Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:46])[CH:8]=1)[CH3:2].SCC(O)=O.O.[OH-].[Li+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:9]([CH3:46])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC)cc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 67 h
Yield: 82 %

Procedure:
To a solution of the residue obtained in Example 34 and mercaptoacetic acid (0.278 mL, 4.00 mmol) in N,N-dimethylformamide (2 mL) was added lithium hydroxide monohydrate (0.336 g, 8.00 mmol), and the mixture was stirred at room temperature for 67 hr. Ethyl acetate was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-40% ethyl acetate/hexane) to give the title compound (0.760 g, yield 82%, 2 steps) as a yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:22]([CH:19]1[CH2:21][CH2:20]1)=[O:23]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C(=O)C1CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-methyl-4-nitroaniline (2 g, 13.1 mmol) in DCM (30 mL) was added Et3N (2.75 mL, 20 mmol) and cyclopropanecarbonyl chloride (1.32 mL, 14.4 mmol) at room temperature, after stirring for 1 h at room temperature, the mixture was diluted with EtOAc, the organics was washed with Sat. NaHCO3, brine, dried and concentrated to give N-methyl-N-(4-nitrophenyl)cyclopropanecarboxamide as crude product (3 g).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[NH:10]1[CH:14]=[CH:13][NH:12][C:11]1=[O:15].[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:20]([C:14]1[NH:10][C:11](=[O:15])[NH:12][CH:13]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]cc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccccc1)c1c[nH]c(=O)[nH]1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 51 ml of nitrobenzene is added 1.68 g of 1,3-dihydro-2H-imidazol-2-one, 5.3 g of aluminum chloride and 3.1 g of benzoyl chloride. The mixture is stirred for 3 hours at 60° C. and poured into ice water. The solids are filtered, washed with ether and recrystallized twice from methyl alcohol-water to afford the title compound. M.P. 329°-30° C.
Reaction SMILES: Cl[CH:2]([Cl:4])C.[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](Cl)=[O:11].[O:18]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:18][CH2:2][Cl:4])=[O:11]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 10 ml of dichloroethane were added 1 g of zirconium tetrachloride and 1 g of 3-trifluoromethylbenzoyl chloride, and the mixture was stirred at room temperature for 30 minutes. At 10° C., 0.16 g of trioxane was added, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 2 hours. The mixture was cooled to 0° C., water was added slowly, the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.4 g of chloromethyl 3-trifluoromethylbenzoate.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][CH2:23][C:24]([O:26][CH:27]2[CH2:32][O:31]C(C3C=CC=CC=3)[O:29][CH2:28]2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H][H]>[Pd].C(O)(=O)C>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH:27]([CH2:28][OH:29])[CH2:32][OH:31])=[O:25])=[CH:39][CH:40]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OC2COC(c3ccccc3)OC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OC(CO)CO)cc1

Procedure:
A mixture of 2-phenyl-1,3-dioxan-5-yl 4-(hexadecylamino)hydrocinnamate, 10% palladium-on-carbon and acetic acid is treated with hydrogen in a Parr apparatus at room temperature until hydrogen uptake ceases. The mixture is filtered and the filtrate is evaporated. Recrystallization of the residue from chloroform provides the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:49])C=1>C(Cl)(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N+:14]([O-:49])=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@@H:24]([C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)[O:25][C:26]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:11]=3[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1nc2c(c3c1[C@@H](c1ccc(C(F)(F)F)cc1)OC31CCCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Solvent: ClC(Cl)Cl
Product: CC(C)c1c2c(c3c([n+]1[O-])CC(C)(C)C[C@@H]3O[Si](C)(C)C(C)(C)C)C1(CCCC1)O[C@@H]2c1ccc(C(F)(F)F)cc1
Reaction time: 18 h

