Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:32])[C:10](=[C:23]2[NH:24][C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[NH:27]2)[C:11]([C:13]2[CH:14]=[C:15]([S:19]([NH:22][C:33](=[O:35])[CH3:34])(=[O:20])=[O:21])[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonamide (hereinafter referred to as starting compound B, 500 mg), acetic anhydride (5 mL), pyridine (10 mL) and DMF (20 mL) was heated with stirring at 55° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed with aqueous saturated sodium hydrogencarbonate solution and water successively. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)acetamide (58 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]1([CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2C(O)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Li]>C(Cl)Cl.CCOCC>[C:7]1([CH2:13][C:14]2[CH:15]=[CH:19][CH:20]=[CH:21][C:22]=2[C:1](=[O:5])[CH3:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
Oxalyl chloride (4.1 ml, 47 mmol) was added to a solution of 2-(phenylmethyl)benzoic acid (from Aldrich) in methylene chloride (100 ml) over 5 minutes at room temperature. The solution was allowed to stir at room temperature for 2 hours. The solution was concentrated and the resultant orange gum azeotroped with benzene (twice) and placed under high vacuum for 1 hour. In a separate flask, methyl lithium (1.4M in THF, 100 ml, 140 mmol) was added over 10 minutes to a slurry of CuI2 (13.432 gm, 42.3 mmole) in ether (125 ml). The slurry was allowed to stir for 2 minutes. The above-prepared acid chloride in ether (50 ml) at -78° C. was cannulated over 20 minutes into the dimethyl lithiumcuprate solution, which was also cooled to -78° C. The solution stirred for an additional 20 minutes, then was quenched with methanol (30 ml) and warmed to room temperature. The solution was then added to saturated NH4Cl (200 ml), and the aqueous layer was extracted with ether (twice). The organic layers were combined and washed with brine, then dried over MgSO4, filtered and concentrated to afford an orange oil. The crude oil was purified by flash chromatography on Merck silica gel in 5% EtOAc in hexane. The fractions containing the product were combined and concentrated to afford the title compound as a pale yellow solid (3.090 gm, 63%).
Reaction SMILES: [CH:1](Br)=[CH2:2].[Mg].[CH3:5][C:6]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[Cl-].[NH4+]>O1CCCC1>[CH:1]([C:8]1([OH:13])[CH2:9][CH:10]([CH3:12])[CH2:11][C:6]([CH3:14])([CH3:5])[CH2:7]1)=[CH2:2]
Reactant: C=CBr
Reactant: CC1CC(=O)CC(C)(C)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC1(O)CC(C)CC(C)(C)C1
Yield: 74.1 %

Procedure:
A Grignard compound is prepared from 80 g of vinyl bromide and 20 g of magnesium in 1 litre of tetrahydrofuran. To this Grignard compound there are added dropwise at room temperature 100 g of 3,3,5-trimethylcyclohexanone (dihydroisophorone) in 100 ml of tetrahydrofuran. The mixture is held at reflux temperature for 12 hours. The mixture is then cooled, treated with saturated ammonium chloride solution and extracted with ether. The organic phase is washed neutral with saturated sodium chloride solution, dried and evaporated. The crude product is distilled in a high vacuum (55° C./0.1 mm Hg). There are obtained 88.9 g of 1-vinyl-1-hydroxy-3,3,5-trimethyl-cyclohexane.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:32]=[O:33].O>C1(C)C=CC=CC=1>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH:9]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:32]=[O:33])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ncc1C(Sc1ccccc1)c1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C=O)ncc1C(Sc1ccccc1)c1cc(F)ccc1F
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo-5-[(2,5-difluorophenyl)(phenylthio)methyl]-4-methyl pyridine (1.2 g, 3.0 mmol) in toluene (30 ml) was cooled to −78° C., and n-butyllithium (1.54 M hexane solution, 2.5 ml, 3.9 mmol) was added in an argon atmosphere. After stirring for 10 minutes at the same temperature, the mixture was allowed to warm to −40° C., stirred for 30 minutes, and cooled again to −78° C., and N,N-dimethylformamide (302 μl, 3.9 mmol) was added thereto. After stirring for 30 minutes at the same temperature, water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=93:7 was concentrated under reduced pressure to obtain the title compound mg, 0.70 mmol, 25%) as a colorless oily substance.
Reaction SMILES: C([Si:4]1([C:11]2[CH:16]=[CH:15]C=CC=2)[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)CC.Cl[C:18]1[CH:23]=[C:22]([F:24])[C:21]([Si](C)(C)C)=[C:20]([F:29])[CH:19]=1.Br[C:31]1[CH:36]=[C:35]([F:37])[C:34]([C:38]([F:41])=[CH:39][F:40])=[C:33]([F:42])[CH:32]=1>>[CH2:11]([Si@H:4]1[CH2:5][CH2:6][C@H:7]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([C:31]3[CH:32]=[C:33]([F:42])[C:34]([C:38]([F:41])=[CH:39][F:40])=[C:35]([F:37])[CH:36]=3)=[C:20]([F:29])[CH:19]=2)[CH2:8][CH2:9]1)[CH2:16][CH3:15]
Reactant: FC=C(F)c1c(F)cc(Br)cc1F
Reactant: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Product: CCC[Si@H]1CC[C@H](c2cc(F)c(-c3cc(F)c(C(F)=CF)c(F)c3)c(F)c2)CC1

