Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCOCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH:1][C:15]([NH:14][CH2:12][CH3:13])=[O:16])=[N:6][C:5]=2[CH:7]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)ccc2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)ccc2s1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-bromo benzothiazole (0.23 g, 1.0 mmol) in 1,4-dioxane (8.0 mL) was added ethylisocyanate (3.96 mL, 5.0 mmol) and the resulting solution was heated to 80° C. for 16 h. After the completion of the reaction (TLC monitoring), 1,4-dioxane was distilled off followed by co-distillation with n-hexane (2 times). The residue was then stirred with water at 90° C. for 2 h followed by filtration to obtain the desired product that was further washed with hot water and then dried. The residue was finally washed with ether to obtain the desired product (0.18 g, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(Cl)=[O:14].C(NC(C)C)(C)C.[CH3:24][N:25]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([NH2:34])[C:28]=2[CH:27]=[N:26]1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:13]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]3[C:28]=2[CH:27]=[N:26][N:25]3[CH3:24])=[O:14])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: O=C(Cl)Cl
Reactant: Cn1ncc2c(N)cccc21
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: Cn1ncc2c(NC(=O)NCc3ccc(C(C)(C)C)cc3)cccc21
Temperature: 25 °C

Procedure:
4-tert-Butylbenzylamine (0.46 mL, 2.62 mmol) in toluene (8 mL) was treated with 20% phosgene solution (1.4 mL) and refluxed for 3 hours. The mixture was allowed to cool to ambient temperature and concentrated under reduced pressure. The residue was then taken up in toluene (10 mL) and treated with diisopropylamine (3 mL) and 1-methyl-1H-indazol-4-amine (prepared as described in J. Med. Chem. 45:742 (2002); 200 mg, 1.36 mmol). The reaction mixture was heated at 80° C. for 3 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography (98:2 CH2C12:CH3OH to 95:5 CH2Cl2:CH3OH, eluant gradient) to provide the title compound. The corresponding hydrochloride salt was prepared with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 8.72 (s, 1H), 8.03 (d, J=0.7 Hz, 1H), 7.66 (dd, J=7.8 Hz, 0.6 Hz, 1H), 7.37 (m, 2H), 7.27 (m, 2H), 7.24 (m, 1H), 7.13 (m, 1H), 6.74 (m, 1H), 4.30 (d, J=5.8 Hz, 2H), 3.99 (s, 3H), 1.27 (s, 9H); MS (ESI+) m/z 337 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1-c1ccn(C(=O)OC(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Yield: 99.9 %

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrole-1-carboxylic acid tert-butyl ester (288 mg, 0.608 mmol) was dissolved in 40 ml of MeOH. Pd(OH)2 (200 mg) was added and the mixture was placed in a Parr bomb and stirred under 200 psi of Hydrogen for 72 hours. The solution was filtered through Celite and the filtrate was concentrated under reduced pressure to give 290 mgs (quantitative) of 3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:10])[CH:7]=[N:8][CH:9]=1)=[O:4].[CH2:11]([N:18]1[CH2:22][CH:21]([C:23]([F:26])([F:25])[F:24])[CH:20]([C:27](O)=[O:28])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:10][C:27]([CH:20]2[CH:21]([C:23]([F:25])([F:24])[F:26])[CH2:22][N:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19]2)=[O:28])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: O=C(O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Reactant: COC(=O)c1cncn1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cncn1NC(=O)C1CN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of compound 2 (2.0 g, 14.1 mmol), 1-Benzyl-4-trifluoromethyl-pyrrolidine-3-carboxylic acid (4.06 g, 14.9 mmol) and DIEA (10 mL, 42.5 mmol) in DMF (30 mL) was added HATU (8.1 g, 21.2 mmol). The resulting reaction mixture was stirred at r.t. overnight. The reaction was monitored by LC-MS. The reaction was quenched with water (100 mL) when it was complete. The aqueous solution was extracted with EtOAc (80 mL×3). The combined organic phase was washed with brine and concentrated to afford the crude product. The residue was purified by silica gel column (eluted with PE/EA=5:1 to 1:2) to afford compound 13 (4.8 g, 85.6% yield) as white oil. LC-MS: m/z 397 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 8.00 (br. s, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.34˜7.28 (m, 5H), 3.81 (s, 3H), 3.78˜3.72 (m, 2H), 3.41˜3.38 (m, 1H), 3.30˜3.24 (m, 2H), 3.14˜3.12 (m, 1H), 2.71˜2.67 (m, 1H), 2.58˜2.53 (m, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])CC(O)=O.CN(C)C=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(CC(=O)O)c1ccc(OC)cc1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCC(CC(=O)Cl)c1ccc(OC)cc1OC