Procedure:
280 mg (3′R,9′S)-9′-(tert-butyldimethylsilyloxy)-4′-isopropyl-7′,7′-dimethyl-3′-(4-(trifluoromethyl)phenyl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline] are dissolved in 5 ml chloroform and treated with 80 mg of meta-chloroperbenzoic acid (MCPBA) (<77%). The mixture is stirred for 18 hours and then partitioned between dichloromethane and a solution of sodium sulfite in water (5%). The organic phase is washed with saturated aqueous sodium bicarbonate and dried with sodium sulphate. After evaporation of the solvents the residue is chromatographed on silica gel (hexane/ethylacetate 4:1).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[Br:9]Br>O1CCOCC1>[Br:9][CH:8]1[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: BrBr
Reactant: CN1CC(=O)NC1=O
Solvent: C1COCCO1
Product: CN1C(=O)NC(=O)C1Br
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1-Methylhydantoin (114 g (1 mol); manufactured by Junsei Chemical Corporation) was dissolved in 1000 mL of dioxane (manufactured by Junsei Chemical Corporation). Trifluoroboron ether complex (0.1 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the solution, and the temperature was raised to 70° C. with stirring. Bromine (160 g (1 mol); manufactured by Junsei Chemical Corporation) was added dropwise thereto at 70° C. over a period of about 60 min. After the completion of dropwise addition, the solvent was removed by distillation under reduced pressure to give a crude crystal of 5-bromo-1-methylhydantoin.
Reaction SMILES: [C:1]1(C=CC(O)=C[CH:3]=1)[OH:2].NC1C=CC=CC=1.[CH:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([OH:23])[CH:17]=1.BrC1C=CC=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([N+:39]([O-:41])=[O:40])[CH:33]=1>[Cl-].[Zn+2].[Cl-]>[NH2:22][C:21]1[CH:20]=[CH:19][C:18]([OH:23])=[CH:17][C:16]=1[N+:39]([O-:41])=[O:40].[C:1]([O:38][C:35]1[CH:36]=[CH:37][C:32]([NH2:31])=[CH:33][CH:34]=1)(=[O:2])[CH3:3]
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Nc1ccc(O)cc1
Reactant: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Nc1ccccc1
Solvent: Brc1ccccc1
Product: CC(=O)Oc1ccc(N)cc1
Product: Nc1ccc(O)cc1[N+](=O)[O-]

Procedure:
4-Hydroxydiphenylamine (m.p. 70° C., b.p. 330° C.) is formed by heating hydroquinone with aniline and zinc chloride at 180°-185° C. (G. Heller, Ann., 1919, 418, p. 265; A. Calm and M. Phillip, Chem. Ber., 1883, 16, p. 1799; 1884, 17, p. 2431), or by reaction of p-aminophenol with bromobenzene and cuprous iodide (German Pat. No. 187,870). 4-Amino-2-nitrophenol (dark red plates, m.p. 128° C.) can be prepared by the procedure described in A. Girard, Bull. Soc. Chim. Fr., 1924, 35, p. 773) and 4-Amino-3-nitrophenol (m.p. 154° C.), can be formed from the nitration of 4-aminophenyl acetate as described in (Girard, loc. cit.);
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1([F:25])[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1.O=O.[OH:28]S([O-])=O.[Na+]>C1COCC1.CCOCC>[F:13][C:14]1([F:25])[CH2:15][CH2:16][C:17]([OH:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: O=S([O-])O
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: O=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(O)CCC(F)(F)CC1
Temperature: -78 °C

