Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][C:7]=1[Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Product: CC1NC(=O)NN=C1c1ccc(N)c(Br)c1
Yield: 83.1 %

Procedure:
6-(4-Aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (5 g) was reacted with N-bromosuccinimide (4.36 g) in the same manner as Example 12 to give 6-(4-amino-3-bromophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (5.76 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][OH:21])[C@H:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[C@H:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@@H](OC(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 5.5 h
Yield: 100.7 %

Procedure:
To a solution of (1R,2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert-butoxy)propanamine (1.6 g, 5.4 mmol) in anh. pyridine (30 mL) at 4° C. was added methanesulfonyl chloride (0.75 mL, 9.7 mmol) dropwise. The reaction was stirred for 5.5 h, then was diluted with EtOAc (200 mL) and washed with a 1N HCl solution (4×200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield (1R,2R)-N-(benzyloxycarbonyl)-1-(methanesulfonyloxymethyl)-2-(tert-butoxy)propanamine as an oil (2.03 g, 100%): TLC (25% EtOAc/hex) Rf0.31.
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:30]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:27][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2CO3 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added MeI (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCl (50 mL) and extracted with ethyl acetate (3×25 mL). The separated organic layer was washed with 10% aq. NaHCO3 (25 mL), brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 58 mg (56%) of the title compound as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:33][CH2:34][CH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1.O>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10](=[N:27][N:28]([CH2:33][CH2:34][CH2:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[CH:29]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:13]=2[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: BrCCCOC1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc3nn(CCCOC4CCCCO4)cc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 52.2 %

Procedure:
A suspension of 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.30 g, 0.8 mmol, obtained in example 1), KOH (0.05 g, 0.8 mmol) and crown ether 18-C-6 (0.01 g, 0.03 mmol) in toluene (10 mL) was heated to 100° C. for 1 h. 2-(3-Bromopropoxy)tetrahydropyran (0.17 g, 0.8 mmol) was, added and stirred at 100° C. for 24 h. It was allowed to cool, water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 0.22 g of the desired compound (yield: 54%).
Reaction SMILES: C(OC([N:8]1[CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH:27]C(OC(C)(C)C)=O)[CH:24]([CH3:26])[CH3:25])[CH3:20])[CH2:16][NH:15][C:14]2[NH:13][C:12]([N:37]=CN(C)C)=[N:11][C:10](=[O:42])[C:9]1=2)=O)(C)(C)C.[ClH:43].O1CCOCC1>O1CCOCC1>[ClH:43].[ClH:43].[NH2:37][C:12]1[NH:11][C:10](=[O:42])[C:9]2[NH:8][CH:17]([CH:18]([OH:36])[CH:19]([O:21][C:22](=[O:35])[CH:23]([NH2:27])[CH:24]([CH3:25])[CH3:26])[CH3:20])[CH2:16][NH:15][C:14]=2[N:13]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC(C)C(O)C1CNc2[nH]c(N=CN(C)C)nc(=O)c2N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(N)C(=O)OC(C)C(O)C1CNc2nc(N)[nH]c(=O)c2N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.6 %

Procedure:
As an alternative to method e,) the product of step c (0.5 g, 0.8 mmol) was dissolved in dioxane (5 mL) and treated with 4N HCl/dioxane (20 mL, 80 mmol) under an atmosphere of argon. After stirring at room temperature for 15 hours, a white solid was formed. This material was isolated and then dried to give 0.24 g (73%) of the title compound.
Reaction SMILES: [CH2:1](OCC)C.O1[CH2:10][CH2:9][CH2:8]C1.C(Cl)Cl.C(Cl)(Cl)Cl.[N:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C(N(CC)CC)C>[CH:9]([N:18]([CH:19]([CH3:20])[CH3:1])[CH2:23][CH3:22])([CH3:10])[CH3:8]
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(C)C)C(C)C

Procedure:
As shown in reaction Scheme G, treatment of 2-arylindole (17) with oxalyl chloride neat or in an inert organic solvent such as methylene chloride, chloroform, dichloroethane, tetrahydrofuran or the like at a temperature of 25°-65° C. for a period of 3-24 hours gives the acylchloride adduct (18). The crude product (18) may be reacted with an amine of type (19) in an inert organic solvent such as diethylether, tetrahydrofuran, methylene chloride, chloroform or the like and an amine base such as triethylamine, diisopropylethylamine or pyridine at a temperature of 0°C.-25° C. for a period of 30 minutes to 4 hours to provide the amide derivative (20). Amide (20) may be further modified by treatment with a reducing agent such as borane or lithium aluminum hydride in an inert organic solvent such as tetrahydrofuran at elevated temperatures, preferably reflux, for a period of 1-5 hours to give compound (21). ##STR16##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:38]5[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Product: c1cc(-c2ccncc2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Yield: 42 %