Procedure:
0.64 ml (7.4 mmol) of oxalyl chloride was added to a solution of 1.03 g (3.7 mmol) of 3-(2,4-dimethoxyphenyl)octanoic acid (prepared as described in Preparation 3) and a catalytic amount of dimethylformamide in 10 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. The solvent and an excess of the reagent were removed by distillation under reduced pressure, to give 3-(2,4-dimethoxyphenyl)octanoyl chloride. A solution of this acid chloride in 9 ml of methylene chloride was then added dropwise to an ice-cooled solution of 772 mg (3.7 mmol) of 2-t-butyl-5-methoxycarbonylaniline (prepared as described in Preparation 5) and 2 ml of pyridine in 5 ml of methylene chloride over a period of 2 minutes. The temperature of the mixture was allowed to rise to room temperature, and then the mixture was stirred for 20 minutes. At the end of this time, the reaction was quenched by adding water, the reaction mixture was diluted with a 1:1 by volume mixture of ethyl acetate and hexane and the diluted solution was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.66 g (yield 96%) of the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>CO>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1ccccc1C(F)(F)F
Yield: 87 %

Procedure:
A solution of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (70 mg, 0.153 mM) and 0.21 mL (0.21 mM) of 1 N NaOH in 5 mL of methanol was sonicated for 23 hours at 50-60° C. The methanol was removed in vacuo and the mixture acidified to pH 1.6 with 1 N HCl. The resultant white precipitate was collected by filtration, washed with H2O, small amounts of MeOH and diethyl ether, then dried in vacuo to afford 59 mg (88%) of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ13.0 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.75 (s, 1H), 7.5-7.3 (m, 6H), 7.1 (d, 1H, J=8 Hz), 7.05 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.3 (d, 1H, J=8 Hz), 5.8 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 1737 and 1635. MS (ES) m/e 441, 443.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]1[S:13][C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:3]=2[N:2]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: CSc1ccccc1C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 175 °C
Yield: 59.5 %

Procedure:
A mixture of 2-amino-4-trifluoromethylbenzenethiol hydrochloride (0.50 g), 2-methylsulfanylbenzaldehyde (0.33 g), diisopropylethylamine (0.28 g), and DMSO (4 ml) was heated to 170-180° C., and stirred with heating for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.42 g of 2-(2-methylsulfanylphenyl)-5-trifluoromethylbenzothiazole (hereinafter referred to as Present Compound 84).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:25](B(O)O)[CH:26]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[C:23]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:22]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: OB(O)c1cc(F)ccc1OCc1cccc(F)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3cc(F)ccc3OCc3cccc(F)c3)n2)c1

Procedure:
Example 31 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and {5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl}boronic acid (Combi-Blocks Inc.). The batch was purified by preparative TLC (DCM/EtOH 95:5).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]/[CH2:15][CH3:16].C(OC(=O)C)(=O)C>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH:13]=[CH:14]/[CH2:15][CH3:16]
Reactant: CC/C=C\C=C/CCCCCCCCCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC/C=C\C=C/CCCCCCCCCC=O

Procedure:
(11Z,13Z)-11,13-hexadecadien-1-ol (3.19 mmol) and acetic anhydride (6.38 mmol), in 5 ml of dry pyridine, are stirred under nitrogen at room temperature for 20 hours. The reaction mixture is then poured in sodium bicarbonate solution and extracted with pentane (2X). The organic layer is washed with dilute HCl and with brine, dried over magnesium sulfate and the solvent removed in vacuo. The crude product is purified to yield the final product, (11Z,13Z)-11,13-hexadecadien-1-al.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(NC(=O)[O-])C.O[C:29]1[C:30]([Cl:42])=[CH:31][C:32]2[CH:33]([CH3:41])[CH:34]3[CH2:38][NH:37][CH2:36][CH:35]3[C:39]=2[CH:40]=1>C(Cl)Cl>[Cl:42][C:30]1[CH:29]=[CH:40][C:39]2[CH:35]3[CH2:36][NH:37][CH2:38][CH:34]3[CH:33]([CH3:41])[C:32]=2[CH:31]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1c2cc(Cl)ccc2C2CNCC12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Pyridine (0.23 mL, 2.85 mmol) and trifluoromethanesulfonic anhydride (0.32 mL, 1.90 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (0.28 g, 0.95 mmol) in CH2Cl2 (10 mL), and stirred for 1.5 hours at room temperature. The reaction was diluted with CH2Cl2 (10 mL), washed with H2O (10 mL), aqueous HCl (1.0 M, 10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic extract was dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C16H17F3ClNO5S+H: 428, observed: 428.
Reaction SMILES: [C:1]1(NC2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[K+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([OH:27])[CH:26]=1>CN1CCN(C)C1=O>[CH3:1][O:27][C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[N+:28]([O-:30])=[O:29]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Product: COc1cc(F)ccc1[N+](=O)[O-]

