Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[OH-].[K+].[F:14][C:15]([F:19])=[C:16]([F:18])[F:17]>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][C:16]([F:18])([F:17])[CH:15]([F:19])[F:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
20 Grams of 2-chloro-4-nitrophenol was dissolved in 200 ml of N,N-dimethylformamide, and 3.4 g of potassium hydroxide was added thereto. Tetrafluoroethylene was blown into the resulting solution at an inner temperature of 50° C., after which stirring was continued for 50 minutes at an inner temperature of 50° C. Thereafter, 3.5 g of potassium hydroxide was added to the stirred solution and the resulting solution was further stirred for 6 hours at an inner temperature of 100° C. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue obtained wa subjected to column chromatography on silica gel with chloroform as an eluent to obtain 12.55 g of 3-chloro-4-(1',1',2',2'-tetrafluoroethoxy)nitrobenzene. 1H-NMR (CDCl3): δ(ppm) 8.37(1H, d, J=3 Hz), 8.20(1H, dd, J=9, 3 Hz), 7.57(1H, d, J=9 Hz), 6.07(1H, tt, J=53, 3 Hz)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][N:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=C(O)c1cccc2ccncc12
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc2ccncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available isoquinoline-8-carboxylic acid (0.4 g, 2.31 mmol), N,O-dimethylhydroxylamine hydrochloride (0.45 g, 4.62 mmol), DMAP (0.28 g, 2.31 mmol), and polymer-supported DCC (0.71 g, 3.46 mmol) were charged in a 50 mL round bottom flask. Then anhydrous THF (23 mL) was added. The reaction was stirred overnight at RT. The reaction mixture was filtered and filtrate was concentrated. Purification by normal phase chromatography (0-50% EtOAc in hexane) yielded N-methoxy-N-methylisoquinoline-8-carboxamide (14-2).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O[CH:11]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17])[C:12]([OH:14])=[O:13].O>OS(O)(=O)=O.C(O)(=O)C>[C:16]([NH:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:12]([OH:14])=[O:13])(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(O)C(=O)O)c1ccccc1
Reactant: c1ccc2c(c1)CCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(NC(C(=O)O)c1ccc2c(c1)CCO2)c1ccccc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
2,3-Dihydrobenzofuran (4.8 g, 40 mmole) is stirred with 9.0 g (40 mmole) of α-hydroxyhippuric acid in 200 ml of 10% H2SO4 -acetic acid mixture. The reaction is run at room temperature for 0.5 hour. After the half-hour, the reaction mixture is poured into 500 ml of water. The aqueous solution is extracted with ethyl acetate (4 × 100 ml). The ethyl acetate extracts are dried over magnesium sulfate and then evaporated to give α-benzamido(2,3-dihydro-5-benzofuranyl)acetic acid. Recrystallization of the crude benzamido compound from hexane-methylene chloride gives 11.56 g (94% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([OH:18])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[C:27]([Br:29])[C:26]([O:30][CH3:31])=[C:25]([Br:32])[CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Cl)=[CH:43][CH:42]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[C:13]([O:18][CH2:45][C:44]3[CH:47]=[CH:48][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:24]=[C:25]([Br:32])[C:26]([O:30][CH3:31])=[C:27]([Br:29])[CH:28]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1c(Br)cc(CC2c3cc([N+](=O)[O-])c(O)cc3CCN2C(=O)OC(C)(C)C)cc1Br
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc3c(cc2[N+](=O)[O-])C(Cc2cc(Br)c(OC)c(Br)c2)N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 100 °C

Procedure:
A mixture of 1-(3,5-dibromo-4-methoxy-benzyl)-6-hydroxy-7-nitro-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (0.002 mol), K2CO3 (0.331 g, 0.0024 mol) and 4-methoxybenzyl chloride (0.376 g, 0.0024 mol) in 10 mL of DMF was heated for 4 h at 100° C. 0.17 g (0.00109 mol) of 4-methoxybenzyl chloride was added additionally. The reaction mixture was heated for 5 h at 100° C., cooled, poured in water, cooled, filtered and dried in vacuum. The residue was dissolved in ethyl acetate and filtered through silica gel. The solution was concentrated. The residue was crystallized from chloroform-hexanes mixture. Yield 0.96 g (72%).
