Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[CH3:20])(=[O:12])=[O:11])[S:7][CH:8]=1.Br[CH2:22][CH2:23][CH2:24][C:25](OCC)=[O:26].CCN(C(C)C)C(C)C.[I-].[K+]>C(O)C.CS(C)=O>[Cl:19][C:15]1[C:14]([CH3:20])=[C:13]([S:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][N:1]3[CH2:22][CH2:23][CH2:24][C:25]3=[O:26])[N:5]=2)(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCCBr
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN)cs1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN2CCCC2=O)cs1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 200A (200 mg, 0.60 mmol), ethyl 4-bromobutyrate (118 mg, 0.60 mmol), DIEA (156 mg, 1.20) and potassium iodide (10 mg, 0.06 mmol) in ethanol (5 mL)/DMSO (2 mL) was refluxed overnight, allowed to cool to room temperature, and extracted with ethyl acetate. The organic phase was separated, dried over sodium sulphate, filtered and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with 20% acetone in DCM giving 18 mg (7%) of solid material: 1H NMR (CDCl3) δ 2.00 (qn, 2H), 2.38 (t, 2H), 2.65 (s, 3H), 2.88 (t, 2H), 3.40 (t, 2H), 3.58 (t, 2H), 6.24 (s, 1H), 7.22 (t, 1H), 7.52 (dd, 1H), 8.01 (dd, 1H); MS (Ionspray, [M+H]+) m/z 399.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:11])=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:12][C:13]([CH:15]=O)=O.O>C(O)C>[CH3:15][C:13]1[CH:12]=[N:10][C:6]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=2)[N:11]=1
Reactant: CC(=O)C=O
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: CCO
Solvent: O
Product: Cc1cnc2cccc([N+](=O)[O-])c2n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To a solution of 3-nitro-1,2-phenylenediamine (5.02 g) in ethanol (500 mL) was added at 60° C. a 40% aqueous solution of pyruvic aldehyde (17.72 g). The reaction solution was refluxed for 10 minutes, and thereto was added water (300 mL). The mixture was cooled to room temperature, and concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with cold water, and dried under reduced pressure to give 2-methyl-8-nitroquinoxaline (4.17 g, 67%) as orange crystals.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]([F:18])([F:17])[CH2:8][CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1.CC(N(C)C)=O.O>C(Cl)(Cl)Cl>[Cl:4][C:14]1[S:13][C:12]([S:11][CH2:10][CH2:9][CH2:8][C:7]([Cl:6])([F:17])[F:18])=[N:16][CH:15]=1
Reactant: FC(F)(Cl)CCCSc1nccs1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(Cl)CCCSc1ncc(Cl)s1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of sulfuryl chloride (2.94 g) and chloroform (10 ml) was added dropwise over a period of one hour to a stirred mixture of 2-(4-chloro-4,4-difluorobutylthio)thiazole (4.85 g), and dimethylacetamide (47 g) maintained at 45° C. under a nitrogen atmosphere and the resultant mixture stirred for a further one hour. A further aliquot of sulfuryl chloride (0.58 g) dissolved in chloroform (5.0 ml) was then added over 45 minutes and the mixture stirred for a further 30 minutes. After cooling the reaction mixture to the ambient temperature water (50 ml) was added and the mixture extracted with hexane (3×50 ml). The hexane solution was washed with water (50 ml), saturated aqueous sodium bicarbonate solution (50 ml) and water (50 ml) and then dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure yielded of 5-chloro-2-(4-chloro-4,4-difluorobutylthio)thiazole (5.0 g, 87%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.CN1CCCC1=O>[CH2:32]([NH:39][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture consisting of 2-bromo-4-methylthiazole-5-carboxylic acid (Sigma-Aldrich, 1.0 g), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (EDC, 1.3 g), 1-hydroxybenzotriazole (0.613 g), N-methyl-2-pyrrolidinone (0.48 mL) in N,N-dimethylformamide was added a mixture consisting of benzylamine (0.54 mL) in N,N-dimethylformamide (5 mL). The reaction mixture was stirred overnight at room temperature and was subsequently partitioned between ethyl acetate (200 mL) and water (200 mL). The layers were separated and the organic phase was further washed twice with water (2×200 mL) and brine solution (150 mL), was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure afforded the title intermediate as a crude yellow oil (1.847 g; major spot Rf 0.45 with 3:1 v/v hexanes-ethyl acetate solvent system) that solidified on standing at room temperature; MS (ESI−) m/z 311.