Procedure:
A solution of butyllithium (1.600 mL, 4.00 mmol) was added to cold (−78° C.) solution of diisopropylamine (0.565 mL, 4.00 mmol) in THF (5 mL) under nitrogen and the mixture was stirred at −78° C. 1 h. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (384 mg, 2 mmol) in THF (2 mL) was added at −78° C. and the mixture was stirred for 1 h. The mixture was gradually warmed to −20° C. over 2 h and then recooled to −78° C. and connected to a balloon of oxygen and stirred at −78° C. for 1 h. The reaction mixture was added satd. NaHSO3 solution (5 mL) and allowed to warm to rt and stirred at rt overnight. The reaction mixture was diluted with ether and organic layer separated, washed with water, brine, dried (Na2SO4). Evaporation of the solvent afforded a light yellow oil which was purified by silica gel FCC (DCM) to afford ethyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate as a colorless oil (143 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.28 (q, J=7.3 Hz, 2H), 2.23 (br. s, 1H), 2.19-1.99 (m, 6H), 1.83-1.73 (m, 2H), 1.33 (t, J=1.0 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH:11]=[C:12]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15][NH:14][CH2:13]1.[C:31](Cl)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:31]([N:14]1[CH2:13][C:12](=[CH:11][C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=2[F:8])[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15]1)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Triethylamine (0.4 ml, 2.85 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in ice-cold 1,2 dichloroethane. A solution of stearoyl chloride (450 mg, 1.49 mmol) in 1,2-dichloroethane was added drop-wise to the ice-cold solution of compound 1. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, 10% potassium carbonate solution (10 ml) was added, and stirred for 30 min. The organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain a shiny solid of 25 (373 mg, 67% yield). 1H NMR (300 MHz, CDCl3): δ 7.92, 7.89 (2s, 2H, C═CH), 7.50-7.35 (m, 4H, Ar—H), 7.30-7.14 (m, 4H, Ar—H), 4.79, 4.55 (2s, 4H), 2.44 (td, 2H, J=7.3, 2.3), 2.09 (t, 2H, J=7.6), 1.65 (t, 2H, J=7.0), 1.41 (t, 2H, J=7.3), 1.40-1.05 (m, 24H), 0.87 (t, 3H, J=6.7, CH3). 13C NMR (75 MHz, CDCl3): δ 172.05, 133.77, 133.40, 133.48, 130.76, 130.23, 124.29, 116.39, 116.09, 115.81, 46.45, 43.48, 35.26, 33.08, 31.92, 29.69, 29.37, 28.86, 25.06, 24.21, 22.69, 14.12. ESI Mass calculated for C37H50F2NO2(M+H)+578.38. found 578.40.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5](O)=[CH:4][CH:3]=1)O.[CH2:9]([NH2:12])C=C>>[CH2:9]=[NH:12].[CH:1]12[CH2:9][CH:5]([CH2:7][CH2:8]1)[CH:4]=[CH:3]2
Reactant: Oc1ccc(O)cc1
Reactant: C=CCN
Product: C1=CC2CCC1C2
Product: C=N

Procedure:
The norbornene derivative of norbornene methylene amine (NBMA) is mainly produced by the reaction of cyclopentadiene (66 g) and allyl amine (50 g). The required reaction condition of the Diels-Alder reaction in the invention is usually controlled at 180° C. for 8 hrs in the presence of hydroquinone (1 g) as a inhibitor. The boiling point of allyl amine is 55-58° C., so the reaction needs to be carried out in autocalve. The resulting solution is distilled under vacuum to obtain norbornene methylene amine (NBMA) (bp=59˜61° C./11 mmHg).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1)=[O:14])(C)(C)C.C1(=O)O[C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.CO>ClCCl>[O:30]=[C:29]1[C:28]2[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13](=[O:14])[N:15]1[C@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC(=O)O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(O)C[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (44.6 mL, 583.0 mmol, 30.0 eq) is added at room temperature to a stirred solution of (trans-4-tert-butoxycarbonylamino-cyclohexyl)-acetic acid (5.0 g, 19.4 mmol, 1.0 eq) in dichloromethane (50 mL). After 3 hours stirring at room temperature, the reaction mixture is concentrated, the resulting residue is dissolved in pyridine (150 mL) and phthalic anhydride (5.0 g, 33.0 mmol, 1.7 eq) is added at room temperature. The reaction mixture is heated to reflux for 4 hours, pyridine is then removed and acetic anhydride (40 mL) is added. The resulting mixture is heated to reflux for 3 hours, then extracted with ethyl acetate (3×200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 50:1 to 10:1, v/v) to afford [trans-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-cyclohexyl]-acetic acid as a white solid (4.82 g, 86% yield).
Reaction SMILES: P(=O)(O)(O)O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH:15](OCC)OCC)=[CH:9][CH:8]=1>ClC1C=CC=CC=1>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[S:13][CH:14]=[CH:15][C:11]=2[CH:12]=1
Reactant: CCOC(CSc1ccc(Br)cc1)OCC
Agent: O=P(O)(O)O
Solvent: Clc1ccccc1
Product: Brc1ccc2sccc2c1
Temperature: 130 °C

