Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=S)[CH:8]=1.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>CO.O>[OH:15][N:14]=[C:9]1[CH:8]=[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[S:11][S:10]1
Reactant: S=c1cc(-c2cnccn2)ss1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=c1cc(-c2cnccn2)ss1
Temperature: 65 °C
Yield: 72.6 %

Procedure:
A suspension of 5-(pyrazin-2-yl)-1,2-dithiole-3-thione (31.85 g.) in methanol (1,400 cc.) is heated at a temperature of about 65° C. Hydroxylamine hydrochloride (24 g.), followed by sodium acetate (35 g.) dissolved in water (75 cc.), are then added. The reaction mixture is then heated for 3 hours at a temperature of about 65° C. After cooling to a temperature of about 20° C., the insoluble product is filtered off and is then washed with methanol (4 × 100 cc.) and with carbon disulphide (4 × 100 cc.). The product is dissolved in dimethylformamide (300 cc.) at 100° C. and is then reprecipitated by adding water (600 cc.). After filtration and drying, 3-hydroxyimino-5-(pyrazin-2-yl)-1,2-dithiole (23 g.) melting at 262° C. is obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[F:37][C:38]1[CH:46]=[C:45]2[C:41]([C:42]([Sn](CCCC)(CCCC)CCCC)=[N:43][NH:44]2)=[CH:40][CH:39]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:42]3[C:41]4[C:45](=[CH:46][C:38]([F:37])=[CH:39][CH:40]=4)[NH:44][N:43]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1)=[O:31])([CH3:35])([CH3:34])[CH3:36]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Temperature: 85 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
In a round-bottomed flask, 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (600 mg, 1.12 mmol) and 6-fluoro-3-(tributylstannyl)-1H-indazole (475 mg, 1.12 mmol) were dissolved in DMF (10 mL) under nitrogen. Pd(PPh3)4 (65 mg, 0.056 mmol) and CuI (43 mg, 0.224 mmol) were added and the mixture sonicated for 5 min while bubbling nitrogen. The reaction mixture was stirred at 85° C. for 16 hours. After solvent removal, the concentrated mixture was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (3:1 v/v) to give N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 27%) as a white solid. LCMS: (M+H)+=595; 1H NMR (300 MHz, DMSO): δ 13.60 (s, 1H), 8.78 (s, 1H), 8.45-8.40 (m, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 7.45-7.33 (m, 10H), 7.21-7.09 (m, 7H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([O:14]CC)=O.[Na+].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].Cl>COCCO.O>[OH:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:14]
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Reactant: NCC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CC(C)c1n[nH]c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 130 °C
Yield: 72 %

Procedure:
To a 100 mL round bottom flask was added ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 14(a), 55 mg, 0.243 mmol) and Glycine Sodium Salt (59.0 mg, 0.608 mmol) in 2-methoxyethanol (10 ml) and the mixture was refluxed at 130° C. for 2 hours. The mixture was diluted with water (10 ml) and acidified with 1N HCl. The aqueous solution was then extracted with ethyl acetate (40 mL), organics dried over MgSO4, filtered and solvents removed by evaporation. The crude oil was purified by HPLC chromatography (ODS silica, gradient 25-95% acetonitrile/water (0.1% TFA)) to afford the title compound, N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (45 mg, 0.175 mmol, 71.8% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 15.74 (br. s., 1H), 13.07 (s, 1H), 10.19 (t, J=5.68 Hz, 1H), 4.11 (d, J=5.81 Hz, 2H), 3.14 (sept, J=6.82 Hz, 1H), 1.17 (d, J=6.82 Hz, 6H). MS (ES+) m/e 256 [M+H]+.
Reaction SMILES: [OH-].[K+].Cl.Cl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][CH2:21][CH:22]2[O:27][C:26]3[C:28]([O:32]S(C4C=CC(C)=CC=4)(=O)=O)=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)[CH2:15][CH2:14]1.C(O)(=O)C>O.C(O)C>[OH:32][C:28]1[C:26]2[O:27][CH:22]([CH2:21][NH:20][CH2:19][CH:16]3[CH2:15][CH2:14][N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH3:5])[CH2:18][CH2:17]3)[CH2:23][O:24][C:25]=2[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccccc1N1CCC(CNCC2COc3cccc(OS(=O)(=O)c4ccc(C)cc4)c3O2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccccc1N1CCC(CNCC2COc3cccc(O)c3O2)CC1
Reaction time: 16 h
Yield: 212.1 %

