3 g (100%) of 5-chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzyl]-1,3-dihydroindol-2-one as a yellow/orange foam.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)(Cl)Cl>[CH2:8]([C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCBr
Reactant: Brc1ccsc1
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccsc1
Reaction time: 2 h

Procedure:
3-Hexylthiophene was synthesized by coupling the Grignard reagent of 3-bromothiophene with 1-bromohexane using bis(1,3-diphenylphosphino)propane nickel(II)chloride as catalyst. The product was purified by fractional distillation under reduced pressure. Polymerization of the monomer was achieved by mixing a 0.1M solution of 3-hexylthiophene in chloroform with a 0.4M chloroform solution of anhydrous ferric chloride. The mixture was stirred for two hours prior to precipitation into acidified methanol. The solid product was filtered, washed with NH4OH, water and methanol. The crude polymer was dissolved in hot dichloromethane and insoluble products were removed by filtration. Low molecular products were removed by cooling the filtrate and adding methanol. The precipitate was filtered and dried in a vacuum oven. The polymer possessed IR bands at 3027, 2930, 2859, 1458, 819, and 725 cm-1. The polymer had a number-average molecular weight of 9300 and a polydispersity index of 2.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:29]1[CH2:30][CH2:31][N:26]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH2:27][CH:28]=1)([O-:3])=[O:2]
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C(c1ccccc1)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.77 mL, 9.250 mmol), 1-benzoyl-4-piperidone (1.0 g, 4.933 mmol) at room temperature and resulting solution was refluxed for 3 days. The reaction cooled to room temperature and the solid was filtered off. The product was washed with cold ethanol (2×10 mL) and dried under vacuum to obtain compound 68 (1.05 g, 98%) as a solid. mp 280-282° C.; 1H NMR (DMSO-d6) δ 2.55-2.61 (m, 2H), 3.54-3.58 (m, 1H), 3.86-3.90 (m, 1H), 4.15-4.34 (m, 2H), 6.14-6.30 (m, 1H), 7.39-7.55 (m, 5H), 7.67 (d, 1H, J=9.6 Hz), 7.72 (s, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70-8.78 (m, 1H), 11.94 (s, 1H); ESI-MS m/z (%): 348 (M+, 100), 276 (83), 244 (40).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[N:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30]([CH3:34])([CH3:33])[CH2:31][NH2:32])[N:29]=2)=[CH:21][CH:20]=1.[ClH:35]>O1CCOCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[O:7][N:6]=4)[CH:9]=3)[N:29]=2)=[CH:23][CH:24]=1.[ClH:35].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[O:26][CH:27]=[C:28]([C:30]([CH3:34])([CH3:33])[CH2:31][NH:32][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([C:5]4[N:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[O:7][N:6]=4)[CH:9]=3)[N:29]=2)=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(CNCc1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2-(4-Chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine was synthesized from 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzaldehyde and 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methylpropan-1-amine as described in example 7 step 3. The free amine was then treated with HCl in dioxane (2 M) at 0° C. and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The crude was purified by washing with dry hexane to get 2-(2-(4-chlorophenyl)oxazol-4-yl)-2-methyl-N-(3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzyl)propan-1-amine hydrochloride (20 mg, yield 6%). 