Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(Br)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(Br)cn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Sodium hydride (461 mg, 11.5 mmol) was slowly added to a solution of 3-bromo-6-nitro-1H-indole (2.32 g, 9.61 mmol) in tetrahydrofuran (10.0 mL). After stirring for 5 min, benzenesulfonyl chloride (1.47 mL, 11.5 mmol) was added dropwise over 10 min. The reaction was stirred an additional 1.5 h before quenching with 5.0 mL of methanol, followed by 10.0 mL water and 20.0 mL methylene chloride. The precipitate was filtered off and washed with an excess of methylene chloride and methanol to give a crème-colored powder for 3-bromo-6-nitro-1-(phenylsulfonyl)-1H-indole (2.80 g, 7.35 mmol, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:12]([NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[C:10](Br)[N:6]2[N:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C=O)C.O.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:12]([NH:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[O:13])[CH:9]=[C:10]([C:27]3[CH:26]=[CH:25][N:24]=[C:23]([F:22])[CH:28]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(Br)cc(C(=O)N[C@H]3CC[C@H](O)CC3)c12
Reactant: OB(O)c1ccnc(F)c1
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: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Nc1ncnn2c(-c3ccnc(F)c3)cc(C(=O)N[C@H]3CC[C@H](O)CC3)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A suspension of 3A (39 mg, 0.11 mmol), 2-fluoropyridin-4-ylboronic acid (31 mg, 0.22 mmol) and aq. potassium carbonate (0.14 mL, 0.21 mmol) in 2 mL of degassed DMF was treated with 6 mg (0.006 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was stirred at 100° C. for 2 h, cooled to RT, and diluted with water. The resulting mixture was extracted three times with 9:1 chloroform-ethanol, and the combined organic extracts dried and concentrated. Trituration from ether afforded 3 (8 mg, 18% yield) as a white powder. HPLC: 5.88 min (YMC S5 ODS, 4.5×50 mm. 4 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 12 min). MS (ES): m/z=371 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (br. s, 1H); 8.36-8.44 (m, 3H); 8.16 (s, 1H); 8.15 (s, 1H); 8.01-8.04 (m, 1H); 7.95 (s, 1H); 4.65 (d, 1H, J=4.3 Hz); 3.75-3.86 (m, 1H); 3.40-3.51 (m, 1H); 1.85-1.96 (m, 4H); 1.23-1.49 (m, 4H).
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].S([O-])([O-])(=O)=O.[Mg+2].[CH3:16][C:17]([CH3:19])=O>C(O)(=O)C>[C:17](=[N:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([CH3:19])[CH3:16]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Product: CC(C)=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of tert-butyl hydrazinecarboxylate (25.1 g, 0.190 mol) in acetone (185 mL) was added the magnesium sulfate (6 g) and 12 drops acetic acid. The mixture was heated to reflux for 2.5 h and cooled to rt and filtered. The filtrate was concentrated to give an off-white solid (32 g, 98%) (used in the next step without further purification). LC-MS [M+H]+=172.9, RT=2.11 min.
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1>O1CCCC1>[NH2:1][C:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([O:10][C:11]([F:14])([F:13])[F:12])[N:4]=1
Reactant: Fc1nc(F)nc(OC(F)(F)F)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc(F)nc(OC(F)(F)F)n1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
4.4 g (0.259 mol) of gaseous ammonia were passed over the course of 45 minutes into a stirred mixture of 26.0 g (0.1293 mol) of 2,4-difluoro-6-trifluoromethoxy-1,3,5-triazine and 100 ml of tetrahydrofuran at -70° to -65° C. The mixture was then stirred for 2 hours at -70° C. and overnight while warming to 22° C. The residue from concentration under reduced pressure was stirred with water, filtered off with suction and washed. Drying yielded 22 g (85.9% of theory) of the title compound of melting point 138°-139° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24](I)=[N:25][CH:26]=1>O1CCCC1.[Cl-].[Cl-].[Zn+2].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>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([C:14]2[C:13]([F:12])=[CH:18][CH:17]=[CH:16][C:15]=2[F:19])=[N:25][CH:26]=1
Reactant: Fc1cccc(F)c1
Reactant: Brc1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1cccc(F)c1-c1ccc(Br)cn1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 251.6 %

Procedure:
