Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(O)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(Cc1cccc(O)c1)CC2

Procedure:
The title compound was synthesized from methyl 6-(3-hydroxybenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (57 mg, 0.21 mmol) and lithium hydroxide (88 mg, 2.10 mmol in 1 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (2 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.04-2.16 (m, 1H) 2.36-2.53 (m, 3H) 2.55-2.64 (m, 1H) 2.96-3.04 (m, 1H) 3.31-3.37 (m, 1H) 6.57 (s, 1H) 6.59-6.67 (m, 3H) 7.04-7.11 (m, 1H). LCMS m/e 258 (M+H). Purity 92% (HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[S:6][C:7]([S:10]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)=[CH:17][CH:16]=3)[CH3:14])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1>C(O)=O>[NH:23]1[CH2:24][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[S:10]([C:7]3[S:6][C:5]4[CH:32]=[CH:33][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH3:9])(=[O:12])=[O:11])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: Cc1c(S(=O)(=O)N(C)c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)sc2ccc(Cl)cc12
Solvent: O=CO
Product: Cc1c(S(=O)(=O)N(C)c2ccc(C3CNC3)cc2)sc2ccc(Cl)cc12
Yield: 98.3 %

Procedure:
tert-Butyl 3-(4-(5-chloro-N,3-dimethylbenzo[b]thiophene-2-sulfonamido)phenyl)azetidine-1-carboxylate (185 mg, 0.36 mmol) was stirred in formic acid (3 ml) at 0° C. for 3.5 h. The solution was concentrated, dissolved in water, concentrated HCl was added and the solution was concentrated by lyophylisation to give the title compound (144 mg, 87%) as a white foam.
Reaction SMILES: C([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][C:20]4([C:27](=[O:29])N)[CH2:21][CH:22]([CH2:26][CH:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=[O:7])(C)(C)C.[OH-:30].[Na+]>C1COCC1.CO>[CH2:17]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]2[CH:24]3[CH2:25][C:20]4([C:27]([OH:30])=[O:29])[CH2:21][CH:22]([CH2:26][C@@H:18]2[CH2:19]4)[CH2:23]3)=[O:15])[CH2:10]1)=[O:7])[CH:18]([CH3:26])[CH3:19]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OC2C3CC4CC2CC(C(N)=O)(C4)C3)C1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)COC(=O)NC1CCN(C(=O)OC2C3CC4C[C@@H]2CC(C(=O)O)(C4)C3)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (3R) (1-(methoxycarbonyl)-4-adamantyl) 3-(isobutoxycarbonylamino)pyrrolidine-1-carboxylate (130 mg, 0.28 mmol) in THF (5 mL) and MeOH (10 mL) was added 5% aq NaOH (5 mL). The mixture was stirred at rt for 3 d. The mixture was concentrated under reduced pressure, diluted with water (15 mL) and washed with ether (80 mL). The aqueous layer was diluted with 10% aq citric acid (30 mL) and extracted with EtOAc (3×40 mL). The combined organic extracts were dried over MgSO4 and concentrated to leave (3R)-4-(3-(isobutoxycarbonylamino)pyrrolidine-1-carbonyloxy)adamantane-1-carboxylic acid (178 mg) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([O:18][C:19]2[CH:34]=[CH:33][C:22]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:33][CH:34]=2)=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(=O)Oc1ccc(C(=O)OCc3ccccc3)cc1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(=O)Oc1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 430 mg (0.94 mmol) of benzyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthoyloxy)benzoate, 60 mg of 10% palladium on carbon and 6 ml of ethyl acetate was stirred under a hydrogen atmosphere at room temperature for 3 hours. A further 6 ml of ethyl acetate was then added to the reaction mixture and mixture heated at 50° C. for 3 hours. The reaction mixture was then cooled, filtered through celite and the residue washed with 5 ml of warm ethyl acetate. The filtrate was then concentrated in-vacuo and the resultant residue recrystallized from a mixture of ethyl acetate and hexanes to give the title compound as a white, crystalline solid. PMR (CDCl3): δ 1.32 (6H, s), 1.34 (6H, s), 1.72 (4H, s), 2.62 (3H, s), 7.24 (1H, s), 7.32 (2H, d, J~8.2 Hz), 8.13 (1H, s), 8.20 (2H, d, J~8.2 Hz).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[O:9][N:8]=1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)O)on1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (209 mg, 0.66 mmol) in dioxane (5 mL) was added aqueous sodium hydroxide (2 N, 2 mL). After heating at reflux for 1 h the mixture was cooled to room temperature and acidified with HCl (4 N, 2 mL). Purification by filtration and drying afforded the title compound (187 mg, 94%) which was obtained as a white solid. MS: m/e=299.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5][C:6]=1[C:7]([O:9]C)=[O:8].O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1sc(NC(=O)c2ccccc2)nc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To a solution of methyl 4-amino-2-benzamidothiazole-5-carboxylate (0.16 g, 0.57 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.007 g, 1.60 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and adjusted to pH 5˜6 with 5% hydrochloric acid. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic extract was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (0.14 g, 88%); MS (ES+) m/z 263.4 (M+1).
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:15]1([C:25]([OH:27])=[O:26])[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:7]2.[Li]CCCC.[Sn:33](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH2:36][CH3:37].O>C1COCC1>[CH2:42]([Sn:33]([CH2:34][CH2:35][CH2:36][CH3:37])([CH2:38][CH2:39][CH2:40][CH3:41])[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:15]1([C:25]([OH:27])=[O:26])[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:7]2)[CH2:43][CH2:44][CH3:45]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)N1CCNCC1(C(=O)O)c1ccc2c(Br)c([N+](=O)[O-])ccc2n1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c([N+](=O)[O-])ccc2nc(C3(C(=O)O)CNCCN3C(C)(C)C)ccc12
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To a -100° C. solution of 15 (200 mg, 0.46 mmol) in dry THF (8 ml) was added nBuLi (1.6M, 0.50 mmol, 0.31 ml) dropwise. The resulting black-green solution was stirred for 10 min. at which time Bu3SnCl (0.15 ml, 0.54 mmol) was added neat. The solution was allowed to reach room temperature and stirred 2 h. Water was added and the mixture was extracted with ether. The combined ether extracts were dried (MgSO4) and concentrated to a brown oil. HPLC purification of the oil (Whatman Partisil 10 column, 90:10 CH2Cl2 :EtOAc) afforded the tributylstannyl derivative 16 (150 mg, 50%). 1H NMR d (ppm): 0.85 t (CH3), 1.15-1.55 m (3 CH2), 1.49 s (3 CH3), 3.58 dd (CH2), 3.83 dd (CH2), 7.00 d (CH arom), 7.63 d (CH arom), 8.18 d (CH arom), 8.30 d (CH arom).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=O)C.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:4]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[C:15]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[N:16][O:17][C:18]=3[CH2:19][OH:20])=[CH:8][N:7]=2)=[O:3])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Product: O=C(NC1CC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reaction time: 8 h
Yield: 26 %