Procedure:
The general procedure of Example 35 was repeated using 4-propyl-4-phenyl-4-silacyclohexanone instead of 4-pentyl-4-phenyl-4-silacyclohexanone, 4-chloro-2,6-difluorophenyltrimethylsilane instead of 4-chlorophenyltrimethylsilane, and 4-bromo-2,6-difluoro-1-(1,2-difluorovinyl)benzene instead of 4-bromo-2,6-difluoro-1-(2,2-difluorovinyloxy)benzene, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].S(Cl)(C)(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)CC(C)C=C[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 84.2 %

Procedure:
After dissolving 9.0 g of 3,5-dimethyl-1-nitro-2-hexanol in 100 ml of dichloromethane, 6.5 g of mesyl chloride and 10.4 g of triethylamine were gradually dropped thereto at 4° C., respectively. The temperature of the solution was allowed to rise to room temperature, and the solution was stirred for 1.5 hours. Water was added to stop the reaction, and the solution was extracted with dichloromethane. The organic layer was dried with magnesium sulfate and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=10/1), thereby obtaining 6.8 g of 3,5-dimethyl-1-nitrohex-1-ene (yield: 83.9%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(F)cc2)CC1

Procedure:
2-(3-Chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (28.1 g), triethylamine (14 cc) and 1-(4-fluorophenyl)piperazine (18.8 g) in toluene (300 cc) are heated for 8 hours at boiling point. The mixture is then cooled to a temperature of about 20.C and stirring is maintained for 15 hours at this temperature. The precipitate formed is separated by filtration and washed with toluene (2×50 cc). The filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.1-1.5 bar) with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (150 cc). 2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide is obtained, m.p. 95°-97° C.
Reaction SMILES: [CH2:1]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].OC(C(O)(C)C)(C)C.[Li]CCCC.[B:24]([O:33][CH:34]([CH3:36])[CH3:35])([O:29][CH:30]([CH3:32])[CH3:31])OC(C)C>C1COCC1.CCCCCC>[CH3:36][C:34]1([CH3:35])[C:30]([CH3:31])([CH3:32])[O:29][B:24]([C:8]2[S:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:10][CH:9]=2)[O:33]1
Reactant: CCCCCc1cccs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 81.7 %