n-Butyllithium in hexane(2.50 M, 9.02 mL, 22.5 mmol) was added dropwise to a solution of 1,3-difluorobenzene (2.03 mL, 20.6 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. and the resulting solution was stirred at the same temperature for 30 min, then warmed to −50° C. and zinc dichloride in tetrahydrofuran 0.50 M, 45.1 mL, 22.5 mmol) was added slowly. After 20 min, 5-bromo-2-iodopyridine (7.0 g, 25 mmol) in tetrahydrofuran (20 mL) and tetrakis(triphenylphosphine)palladium(0) (1.19 g, 1.03 mmol) were added sequentially. The vessel was partially evacuated and back filled with nitrogen three times, sparged with a gentle stream of nitrogen for 5 minutes, and warmed to ambient temperature. The bright yellow, translucent reaction solution was stirred for 15 minutes at ambient temperature, then heated at 40° C. for 16 hr. The reaction mixture as then cooled to ambient temperature, concentrated, and purified by flash chromatography (90 g silica gel, 0 to 10% ethyl acetate in hexanes) to afford the title compound (14 g) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11](Br)=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Cu][C:17]#[N:18].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([C:17]#[N:18])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of 4-bromoisophthalic acid dimethyl ester 202 (2.95 g, 10.8 mmol) in anhydrous DMF (50 ml), Copper(I) cyanide (1.20 g, 13.5 mmol) was added in one portion. The slurry solution was heated at reflux temperature for one hour. When the solution was cooled to ambient temperature, it was poured into 300 mL of ammonium chloride solution (10%) at 0° C. White precipitate was formed. The slurry solution was stirred at ambient temperature for 30 minutes. Then it was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate. Removal of solvent gave white solid which was washed with cold methanol to give 1.89 g (80%) of 4-cyanoisophthalic acid dimethyl ester 203: 1H NMR (400 MHz, CDCl3) δ 3.95 (s, 3H), 4.05 (s, 3H), 7.91 (d, J=8 Hz, 1H), 8.30 (dd, J=1.7 Hz, J=8 Hz, 1H), 8.77 (d, J=1.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]1([S:15]([OH:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na].N1CCC[C@H]1C(O)=O.[OH-].[Na+]>CCOC(C)=O.[Cu]I.CS(C)=O>[C:9]1([S:15]([C:2]2[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=S(O)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Nc1cncc(S(=O)(=O)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 11 %

Procedure:
To 5-bromopyridin-3-amine (1.59 g, 9.19 mmol) (Aldrich) was added benzenesulfinic acid, sodium salt (1.810 g, 11.03 mmol) (Sigma-Aldrich), copper(I) iodide (0.175 g, 0.919 mmol), (S)-pyrrolidine-2-carboxylic acid (0.212 g, 1.838 mmol), sodium hydroxide (0.074 g, 1.838 mmol), and DMSO (18 mL), and the resulting mixture was stirred at 100° C. for 3 days. The reaction mixture was then diluted with 200 mL of EtOAc, added to a separatory funnel, and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was separated, washed 4 times with 150 mL of sodium bicarbonate (saturated, aqueous), dried over sodium sulfate, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 3% (2 M ammonia in MeOH)/DCM) furnished the title compound (11% yield). m/z (ESI, +ve ion) 235.3 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[CH2:25][N:24]([CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccccc2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
Ethyl 4-(bromomethyl)-3-phenylisoxazole-5-carboxylate (28.1 g, 90.6 mmol) was dissolved in 200 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (22.9 g, 90.6 mmol) and potassium carbonate (9.2 g, 66.4 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (200 mL) and water (100 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude product was purified by flash chromatography (0-40% EtOAc/hexanes) to give 29.6 g of the title compound. MS: (+) m/z 483.73 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccc4ccccc4c3)C2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1ccc2cc(CC[C@H]3CNCCN3)ccc2c1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 76.8 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-(2-naphthalen-2-yl-ethyl)-piperazine (6.53 g, 15.5 mmol) in ethanol (80 mL). Add ammonium formate (5.9 g, 93.6 mmol) and palladium hydroxide (1.5 g, 20 wt. % on carbon) and heat to reflux. After 8.5 h, cool and stir at ambient temperature 18 h. Filter the palladium hydroxide and concentrate the filtrate. Purify by silica gel chromatography using 7N ammonia in methanol-methylene chloride (2.5%–10%) as the eluent to give 2.86 g (77%) of the title compound: mp 151–4° C.; mass spectrum (ion spray): m/z=241 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:26]([CH2:31][OH:32])[CH2:25]3)=[CH:20][CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13].ClCCl.C(N(C(C)C)CC)(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>C(Cl)(Cl)Cl.O>[C:48]([NH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[C@@H:26]([CH2:31][OH:32])[CH2:25]3)=[CH:22][CH:23]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13])(=[O:51])[CH:49]=[CH2:50]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)[C@@H](CO)C3)cc2)nc1Oc1cccc(N)c1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)[C@@H](CO)C4)cc3)c(C(N)=O)nc2CC)c1
Reaction time: 2 h

Procedure:
