Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O>>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[CH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=1
Reactant: O=Cc1ccccn1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CC(=O)N2
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Cc1ccccn1)C(=O)N2
Yield: 77 %

Procedure:
Starting from 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1,3-dihydro-2H-indol-2-one and pyridine 2-carboxaldehyde and following the method described in Example 10, the desired compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[CH:9]2[CH2:30][CH:6]1[CH:7]=[CH:8]2)=[O:4]>C(O)C.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([N:11]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH3:12])[CH:9]2[CH2:30][CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1C2C=CC(C2)C1N(C)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)C1C2CCC(C2)C1N(C)S(=O)(=O)c1ccc(O)cc1
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of 3-[(4-benzyloxy-benzenesulfonyl)-methyl-amino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid methyl ester (1.5 g, 3.51 mmol) in ethanol-CH2Cl2 (45 mL-5 mL) were added 10% Pd—C (1.12 g, 1.05 mmol) and 1,4-cycloexadiene (3.32 mL, 35.1 mmol) at room temperature. The mixture was stirred for 12 h and then filtered through celite. The organic solution was concentrated and the residue was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to give 3-[(4-hydroxy-benzenesulfonyl)-methyl-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (97% yield). Mp=163-164° C. (white solid).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].[C:17](Cl)(=[O:25])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:17](=[O:25])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(F)c1cc(N)on1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a mixture of 3-(2-fluoropropan-2-yl)isoxazol-5-amine (4.32 g, 0.03 mol) and K2CO3 (8.28 g, 0.06 mol) in THF (100 mL) at 0° C. was added dropwise a solution of phenyl carbonochloridate (6 mL, 0.045 mol) in THF (50 mL). The mixture was stirred at 0° C. for 1 h, then at 40° C. for 20 h. Analysis by LC-MS and TLC indicated that the starting material was almost completely consumed and a new product had formed. The mixture was poured into water (150 mL) and the resulting mixture was extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-4% EtOAc in petroleum ether to afford phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate as a white solid (6 g, 76%).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[N:34]([CH3:36])[CH3:35])[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:23]([C:22]1[CH:31]=[CH:32][C:33]([N:34]([CH3:36])[CH3:35])=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:21]=1)(=[O:24])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C)c1ccc(C(=O)c2ccccc2)cc1NC(=O)c1ccn2c1CSC2c1cccnc1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 25.7 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 70° and 76° C., to a solution of 3-amino-4-dimethylaminobenzophenone (4.8 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 70° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and 10 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 1N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (10.1 g) is thereby obtained, which is dissolved in boiling acetonitrile (80 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 2 hours. The crystals formed are separated by filtration, washed twice with acetonitrile (50 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(5-benzoyl-2-dimethylaminophenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.4 g) in the form of yellow crystals, m.p. 186° C., is thereby obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: Nc1cccc2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
2-Nitrobenzenesulfonyl chloride (1.15 g, 5.21 mmol) was added to a stirred solution of 8-aminoquinoline (500 mg, 3.47 mmol) and TEA (0.72 ml, 5.21 mmol) in DCM (5 ml), at 0° C., under argon. The reaction was allowed to warm to room temperature and was stirred for 5 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with water and a sat. sodium bicarbonate solution. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (980 mg, 86%).
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C@H:28]([CH2:33][CH3:34])[C:29]([O:31]C)=[O:30])[CH2:23][CH2:22]2.CCOC(C)=O.CCCCCC>O.CO.C1COCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C@H:24]([C@H:28]([CH2:33][CH3:34])[C:29]([OH:31])=[O:30])[CH2:23][CH2:22]2
Reactant: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)cc4)oc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OCCc3nc(-c4ccc(C)cc4)oc3C)ccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of LiOH (90.4 g, 3.76 mol) in 1.3 L water and 1.3 L MeOH, was added a solution of the ester prepared in Example 11 (325 g, 0.75 mol) in 3.9 L THF at rt. The solution turned cloudy. This mixture was heated at 60° C. (pot temperature) for 4 hours, and TLC (50% EtOAc/hexane) analysis showed ca. 50% conversion. A solution of LiOH (30.1 g, 1.25 mol) in water (200 mL) was added to the reaction mixture. After 2 hours, TLC analysis showed ca. 85% reaction. Again, a solution of LiOH (30.1 g, 1.25 mol) in water (200 mL) was added to the reaction mixture. After 2 hours, TLC analysis showed very little starting ester left. After the reaction mixture was cooled to rt, THF and MeOH were removed at a reduced pressure. The residue was diluted with water until the solids dissolved (a total of 60 L of water used). Conc. HCl solution was slowly added to this aqueous solution until pH 2.0–3.0. The solid was collected by filtration, and dried under house vacuum overnight. This solid was stirred with 15 L EtOAc and 2 L of 1N HCl solution for 30 minutes. The EtOAc layer was separated and washed with 1N HCl solution (2×1 L). The organic phase was then washed with water (4×2 L) until pH=5.0–6.0. Under Ar protection, the EtOAc solution was reduced to 2.5 L by normal pressure distillation, then cooled to rt without disturbance. White solid precipitated out. After further cooling in an ice water bath for 2 hours, the solid was filtrated and washed with 500 mL cold EtOAc. After drying under high vacuum at 35° C. to a constant weight, the final product (266 g, 81%, 98% ee,) was collected as a white crystal. 1H NMR (CDCl3) δ 7.82(d, 2H), 7.20(d, 2H), 7.05(d, 1H), 6.75(d, 1H), 6.70(dd, 1H), 4.20(t, 2H), 3.42(q, 1H), 2.95(t, 2H), 2.80(m, 2H), 2.50(m, 1H), 2.35(s, 3H), 2.32(s, 3H), 2.20(m, 1H), 1.90(m, 1H), 1.65(m, 1H), 1.45(m, 1H), 0.90(t, 3H). Chiral purity, 99% ee, [α]D=+16.11(CHCl3), mp 149.5–150.5° C.
Reaction SMILES: C([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C@H:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]4[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C@H:27]4[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]4[NH:25][C:24]3=[O:32])[CH2:21][CH2:22]2)[CH2:13][CH2:12]1)(=[O:8])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of cis-(+/−)-benzyl-4-(2-oxooctahydro-1H-benzimidazol-1-yl)-1,4′-bipiperidine-1′-carboxylate (800 mg, 1.82 mmol) in EtOH (50 mL) was added 10% Pd/C (80 mg) and the mixture was hydrogenated at 40 psi for 3 h. Filtration of catalyst on celite and removal of solvent afforded the title compound (372 mg, 67%), which was used without further purification. MS (M+1): 306.0
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[N+:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[CH:17]=[CH:18][C:6]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:7][C:8]=3[CH2:9]2)=[CH:14][CH:13]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CC(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cc([N+](=O)[O-])ccc1-2