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.CC(C)([O-])C.[K+].ClCCl>CN(C=O)C.C1(C)C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: COC(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 130 °C
Yield: 46.1 %

Procedure:
Methyl piperidine-4-carboxylate (2.0 g, 14 mmol), 1-bromo-3-(trifluoromethyl)benzene (1.5 g, 6.8 mmol), and potassium tert-butoxide (0.76 g, 6.8 mmol) in a mixed solvent of toluene (20 mL) and DMF (4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.3. g, 0.4 mmol) under nitrogen. The mixture was heated at 130° C. in an oil bath overnight. After cooling to room temperature, the mixture was filtered through celite and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried (MgSO4), concentrated and flash chromatographed with EtOAc/hexanes (20% to 40%) to give 0.90 g of product. MS (M+H) 288.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17]([O-])([O-])OCC>C(OCC)C>[F:10][C:8]([F:9])([F:11])[C:6]1[C:5]([F:12])=[CH:4][C:3]2[S:13](=[O:14])(=[O:15])[NH:16][CH:17]=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(F)cc1S(N)(=O)=O
Reactant: CCOC([O-])[O-]
Solvent: CCOCC
Product: O=S1(=O)NC=Nc2cc(C(F)(F)F)c(F)cc21
Yield: 91.5 %

Procedure:
A mixture of 6 g 2-amino-4-trifluoromethyl-5-fluoro-benzenesulfonamide, m.p.= 152° C. (formula V: R2 = F) and 18 g ethyl orthoformate is heated at 120°-125° C., during 30 minutes to one hour, in an open vessel. After cooling, the reaction mixture is diluted with 150 ml dry diethyl ether. The resulting precipitate is collected and recrystallized from aqueous ethanol, to give 5.7 g of 6-trifluoromethyl-7-fluoro-2H-1,2,4-benzothiadiazine-1,1-dioxide, M.p.= 234° C. B. Action of formic acid
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[C:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[NH:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)([CH3:56])([CH3:55])[CH3:54]>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:67]2[CH2:68][CH2:69][CH:64]([NH:63][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=3[C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:65][CH2:66]2)=[O:12])=[CH:5][CH:6]=1
Reactant: CC(C)(C)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccccc1NC1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.091 g, 0.00036 mole) in DMF (1 mL) was added DIPEA (0.211 g, 0.0016 mole), HOBt (0.048 g, 0.00036 mole) and EDCI.HCl (0.125 g, 0.00065 mole). After 2 minutes (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00033 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.062 g (40%) of N-biphenyl-4-yl-3-[4-(2-tert-butyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 470.27 (M+1)+, 96.38%, 1H NMR (DMSO-d6): δ 7.8-7.6 (m, 6H), 7.5 (t, 2H), 7.3 (d, 1H), 7.1 (d, 1H), 7.0 (t, 1H), 6.8 (d, 1H), 6.6 (t, 1H), 4.3 (d, 1H), 3.9 (d, 2H), 3.7 (s, 1H), 3.6 (s, 2H), 3.2 (t, 1H), 2.9 (t, 1H), 2.0 (t, 2H), 1.5 (t, 1H), 1.4 (s, 9H).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[CH2:34][C:33]1=[O:38].[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[C:49](Br)[C:50]([CH3:53])=[CH:51][CH:52]=2)=[CH:43][CH:42]=1>O1CCOCC1.CO>[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[C:51]([CH:34]3[C:33](=[O:38])[C:32]([CH3:39])([CH3:31])[NH:36][C:35]3=[O:37])[C:50]([CH3:53])=[CH:49][CH:48]=2)=[CH:45][CH:46]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: CC1(C)NC(=O)CC1=O