1H NMR (400 MHz, DMSO-d6) δ 8.87 (br s, 2H), 8.26 (s, 1H), 8.11-8.08 (m, 2H), 7.85-7.80 (m, 3H), 7.69-7.65 (t, J=7.6 Hz, 1H), 7.55-7.52 (d, J=8.5 Hz, 2H), 4.28 (br s, 2H), 3.12 (m, 2H), 1.33 (s, 6H). MS (ESI) m/z: Calculated for C23H20ClF3N4O2: 476.12. found: 477.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)c(I)cc1OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzoic acid (reference example 5-1) (2 g), 2-iodoethane (0.5 mL), potassium carbonate (1.08 g) and N,N-dimethylformamide (17 mL) was stirred at room temperature for 2 hours. Water was added to the mixture. Insoluble materials were collected by filtration to give the title compound (2.07 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:32][CH:31]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=2)[CH2:12][C:13]2[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=2)[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH:19]=2)=[O:17])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)Cc1ccc(C(Cc2cccc(C(=O)c3c[nH]c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 20 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A mixture of 3-[3-[2,2-bis(4-isobutylphenyl)ethyl]-benzoyl]indole (442 mg), ethyl 4-bromobutyrate (185 mg) and potassium carbonate (360 mg) in N,N-dimethylformamide (10 ml) was stirred at 20° C. for 4 hours. Ethyl 4-bromobutyrate (185 mg) and potassium carbonate (120 mg) were added, and resulting mixture was stirred at 20° C. for 16 hours. The reaction mixture was poured into a mixture of ethyl acetate and 1N-hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (20 g) eluting with a mixture of hexane and ethyl acetate (10:1) to give ethyl 4-[3-[3-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indol-1-yl]butyrate (480 mg) as an oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[NH:16][C:15]([CH2:17][CH2:18][CH3:19])=[N:14][C:13]=1[C:20]([OH:23])([CH3:22])[CH3:21])=[O:11])[CH3:8].[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>C(#N)C>[CH2:7]([O:9][C:10]([C:12]1[N:16]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([Br:24])=[CH:26][CH:27]=2)[C:15]([CH2:17][CH2:18][CH3:19])=[N:14][C:13]=1[C:20]([OH:23])([CH3:21])[CH3:22])=[O:11])[CH3:8]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
The mixture of 240 ml acetonitrile, 20.7 g (150 mmol) of K2CO3, 18 g (75 mmol) of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate and 20.4 g (81.6 mmol) of 4-bromobenzylbromide was heated under reflux temperature for 7 h. The suspension is cooled, filtered and concentrated under reduced pressure to approximately ⅓ of the starting volume and stirred at about 0° C. for 1 h. The precipitate is filtered and dried at 35° C. for 1 h and afterwards suspended in 218 ml of water. The mixture is stirred for 2 h, filtered and dried again. 21.56 g of the crude product were isolated. Crude product was recrystallized from acetonitrile (87%, 55% of the synthesis)
Reaction SMILES: [SH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10](=[N:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1C)[O-].[CH3:20]O>>[CH3:20][N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3])[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CO
Reactant: Cc1ccccc1N=[N+]([O-])c1ccccc1C
Agent: [Na+]
Agent: [SH-]
Product: Cc1ccccc1N(C)Nc1ccccc1
Temperature: 75 °C
Yield: 84 %