To a mixture of 5-(3-aminophenoxy)-6-ethyl-3-({4-[(3R)-3-(hydroxymethyl)-4-methylpiperazin-1-yl]phenyl}amino)pyrazine-2-carboxamide (227 mg), dichloromethane (6.8 mL), and diisopropylethylamine (326 μL) was added acryloyl chloride (116 μL) at 0° C., followed by stirring at the same temperature for 2 hours. To the mixture were added water and chloroform, followed by liquid separation. The separated organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue were added tetrahydrofuran (4.5 mL) and a 1 M aqueous sodium hydroxide solution (1.1 mL), followed by stirring at room temperature overnight. The mixture was neutralized by the addition of 1 M hydrochloric acid, and extracted with a mixed solvent of chloroform:methanol (9:1) three times. The separated organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=9:1). A mixed solution of hexane:ethyl acetate (19:1) was added thereto, and the solid was collected by filtration, then washed, and dried under reduced pressure to obtain 5-[3-(acryloylamino)phenoxy]-6-ethyl-3-({4-[(3R)-3-(hydroxymethyl)-4-methylpiperazin-1-yl]phenyl}amino)pyrazine-2-carboxamide (27 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:34])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:25]([N:26]=2)=[C:24]([CH3:27])[N:23]=[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[N:21]=3)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:39][CH:40]([CH2:43][CH3:44])[CH:41]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CO.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:34])[CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:25]([N:26]=2)=[C:24]([CH3:27])[N:23]=[C:22]([N:28]2[CH2:33][CH2:32][N:31]([CH2:39][CH:40]([CH3:41])[CH2:43][CH3:44])[CH2:30][CH2:29]2)[N:21]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(N2CCNCC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Reactant: CCC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(C)CN1CCN(c2nc(C)c3nc(-c4c(NC[C@@H](O)c5cccc(Cl)c5)cc[nH]c4=O)[nH]c3n2)CC1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(3-chloro-phenyl)-2(S)-hydroxy-ethylamino]-3-(6-methyl-2-piperazin-1-yl-9H-purin-8-yl)-1H-pyridin-2-one (20 mg, 0.042 mmol) in a mixture of THF:DMF (1.5 mL:0.5 mL) was added glacial acetic acid (2.3 μl, 0.042 mmol) and 2-methylbutyraldehyde (12 μl, 0.117 mmol). The reaction mixture was stirred at 23° C. for 3 hours followed by the addition of NaBH(OAc)3 (24.9 mg, 0.117 mmol) to the reaction mixture and stirred for an additional 18 hours. MeOH (0.5 mL) was added and the solution was passed through a SCX cartridge (1 g, 0.79 meq/g, varian). The cartridge was eluted with MeOH (16 mL) and with 2N ammonia in MeOH (16 mL). The ammonia solution was evaporated in vacuo and the solid obtained was purified using a Shimadzu automated preparative HPLC System with the method described below. The solution was evaporated on a Savant Speedvac system to give the title compound as a light yellow solid. (14.2 mg, 62%). HPLC 95%; LCMS (+ESI, M+H+) m/z 551; IR (KBr, cm−1) 3403, 2958, 1645, 1616, 1496, 1233; 1H NMR (400 MHz, DMSO+D2O) δ 10.78 (brs, 1H), 7.60-7.29 (m, 5H), 6.22 (m, 1H), 4.97 (m, 1H), 3.80-3.55 (m, 6H), 2.52-2.15 (m, 8H), 1.75 (brs, 1H), 1.41 (brs, 1H), 1.15 (m, 1H) 0.86 (m, 6H). Preparative HPLC Method:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:10][C:11]1[CH:16]=[CH:15][C:14](F)=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1>CN(C=O)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: O=Cc1ccccc1O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A mixture of 2-hydroxybenzaldehyde (16.7 g) and Al2O3 /KF (65.5 g) in DMF was heated to 120° C. under a N2 atmosphere and 4-bromo-1-fluoro-2-nitrobenzene (30 g) in DMF was added. The mixture was stirred at 120° C. for 3 hours. The precipitate was filtered off and the filtrate evaporated. The residue was purified by open column chromatography over silica gel (eluent 1: hexane/CH2Cl2 /AcOEt 8/1/1; eluent 2: CH2Cl2 /2-propanone 9/1) and the pure fractions were collected, yielding 26 g (59%) of 2-(4-bromo-2-nitrophenoxy)benzaldehyde (interm. 3). Analogously, 5-chloro-2-(2-nitrophenoxy)benzaldehyde (interm. 4) was prepared.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>ClCCl>[CH3:22][C:15]1[CH:16]=[C:17]([CH3:21])[C:18]([CH3:20])=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C)c(N2CCNCC2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a mixture of 1-Boc-piperazine (1.39 g), 1-bromo-2,4,5-trimethylbenzene (1 g), tris(dibenzylideneacetone)dipalladium (0) (257 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (481 mg) and sodium tert-butoxide (669 mg) was added toluene (10 mL), and the mixture was refluxed for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g). 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g) was dissolved in dichloromethane (10 mL), 4N hydrogen chloride/dioxane (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4,5-trimethylphenyl)piperazine (920 mg). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (412 mg) and 1-(2,4,5-trimethylphenyl)piperazine (440 mg), the title compound (800 mg) was obtained.