Procedure:
As described for example 29e, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) was converted, at 85° C. overnight, using cyclopropylamine instead of isopropylamine, to the title compound (20 mg, 26%), which was obtained as a colourless gum. MS: m/e=384.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][N:11]([CH3:13])[CH3:12])=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])[N:11]([CH3:13])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NN(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: ClCCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)N(C)C
Reaction time: 1.5 h
Yield: 5.3 %

Procedure:
To a solution of 3-(N′,N′-Dimethyl-hydrazino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.200 g, 0.72 mmol) in 1,2-dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichloro-benzoyl chloride (0.228 g, 1.08 mmol). The reaction mixture was stirred for 1.5 h at reflux. Then, the solvents were removed and the residue was purified by preparative tlc (8:2 Hexane/EtOAc) to obtain 0.017 g (5%) of 3-[N-(2,4-Dichloro-benzoyl)-N′,N′-dimethyl-hydrazino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): δ 7.62 (m, 2H), 7.40 (m, 3H), 7.23 (d, 1H), 3.87 (s, 3H), 2.52 (s, 6H).
Reaction SMILES: Br[C:2]1[C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:4][N:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH3:39])C=CC=C[CH:34]=1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:5]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:4]=[C:3]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:2]=2[CH:39]2[CH2:33][CH2:34]2)=[CH:8][CH:9]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C1CC1
Yield: 44 %