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10](O)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2>CCCCCCCC>[C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([C:22]3[CH:21]=[CH:20][C:19]4[N:18]([CH3:17])[C:30]5[C:25]([C:24]=4[CH:23]=3)=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c2ccccc2c2ccccc21
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: CCCCCCCC
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc2c(c1)c1ccccc1n2C
Yield: 18.3 %

Procedure:
A mixture of 2.2 g (10.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (202), Example 1a, Table 2), 1.8 g (10.0 mmol) of N-methylcarbazole and 0.2 g of Fulcat 22B and 20 ml of n-octane is refluxed for 5 hours under nitrogen. The Fulcat 22B catalyst is subsequently removed by filtration and excess n-octane is distilled off on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system dichloromethan/hexane=1:2 to 1:1 and subsequent crystallisation of the pure fractions from methanol yields 0.70 g (10%) of 7-tert-butyl-5-methyl-3-(9-methyl-9H-carbazol-3-yl)-3H-benzofuran-2-one, m.p. 84-90° C. (compound (120), Table 1). The product may additionally contain minor amounts of other structural isomers in accordance with the substitution at the carbazole ring.
Reaction SMILES: [CH3:1][S:2]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Li])CCC.[Br:16][C:17]1[CH:18]=[C:19](/[C:24](=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])/[CH3:25])[C:20]([F:23])=[N:21][CH:22]=1.C[Al](C)C>C1COCC1.C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([C@:24]([NH:26][S:27]([C:29]([CH3:30])([CH3:32])[CH3:31])=[O:28])([CH3:25])[CH2:1][S:2]([C:5]2([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]2)(=[O:4])=[O:3])[C:20]([F:23])=[N:21][CH:22]=1
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)cnc1F
Reactant: CS(=O)(=O)C1(C#N)CCC1
Agent: C[Al](C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)N[C@@](C)(CS(=O)(=O)C1(C#N)CCC1)c1cc(Br)cnc1F
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A solution of 1-(methylsulfonyl)cyclobutanecarbonitrile (8 g, 50.4 mmol) in THF (50 mL) was brought to −78° C. followed by the dropwise addition of butyllithium solution, 2.5M in hexanes (20.17 mL, 50.4 mmol). The resulting mixture was stirred at this temperature for 20 min. A solution of (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (9.0 g, 28.02 mmol) in toluene (40 mL) at −78° C. was treated with trimethylaluminum solution, 2.0 M in toluene (14 ml, 28.02 mmol) for 10 min. This solution was added dropwise to the previous mixture containing the nitrile and the resulting mixture was stirred at −78° C. for 1 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford an off-white solid as N—((R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((1-cyanocyclobutyl)sulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (7.07 g, 14.72 mmol, 59.1% yield). LC/MS (ESI+) m/z=479.8 (M+H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:10][CH:9]=2)[C:5](=[O:23])[CH2:4]1.C(N(C(C)C)C(C)C)C.[F:33][CH:34]([F:38])[C:35](O)=[O:36].N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F>CN(C)C=O>[F:33][CH:34]([F:38])[C:35]([NH:2][C@H:3]1[CH2:4][C:5](=[O:23])[N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:7]1)=[O:36]
Reactant: N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1)C(F)F
Reaction time: 6 h
Yield: 18.5 %

Procedure:
A solution of 103 mg (0.3 mmol) of (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one hydrochloride [Example 2g)] in 0.5 ml of N,N-dimethylformamide is treated successively with 180 μl (1.0 mmol) of N-ethyl-diisopropylamine, 20 μl (0.3 mmol) of difluoroacetic acid, and 102 mg (0.3 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TBTU) at RT, and thereafter, stirred for 6 hours. For the working-up, the reaction mixture is evaporated under reduced pressure. The resulting residue is dissolved in 3 ml of dichloromethane and the solution is washed with 1.5 ml of a saturated solution of sodium hydrogenate and with 1.5 ml of hydrochloric acid (0.1 N). The organic phase is dried over sodium sulfate and evaporated. For purification, the crude material is chromatographed on silica gel using a 98:2-mixture of dichloromethane and methanol as the eluent. There are obtained 21 mg (18% of theory) of (S)-2,2-difluoro-N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide as a white solid. MS: m/e=396 (M+NH4)+.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:20])[C:12]([Cl:19])=[C:13]([Cl:18])[C:14](=[O:17])[C:15]=1[Cl:16].Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:11](=[O:20])[C:10]([Cl:9])=[C:15]1[Cl:16])[CH3:8]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.82 g (3.33 mmol) of 2,3,5,6-tetrachloro-1,4-benzoquinone in 26 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 50 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.04 g of the desired product (yield 94%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[N:14]=[N:15]NN=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[O:28][C:18]([C:19]4[CH:27]=[CH:26][CH:25]=[C:21]([C:22]5[O:23][C:13]([C:9]6[N:8]=[C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)[CH:12]=[CH:11][CH:10]=6)=[N:14][N:15]=5)[CH:20]=4)=[N:15][N:14]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4cccc(-c5nnc(-c6cccc(-c7ccccc7)n6)o5)c4)o3)n2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
5.0 g of 2-phenyl-6-(2H-tetrazol-5-yl)pyridine was dissolved in 125 ml of dehydrated pyridine. Temperature was elevated to 120° C., and 75 ml was dehydrated by azeotropy. After cooling to 50° C., 2.28 g of isophthaloyl dichloride was added. Temperature was elevated to 100° C., and stirring was conducted for 1 hour. After cooling to room temperature, the reaction solution was poured into 300 ml water, and after adjusting pH to 12 with 20% sodium hydroxide aqueous solution, stirring was conducted for 1 hour. A precipitated brown solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 70° C. for 20 hours, and purified with column chromatography (carrier: NH silica gel, eluting solution: chloroform) to obtain 4.27 g (yield 73%) of PhpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.07 ppm (1H), 8.46 ppm (2H), 8.28 ppm (2H), 8.17 ppm (4H), 7.92-8.15 ppm (4H), 7.78 ppm (1H), 7.46-7.55 ppm (6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=O)=[CH:7][CH:6]=1)=[O:4].C[Si]([C:20]#[N:21])(C)C.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(C1C=CC(C(CC)C(O)=O)=CC=1)(O)=O.[I-].[Zn+2].[I-]>[C:20]([C:12]1[C:13]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Agent: CCC(C(=O)O)c1ccc(C(=O)O)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Yield: 47.1 %

Procedure:
Part B--A solution of 1-tetralon-7-carboxylic acid methyl ester (3.50 g, 0.017 mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and zinc iodide (0.10 g) in benzene 5 (20 mL) was stirred at ambient temperature over 15 hours. Then added, sequentially and dropwise, was pyridine (20 mL) and phosphorous oxychloride (4.0 mL, 6.55 g, 0.0425 mol). The reaction mixture was stirred at reflux over 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in chloroform, backwashed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give methyl 8-cyano-5,6-dihydro-2-naphthoate (1.70 g, 0.008 mol, 47%) as a yellow solid. mp=73°-75° C.; 1H NMR (CDCl3) d 8.0-7,9 (m, 1H), 7.3-7.2 (m, 1H), 6.95 (t, 1H, J=4.8 Hz), 3.95 (s, 3H), 2.9 (t, 2H, J=8.3 Hz), 2.6-2.4 (m, 3H)
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[NH3:24]>>[NH2:24][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Reactant: N
Product: CCCOc1ccccc1-c1nc2nc(N)nnc2c(=O)[nH]1

Procedure:
In a similar manner to that described in Example 87, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (1.42 g) was reacted with ethanolic ammonia (70 ml) for 20 hours to give the crude title compound, (0.80 g) which together with another sample (0.17 g), similarly prepared, was recrystallized from ethanol to afford the title compound, 0.54 g, m.p. 255-256° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1(O)[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)[C:5]([O:7][CH3:8])=[O:6].[OH:20]C1C2C(=CC=CC=2)C=CC=1C(=O)C(OC)=O.Cl.CON>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON=C(C(=O)OC)C1(O)C=Cc2ccccc2C1
Reactant: COC(=O)C(=O)c1ccc2ccccc2c1O
Agent: CON
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc2ccccc2c1O
Yield: 77 %

Procedure:
Preparation of methyl 2-hydroxy-2-naphthylglyoxylate O-methyl oxime ##STR53## 69 g (0.26 mol) of methyl 1-hydroxy-2-naphthylglyoxylate and 44 g (0.53 mol) of O-methylhydroxylamine hydrochloride are introduced into 800 ml of methanol and heated to reflux temperature for 6 h with stirring. The mixture is then concentrated, the residue is taken up in ethyl acetate, and the solution is washed with H2O, dried over sodium sulfate and concentrated again. 52 g (0.20 mol) of methyl 1-hydroxy-2-naphthylglyoxylate O-methyl oxime are obtained (77% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[N:8][C:7]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:6]2.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:15])=[N:8][C:7]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:6]2