Procedure:
A suspension of α-methylfluorene-2-acetic acid (11.9 g) in acetic acid (10 ml) is stirred and heated to 60°, and then treated dropwise with concentrated nitric acid (12.7 ml) over a 0.5 hour period. The temperature is kept at 80° by cooling. After the addition is completed, the mixture is heated at 80° for 15 minutes then cooled. The crystalline material is collected by filtration to give 7.5 g, mp 206°-209° of the titled product. The analytical sample is prepared by recrystallization from acetic acid, mp 215°-216°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][O:14][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][C@@H:10]([CH3:32])[C:9]1=[O:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH3:32])[C:9]1=[O:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,5S)-1-t-butoxycarbonyl-5-t-butyldiphenylsiloxymethyl-3-methyl-pyrrolidine-2-one (17.8 g, 38.1 mmol) and glacial acetic acid (2 eq) in dry THF (50 mL) at 0° C. was added a 1.0M solution of tetrabutylammonium fluoride in THF (150 mL, 150 mmol). The solution was allowed to warm room temperature and stir overnight. Ethyl acetate (500 mL) was added and the organic phase extracted with aqueous ammonium chloride (20%, 3 x 200 mL). The combined aqueous phases were extracted with ethyl acetate (200 mL). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by filtration through silica gel, eluted with 70% EtOAc in hexane to give the product as a clear oil, which was carried on for next step without further characterization.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH2:50][OH:51])=[CH:31][CH:30]=1>C(Cl)Cl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH:50]=[O:51])=[CH:31][CH:30]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of Dess-Martin periodinane (1.54 gm, 3.63 mmol) in dry CH2Cl2 (17 ml) was treated with t-butanol (267 mg, 3.60 mmol) and stirred for 15 minutes at room temperature. A solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (895 mg, 2.78 mmol) in CH2Cl2 (12 ml) was then added and stirring was continued 30 minutes, after which time the mixture was quenched by the addition of Et2O (70 ml) and 1N NaOH (35 ml). The biphasic mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with 1N NaOH, H2O and brine, then dried (Na2SO4), filtered and stripped. The solid residue was chromatographed (Flash, Merck SiO2, 10% EtOAc in hexane) to afford pure 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (782 mg, 88%) as a white solid. Analytically pure material was obtained by recrystallization of the solid from a minimum amount of hot hexane.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[N:13]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([CH:19]2[CH2:24][CH2:23][N:22]([C:2]([Cl:1])=[O:4])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: ClCCl
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Reaction time: 1.5 h

Procedure:
In a solution of Triphosgene (16.48 gm) in methylene chloride (200 ml) was added a solution of 4-piperidinopiperidine (20 g) in methylene chloride (200 ml) at 20-25° C. within 1-2 hours. Part of the methylene chloride was distilled off and acetonitrile was added. Further, methylene chloride and acetonitrile was distilled off completely until the temperature rises to 70° C. At room temperature fresh methylene chloride was added to the reaction mixture to make homogenous slurry followed by potassium carbonate (30-35 gm) and reaction mixture was stirred for 1-2 hours. The reaction mixture was filtered and subsequently the filtrate was concentrated. Hexane was added slowly into the reaction mixture under stirring. Solid compound so obtained was filtered, washed with hexane and dried under reduced pressure at about 40° C.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[CH:2][CH3:3].[ClH:11]>>[Cl:11][CH:1]([N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3]
Reactant: CC=CN1C(=O)CCC1=O
Reactant: Cl
Product: CCC(Cl)N1C(=O)CCC1=O
Reaction time: 240 h