Procedure:
5.4 g (32.1 mmol) of diphenylamine was dissolved in 50 ml of 1,3-dimethyl-2-imidazolidinone (DMI) and stirred under cooling in an ice-bath. Next, 3.6 g (32.1 mmol) of t-BuOK was added thereto. Subsequently, 5.0 g (29.2 mmol) of 2-methoxy-4-fluoronitrobenzene (obtained by methylation of commercially available 5-fluoro-2-nitrophenol) dissolved in 5 ml of DMI was dropped thereinto. After the completion of the dropping, the ice-bath was taken off and the mixture was allowed to stand at room temperature overnight. Next, the liquid reaction mixture was poured into water and extracted with ethyl acetate thrice. After washing with water, drying and concentrating under reduced pressure, the residue was recrystallized from methanol containing a small amount of acetonitrile. Thus, 6.0 g (yield 65%) of the compound (II-2) (2-methoxy-4-diphenylaminonitrobenzene) could be obtained as yellow powdery crystals.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O.[BrH:21].S(=O)(=O)(O)O>O>[Br:21][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:13])([F:12])[C:3]([F:15])([F:14])[C:2]([F:20])([F:1])[C:16]([F:19])([F:18])[F:17]
Reactant: OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 18.00 g of 6-(nonafluorobutyl)-1-hexanol and 225 mL of 48 weight percent hydrobromic acid was slowly added 23 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 12 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were then washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The hexanes solution was concentrated to a light amber liquid, which was eluted through 2 inches (5 cm) of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 18.29 g of 1-bromo-6-(nonafluorobutyl)hexane as a clear, colorless liquid, b.p. 70-80° C. at 0.05 torr (7 Pa).
Reaction SMILES: [OH:1]O.[CH:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11]C(=O)[C:9]2=[O:16])([CH3:5])[CH3:4].[OH-].[Na+]>O>[CH:3]([C:6]1[CH:7]=[C:8]([C:9]([OH:16])=[O:1])[C:12]([NH2:11])=[CH:13][CH:14]=1)([CH3:4])[CH3:5]
Reactant: CC(C)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step 1): 30% H2O2 (6 ml) was added to a solution of 5-isopropyl-1H-indole-2,3-dione [J. Med. Chem., 19, 391(1976)] (4.0 g, 21.1 mmol) in 1N-NaOH (15 ml) at 5° C. The mixture was stirred for 3 hours at room temperature and then poured into H2O and acidified. The precipitates were filtered to give 5-isopropylanthranilic acid, 2.6 g (68.6%): mp 93°-95° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:13]2[N:14]=[CH:15][O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH3:17][S:18]SC>O1CCCC1>[CH3:6][O:7][C:8]1[C:13]2[N:14]=[C:15]([S:18][CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CSSC
Reactant: COc1cccc2ocnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2oc(SC)nc12
Reaction time: 18 h