Procedure:
In a similar manner as described in Example 29 from 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.19 mmol) and pyridine-4-boronic acid, N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(4-pyridinyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (41 mg, 42%) was obtained as a yellow foam. 1H NMR (CDCl3): δ 8.66 (d, 2H), 8.02 (d, 1H), 7.96 (s, 1H), 7.76–7.69 (m, 3H), 7.58–7.51 (m, 3H), 7.33 (t, 1H), 6.36 (d, 1H), 6.06–6.04 (m, 2H), 5.15 (m, 1H), 4.32 (m, 1H), 4.01 (m, 1H), 2.17–2.03 (m, 4H), 1.81–1.52 (m, 12H); MS m/z 516 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:15]#[N:16]>CN1C(=O)CCC1.O>[C:15]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: CCc1ccc(C(=O)OC)cc1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc(C(=O)OC)cc1C#N
Temperature: 20 °C
Yield: 48.8 %

Procedure:
Methyl 3-bromo-4-ethyl-benzoate (D44) (5 g) in NMP (180 mL) was treated with copper (I) cyanide (3.69 g). The mixture was then heated at reflux for 5 h, under argon. After cooling to 20° C. the reaction mixture was diluted with water, then filtered through kieselguhr, washing well with water and EtOAc. The organic layer was washed with water, brine and dried over MgSO4. The solvent was evaporated to dryness in vacuo and the residue was purified by chromatography on silica eluting with EtOAc-Hexane (1:9) to give the title compound (1.9 g) 1H NMR (CDCl3) δ 1.33 (3H, t), 2.94 (2H, q), 3.94 (3H, s), 7.43 (1H, d), 8.17 (1H, dd), 8.28 (1H, d).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=3)[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Cl:22][C:5]1[C:6]([C:18]([F:19])([F:20])[F:21])=[N:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Intermediate 16 (1.5 g, 5.0 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.8 g, 6 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) and purification afforded the title compound (0.802 g). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.34 (d, J 2.5, 1H), 8.65 (dd, J 2.5, 9, 1H), 8.09 (d, J 9, 1H), 2.48-2.38 (m, 1H), 1.13-1.03 (m, 2H), 0.90-0.82 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:6]=CS[C:3]=1[C:7](=[C:9]([C:12]#[N:13])[C:10]#[N:11])[OH:8].C(#N)CC#N.ClC1C=CSC=1C(Cl)=O>>[CH:3]1([C:7](=[C:9]([C:10]#[N:11])[C:12]#[N:13])[OH:8])[CH2:2][CH2:6]1
Reactant: N#CC(C#N)=C(O)c1sccc1Cl
Agent: O=C(Cl)c1sccc1Cl
Solvent: N#CCC#N
Product: N#CC(C#N)=C(O)C1CC1

Procedure:
In a similar manner as described above, [(3-chloro(2-thienyl))hydroxymethylene]methane-1,1-dicarbonitrile was prepared from malononitrile and 3-chlorothiophene-2-carbonylchloride. The NMR data and ESI/MS data of the compound are given below.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][C:3]([C:6]([OH:8])=[O:7])([OH:5])[CH3:4].C(O)(=O)/C(=C\[C:15]([OH:17])=[O:16])/C.C(O)(=O)C(CC(O)=O)=C.C(C(O)=O)/C(/C(O)=O)=C\C(O)=O>>[C:1]([OH:10])(=[O:9])[CH2:2][C:3]([CH2:4][C:15]([OH:17])=[O:16])([C:6]([OH:8])=[O:7])[OH:5]
Reactant: CC(O)(CC(=O)O)C(=O)O
Reactant: C/C(=C/C(=O)O)C(=O)O
Agent: C=C(CC(=O)O)C(=O)O
Agent: O=C(O)/C=C(\CC(=O)O)C(=O)O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Yield: 47 %

