Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=1
Reactant: CCCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCCNC(=O)c1ccc(N)cc1
Yield: 74 %

Procedure:
A solution of 4-nitro-N-propylbenzamide (1.00 g, 4.80 mmoles) in MeOH (25 ml) was hydrogenated in the presence of a 5% palladium-on-charcoal catalyst at about 25° and atmospheric pressure. The catalyst was removed by filtration, and the filtrate was evaporated to dryness in vacuo to give 4-amino-N-propylbenzamide as a gummy residue; yiel 836 mg. This product was dissolved in DMAC (10 ml) containing I (504 mg, 1.50 mmoles), and the whole was stirred at room temperature for 72 hrs. The precipitate of the product was collected by filtration, washed with Et2O and dried in vacuo over P2O5 ; yield 74% (482 mg), mp > 340° (Mel-Temp). This sample was homogeneous on tlc (5:1 CHCl3 -MeOH). Anal. Calcd for C17H20N8O.HBr: C, 47.12; H, 4.88; N, 25.86. Found: C, 47.10; H, 5.18; N, 25.55. Spectral data: λ max, nm (ε × 10-3), 0.1 N HCl, 244 (18.5), 284 (18.3), 337 (10.5), 345 (sh) (9.70); pH 7, 261 (26.9). 279 (24.2), 371 (7.65); 0.1 N NaOH, 261 (27.1), 279 (24.2), 371 (7.73); δ 0.96 (t, 3, CH3), 1.50 (m, 2, CH2CH3), 3.17 (m, 2, NHCH2CH2), 4.62 (s, 2, CH2N), 7.23 (m, 4, C6H4), 8.07 (m, 1, NHCO), 8.87 (s, 1, C7 --H), 9.35 (NH). Some of the NH2 peaks were too broad to locate but are observed in the integral.
Reaction SMILES: [CH2:1]([C:14]([OH:16])=[O:15])[CH:2]([C:11]([OH:13])=[O:12])[CH:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>>[CH2:28]([O:6][C:5]([CH2:4][CH:3]([C:8]([OH:10])=[O:9])[CH:2]([C:11]([OH:13])=[O:12])[CH2:1][C:14]([OH:16])=[O:15])=[O:7])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: O=C(O)CC(C(=O)O)C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCOC(=O)CC(C(=O)O)C(CC(=O)O)C(=O)O

Procedure:
A blend of 1,2,3,4-butane tetracarboxylic acid (28.5 g., 0.121 mole), dodecyl alcohol (21.8 grams, 0.118 mole), p-toluenesulfonic acid (0.1 gram, 0.6 mole) and 300 ml. (3.4 moles) of dioxane was placed in a Soxhlet apparatus containing 4A molecular sieve. The mixture was brought to reflux with the vapor condensate passing through the molecular sieve to remove water formed during the reaction. After 48 hours reflux, the dioxane solution was removed and stripped of solvent under reduced pressure (20 mm.). The residue (50 grams) showed the presence of both carboxylic acid and ester groups in the infrared.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13]C(=O)[C@@H](O)C1C=CC=CC=1)[CH2:6]2)#[N:2].S(=O)(=O)(O)O>CCO>[NH2:13][C@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:9][CH2:8]1
Reactant: N#Cc1ccc2c(c1)C[C@H](NC(=O)[C@@H](O)c1ccccc1)CN2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N#Cc1ccc2c(c1)C[C@H](N)CN2
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To a solution of 1E (2.5 g, 8.14 mmol) in EtOH (25 mL) was added 15% aqueous sulfuric acid (25 mL). The resulting mixture was refluxed overnight, then cooled to RT. After removal of most of the EtOH, the mixture was diluted with water (200 mL), extracted with CH2Cl2 (3×50 mL). The aqueous layer was basified with 4N NaOH to pH=10, then extracted with CH2Cl2 (3×50 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was crystallized from EtOAc/hexane to afford the title compound (1.026 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[OH:14].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[O:14][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(S(N)(=O)=O)ccc1O
Reactant: COc1ccc(CO)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4.8 mmol 2-hydroxy-5-sulfamoyl-benzoic acid methyl ester, 5.2 mmol 4-methoxybenzyl alcohol and 5.2 mmol triphenylphosphine in 8 ml THF was added 5.2 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 350.2 ([M−H]−, 100%)
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[N:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:16]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C:15]=3[N:27]=2)=[C:6]([O:28][CH3:29])[CH:5]=1.Cl>O.CO.C(Cl)Cl>[CH:22]1([N:16]2[CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[C:14]3[CH:13]=[N:12][C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][C:6]=4[O:28][CH3:29])=[N:27][C:15]2=3)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCC2)CCCN3C)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCCN2C
Temperature: 25 °C
Yield: 99 %