Procedure:
Anhydrous hydrogen chloride is bubbled through a mixture of 10 g. (0.072 mole) of N-propenylsuccinimide and 1.04 g. of stannic chloride for 6 hours. The solution is allowed to stand at room temperature for 10 days, the solution being saturated again with hydrogen chloride gas after 3 days and 4 days. Solvents are removed under reduced pressure at 30°-40° C. to give 1-chloro-1-succinimido-propane as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:24](=[O:25])[C:23]5[CH:27]=[CH:28][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=5)=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc(-n2ccc3cc(N)ccc32)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-n3ccc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc43)cc2)cc1

Procedure:
Compound 370 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indole and 4-dimethylaminobenzoate. [M+H]+ calcd for C32H31N5O2: 518.25; found: 517.95.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOC(C)=O>C1COCC1.CC(O)=O.[Fe]>[NH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:8]([O:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:9]=1[C:10]#[N:11]
Reactant: N#Cc1c(OC2CCCCC2)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(N)cccc1OC1CCCCC1
Temperature: 25 °C
Yield: 104 %

Procedure:
To a solution of 2-(cyclohexyloxy)-6-nitrobenzonitrile (Example 36c, 50.0 g, 0.20 mol) in THF/AcOH (1:1 by volume, 500 mL) was added iron powder (34.0 g, 0.61 mol) in one portion at room temperature under nitrogen. The reaction mixture was refluxed for 40 min under nitrogen and cooled down to room temperature and EtOAc (2 L) was added. The precipitate that formed was filtered off and washed with EtOAc. The organic layer was separated and washed successively with water (2×300 mL), aqueous NaOH (1.0 N, 2×300 mL), saturated Na2CO3 solution (300 mL), brine (300 mL), dried over Na2SO4 filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a pale yellow oil (45.0 g, 94%), which solidified after storage overnight at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)(C(OCC)=O)[C:19]([O:21]CC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+]>Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CCCCCCNS(=O)(=O)c1ccc(Cl)cc1)(CCCCCc1cccnc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C(CCCCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCCCc1cccnc1

Procedure:
A solution of 1.4 g of ethyl 8-(p-chlorophenyl-sulfonamido)-2-[5-(3-pyridyl)-pentyl]-2-(ethoxycarbonyl)-octanoate in 50 mL of 6N HCl and 10 mL of acetic acid is heated to reflux for 23 hours after which time it is evaporated to give an oil. This is treated with water, the solution is neutralized with solid sodium bicarbonate to a pH of 6.4 and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give crude product which is first purified by column chromatography over silica gel using ethyl acetate as eluent, and then further purified by preparative TLC chromatography using ethyl acetate, acetic acid (99.5:0.5) as eluent to give 8-(p-chlorophenylsulfonamido)-2-[5-(3-pyridyl)pentyl]-octanoic acid as an oil, NMR (CDCl3): delta 7.77 (d,2H), 7.4 (d,2H), 2.85 (t,2H), 2.55 (t,2H).
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:27])[CH2:11][CH:12]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][C:29]=1[C:38](O)=[O:39].CN1CCOCC1>C(Cl)Cl>[C:21]1([S:18]([CH:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][CH:10]([OH:27])[CH:2]([NH:1][C:38]([C:29]2[CH:30]=[N:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]=2)=[O:39])[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)CCC(CC(O)C(N)Cc1ccccc1)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cnc2ccccc2n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of one equivalent of 2-amino-5-benzenesulfonyl-8-methyl-1-phenyl-nonan-3-ol in methylene chloride is added 1.05 equivalents each of 2-quinoxalinecarboxylic acid, N-methyl morpholine, and O-benzotriazol-1-yl-N,N,N′,N′-teteramethyluronium hexafluorophosphate. The reaction mixture is stirred at ambient temperature for 18 h. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:26][N:14]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:26][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)OC(C)(C)C)CCN3C2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CNCCN3C2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product from Example 202B (100 mg, 0.277 mmol) in 1,4-dioxane (1 mL) was added 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol). The resulting mixture was stirred at ambient temperature for 3 hours, and the mixture was then concentrated to give the title compound as an off-white solid (82 mg, quantitative).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH2:29]>>[CH3:25][O:26][C:27](=[O:30])[CH2:28][NH:29][C:15]([C:13]1[N:14]=[C:10]([NH:9][C:8]([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[S:11][CH:12]=1)=[O:16]
Reactant: COC(=O)CN
Reactant: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Product: COC(=O)CNC(=O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Yield: 30 %

Procedure:
Prepared in 30% yield (76 mg) as described in general procedure (K) from 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.6 mmol) and glycine methyl ester (HCl salt, 75 mg, 0.6 mmol).