Procedure:
A solution of potassium hydroxide (1. 0 g) in water (19.7 ml) and ethanol (19.7 ml) was added in portions (~10 ml) at 15 minute intervals to [2-({[1-(2-methoxyphenyl)piperid-4-yl]methylamino}methyl)-1,4-benzodioxan-8-yl]toluene-4-sulphonate dihydrochloride (0.15 g). The mixture was heated under reflux for 21/2 hours, cooled and neutralised with glacial acetic acid. The product was extracted into ether (3×100 ml) and the combined extracts allowed to stand for 16 hours. The precipitate which had then formed was collected by filtration and dried to give N-(8-hydroxy-1,4-benzodioxan-2-ylmethyl) -1-[1-(2-methoxyphenyl) piperid-4-yl]methylamine as a colourless solid (0.2 g), m.p. 116°-119° C.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:20][S:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:31]=1[NH:30][CH:29]=[CH:28]2>ClCCl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[C:28]2[C:27]3[C:31](=[C:23]([CH2:22][S:21][CH3:20])[CH:24]=[CH:25][CH:26]=3)[NH:30][CH:29]=2)=[CH:7][CH:8]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
515 mg (2.82 mmol) of the compound from Example 153A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 20 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 500 mg (50% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:19][CH2:18][CH2:17][CH:10]1[C:9](=[O:12])[NH:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (800 mg, 4.5 mmol) in DMF (16 mL) was added sodium hydride (60% in mineral oil, 260 mg, 6.5 mmol). After 20 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.5 mmol) was added and it was heated to 70° C. in the microwave for 40 minutes. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (4×50 mL). The combined organic phases were washed with water (6×250 mL), dried over magnesium sulfate and concentrated at reduced pressure to afford the product as a yellow oil which was used without further purification. (1.38 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[C:4]([CH3:27])[CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3C)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(F)ccc1-c1nc2ccc(C(=O)O)cc2nc1N(C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of methyl 2-(4-fluoro-2-methylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (45 mg, 0.12 mmol) in methanol (35 mL) and water (2.0 mL) was added sodium hydroxide (20 mg, 0.50 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (20 mL) and adjusted to pH 4 with aqueous HCl (3N). The solids were collected by filtration to afford 2-(4-fluoro-2-methylphenyl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (36 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[C:9](=[O:12])[NH:8][C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[N:5]([C:17](=[O:20])[CH2:18]Cl)[C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>O1CCOCC1CCO>[CH3:1][C:2]1[S:11][C:10]2[C:9](=[O:12])[NH:8][C:7]3[CH:13]=[CH:14][CH:15]=[N:16][C:6]=3[N:5]([C:17](=[O:20])[CH2:18][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)C(=O)Nc1cccnc1N2C(=O)CCl
Agent: OCCC1COCCO1
Product: Cc1cc2c(s1)C(=O)Nc1cccnc1N2C(=O)CN1CCN(C)CC1

Procedure:
A suspension of the product obtained in (a) (5 g) and N-methylpiperazine (4.3 ml) in dioxane-ethanol 9:1 (50 ml) is heated to reflux for 2 hours. After cooling and filtration of the insoluble impurities, the clear filtrate is evaporated and the residue dissolved in chloroform (100 ml). The solution is washed with a diluted ammonium hydroxyde solution (20 ml), dried, decolorized and evaporated. The residue, crystallized from methanol, yields 2.2 g of the title product, melting at 273°-275° C. (dec.).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][N:14]=2)=[CH:9][C:8]=1[N+:21]([O-])=O)C.C(=O)([O-])O.[Na+]>C(O)(=O)C.[Fe]>[CH3:20][O:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:10]2[CH:9]=[C:8]3[C:7]([CH:6]=[CH:5][C:4](=[O:3])[NH:21]3)=[CH:12][CH:11]=2)[CH:18]=1
Reactant: CCOC(=O)C=Cc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccnc(-c2ccc3ccc(=O)[nH]c3c2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)-2-nitrocinnamic acid ethyl ester (659 mg) in acetic acid (11 ml) was added iron powder (673 mg), and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and filtered, and the filtrate was extracted with dichloromethane-methanol (5:1). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethanol (5 ml). To the solution was added a solution of sodium methoxide in methanol (28%, 3 ml), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give 7-(4-methoxypyridin-2-yl)-2-quinolone (140 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[CH2:26]([O:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([O:8][CH2:14][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1-c1ccccc1
Yield: 168.1 %