Procedure:
Methyl4-[(9-cyclopentyl-5-methyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxybenzoate (Intermediate 7; 250 mg, 0.61 mmol) and HCl (2 mL, concentrated aqueous) were suspended in water (4 mL) and heated at reflux for 24 h. The reaction mixture was then cooled to ambient temperature and the volatiles were removed under reduced pressure. The solid obtained was dissolved in MeOH:DCM (1:10, 40 mL) and washed with NaHCO3 (saturated aqueous, 40 mL). The organic layer was then dried (MgSO4), filtered and the volatiles removed under reduced pressure to afford the title compound (240 mg, 99%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[CH:32]4)[CH:26]=3)[CH2:22][C:21](=[O:36])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CNc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-5-isobutylamino-phenyl}-carbamic acid tert-butyl ester (Example M126) (0.33 g, 0.63 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (240 mg, 94%).
Reaction SMILES: [N:1]1([C:6]2[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1>[Pd].C(O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:32][CH:33]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1

Procedure:
Benzyl 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carboxylate (Intermediate 13; 2.90 g, 6.49 mmol) and palladium on activated carbon (10%, wet, 600 mg) in ethanol (50 mL) were stirred under an atmosphere of hydrogen (1 atm) at RT for 2 h. The mixture was filtered (glass wool filter paper, Whatman 1821 110), and washed with ethanol. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (120 g RediSep, eluted with a gradient of dichloromethane/CMA, 9:1, 500 mL; 4:1, 1 L; 7:3, 3 L provide the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 4.12 (t, J=6.7 Hz, 2H), 3.17-3.00 (m, 2H), 2.65-2.45 (m, 2H), 2.25-2.05 (m, 1H), 1.90-1.70 (m, 3H), 1.63-1.47 (m, 1H), 1.43-1.23 (m, 2H), 1.02-0.84 (m, 2H), 0.74-0.57 (m, 2H), −0.12 (q, J=4.3 Hz, 1H). MS (Multimode) m/z 314 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]=[N:5]1)[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([N:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cnnn1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1nncc1C(=O)O
Temperature: 20 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of ethyl 1-(1-methylethyl)-1H-1,2,3-triazole-5-carboxylate (0.315 g) in methanol (5 ml) was added sodium hydroxide (5 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue taken up in water (5 ml) and acidified with 2M hydrochloric acid. The mixture was extracted with ethyl acetate and dried over sodium sulphate then filtered and evaporated to give the title compound (0.2 g) a white solid.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H]([C@H](CO)O)C(O)=[C:3]1O.[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18]C(=N)N.C(O)(=O)C>O.S([O-])([O-])(=O)=O.[Mn+2].O>[C:2]([OH:8])(=[O:1])[CH3:3].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: [Mn+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: NCCC[C@H](N)C(=O)O
Reaction time: 48 h

Procedure:
42.3 mg manganese sulfate hydrate (2.5×10-4 molar), 21.8 mg ascorbic acid (1.25×10-4 molar) and 15000 units calf's liver arginase of the Boehringer Mannheim company were added to 1 liter of a 0.75 molar L-arginine solution. After 48 hours the conversion was 100% according to HPLC. The mixture was adjusted with acetic acid to pH 6.8, three quarters of the water drawn off and the ornithine acetate precipitated with one liter ethanol at room temperature. After 15 min. of postagitation the precipitate was filtered off, postwashed with ethanol and dried in a vacuum (40 mbars). The yield of pure ornithine acetate was 137.0 g, 95% of theory). Amount of rotation (c=5 in water)+10.0° (theoretical: +9.0 to +11.0).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:7]([O:14][CH3:15])=[N:8][CH:9]=[N:10][C:11]=1[O:12][CH3:13])=[O:4].[OH-].[Na+].Cl.Cl[CH:20]([N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1)[CH3:21]>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]([C:6]1[C:11]([O:12][CH3:13])=[N:10][CH:9]=[N:8][C:7]=1[O:14][CH3:15])[CH:20]([N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1)[CH3:21])=[O:4]
Reactant: CC(Cl)n1cccn1
Reactant: COc1ncnc(OC)c1NC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ncnc(OC)c1N(C(=O)CCl)C(C)n1cccn1
Yield: 37.9 %

