Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])([O-:8])=[O:7].[C:18]([OH:22])(=[O:21])[CH:19]=O>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([CH:16]=[CH:19][C:18]([OH:22])=[O:21])=[O:17])([O-:8])=[O:7]
Reactant: O=CC(=O)O
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: O=C(O)C=CC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 30.3 %

Procedure:
To a solution of 225 ml of glacial acid and 8.5 ml of concentrated sulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and 47.02 g (0.50 mol) of glyoxylic acid (hydrated). The mixture is heated at 100° C. 16 hours. The mixture is cooled and poured over crushed ice. After the ice melts, the mixture is filtered and the solid washed with cold water. The solid is dried and recrystallized from dichloroethane-hexane to give 20.1 g of 3-(2-nitrobenzoyl)acrylic acid as white crystals, m.p. 153°-158° C. A solution of the preceding compound (9.0 g) in 80 ml of ethanol and 1.6 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 30 pounds per square inch of hydrogen for 20 hours. The mixture is filtered through diatomaceous earth and the solvent is removed. The residue (7.0 g) is chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 4.0 g of 3-(2-aminobenzoyl)acrylic acid as an orange solid, m.p. 103°-107° C. A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and 0.43 ml of diethoxyphosphinyl cyanide in 20 ml of dichloromethane is stirred at room temperature for 5 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue purified by chromatography over silica gel with ethyl acetate-hexane (1:1) as solvent to give 0.190 g of light brown crystals, m.p. 168°-170° C.
Reaction SMILES: C([C:6]([CH:20](OCC)OCC)([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:29][C:30]([NH2:32])=[NH:31]>C(O)C>[NH2:32][C:30]1[N:31]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:20][N:29]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccc(OC)c(OC)c1)C(OCC)OCC
Reactant: N=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OC
Yield: 52.4 %

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4-dimethoxyphenyl)-propionitrile (3.75 g) and an equivalent amount of potassium hydroxide in ethanol (70 ml) was heated at reflux for one hour. A solution of guanidine (0.035 mol) in ethanol (50 ml) was added and reflux was resumed. Ethanol was boiled off until the reaction temperature reached 85° C. After 17 hours at reflux the mixture was allowed to cool and the product was filtered and washed with ethanol giving a white solid which was purified as described in Example 5 to yield 1.4 g (54%) of the title compound, m.p. 231°-233° C.
Reaction SMILES: [CH3:1][S:2]([CH2:4][CH2:5][C:6]1[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:3].C1C=C(Cl)C=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][S:2]([CH2:4][CH2:5][C:6]1[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:42])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC[C@H](NC(=O)c1c(CCS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC[C@H](NC(=O)c1c(CCS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a stirring solution of 3-[2-(methylsulfinyl)ethyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (12) (60 mg, 0.13 mmol) in CH2Cl2 at 0° C. was added MCPBA (70-75%, 36 mg, 0.16 mol). The cooling bath was removed and reaction stirred for 2 h, then sodium thiosulfate (1.2 eq.) and H2O (1 mL) were added and suspension stirred until all solids had dissolved. Aqueous 1 N NaOH (1 mL) and CH2Cl2 (2 mL) were then added, the layers shaken together, separated, the organics dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-20% EtOAc/CH2Cl2) to give the desired product (40 mg, 65% yield) as a solid. 1H NMR (300 MHz, CDCl3, 52° C.) δ 8.12 (d, J=8.2 Hz, 1H), 7.78-7.65 (m, 2H), 7.56-7.26 (m, 11H), 6.31 (d, J=7.7 Hz, 1H), 5.23 (q, J=7.6 Hz, 1H), 3.36-2.88 (m, 4H), 2.45-2.34 (m, 3H), 2.16-1.88 (m, 2H), 1.04 (t, J=7.4 Hz, 3H); HRMS m/z 473.1878, calcd 473.1899.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[CH2:20]([C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[C:25]([C:27](O)=[O:28])[N:26]=1)C>>[CH3:20][C:22]1[S:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:28])[N:26]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2C)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccccc2C)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-M ethyl-5-o-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.31 min; [M+H]+=492.1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[C:18]([CH3:17])[CH:19]=2)[NH:23][C:22]1=[O:27])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: Cc1ccc2c(c1)CC(=O)N2
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ccc(C)cc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 5-methyl-2-oxindole to give 0.3 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-5-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:15].Cl.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>O1CCOCC1>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([CH3:15])[C:7]=3[N:6]=[N:5][C:4]=2[CH2:3][CH2:2]1
Reactant: Cc1ccccc1N
Reactant: Cc1cccc2c(Cl)c(CCCl)nnc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccccc1N1CCc2nnc3c(C)cccc3c21