Reactant: COc1ccc2c(C(=O)O)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)N3CCOCC3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid (100 mg) (example 9A), morpholine (70 mg), 1-hydroxybenzotriazole (HOBt) (130 mg), NMP (100 mg), N,N-dimethylformamide (DMF) (2 ml), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDCI) (180 mg) was stirred at room temperature overnight. The reaction mixture was purified by preparative LC-MS to give 20 mg of [6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-morpholin-4-yl-methanone. LC-MS: m/e 368(MH+).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C>[Br:46][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[CH:17][CH:18]=3)[N:13]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy-3H-quinazolin-4-one (1.20 g, 3.52 mmol) in anhydrous DMF (15 mL) were added triphenylphosphine (1.00 g, 3.80 mmol) and carbontetrabromide (1.27 g, 3.80 mmol). The reaction mixture was stirred at room temperature for 16 hours. DMF was removed under reduced pressure. The residue was purified by column chromatography (silica gel 230-400 mesh; 3% methanol in dichloromethane as eluent) to give 2-[4(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-7-methoxy3H-quinazolin-4-one as an off-white solid. Yield: 0.37 g (26%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13]CCCCC.C[Si](C=[N+]=[N-])(C)C>CC(C)=O>[Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
206 mg (1.0 mmol) of 2,5-Dichloro-3-aminobenzoic acid was dissolved in 4 mL of acetone. 0.7 mL (1.4 mmol) of A hexane solution of 2.0M trimethylsilyldiazomethane was added thereto and stirred at room temperature for 1.5 hours. A solvent was removed to obtain methyl 2,5-dichloro-3-aminobenzoate.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH2:14][CH2:15][OH:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:17]S(O)(=O)=O>C(Cl)Cl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:9]1[CH:13]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(c1ccccc1)c1cc(CCO)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 8.8 g of 2-(3-benzoylisoxazol-5-yl)ethanol, in 1 liter of CH2Cl2, a few crystals of tetra-n-butylammonium hydrogen sulfate and 150 ml of 9M H2SO4 was added 11.9 g (41 mmol) of pulverized K2Cr2O7. The resulting mixture was stirred at room temperature for 1.5 hour. After allowing the mixture to settle, it was decanted from the unreacted dichromate. The aqueous phase was extracted with CH2Cl2, and the organics were washed with water and brine, and dried over MgSO4. Concentration gave a wet solid which was triturated with cyclohexane and collected to give 7.1 g of a solid. Recrystallization from toluene gave 4.0 g (43%) of a solid, m.p. 108°-110°.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:25])[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([F:21])[C:15]([F:22])=[C:14]([Cl:23])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C([N+]([O-])=O)=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:47][C:48]1[C:53]([F:54])=[CH:52][C:51]([F:55])=[C:50]([NH:56][C:57]([CH3:60])([CH3:59])[CH3:58])[N:49]=1>C(Cl)(Cl)Cl>[C:57]([NH:56][C:50]1[N:49]=[C:48]([N:47]2[C:13]3[C:12](=[C:17]([N+:18]([O-:20])=[O:19])[C:16]([F:21])=[C:15]([F:22])[C:14]=3[Cl:23])[C:11](=[O:25])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:53]([F:54])=[CH:52][C:51]=1[F:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Agent: CCOC(=O)CC(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To 10 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluoro-6-nitrobenzoyl)acrylate prepared from 3.25 g of ethyl 3-chloro-2,4,5-trifluoro-6-nitrobenzoylacetate by normal process was added 2.14 g of 2-amino-3,5-difluoro-6-t-butylaminopyridine. The solution was concentrated under reduced pressure, and to the residue were added 2.7 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 5 minutes and allowed to cool. The solution was separated by adding 100 ml of chloroform and 500 ml of 2% aqueous solution of citric acid, and the chloroform layer was washed twice with 500 ml of 2% aqueous solution of citric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, washed with ethanol and diisopropylether successively to obtain 3.13 g of the title compound as a pale yellow powder.