Procedure:
n-Butyllithium (20.13 ml of a 1.6N solution in hexanes) was added gradually to a solution of 4-methoxybenzoxazole (4.0 g) in tetrahydrofuran (150 ml) cooled in a cardice-acetone bath under an atmosphere of nitrogen. After stirring for 20 minutes dimethyl disulfide (2.9 ml) was added. The mixture was warmed to room temperaturee and stirred for 18 hours. The tetrahydrofuran was removed by evaporation in vacuo and the residue partitioned between ethyl acetate (150 ml) and water (150 ml). The organics were washed with water (150 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 10% ethyl acetate in heptane afforded the title compound as a white solid (2.63 g).
Reaction SMILES: [N+](=[CH:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:12])=[O:5])=[N-].[O:28]1CCOCC1.O>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:28][CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:12])=[O:5]
Reactant: [N-]=[N+]=CC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Reactant: C1COCCO1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: O=C(CO)[C@@H]1CCCN1C(=O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
1,4-Dioxane-water (5 ml-5 ml) was added to the crude (R)-4[[(S)-2-(diazoacetyl)-1-pyrrolidinyl]carbonyl]-3-(phenylmethyloxycarbonyl)thiazolidine (970 mg) and copper sulfate pentahydrate (several mg), and the mixture was heated at 100° C. for 0.5 hour. 1,4-Dioxane was distilled away under reduced pressure and a saturated sodium hydrogencarbonate was added. The mixture was extracted with ethyl acetate. The extract was washed with 10% citric acid and saturated brine in order, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: chloroform - methanol) to give the title compound (92 mg) (see Table 4).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=[N:23][NH:22]C=2C=CC=1.C(N1CCOCC1)C.N#N.[NH2:36][C@@H:37]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@H:38]([OH:54])[CH2:39][C@@:40]1([C:51]([NH2:53])=[O:52])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[CH2:62]([O:69][C:70]([NH:72][C@H:73]([C:78](O)=[O:79])[CH2:74][C:75](=[O:77])[NH2:76])=[O:71])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>O1CCCC1.C(OCC)(=O)C>[N:22]#[N:23].[CH2:62]([O:69][C:70]([NH:72][C@H:73]([C:78]([NH:36][C@@H:37]([CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C@H:38]([OH:54])[CH2:39][C@@:40]1([C:51]([NH2:53])=[O:52])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:79])[CH2:74][C:75](=[O:77])[NH2:76])=[O:71])[C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: NC(=O)[C@]1(C[C@@H](O)[C@@H](N)Cc2ccccc2)CCCN1c1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@]1(C(N)=O)CCCN1c1ccccc1
Reaction time: 16 h
Yield: 42.3 %

Procedure:
0.208 g of dicyclohexylcarbodiimide, 0.124 g of hydroxybenzotriazole and 0.106 g of N-ethylmorpholine were added to a stirred solution of 0.315 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -phenyl-L-prolinamide and 0.244 g of N-(benzyloxycarbonyl)-L-asparagine in 10 ml of tetrahydrofuran at 0° C. The mixture was stirred for 16 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with sodium bicarbonate solution and sodium chloride solution and the solvent was then removed by evaporation. The residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 0.22 g of N2 -[3(S)-[[N-(benzyloxycarbonyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -phenyl-L-prolinamide in the form of a white solid of melting point 169°-171° C. (from methanol).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C(Br)c1ccc(OC)cc1
Reactant: Nc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccccc1)c1ccc(OC)cc1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
Methyl 2-bromo-2-(4-methoxyphenyl)acetate (1.10 g, 4.25 mmol), DIPEA (0.89 mL, 5.09 mmol), and aniline (0.43 mL, 4.67 mmol) are dissolved in acetonitrile (12 mL). The reaction is heated for 18 minutes at 100° C. under microwave irradiation. Acetonitrile is evaporated and the residue is diluted with DCM and washed with water and brine, dried over Na2SO4, filtered and evaporated to dryness. The crude is purified by flash chromatography (Petroleum Ether/EtOAc=9/1) to give intermediate I139 as a yellow oil (745 mg, 65% yield).
Reaction SMILES: [OH:1]CCNCCO.CO[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1COCC1>[C:13]1([S:16]([OH:18])(=[O:1])=[O:17])[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: OCCNCCO
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 2-(2-hydroxy-ethylamino)-ethanol (7 g, 67 mmol) and 4-methoxybenzenesulfonyl chloride (40 g, 194 mmol) in THF (400 mL) KOH (100 mL, 40%) was added dropwise at 0° C., after stirring over 3 hr the mixture was filtrated and THF was evaporated in vacuo, then extracted with EtOAc (500 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column to afford Benzenesulfonic acid, 4-methoxy-, [[(4-methoxyphenyl)sulfonyl]imino]di-2,1-ethanediyl ester as a colorless gum (20 g, 49%). 1H NMR (DMSO-d6) δ 7.81 (d, J=4.8 Hz, 4H), 7.79 (d, J=5.2 Hz, 2H), 7.01 (d, J=4.8 Hz, 4H), 6.93 (d, J=5.2 Hz, 2H), 4.08 (t, J=6 Hz, 4H), 3.88 (s, 6H), 3.86 (s, 3H), 3.35 (t, J=6 Hz, 4H). MS (ESI) m/z (M+1)+: 615.7.