Procedure:
In a 500 ml eggplant-shaped flask equipped with a stirrer, 17.4 g (75.1 mmoles) of 2-chloro-N-(4,6-dimethoxy-5-pyrimidinyl)acetamide was dissolved in 300 ml of dichloromethane, and 5.22 g of benzyl tributyl ammonium chloride was added. Under ice cooling, 41.5 ml of a 50% aqueous solution of sodium hydroxide was added to the mixture with stirring. Thereafter, a solution of 13.8 g (82.6 mmoles) of N-(1-chloroethyl)pyrazole hydrochloride in 70 ml of dichloromethane was added dropwise over about 30 minutes. The mixture was stirred further at room temperature for 2 hours. The reaction mixture was washed with water, dried and concentrated. The resulting solid was recrystallized from isopropanol to give 9.26 g of 2-chloro-N-(4,6-dimethoxy-5-pyrimidinyl)-N-(1-(1-pyrazolyl)ethyl)acetamide as a pale yelllow solid which had the following properties.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[N:7][CH:8]=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[CH2:10][NH:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]3)=[CH:4][CH:5]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: ClCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(OCc3ccc(NCc4ccc(Cl)c(Cl)c4)nc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
A mixture of 5-(chloromethyl)-N-(3,4-dichlorobenzyl)pyridin-2-amine (0.1 g, 0.332 mmol), 6-hydroxyquinolin-2(1H)-one (0.048 g, 0.298 mmol) and Cs2CO3 (0.864 g, 2.65 mmol) in DMF (3.3 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and the resulting suspension was filtered. The filter cake was stirred in methanol for 1 h, filtered, washed with methanol, and dried to yield 6-((6-(3,4-dichlorobenzylamino)pyridin-3-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.033 g, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (1H, s), 8.06 (1H, d, J=2.01 Hz), 7.85 (1H, d, J=9.54 Hz), 7.46-7.63 (3H, m), 7.08-7.37 (5H, m), 6.39-6.62 (2H, m), 4.91 (2H, s), 4.49 (2H, d, J=6.02 Hz). LCMS: R.T.=3.15; [M+H]+=426.00.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCC/C=C/CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)CCC/C=C/CCc1ccccc1

Procedure:
A stirred solution of methyl (E)-8-phenyl-5-octenoate (13.6 g) in dioxan (125 ml) and 10% sodium carbonate solution (125 ml) was heated under reflux for 7 hours then evaporated. The residue in water was washed with ether, acidified and extracted with ether and the extract was dried and evaporated. The residue was distilled under vacuum to give the title compound, b.p. 150° to 153° C./0.2 mm.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[CH:7]=[CH:6][S:5][C:4]=1[N+:8]([O-:10])=[O:9].[OH-:12].[Na+]>C(O)=O>[N+:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[CH:2]=[O:12])([O-:10])=[O:9]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1sccc1C(Cl)Cl
Agent: [Na+]
Solvent: O=CO
Product: O=Cc1ccsc1[N+](=O)[O-]
Yield: 41 %

Procedure:
3-Dichloromethyl-2-nitro-thiophene described in Preparation Example T-1 (1.54 g, 7.26 mmol) was dissolved in formic acid (10 mL), and the solution was refluxed for 24 hours under nitrogen atmosphere. An aqueous solution of 5N sodium hydroxide was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (472 mg, 3.00 mmol, 41%) was obtained as a light brown solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][N:16]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=[C:15]3[C:14]=2[CH:28]=1>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[NH:19][C:18](=[O:20])[CH2:17][N:16]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:27]([Cl:1])=[C:15]3[C:14]=2[CH:28]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1Cn2c(cc3ccccc32)-c2cc(Cl)ccc2N1
Solvent: CN(C)C=O
Product: O=C1Cn2c(c(Cl)c3ccccc32)-c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.5 %

Procedure:
A solution of 2.08 g N-chlorosuccinimide in 50 ml dimethylformamide was added dropwise at 15° C. to a solution of 4.00 g 2-chloroindolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 125 ml dimethylformamide. The solution was stirred for two hours at room temperature. Upon dilution with water, a solid precipitated, which was collected and washed with hexane. Recrystallization from toluene yielded 2.67 g solid, m.p. 267°-271° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][OH:27])[N:21]=1)=[CH:16][CH:15]=3.Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>>[CH:35]1([CH2:34][O:27][CH2:26][CH2:25][N:22]2[CH:23]=[CH:24][C:20]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:28])[C:12]3[N:29]([CH3:32])[C:30](=[O:31])[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])=[CH:10][C:11]4=3)=[N:21]2)[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCO)n4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(CCOCC5CC5)n4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 51, 3-(2,4-dichlorophenyl)-6-[1-(2-hydroxyethyl)-1H-pyrazol-3-yl]-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and (bromomethyl)cyclopropane.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:20]=2)(=[O:18])=[O:17])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CCCC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCC)CC2)cc1