Procedure:
Compound 1 (1.81 g, 7.00 mmol) obtained in Example 1 was dissolved in acetone (50 mL), and potassium carbonate (5.88 g, 42.6 mmol) and benzyl bromide (3.33 mL, 28.0 mmol) were added thereto and stirred with heating under reflux for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=20/1 to 9/1) to obtain methyl 3,5-bis(benzyloxy)-2-phenylphenylacetate (2.58 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[CH:35][NH:36]5)=[C:32]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:31]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]5[C:33]([CH:34]=[CH:35][NH:36]5)=[C:32]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:31]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)c5cc[nH]c5c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(C)(=O)=O)c6cc[nH]c6c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 57.3 %

Procedure:
(S)—N-(6-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-4-yl)methanesulfonamide (37 mg, 0.05 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 1 ml, 7 mmol) according to the method described in Example 27 to give 17 mg (53% yield) of the title compound. Purity 95%. LRMS (m/z): 594 (M+1)+.
Reaction SMILES: [C:1]1(C=CC=C(O)C=1)O.COC1C=C(C=CC=1)C(Cl)=O.[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[O:29].CI>>[OH:20][C:21]1[CH:26]=[C:25]([O:27][CH3:1])[CH:24]=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)=[O:29]
Reactant: Oc1cccc(O)c1
Reactant: COc1cccc(C(=O)c2ccc(O)cc2O)c1
Agent: COc1cccc(C(=O)Cl)c1
Solvent: CI
Product: COc1cccc(C(=O)c2ccc(OC)cc2O)c1

Procedure:
Synthesized from resorcinol and 3-methoxybenzoyl chloride according to an analogous synthetic method to Preparation Example 66, (2,4-dihydroxyphenyl)(3-methoxyphenyl)methanone (14.7 g) and methyl iodide (9.4 g) were used according to an analogous synthetic method to Example 383 to provide the title compound (10.3 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:7][CH:6]=1.Cl.Cl.NCC1C=CC=CC=1[CH2:39][C:40](N(C)[C@@H](C1C=CC=CC=1)CN1CCCC1)=[O:41]>>[C:40]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:14]([CH3:28])[C@@H:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:13])=[CH:7][CH:6]=1)(=[O:41])[CH3:39]
Reactant: CN(C(=O)Cc1ccccc1CN)[C@H](CN1CCCC1)c1ccccc1
Reactant: CN(C(=O)Cc1ccc(CN)cc1)[C@H](CN1CCCC1)c1ccccc1
Agent: Cl
Product: CC(=O)NCc1ccc(CC(=O)N(C)[C@H](CN2CCCC2)c2ccccc2)cc1

Procedure:
Compound 9c was prepared by following the procedure of Example 7, Step h, except 8c was substituted for 8a. (87%) 1H NMR (400 MHz, CDCl3) δ 7.07-7.36 (m, 9H), 6.11 (m, 1H), 5.80 (m, 1H), 4.39 (m, 2H), 3.76 (m, 2H), 2.78-3.19 (m, 2H), 2.71 (s, 4H), 2.49 (m, 2H), 2.01 (m, 3H), 1.75 (m, 5H). Mass Spectral Analysis m/z=394.3. (M+H)+ tR=3.13 min (99%)
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]2([C:36]([F:39])([F:38])[F:37])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:34])[CH:27]([S:31][CH2:32][CH3:33])[S:28][CH2:29][CH3:30])=[C:20]([Cl:35])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:50])C=1.S([O-])(O)=O.[Na+]>ClCCl>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2([C:36]([F:38])([F:37])[F:39])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:34])[CH:27]([S:28]([CH2:29][CH3:30])=[O:50])[S:31][CH2:32][CH3:33])=[C:20]([Cl:35])[CH:19]=3)[CH2:14]2)[CH:4]=[C:3]([C:2]([F:40])([F:1])[F:41])[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC(SCC)C(=O)NCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCSC(C(=O)NCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Cl)S(=O)CC
Temperature: 25 °C