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon, in a heat-dried apparatus, 7.4 mg of Pd(OAc), 22 mg of di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine and 0.78 g of K3PO4 in 4.8 ml of air-free dioxane are introduced as initial charge. 203 mg of 5,5-dimethylpyrrolidine-2,4-dione and 659 mg of 3-(4-chlorophenyl)-6-methylbromobenzene are added and the mixture is stirred for 16 hours under reflux. The mixture is 10 then left to cool to room temperature, diluted with ca. 6 ml of methanol and filtered, and the filter residue is after-washed with ca. 3 ml of MeOH. The combined filtrates are concentrated by evaporation on a rotary evaporator. The residue is taken up in ca. 6 ml of water and rendered weakly acidic using 1 N hydrochloric acid. The precipitated solid is filtered off with suction and washed with ca. 3 ml of water. It is then washed from the filter with acetone and the filtrate is concentrated by evaporation. This gives 0.597 g of solid. Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6% according to HPLC/MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(Cl)([Cl:18])=O.N1C=CC=CC=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[Cl:18][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:12][C:13]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:15]
Reactant: O=S(Cl)Cl
Reactant: C1COCCN1
Reactant: COc1ccc(C#CC(=O)O)cc1OC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(Cl)=CC(=O)N2CCOCC2)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20.6 g (0.1 mol) of 3-(3,4-Dimethoxyphenyl)prop-2-ynoic acid and 36 ml (0.5 mol) of thionylchloride are stirred at room temperature for 2 hours. The excess thionylchloride is evaporated and the residue dissolved in 50 ml of toluene. This solution is added under ice cooling and stirring to a solution of 50 ml of pyridine and 10.9 g (0.125 mol) of morpholine in 100 ml of toluene. After 10 minutes of further stirring at room temperature the mixture is heated to 90° C. for 10 minutes. The mixture is cooled and then extracted twice with 250 ml of 2N hydrochloric acid and once with water, dried and evaporated. The resulting compound is purified by flash column chromatography using as eluant 1000 ml of toluene/acetone (10 and 20% of acetone). The fractions with Rf-value 0.52 and 0.43 in TLC (toluene/acetone 7:3) are gathered and the solvent is evaporated.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:11][CH:12]([OH:35])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1>CN(C=O)C>[OH2:35].[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH:12]([OH:35])[CH2:11][S:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:19][CH2:18]2)=[CH:22][CH:23]=1.[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH:12]([OH:35])[CH2:11][S:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:19][CH2:18]2)[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:33][CH:32]=1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Sc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O
Product: OC(CSc1ccccn1)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To NaH (10 mmol, 0.48 g, pentane washed) in DMF (10 mL) was added 2-mercaptopyridine (10 mmol, 1.11 g) at 0° C. After stirring for 2 hours at 0° C., 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4, 4'-difluorobenzhydryl)piperazine (5 mmol, 1.91 g) in DMF (20 mL) was added dropwise under nitrogen over 10 minutes. The mixture was stirred 15 minutes at 0° C. and 5 days at room temperature. The mixture was then filtered and the filtrate concentrated in vacuo (1 mmHg, 70° C.). The concentrated mixture was purified on a silica gel column using 5% methanol:methylene chloride. Crude material thus obtained was rechromatographed on silica gel using 10% acetone:methylene chloride and then 10% methanol:methylene chloride. After drying in a vacuum dessicator overnight, the pure product was an amber glass (0.87 g, 38.1%); DCI MS (M+1)=456; (300 MHz) 1H NMR (CDCl3)δ:8.4 (d,1H) and 7.5 (m,1H), 7.3 (m,4H), 7.25 (m,1H), 7.0 (m,5H), 4.0 (m, 1H), 3.2-3.6 (m,4H), 2.5 (m,10H).