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]2[CH2:10][CH2:11][CH2:12][C:2]1=2.C1COCC1.CCO.O.[Li+].[OH-].Cl>O>[S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: COC(=O)c1cc2c(s1)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(s1)CCC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of methyl 4H,5H,6H-cyclopenta[b]thiophene-2-carboxylate (1 g, 5.49 mmol, 1.00 equiv) in a THF/EtOH/water (10/10/10 mL) mixture was added LiOH (660 mg) at room temperature. The resulting solution was stirred for 3 h at 50° C. in an oil bath and then diluted with 20 mL of water. The pH value of the solution was adjusted to 5 with 2 M aqueous hydrochloric acid. The precipitate was collected by filtration and dried in an oven under reduced pressure to give the desired 4H,5H,6H-cyclopenta[b]thiophene-2-carboxylic acid (0.84 g, 91%) as an off-white solid.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[H-].[Na+].[O:7]=[C:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]([C:18]2[N:23]=[C:22]([CH2:24]S([O-])(=O)=O)[CH:21]=[CH:20][CH:19]=2)=[N:9]1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:4][CH2:24][C:22]1[N:23]=[C:18]([C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:8](=[O:7])[N:9]=2)[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH3:3]
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Reactant: CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.3 %

Procedure:
n-Propyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs, combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.20 g, 20%) as pale yellow crystals.
Reaction SMILES: CN1C2C(=CC(S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=CC=2)C(=O)C1=O.[O:29]([CH2:36][C@@H:37]1[CH2:40][CH2:39][N:38]1[S:41]([C:44]1[CH:45]=[C:46]2[C:50](=[CH:51][CH:52]=1)[NH:49][C:48](=[O:53])[C:47]2=[O:54])(=[O:43])=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[F:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60]Br)=[CH:58][CH:57]=1>>[F:55][C:56]1[CH:63]=[CH:62][C:59]([CH2:60][N:49]2[C:50]3[C:46](=[CH:45][C:44]([S:41]([N:38]4[CH2:39][CH2:40][C@H:37]4[CH2:36][O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)(=[O:43])=[O:42])=[CH:52][CH:51]=3)[C:47](=[O:54])[C:48]2=[O:53])=[CH:58][CH:57]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc2C1=O
Agent: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CC[C@H]3COc3ccccc3)cc21
Yield: 71 %

Procedure:
(S)-1-(4-Fluorobenzyl)-5-(2-phenoxymethyl-azetidine-1-sulfonyl)-1H-indole-2,3-dione (18e) was prepared according to the same procedure for compound 11a, except using compound 17 and 4-fluorobenzyl bromide, and purified with hexanes-ether (1:2) to afford 85 mg (71%) of 18e as an orange solid, mp 164.6-165.7° C. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8 Hz, 1H), 7.97 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.34-7.20 (m, 4H), 7.07 (t, J=8.7 Hz, 2H), 6.94 (t, J=7.2 Hz, 1H), 6.86-6.77 (m, 3H), 4.90 (s, 2H), 4.47 (m, 1H), 4.10 (m, 2H), 3.85 (m, 2H), 2.36-2.22 (m, 2H). Anal. Calcd for C25H21FN2O5S: C, 62.49, H, 4.41; N, 5.83. Found: C, 62.27, H, 4.48; N, 5.69.