Procedure:
5-Bromobenzo[b]thiophene (Chemical Abstracts number 4923-87-9) was prepared as described in Banfield et al.; J. Chem. Soc.; 1956; 2603-2607, and in Seed, Alexander J.; et al. J. Mater. Chem.; vol10; 2000; 2069-2080. A mixture of phosphoric acid (218 g) and chlorobenzene (2 L) was heated at 130° C. and then treated with the product from Example 165A (107.0 g) over 2 hours using a syringe pump. The mixture was heated at 130° C. for 15 hours. Dean-Stark trap was used at the beginning of the reflux to remove water from the mixture. The mixture was allowed to cool to room temperature and quenched with 400 mL of water. The bottom aqueous layer was extracted with 200 mL of methylene chloride. The combined organic layer was washed with 200 mL of 10% Na2CO3, and concentrated to brown oil (129.4 g). The crude oil was dissolved in 1L of 10:90 EtOAC:hexane, filtered through a short pad of silica gel and concentrated to a yellow oil (85.54 g, 95.8% yield). Further purification was done by column chromatography (silica gel, 5:95 EtOAc:hexane).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2.N1CCCCC1>C(O)C>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Temperature: 25 °C
Yield: 58034.5 %

Procedure:
3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (50 mg, 0.165 mmol) and 5-fluoro-1,3-dihydro-indol-2-one (22.4 mg, 0.15 mmol) were dissolved in 0.3 ml of ethanol under stirring, and added with piperidine (0.05 ml, 0.5 mmol) to the solution at room temperature. Upon completion of the addition, the mixture was stirred at 40˜50° C. in an oil bath for 5 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered to obtain yellow solid. The solid was dissolved in ethanol (2 ml), heated to reflux for 30 minutes, cooled down to room temperature and filtered to obtain the title compound (Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 32 (38 g, yield 58%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].[F:11][C:12]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:23]2[C:22]([F:26])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[C:12]([F:11])[CH:24]=2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of (5,6-dichloropyridin-3-yl)methanol (275 mg, 1.55 mmol) in DMSO (5 mL) were added tert-butyl 2,4,5-trifluorobenzoate (Preparation 97, 300 mg, 1.30 mmol), and potassium carbonate (535 mg, 3.88 mmol) and the mixture stirred for 18 hours at room temperature under a nitrogen atmosphere. Water (10 mL) was added and the mixture extracted with EtOAc (3×20 mL). The combined organics were washed with water (20 mL) and concentrated in vacuo to yield the title compound (490 mg, 96%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Yield: 11.6 %