Procedure:
Trans-aconitic acid, 17.4 g (0.10 mole) is dissolved in 300 mls of water. An excess of magnesium hydroxide, 25 g (0.43 mole), is added. This brings the pH to 9.0 and produces a mixture of the magnesium salt of trans-aconitic acid and free magnesium hydroxide. The resulting mixture is then stirred and heated for 6 hours in a Parr pressure reactor at a temperature of 170° C. The reaction mixture is then cooled, mixed with 143 g of 30% sulfuric acid solution and the resulting solution evaporated to dryness in vacuo. The evaporation residue is then extracted with 400 mls of acetone and the acetone extract filtered to remove MgSO4. The acetone filtrate is then evaporated to give 19 g of a residue containing 47% (47% yield) of citric acid, 9% citramalic acid, 5% citraconic acid, 10% itaconic acid, 12% trans-aconitic acid and the balance, water.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH2:39][CH3:40])[N:37]=[CH:36][CH:35]=1.NN.[CH3:43][OH:44].C1C[O:48]CC1>>[C:43]([OH:48])([C:30]([F:33])([F:32])[F:31])=[O:44].[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH2:39][CH3:40])[N:37]=[CH:36][CH:35]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: C1CCOC1
Reactant: CCn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reactant: CO
Agent: NN
Product: CCn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)sc1Cl
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (110 mg, 0.19 mmol) in MeOH/THF (5 mL/0.5 mL) was added hydrazine (0.5 mL, 15.9 mmol). After stirring overnight at RT, the reaction mixture was concentrated, and purified by reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) to afford the bis-TFA salt of the title compound. The bis-TFA salt was dissolved in water, and neutralized by ammonium hydroxide. The mixture was extracted with DCM (5 mL×3), dried over Na2SO4, and concentrated to give a free base of the title compound, which was dissolved in MeOH (2 mL), and treated with HCl (aq, 37%). After stirring overnight, the reaction solution was concentrated to give the title compound (26 mg, 26%) as a di-HCl salt: LC-MS (ES) m/z=457 (M+H)+. 1H NMR (d4-MeOD, 400 MHz) δ ppm 8.28 (d, J=2.5 Hz, 1H), 8.07 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.53 (dd, J=7.3, 7.6 Hz, 1H), 7.43 (dd, J=7.6, 7.6 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 4.66 (m, 1H), 4.43 (q, J=7.3 Hz, 2H), 3.37-3.16 (m, 4H), and 1.50 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]([CH:9]([C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(=O)C.[NH4+:23]>O.[OH-].[Na+]>[C:17]1([C:12]2[NH:23][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:11]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:19]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(-c2ccc(-c3ccccc3)[nH]2)cc1
Temperature: 100 °C

Procedure:
Dibenzoylethane (1.50 g, 6.30 mmol) and ammonium acetate (2.00 g, 25.2 mmol) were mixed together and the mixture was heated to 100° C. for 4 hours. The reaction mixture was cooled down to room temperature, diluted with 30 ml of water and basified with 1N NaOH until pH 14. The reaction mixture was extracted several times with chloroform. The combined organic phases were washed with 1N NaOH, water, brine and dried over MgSO4. Filtration and concentration afforded a crude product which was purified on silica gel column with hexanes/ethyl acetate (10/1) as eluant, the product was collected to yield after evaporation to dryness 0.90 g (65.2%). A light yellow solid; 1H-NMR (CDCl3): 67 ppm 7.20-7.60 (m, ArH, 10H), 6.6 (d, ArH, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:18])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]=2[CH:17]=1.[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2[CH2:25][CH2:26][CH2:27][CH2:28][C:20]1=2.O>C(O)(=O)C>[CH2:15]([O:14][C:12]([CH2:11][N:7]1[C:6]2[CH:17]=[C:2]([N:1]3[C:22](=[O:23])[C:21]4[CH2:25][CH2:26][CH2:27][CH2:28][C:20]=4[C:19]3=[O:24])[C:3]([F:18])=[CH:4][C:5]=2[S:9][C:8]1=[O:10])=[O:13])[CH3:16]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCOC(=O)Cn1c(=O)sc2cc(F)c(N)cc21
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cn1c(=O)sc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 19.1 %