Procedure:
To a cooled (−78° C.) mixture of 2-n-pentylthiophene (5.0 g, 32.1 mmol) and pinacol (11.5 g, 97.23 mmol) in anhydrous THF (60 mL) was added dropwise to a solution of n-BuLi (22.3 mL, 35.6 mmol) in hexane. The mixture was stirred at −78° C. for 10 minute. The reaction mixture was then brought to 0° C. and stirred for 1 h before cooling to −78° C. before the addition of triisopropyl borate (7.3 g, 38.9 mmol) in THF (24 mL) using a dropping funnel. The mixture was slowly brought to room temperature while stirring overnight. The crude product was purified by flash chromatography (silica gel. eluent: hexane/EA) 10:1) to afford a reddish brown liquid 7.35 g (81.0%).
Reaction SMILES: C(OC([N:8]1[CH:16]([CH3:17])[C:15]2[C:14]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:40])[NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)[CH:23]=[CH:22]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:36]([F:37])([F:38])[C:32]1[CH:31]=[C:30]([NH:29][C:28]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][C:14]4[C:15]5[CH:16]([CH3:17])[NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:27][CH:26]=3)[CH:22]=[CH:23]2)=[O:40])[CH:35]=[CH:34][CH:33]=1
Reactant: CC1c2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NCc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c21
Temperature: 25 °C

Procedure:
To a solution of 5-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 ml, 134 mmol) is added at 0° C. After 30 min the reaction is warmed to rt. At this point, the reaction is evaporated and the crude product is dissolved in EtOAc. A Few drops of NH4OH are added to freebase the amine and the whole mixture is then evaporated. The crude product is added to a silica gel column and is eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1) to give racemic 5-(5-Methyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 454.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.50 (s, 1H) 8.33 (s, 1H) 8.06 (s, 1H) 7.94 (br. S., 2H) 7.57 (s, 1H) 7.42 (br. S., 2H) 7.12 (d, J=9.09 Hz, 1H) 6.75 (d, J=3.03 Hz, 1H) 4.70 (br. S., 1H) 4.10-4.22 (m, 2H) 1.60 (d, J=6.57 Hz, 3H). Racemate is then separated using chiral HPLC (IA column; 40% heptane, 60% Ethanol) to give the corresponding enantiomers D-1 and D-2.
Reaction SMILES: [N+:1]([C:4]1[C:5]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[C:5]([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Oc2ccc([N+](=O)[O-])c(Oc3cccc(C#N)c3)n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1

Procedure:
To 3,3'-[3-nitro-2,6-pyridinediylbis(oxy)]bis(benzonitrile)(18.5 g, 50 mmol) dissolved in ethanol/ethyl acetate (500 mL, 2/3) was added 10% palladium on carbon (1.8 g). After subjecting the mixture to hydrogen at 15 psi for 2 hours, the reaction was suction filtered through celite. The solvent was removed in vacuo to give 3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile); NMR (CDCl3) 7.5 (m,7), 7.2 (m,2), 6.6 (d,1), 3.8 (br,2) ppm.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCCCCCCCCCCCCCCCBr
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.3 g of sodium ethoxide was added thereto. A solution of 6.5 g of docosyl bromide in 20 ml of dry ethanol was added thereto while stirring at room temperature. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4.2 g of diethyl 2-acetamido-2-docosylmalonate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=O)[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[S:34])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2cc(C)c(C)cc2C(=S)N1c1cccnc1
Yield: 167.6 %

Procedure:
5,6-Dimethyl-3-ethoxycarbonylmethyl-2-(3-pyridyl)-isoindolin-1-one [IUPAC name: ethyl 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetate] (0.10 g, 0.31 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (69 mg, 0.17 mmol) were heated under reflux in toluene (1.5 ml) under an argon atmosphere for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=10:1) to give 97 mg of the title compound.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([I:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.F[C:13]1C(F)=CC=CC=1N.FC1C=CC(C)=CC=1N>>[I:11][C:8]1[S:9][C:10]2[CH:2]=[CH:3][C:4]([CH3:13])=[CH:5][C:6]=2[N:7]=1
Reactant: Nc1cccc(F)c1F
Reactant: Fc1cccc2nc(I)sc12
Agent: Cc1ccc(F)c(N)c1
Product: Cc1ccc2sc(I)nc2c1