Procedure:
90 Parts of an aqueous solution of technical sodium hydrosulfide (35 percent NaHS, 10 percent Na2S2O3) were added to a mixture of 45.2 parts of 2,2'-dimethylazoxybenzene in 150 parts methanol at 70° C to 75° C. Subsequently, the reaction mixture was refluxed at 75° C for 4 hours with pH kept between 9 and 9.4. Thereafter, the reaction mixture was cooled down to 0° C to 5° C, and the resulting precipitate filtered off and washed with water until alkali-free. The press-cake was dried below 70° C. There were obtained 35.6 parts of 2,2'-dimethylhydrazobenzene of a melting point of 162° C to 164° C, this representing a yield of 84 percent of the theory, of acceptable purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[ClH:41].O1CCOCC1>C(Cl)Cl>[ClH:41].[CH2:1]([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=3)=[CH:16][C:15]=2[CH2:29][NH:30][CH2:31][CH3:32])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(OCC)nc3)cc2CN(CC)C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCNCc1cc(-c2ccc(OCC)nc2)ccc1-c1cc(CC(=O)OCC)ccc1OC

Procedure:
[2′-[(tert-Butoxycarbonyl-ethyl-amino)-methyl]-4′-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester (1.09 g, 2.0 mmol) in CH2Cl2 (10 mL) was treated with 4N HCl in 1,4-dioxane (6 mL, 24.0 mmol) at room temperature, until complete conversion was seen by analytical LCMS. The mixture was concentrated to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:20][C:21](N1C=CC=CC1=O)=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:21]([O:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])[C:6]([OH:8])=[O:7]
Reactant: CCCCCCOC(=O)n1ccccc1=O
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a stirred mixture of D-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing hexyl-2-pyridyl-carbonate and hexyl-2-oxopyridine-1-carboxylate (0.45 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.27 g, 88%) as transparent oil, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 0.83-0.90 (m, 3H), 1.08 (d, J=6.3 Hz, 3H), 1.21-1.36 (m, 6H), 1.49-1.59 (m, 2H), 3.89-3.99 (m, 3H), 4.01-4.11 (m, 1H), 6.67 (d, J=9.0 Hz, 1H), 12.30 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Product: CCOC(=O)COc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
4-amino phenol (500 mg, 4.58 mmol) was suspended in acetonitrile (60 mL), the mixture cooled to 0° C. and ethyl 2-bromoacetate (0.53 mL, 4.81 mmol) added. CsCO3 (1.9 g, 10 mmol) was added in portions and the mixture stirred for 16 h, allowing to warm to RT. The mixture was filtered, the residue washed with acetonitrile and the filtrate evaporated to dryness. The crude product was suspended in DCM (˜30 mL), filtered and this filtrate evaporated to dryness to afford ethyl 2-(4-aminophenoxy)acetate (860 mg) as a dark oil that solidified on standing. 1H NMR (400 MHz, CDCl3) δ 6.79-6.74 (m, 2H), 6.66-6.60 (m, 2H), 4.53 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C1C=CC2N(O)N=NC=2C=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][C:29]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)=[O:30])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(Cl)c1)Nc1ccc2[nH]ncc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 5-aminoindazole (1 mmol), HOBt (1 mmol) and 3-chlorophenylacetic acid (1.1 mmol) in DMF (4 mL) was added N-methylmorpholine (1.1 mmol). After stirring for 10 minutes, EDC-HCl (1.1 mmol) was added and the reaction mixture stirred overnight at ambient temperature. The reaction mixture was concentrated and the residue purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100A column, gradient 10%–100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to afford compound I-6 (79 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 3.68 (2H, s), 7.12–7.73 (6H, m), 8.00 (1H, s), 8.11 (1H, s), 10.10 (1H, s), 12.97 (1H, bs); MS (ES+): m/e=(M+H) 286.
Reaction SMILES: [OH:1][C@@H:2]1[C:19]2[C@:14]([CH3:23])([CH2:15][CH2:16][C:17](=[O:22])[C:18]=2[CH2:20][CH3:21])[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([O:24][C:25](=[O:27])[CH3:26])[CH2:7][CH2:6]3)[CH2:3]1.O[C@H]1C2[C@](C)(CCC(=O)C=2CC)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)[C@@H](OC(=O)C)CC3)C1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(Cl)Cl>CC(C)=O>[C:25]([O:24][C@H:8]1[CH2:7][CH2:6][C@H:5]2[C@H:4]3[C@H:13]([CH2:12][CH2:11][C@:9]12[CH3:10])[C@:14]1([CH3:23])[C:19](=[C:18]([CH2:20][CH3:21])[C:17](=[O:22])[CH2:16][CH2:15]1)[C:2](=[O:1])[CH2:3]3)(=[O:27])[CH3:26]
Reactant: CCC1=C2[C@@H](O)C[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Agent: O=[Cr](=O)=O
Agent: CCC1=C2[C@H](O)C[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCC1=C2C(=O)C[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Yield: 92 %

Procedure:
To a solution of a 6α-hydroxy-17β-acetoxy-4-ethylandrost-4-en-3-one and 6β-hydroxy-17β-acetoxy-4-ethylandrost-4-en-3-one (510 mg) in acetone (34 ml) cooled at 0° C., Jones reagent (1.1 ml) was added dropwise. 5 min after completion of the addition, DCM (140 ml) was added and the mixture was washed with 10% Na2SO3 aqueous solution, 5% aqueous NaHCO3 solution, and brine. The organic phase was dried over Na2SO4, and evaporated to dryness to give 17β-acetoxy-4-ethylandrost-4-en-3,6-dione (465 g, 92%).
Reaction SMILES: C(O[CH:5]1[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([NH:36][C:37](=[O:39])[CH3:38])[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.Cl.C([Cl:44])(=O)C>O1CCOCC1>[C:37]([NH:36][C@H:15]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][C@H:5]([Cl:44])[C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: CC(=O)N[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(OC(C)=O)[C@@H]1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@@H](Cl)O[C@H](COCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 16 h