Procedure:
5-Amino-3-ethoxycarbonylmethyl-6-fluoro-2(3H)benzothiazolone (140 mg) and 3,4,5,6-tetrahydrophthalic anhydride (90 mg) were suspended in acetic acid (3 ml), and the resultant suspension was heated under reflux for 5 hours. After being allowed to cool, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel thin layer chromatography with a mixture of ethyl acetate and hexane (1:2) to give 2-[3-ethoxycarbonylmethyl-6-fluoro-2(3H)-benzothiazolon-5-yl]4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (40 mg). m.p., 155.5°-156.5° C.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.N12CCCN=C1CCCCC2.[C:35]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)C>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([S:42]([CH2:41][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:44])=[O:43])[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: I
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1onc2c1c(=O)n(C1CCCN(S(=O)(=O)Cc3ccccc3)C1)c1cccc(Cl)c21
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a 0° C. suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol) in ethanol (5 mL) add 1,8-diazabicyclo[5.4.0]undec-7-ene (42 μL, 0.28 mmol). Stir the solution for 10 mins. To the solution add α-toluene-sulfonyl chloride (21 mg, 0.11 mmol) and stir the reaction at 0° C. under nitrogen for 30 minutes. Quench the reaction with 1N HCl, concentrate, and extract with 20% isopropanol/chloroform (×2). Wash the combined organic layers with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.4% methanol/chloroform) to give 37.9 mg of the title compound as a white solid, 72% yield. 1H NMR: consistent with structure. MS (ion spray) 472 (M+).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:27])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1F
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-fluoro-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.73 (s, 1H), 8.69 (d, 1H), 8.28 (d, 1H), 8.21 (d, 1H), 8.11 (d, 1H), 7.99 (d, 1H), 7.83 (t, 1H), 7.76 (m, 2H), 7.64 (m, 1H), 7.40 (q, 2H), 4.00 (d, 1H), 3.60 (d, 1H), 3.26 (m, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.17 (t, 2H), 1.46 (m, 2H), 1.43 (q, 2H), 1.17 (m, 1H), 0.82 (t, 3H); LC/MS m/z 496 (M−H)−, 498 (M+H)+
Reaction SMILES: [CH2:1]([P:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:26][CH3:27]>CCCCCC>[I-:26].[CH2:18]([P+:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CI
Reactant: CCCCCCCCP(CCCCCCCC)CCCCCCCC
Solvent: CCCCCC
Product: CCCCCCCC[P+](C)(CCCCCCCC)CCCCCCCC
Product: [I-]
Yield: 80 %

Procedure:
To 185 g (0.5 mol) of a commercially available tri-n-octylphosphine (product name: HISHICOLIN (registered trademark) P-8, manufactured by Nippon Chemical Industrial Co., Ltd.), 71 g (0.5 mol) of iodomethane (reagent, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise under a nitrogen atmosphere, and the mixture was reacted at 30 to 40° C. for 5 hours. After the reaction was completed, 100 ml of hexane was added to the reaction mixture to separate layers. The resulting liquid was then washed three times with hexane and vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours to obtain 205 g (yield 80%) of tri-n-octylmethylphosphonium iodide. To 41 g (0.08 mol) of the resulting tri-n-octylmethylphosphonium iodide, was added 41 g of pure water. To the mixture with stirring, was added 23 g (0.08 mol) of lithium bis(trifluoromethylsulfonyl)imide (reagent, manufactured by Kanto Chemical Co., Inc.) to allow them to react with each other, followed by stirring for 2 hours at room temperature for aging. After the completion of aging with stirring, the lower layer (product) was separated from the mixture and washed four times with pure water. After the completion of the washing, the product was vacuum dried under a degree of vacuum of 0.5 kPa at 80° C. for 3 hours. The structure of the resulting product was examined by 1H-NMR, 13C-NMR, 19F-NMR, and 31P-NMR. The product was identified as tri-n-octylmethylphosphonium bis(trifluoromethylsulfonyl)imide (TOMP-TFSI), and it had a purity of 99%. The resulting TOMP-TFSI was a colorless transparent liquid at room temperature (25° C.), which had a moisture content determined by the Karl Fischer titration method of 65 ppm and a chlorine content determined by ion chromatography of 10 ppm. The amount of the product yielded was 49 g (yield 92%). The product had an electrical conductivity at 25° C. of 0.09 mS/cm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2=O)[C:5]([O:7][CH3:8])=[O:6].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2)[C:5]([O:7][CH3:8])=[O:6]
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C(C(=O)OC)c1cccc2c1NC(=O)C2

Procedure:
A solution of 2,3-dihydro-2,3-dioxo-1H-indole-7-propandioic acid dimethyl ester (1.4 g, 0.0048 mole) is dissolved in acetic acid (100 ml) and in the presence of 20% Pd/C is treated with hydrogen gas at 50 psi. The solution is filtered and concentrated to yield 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester. This is purified by flash chromatography on silica (elution with 7:3 hexane: ethyl acetate) to give after concentration pure 2,3-dihydro-2-oxo-1H-indole-7-propandioic acid dimethyl ester, mp 161°-161.5° C.