Procedure:
1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-n-Butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (8.5 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 7.5 g (88%); white solid; mp 182° C.; MS: 398 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[OH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1
Reactant: [H][H]
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: [Ni]
Solvent: CCO
Product: NC1CCc2[nH]c3ccc(O)cc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
To a solution of 0.871 gm (2.98 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 200 mL ethanol were added about 2.0 gm Raney Nickel and hydrogen introduced to the reaction mixture under balloon pressure. After stirring for 18 hours at room temperature the balloon was refilled with hydrogen and the reaction stirred an additional 3 days at room temperature. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a colorless solid. The residual solid was subjected to silica gel chromatography, eluting with 80:15:5 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.335 gm (56%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:21])([O:19]C)[O:17]C)[O:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])[CH3:2].C[Si](C)(C)Br>O>[CH2:1]([O:3][C:4]([N:6]([CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:17])([OH:21])[OH:19])[O:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)ON(C/C=C/P(=O)(OC)OC)C(=O)OCC
Agent: C[Si](C)(C)Br
Solvent: O
Product: CCOC(=O)ON(C/C=C/P(=O)(O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A mixture of dimethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-trans-1-propenylphosphonate (3.70 g.) and trimethylbromosilane (8.71 g.) was stirred for 30 minutes under ice-cooling and for 30 minutes at ambient temperature. Subsequently, the reaction mixture was concentrated under reduced pressure to give a residue. To the residue was added water (25 ml.). After the mixture was stirred for an hour at ambient temperature, the mixture was washed three times with chloroform (10 ml.), and then concentrated under reduced pressure to give oily 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-trans-1-propenylphosphonic acid (2.80 g.). Furthermore, the combined chloroform layer was extracted with water (20 ml.). The aqueous layer was washed twice with chloroform (5 ml.) and concentrated under reduced pressure to recover the same object compound (0.43 g.).
Reaction SMILES: O=[O+][O-].[C:4]([O:7][C:8]1[C:13]([CH2:14]C=C)=[CH:12][CH:11]=[CH:10][C:9]=1[O:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1)(=[O:6])C.OO.S([O-])(O)=O.[Na+]>C(O)(=O)C>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:9]1[C:8]2[O:7][C:4](=[O:6])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C=CCc1cccc(Oc2ccccc2C)c1OC(C)=O
Agent: O=S([O-])O
Agent: O=[O+][O-]
Agent: OO
Solvent: CC(=O)O
Product: Cc1ccccc1Oc1cccc2c1OC(=O)C2
Reaction time: 0.75 h
Yield: 22.9 %

Procedure:
Ozone gas was introduced into a solution of o-tolyl 2-acetoxy-3-allylphenyl ether (5.64 g) in acetic acid (80 ml) at 15° C. with stirring for 45 minutes. 30% Hydrogen peroxide (4 ml) was added to the solution and allowed to stand overnight at room temperature. Aqueous sodium hydrogen sulfite was added to the solution, and the mixture was extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and then evaporated. The oily residue (4.0 g) was dissolved in a mixture of sodium hydroxide and methanol. The solution was allowed to stand at room temperature for 30 minutes, and methanol was distilled off. The residue was washed with diethyl ether, acidified with dil. hydrochloric acid and then extracted with diethyl ether. The extract was dried over magnesium sulfate and evaporated. The oily residue (2.10 g) was dissolved in acetic anhydride (20 ml), heated on a water bath for 10 minutes and then evaporated. The crystalline residue was recrystallized from methanol to give colorless needles of 7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (1.10 g). mp 110°-111° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:19]([O:26][C:27](=[O:35])[CH2:28][C@@H:29]([NH2:34])[CH2:30][N:31]([CH3:33])[CH3:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27](=[O:35])[CH2:28][C@@H:29]([NH:34][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:30][N:31]([CH3:32])[CH3:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: O=C(O)CCCCCCCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCc1ccccc1

Procedure:
The title compound, m/e=347.4 ([M−H]−), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 8-phenyloctanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(8-phenyl-octanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.