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.S(Cl)([Cl:25])=O.S(=O)=O.Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([Cl:25])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Agent: Cl
Agent: O=S=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A 1 liter dry, clean jacketed split reaction vessel equipped with agitator, thermometer, condenser, nitrogen blanket and vent to a scrubber system was charged with toluene (450 ml) and agitated whilst 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropane carboxylic acid (89.4 gm=0.369 mol) was added followed by triethylamine (0.21 gm=2.1 mmol). The reaction mixture was then heated to 45° C., using oil circulation on the jacket, and thionyl chloride (62.0 gm=0.52 mol) was then charged over 105 minutes maintaining on temperature. The reaction mass was then agitated for 5 hours at 45° C. then tested by GLC for completion of reaction showing 2% residual acid. A further addition of thionyl chloride (4.4 gm=37 mmol) was then made and the reaction mass allowed to cool with stirring overnight. The following day, residual thionyl chloride, dissolved sulphur dioxide and hydrogen chloride gases were removed by distillation of about 320 ml toluene under vacuum. GC, GCMS and NMR analysis of the product were consistent with the structure of the acid chloride (IIIa). Yield, 175 gm of a 54% solution of the acid chloride in toluene, ˜97% theory. αD=+46° (c=0.012, DCM).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[F:20][C:21]1[CH:22]=[C:23]([CH:32]=[CH:33][CH:34]=1)[CH2:24][C:25]1[CH:29]=[CH:28][NH:27][C:26]=1[CH2:30]O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:30][C:26]1[NH:27][CH:28]=[CH:29][C:25]=1[CH2:24][C:23]1[CH:32]=[CH:33][CH:34]=[C:21]([F:20])[CH:22]=1)=[O:15]
Reactant: OCc1[nH]ccc1Cc1cccc(F)c1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1[nH]ccc1Cc1cccc(F)c1

Procedure:
The acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with 3-(3-fluorobenzyl)-pyrrolylmethyl alcohol using the procedure of Example 1 to give 3-(3-fluorobenzyl)-pyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:34].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:12]2[NH:34][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][O:26]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCO2)C(=O)CCC(=O)c2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCO2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydrofuran-2-yl)hexane-1,4-dione (302 mg) in acetic acid (7.3 mL) was added ammonium acetate (897 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (177 mg, yield 61%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 397 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:28].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37].[C:40](OCC)(=[O:42])[CH3:41]>O1CCCC1.O>[C:36]([N:1]([C:40](=[O:42])[CH3:41])[N:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:28])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCOC(C)=O
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1N(C(C)=O)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound obtained in Example 68 (200 mg) and triethylamine (145 μd) in tetrahydrofuran (15 ml) is cooled to −20° C., and thereto is added a solution of acetyl chloride (61 mg) in tetrahydrofuran (5 ml). The reaction mixture is stirred at the same temperature for one hour, and warmed to room temperature. To the reaction mixture are added acetyl chloride (122 mg) and triethylamine (290 μl), and the mixture is stirred at room temperature overnight. To the reaction mixture are added ethyl acetate and water, and the ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=2:1) to give 2-diacetylamino-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (75 mg) as listed in Table 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[N:17]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCC2)cc1
Temperature: 115 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To a suspension of crude 6-Bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (56.4 mg, 0.2 mmol) in N,N-dimethylformamide (500 μL) is added 4-pyrrolidin-1-ylmethyl-phenylamine (35.2 mg, 0.2 mmol). The reaction mixture is shaken at 115° C. for 1.5 hours. Upon cooling to room temperature, the product precipitated out. The precipitate is then filtered off, rinsed with copious amounts of ether, and dried to yield 78.8 mg of 6-Bromo-4-[(4-pyrrolidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2O.P(Cl)(Cl)([Cl:28])=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:28]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: CCc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 1.08 h

Procedure:
A round-bottomed flask containing a mixture of 6-bromo-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-4-ol (4.00 g, 8.29 mmol, Intermediate 5: step b), phosphorous oxychloride (3.50 mL, 37.3 mmol) and acetonitrile (27 mL) was placed into a metal heating block at 90° C. After 65 minutes, the reaction mixture was cooled to room temperature. The acetonitrile and excess phosphorous oxychloride were removed by rotary evaporation. The residue was dissolved in dichloromethane (100 mL) and the solution was cooled in an ice-water bath. Ice (50 mL) was added. Concentrated aqueous ammonia solution was added dropwise until the pH=8-9 by litmus paper test. The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organics were dried with sodium sulfate and the dried solution was filtered. Silica gel (8 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with hexanes initially, grading to 20% ethyl acetate-hexanes provided the title compound as an off-white solid.