Procedure:
To a solution of 0.37 g of N-[4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-chlorophenyl]methyl-2,2-bis(ethylthio) acetamide (compound of the present invention No. 1-215) in 5 mL of dichloromethane, 0.098 g of 3-chloroperbenzoic acid (75%) was added while stirring the solution at room temperature and the resultant reaction mixture was stirred at the same temperature for 1 hour. After the completion of the reaction, 5 mL of a saturated sodium hydrogen sulfite aqueous solution was added to the reaction mixture and the resultant mixture was extracted with dichloromethane (5 mL×2). The organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous magnesium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative medium pressure liquid chromatography eluting with ethyl acetate-hexane (a gradient from 1:1 to 1:5) using a medium pressure preparative apparatus (trade name: YFLC-Wprep; manufactured by Yamazen Corporation) to obtain 0.282 g of the objective substance as a colorless resinoid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][CH3:25])=[CH:22][CH:23]=3)=[C:14]([CH3:26])[N:13]=[C:12]([NH2:27])[N:11]=2)=[CH:6][C:5]=1[Cl:28]>C1COCC1>[NH2:27][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([Cl:28])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH:24][CH3:25])=[CH:22][CH:23]=2)=[C:14]([CH3:26])[N:13]=1
Reactant: CNc1ccc(C#Cc2c(C)nc(N)nc2-c2ccc(C(=O)OC)c(Cl)c2)cn1
Solvent: C1CCOC1
Product: CNc1ccc(C#Cc2c(C)nc(N)nc2-c2ccc(C(=O)O)c(Cl)c2)cn1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 700 mg (1.7 mmol) 4-[2-amino-6-methyl-5-(6-methylamino-pyridin-3-ylethynyl)-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 2.6 mL (2.6 mmol) 1 N NaOH in 10 mL THF. The product precipitates and is isolated by filtration. The product is washed with water and used without further purification. Yield: 370 mg (55%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10](O)=[O:11])[CH:7]=[CH:6][C:5]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH:30]2[CH2:32][CH2:31]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18])(O)=[O:2].B.C(=O)([O-])[O-].[K+].[K+].CO>O1CCCC1.O>[OH:2][CH2:1][C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:13]1[N:14]=[C:15]([N:19]([CH:23]([CH:30]2[CH2:31][CH2:32]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH3:22])[S:16][C:17]=1[CH3:18]
Reactant: CCCN(c1nc(-c2ccc(C(=O)O)cc2C(=O)O)c(C)s1)C(c1ccccc1)C1CC1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(c1nc(-c2ccc(CO)cc2CO)c(C)s1)C(c1ccccc1)C1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1 g of the compound obtained in Step A is dissolved in 20 ml of anhydrous tetrahydrofuran, followed, at -7° C., by addition of 5 ml of 1M borane solution in tetrahydrofuran, and the mixture is stirred overnight. 0.5 g of potassium carbonate and 10 ml of a mixture of methanol and water (1:1 v/v) are then added. The mixture is maintained at 60° C. for 2 hours and then cooled and evaporated under vacuum. The residue is taken up in water and extracted with ethyl ether, and the organic phase is washed with water, then with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. It is evaporated to dryness and the residue is taken up in pentane. The expected product is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:16])[NH:9][CH:8]=[CH:7]2
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1ccc2cccc(Br)c2c1
Solvent: CN(C)C=O
Product: O=c1[nH]ccc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of (a) (630 mg, 2.8 mmol) in DMF (10 ml) was treated with trifluoroacetic acid anhydride (4 ml). The clear solution was stirred at room temperature overnight then evaporated. The residue was treated with dilute aqueous sodium carbonate solution and extracted several times with 5% methanol/dichloromethane. The combined organic extracts were washed with brine, dried and evaporated. The crude product was chromatographed on silica eluting with 0-10% methanol in dichloromethane affording a white solid (180 mg, 29%).
Reaction SMILES: [CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[ClH:30].O1CCOCC1>CCOC(C)=O>[ClH:30].[CH:1]([S:4]([C:7]1[C:8]([C@H:13]2[C@@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:15][NH:14]2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1S(=O)(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCN[C@H]1c1ncccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 65J (0.38 g, 0.89 mmol) in EtOAc (5 mL) at rt was added 4.0 N HCl in dioxane (5 mL, 20 mmol). The mixture was stirred at rt for 8.0 h. After removal of the solvent, the crude was diluted in methylene chloride and washed with sat. NaHCO3. The aqueous was extracted with methylene chloride (3×80 mL). The combined organic layer was dried over Na2SO4. After removal of solvent 65K (0.28 g, 95% yield) was obtained as viscous oil. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15 (t, J=7.03 Hz, 3H) 1.23-1.27 (d, J=7.03 Hz, 3H) 1.30 (d, J=7.03 Hz, 3H) 2.21-2.27 (m, 2H) 3.07 (ddd, J=11.10, 7.47, 7.36 Hz, 1H) 3.41 (ddd, J=9.34, 7.25, 7.14 Hz, 1H) 3.54-3.63 (m, 1H) 4.03-4.12 (m, 2H) 5.14 (d, J=7.03 Hz, 1H) 7.58 (dd, J=7.91, 4.83 Hz, 1H) 8.32 (dd, J=8.35, 1.76 Hz, 1H) 8.86-8.91 (m, 1H), LC-MS 327 (M+H).