Procedure:
Dissolve 1.5 g. of 3-acetamido-3-deoxy-2,4,6-tri-O-benzyl-D-galactopyranosyl acetate in 75 ml. of dioxane containing 4% by weight of hydrogen chloride and add 35 ml. of acetyl chloride to the solution. Allow the mixture to stand in a dry nitrogen atmosphere for 16 hours at 40°. Evaporate the mixture to dryness in vacuo to a syrup. Repeatedly co-distil this residue with dry toluene until all hydrogen chloride is removed. Crystallize the resultant residue with hexane to obtain the title product of this example. Yield 1.1 g., m.p. 158°-159° (decomp.), [α]D26 + 169.9°.
Reaction SMILES: [CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.ClC(=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH:1]1([C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10](=[O:12])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCC(NC(=O)C1CCCC1)C(=O)O
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)C(CC)NC(=O)C1CCCC1
Temperature: 25 °C

Procedure:
1.6 g (8 mmol) 2-[(cyclopentylcarbonyl)amino]butanoic acid are suspended in 30 ml tetrahydrofuran and heated to reflux together with 1.91 g (24 mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating at reflux, 2.19 g (16 mmol) ethyl chloro(oxo)acetate are added dropwise. The reaction mixture is heated at reflux until no more evolution of gas can be observed. After cooling down to room temperature, the reaction mixture is added to ice water and the organic phase extracted with ethyl acetate. The dried organic phase is evaporated to dryness in vacuo, dissolved in ethanol and the solution directly used for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24]([O:32][CH3:33])(=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([O-])=[O:29]>>[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:29])[CH2:27][CH2:26][CH2:25][C:24]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: COC(=O)CCCC(=O)[O-]
Product: COC(=O)CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and mono-methyl glutarate to yield (3aR,4S,7aR)-1-(methoxycarbonyl)-4-(m-tolylethynyl)octahydro-1H-indol-4-yl methyl glutarate. MS [M+H]=296 (ester elimination ion); RT=1.26 min; UPLC Method I
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10](I)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].CN(C=O)C>C(#N)C>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH:24]=[CH2:25])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=Cc1c(OCc2ccccc2)ccn(Cc2ccccc2)c1=O
Temperature: 65 °C
Yield: 50 %

Procedure:
A solution of 1-benzyl-4-(benzyloxy)-3-iodopyridin-2 (1H)-one (1.9 g, 4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in acetonitrile (200 mL) containing DMF (2.0 mL) was degassed using house vacuum and purged with argon. Then added PdCl2(PPh3)2 (0.3 g) and the mixture was heated at 65° C. under argon atmosphere for 4 h, with stirring. The solvents were distilled in vacuo, and the residue was triturated with EtOAc and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes to give the title compound (0.75 g. 50%) as an orange colored solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C:26]1([CH2:30][C:31]([OH:33])=[O:32])[CH2:29][CH2:28][CH2:27]1.C[O-].[Na+].Cl>CC(N(C)C)=O.O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C:26]2([CH2:30][C:31]([OH:33])=[O:32])[CH2:29][CH2:28][CH2:27]2)=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NC1(CC(=O)O)CCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1nc(C(=O)NC2(CC(=O)O)CCC2)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 92.9 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (45 mg, 0.14 mmol) and (1-amino-cyclobutyl)-acetic acid (91 mg, 0.70 mmol) (APAC Pharmaceuticals LLC, Columbia Md.) in DMA (2 mL) was added NaOMe solid (38 mg, 0.70 mmol). The resultant mixture was heated in a 150° C. oil bath for 3 h. Reaction mixture was diluted with water and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo to provide the title compound 54 mg (0.13 mmol) in 92% yield. LC-MS ESI−: 416.17 (M−1)−.