Procedure:
Following the procedure described in Step 2 of Example 5 1-benzyl-5-bromo-1H-indole (2.22 g , 7.76 mmol) was coupled to 4-trifluoromethylphenyl boronic acid (1.62 g, 8.54 mmol), using tetrakis(triphenylphosphine)palladium (0.892 g, 0.772 mmol), and potassium carbonate (4.29 g, 31.1 mmol) in water (17 mL), ethanol (4 mL), and toluene (37 mL). Purification by flash chromatography using 0.5-1.0% ethyl acetate in hexane as eluant afforded the title compound as a light yellow solid (0.317 g, 12%). 1HNMR (200 MHz, DMSO-d6): δ 7.7-8.0 (m, 5H), 7.4-7.6 (m, 3H), 7.15-7.4 (m, 5H), 6.6 (d, 1H, J=3.6 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([OH:27])[C:13]2[C:18]3[CH:19]=[C:20]([O:23]C)[CH:21]=[CH:22][C:17]=3[C:16](=[O:25])[O:15][C:14]=2[CH:26]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B(Br)(Br)Br.O>ClCCl>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([OH:27])[C:13]2[C:18]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=3[C:16](=[O:25])[O:15][C:14]=2[CH:26]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)oc(=O)c1ccc(OC)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)oc(=O)c1ccc(O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
3-(1,1-Dimethylheptyl)-1-hydroxy-9-methoxy-6H-dibenzo[b,d]pyran-6-one (4b) (200 mg, 0.54 mmol) was dissolved in 12 mL of dry dichloromethane, 2 mL of a 1 M solution of boron tribromide in dichloromethane (2 mmol) was added and the resulting mixture was stirred at room temperature for 3 days. Water was added and the mixture was extracted with diethyl ether. The organic extract was dried and rotary evaporated. The residue was chromatographed on silica gel (50% ethyl ether-petroleum ether) to afford 150 mg of a flaky off-white foam: m.p. 103–108° C.; Rf; 0.28 (50% diethyl ether-petroleum ether); 1H NMR δ 8.60 (m, 1H), 8.35 (d, 1H), 7.05 (d, 1H), 6.90 (s, 1H), 6.73 (s, 1H), 6.10 (br s, 2H), 1.70–0.98 (series of m, 10H), 1.27 (s, 6H), 0.82 (t, J=6.6 Hz, 3H); Anal. calcd. for C23H28O4 74.55% C, 7.39% H; Found 72.70% C, 7.25% H.
Reaction SMILES: [O-:1][S:2]([O-:5])(=[S:4])=[O:3].[Na+:6].[Na+].[OH:8]C(C(F)(F)F)=O.[NH2:15][C@H:16]1[CH2:19][O:18][C:17]1=[O:20]>O>[OH2:1].[OH2:8].[Na+:6].[S:2]([S:4][CH2:19][C@@H:16]([C:17]([O-:20])=[O:18])[NH2:15])([OH:5])(=[O:1])=[O:3]
Reactant: O=C(O)C(F)(F)F
Reactant: O=S([O-])([O-])=S
Reactant: N[C@H]1COC1=O
Agent: [Na+]
Solvent: O
Product: N[C@@H](CSS(=O)(=O)O)C(=O)[O-]
Yield: 83.4 %

Procedure:
To Na2S2O3 (73.2 mg, 0.463 mmol) in H2O (I mL) at pH 5.0 was added (S)-3-amino-2-oxetanone TFA salt (produced from BOC-L-serine β-lactone (43.0 mg, 0.23 mmol)) in H2O (1 mL). The pH was maintained at 5.0 for 1 h and the solvent was removed in vacuo at 25° C. The residue was dissolved in H2O (1.0 mL), applied to a column of Rexyn 102 trademark) (1×10 cm, H+ form) and eluted with (0.25 mL/min). S-sulfo-L-cysteine (Rf 0.81, System A; characteristic brown color with ninhydrin) eluted chromatographically pure as the monosodium salt after 15-20 mL. Lyophilization and recrystallization from H2O/Et2O (pH 5) provided 49.7 mg (83%) of S-sulfo-L-cysteine monosodium salt dihydrate as a white solid: mp 35° C. foams but remains white (loss of H2O), 202°-204° C. (dec); [α]D 25-83.7 (±0.2)° (c 2.5, H2O (lit. [α]D 25 -86.8° (c 4.73, H2O)37 for the 1κ hydrate); IR (KBr disk) 3450 (m, br), 3150 (m, br), 1635 (s, br), 1515 (m), 1400 (m), 1358 (m), 1235 (s), 1217 (s), 1200 (s), 1137 (s), 1030 (s), 636 (s) cm-1 ; 1H NMR (300 MHz, D2O δ 4.18 dd, 1H, 3.7, 8.0 Hz, CH), 3.68 (dd, 1H, 3.7, 15.5 Hz, CHHSSO3-), 3.50 (dd, 1H, 8.0, 15.5 Hz, CHHSSO3-). Anal. Calc. for C3H6NO5S2Na.2H2O (FW 259.2 : C, 13.90; H, 3.89; N, 5.40; S, 24.74. Found: C, 14.11; H, 3.85; N, 5.21; S, 24.59; NEGFAB-MS (glycerol) 200 (-O3SSCH2CH(NH2)COOH).