Procedure:
To a solution of ethyl 4-bromo-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (68) (500 mg, 1.1 mmol) in aqueous toluene, tetrakis(triphenylphsophine)palladium (122 mg, 0.11 mmol) and potassium carbonate (510 mg, 3.9 mmol) were added. The reaction mixture was placed under microwave irradiation with the temperature set to 140° C. The resulting solution was filtered with syringe filter, and then solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography to obtain the title compound (283 mg, 44%) as white solid.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:33]=[CH:34][C:35]=1[O:36][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1Cl
Agent: Cl
Product: COC(=O)[C@H](C)Oc1ccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[F:16][C:17]1[C:25]2[CH:24]=[C:23]([CH2:26]O)[S:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([O:14][CH2:26][C:23]2[S:22][C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[C:25]=3[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: OCc1cc2c(F)cccc2s1
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2cc3c(F)cccc3s2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred suspension of 3-hydroxyphthalic acid dimethyl ester (1.1 g, 5.2 mmol), (4-fluoro-benzo[b]thiophen-2-yl)-methanol (0.96 g, 10.5 mmol), and polymer-supported triphenyl phosphine (3.0 g, 10.5 mmol) in THF (35 mL) in an ice-bath was slowly added diisopropyl azodicarboxylate (2.1 mL, 10.5 mmol) and stirred at r.t. overnight. The mixture was filtered and the solid was washed with ethyl acetate (10 mL). The filtrate was evaporated and the residue was purified by flash column chromatography (EtOAc/Hexane) to give 3-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (1.5 g, 76% yield). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33]CC3C=CC=CC=3)=[CH:29][CH:28]=2)[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:8]([C:27]2[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=2)[N:9]2[C:14]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10% Pd/C was added to a solution of 37 in 95% EtOH (20 mL). The reaction mixture was stirred at ambient temperature under a H2 atmosphere for 24 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting residue was triturated in 1:1 Et2O/hexane and the precipitate was collected by vacuum filtration to provide the title compound as an off-white solid. 1H NMR (DMSO-d6) δ 0.85 (t, J=7.1 Hz, 3H), 1.07 (t, J=7.1 Hz, 3H), 3.38 (m, 4H), 3.51 (q, J=7.2 Hz, 2H), 3.66 (m, 4H), 4.06 (q, J=7.1 Hz, 2H), 6.83 (m, 3H), 7.40-7.49 (m, 7H), 9.67 (s, 1H). Mass Spectrum (ESI+) m/e=516.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.O[CH2:18][CH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:29]([O:28][C:27]([NH:26][C:24]1[N:25]=[C:20]([CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)[CH:21]=[CH:22][CH:23]=1)=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCO)n1
Reactant: COC(=O)CC(C)(C)Cc1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CC(C)(C)Cc1ccc(OCCc2cccc(NC(=O)OC(C)(C)C)n2)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the product of STEP 4 (0.45 g), the product of STEP 6 (0.723 g), triphenyl phosphine (0.80 g, Aldrich) in THF (10 mL) at −78° C. was added diisopropyl azodicarboxylate (Aldrich, 0.63 mL) over 3 minutes. The mixture was stirred at −78° C. for 3 hours and at 22° C. for 16 hours. The mixture was concentrated in vacuo and the residue was chromatographed over silica gel using 20% ethyl acetate in hexane as eluant. The fractions containing the desired product were pooled and concentrated to provide the above product as a thick gum.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH-].[Na+]>[Pd].CO>[NH2:11][C:8]1[CH:9]=[CH:10][CH:2]=[C:3]2[C:7]=1[NH:6][CH:5]=[CH:4]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2cc[nH]c12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc2cc[nH]c12
Reaction time: 2 h
Yield: 43 %

Procedure:
To a slurry of 1.96 g. of 4-chloro-7-nitroindole in 100 ml. of methanol containing 400 mg. of sodium hydroxide in a 500-ml. Parr bottle was added 196 mg. of 10% palladium on charcoal. The suspension was shaken for 21/2 hours under an initial hydrogen pressure of 3 atmospheres (absorption ceased after 11/2 hours). The catalyst was removed by filtration and the pale yellow solution was evaporated on a rotary evaporator under reduced pressure. The residue was partitioned between 75 ml. of toluene and 35 ml. of water, and the toluene layer washed with 35 ml. of water. The water phases were then extracted with three 75 ml. portions of chloroform. The toluene and chloroform extracts were evaporated to give 950 mg. and 420 mg. respectively, of greyish crystals. On sublimation on the steambath at 0.08 mm., 567 mg. (43%) of 7-aminoindole having a melting point of 98°-99° was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.S(=O)(=O)(O)O.[N+:15]([O-:18])([OH:17])=[O:16]>>[N+:15]([O-:18])([OH:17])=[O:16].[N+:15]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH2:3][NH:2][CH2:1]2)([O-:17])=[O:16]
Reactant: c1ccc2c(c1)CNC2
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc2c(c1)CNC2
Reaction time: 1 h
Yield: 46 %