Procedure:
The title compound was prepared following the route for 7-fluoro-2-iodo-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2-fluoro-5-methylaniline and conducting the first step at 180° C. for 48 h in a sealed tube.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[CH:36]=[CH:35][C:23]([CH2:24][O:25][C:26]3([C:30]([O:32]CC)=[O:31])[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C1COCC1.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[N:3]([C:20]2[CH:36]=[CH:35][C:23]([CH2:24][O:25][C:26]3([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:4]2[C:9]([C:10]=1[C:11](=[O:19])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCOC(=O)C1(OCc2ccc(-n3c(C)c(C(=O)c4ccc(C)cc4)c4ccccc43)cc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)n(-c3ccc(COC4(C(=O)O)CCC4)cc3)c3ccccc23)cc1
Yield: 44.1 %

Procedure:
The compound of Example 86-1 (36 mg, 0.07 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 1N aqueous sodium hydroxide solution (1 ml), followed by stirring under reflux for 20 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (14 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.I[CH3:17]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:17])[C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: CI
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Yield: 88.9 %

Procedure:
8-Fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (Step 1, 3.13 g, 0.0149 mol) and iodomethane (1.39 ml, 0.0223 mol) in DMF (25 ml) are stirred at room temperature overnight. The reaction is diluted with water and the resulting precipitate collected by filtration, washed well with water, and dried under vacuum to give the title compound as an orange solid (2.97 g, 89%); 1H NMR (300 MHz, CDCl3) δ 2.56-2.61 (m, 2H), 2.99-3.04 (m, 2H), 3.32 (s, 3H), overlapping 8.06 (s, 1H) and 8.08 (dd, 1H); [M+H]+=225.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.P(Br)(Br)[Br:14].CCOCC>C(Cl)Cl>[Br:14][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: BrP(Br)Br
Reactant: SCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCc1c[nH]c2ccccc12

Procedure:
The starting materials of formula II in which X1 is mercapto, --S--SO3Na or --S--SO3K, and R2, R3, R4, R5, R6 and R7 are as defined in the first instance are obtained by the following process: The appropriate compound of formula II (XI =OH) described above, is treated with phosphorus tribromide in an inert solvent, for example, ether or methylene chloride- to afford the corresponding 3-(2-bromoethyl)-indole derivative. The latter compound is then converted to the desired starting material of formula II (X1 = SH) by a procedure similar to that described by N. N. Suvorov and V. N. Buyonav, Khim.-Farm. Zh., 1, (1967), [Chem. Abstr. 67, 7347a (1967)], for converting 3-(2-bromoethyl)-indole to indole 3-ethanethiol (II; R2, R3, R4, R5 and R6 = H and X1 = SH). Accordingly, the appropriate 3-(2-bromoethyl)-indole derivative is treated with sodium or potassium thiosulfate to afford the corresponding sodium or potassium β-(3-indolyl)ethyl thiosulfate derivative, respectively: namely the desired starting materials of formula II (X=--S--SO3Na or --S--SO3K). Treatment of the latter product with strong alkali, for example, sodium or potassium hydroxide, yeilds the corresponding bis[ω-(3-indolyl)ethyl]-disulfide derivative. Reduction of the latter compound with lithium aluminum hydride gives the desired compounds of formula II (X1 = SH).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[C:18]([NH:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)C(N)CS
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NC(CS)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mL) was added to a suspension of ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DCM (50 mL). The resulting mixture was cooled in an ice/salt bath and butyryl chloride (3.3 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 3 g.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH2:4][CH2:3][NH:2]1.[Br:15]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:15][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:5]2[CH2:4][CH2:3][NH:2][C:1](=[O:14])[C:6]=12
Reactant: O=C1NCCn2c1cc1c2CCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCn2c3c(c(Br)c21)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 1H,2H,3H,4H,6H,7H,8H,9H-pyrazino[1,2-a]indol-1-one 104j (9.5 g, 49.94 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL), followed by the addition of N-bromosuccinimide (9.8 g, 55.06 mmol, 1.10 equiv) in several batches at 0° C. The resulting solution was stirred at room temperature for 2 h and diluted with 500 mL of water. The precipitate was filtered and dried in a vacuum oven to afford 9.5 g (71%) of 119a as a light brown solid.