Procedure:
Isoindoline (4 g, 33.1 mmol) was added to 95%. sulphuric acid, the reaction was treated carefully with fuming nitric acid (2.2 ml) at 0° C. and stirred for 1 hour, then the mixture was poured onto ice and the resulting precipitate was collected by filtration and dried in vacuo to afford the title compound (4.1 g, 46%); 1H NMR (DMSO-d6) 8.35 (1H, s), 8.35 (1H, d, 8.4 Hz), 7.70 (1H, d, 8.4 Hz), 4.64 (4H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]=2[C:10](=O)[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH3:17])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1n[nH]c2c1C(=O)CC(c1ccccc1O)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1O)C2
Yield: 108.5 %

Procedure:
A mixture of 6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.04 g), aminoguanidine hydrochloride (0.02 g), concentrated hydrochloric acid (0.041 ml), water (0.041 ml) and ethanol (10 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 4-guanidinoimino-6-(2-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 26) (0.06 g) as colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[SH:11].[Br-].[Na+]>[O-]CC.[Na+]>[CH2:2]([S:11][C:7]1[S:6][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCBr
Reactant: Sc1cccs1
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Product: CCCCSc1cccs1
Temperature: 80 °C

Procedure:
1-Bromobutane (32.76 g, 0.239 mol) was added dropwise to a stirred solution of compound 5 (13.87 g, 0.120 mol) in sodium ethoxide (2.75 g of sodium metal in 100 ml of super-dry ethanol) at room temperature. The solution was heated at 80° C. for 2 h (glc and tlc analysis revealed a complete reaction) and the sodium bromide was filtered off. The solvent was removed in vacuo and the residue was distilled to give a colourless liquid.
Reaction SMILES: CO[CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([O:16][S:17]([C:20]3[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5].[CH:27]([NH:30][CH2:31][CH2:32][NH2:33])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH:3]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:21]=[CH:22][C:23]([NH:33][CH2:32][CH2:31][NH:30][CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:12][CH2:10][CH2:9][CH2:15]1
Reactant: COCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)NCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)NCCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CCCC4)sc3c2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-(2-methoxyacetylamino)-benzothiazol-6-yl ester (intermediate 68) (90 mg, 0.214 mmol), N-isopropylethylenediamine (65.6 mg, 0.642 mmol) and cesium carbonate (69.7 mg, 0.214 mmol) in 2 ml of dimethyl sulfoxide in a test tube, equipped with a magnetic bar, is stirred overnight at 80° C. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is then washed with water, dried over magnesium sulfate and evaporated. The residue, purified by LC/MS, gives 26.2 mg of 4-(2-isopropylaminoethylamino)benzenesulfonic acid 2-(cyclopentanecarbonyl-amino)benzothiazol-6-yl ester (white powder) in a yield of 24%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1Br
Temperature: 100 °C
Reaction time: 5 h

Procedure:
The procedure described in R. K. Bentley and F. G. Holliman, J. Chem. Soc. (c), 2447 (1970) was used. A mixture of 2,5-dibromobenzoic acid (50 g, 0.18 mol) in concentrated sulfuric acid was vigorously stirred as fuming nitric acid (62.5 mL) was added dropwise at a rate to keep the temperature below 70° C. The reaction mixture was vigorously stirred, heated to 100° C. and then kept at 100° C. for 5 hours. The cooled reaction was cautiously poured into 2 liters of ice and vigorously stirred, the precipitate was filtered through a sintered glass funnel and the solid was washed well with water. Crystallization was achieved by dissolving the solid in acetic acid (150 mL) and after concentration to a half of the volume, crystals separated (16.72 g); mp 225-229° C. An additional crop of 7.52 g was obtained to give a total yield of 24.24 g (41%).