Procedure:
3-(2-Chloroethyl)-4-chloro-8-methylcinnoline (2.5 g, 0.01mol) and o-toluidine hydrochloride (1.4 g, 0.01 mol) in 1,4 dioxan (20 ml) were heated under reflux for 20 hours. The solvent was evaporated under reduced pressure to give an oil. The oil was partitioned between chloroform and dilute sodium carbonate solution and extracted further with chloroform (4×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, filtered and evaporated to give an oil. The oil was purified by column chromatography using dichloromethane then chloroform as eluant. The solid obtained was recrystallized from diethyl ether/ dichloromethane to give the title compound, 0.6 g, m.p. 135-137°.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:33][CH2:34][O:35]S(C)(=O)=O)[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:33][CH:34]=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCOS(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CS(C)=O
Product: COC(=O)CCC(CC=O)CCCCNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.47 ml dimethylsulfoxide in 19 ml methylene chloride is cooled to -70° and 0.41 ml oxalyl chloride is added slowly. The solution is stirred at -70° for 15 min and a solution of 0.38 g of methyl 8-(p-chlorophenylsulfonamido)-4-(2-hydroxyethyl)-octanoate (example 28) in 1 ml methylene chloride is added slowly. The solution is stirred at -60° for 15 min and 1.9 ml triethylamine is added. The mixture is allowed to warm up to room temperature, washed with saturated sodium bicarbonate solution, and the organic phase is dried, filtered and evaporated to obtain a yellow oil. This oil is taken up in ether and washed with saturated sodium bicarbonate solution. The ether layer is dried, filtered and evaporated to yield methyl 8-(p-chlorophenylsulfonamido)-4-(formylmethyl)-octanoate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[Si:13]([O:20][CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(O)(C)C>[Si:13]([O:20][CH2:21][CH2:22][CH2:23]/[C:24](=[N:7]\[NH:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:2]=1[F:1])/[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCCC/C(=N\NC(=O)c1cc(F)ccc1F)c1ccccc1

Procedure:
A solution of 2,5-difluorobenzohydrazide (1-2, 90 mg, 0.52 mmol, 1 equiv) and 4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbutan-1-one (3-3) (146 mg, 0.523 mmol, 1.00 equiv) in isopropanol (10 mL) was heated at 75° C. for 1 day. The reaction mixture was concentrated to give N′-((1E)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylbutylidene)-2,5-difluorobenzohydrazide (3-4); LRMS m/z (M+H) 433.4 found, 433.2 required. A solution of 3-4 in acetic anhydride (5 mL) was heated at reflux for 1.5 h. The reaction mixture was concentrated and the residue was purified by reverse-phase LC(H2O/CH3CN gradient w/0.1% TFA present) to provide 3-[3-acetyl-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-oxadiazol-2-yl]propan-1-ol (3-5) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.57 (m, 2H), 7.52 (m, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 3.75 (t, 2H, J=6.4 Hz), 3.07 (m, 1H), 2.64 (m, 1H), 2.39 (s, 3H), 1.72 (m, 2H). LRMS m/z (M+H) 361.3 found, 361.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Cl.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[H-].[Na+].C(Cl)Cl>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:5][C:4]=1[N:19]([CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(C)C(=O)OC(C)(C)C)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.4 %

Procedure:
tert-Butyl 4-methoxy-3-(methylsulfonamido)benzyl(methyl)carbamate (189.1 mg, 0.549 mmol) was dissolved in dry DMF (10 ml) and cooled to 0° C. Nan (60% w/w dispersion in mineral oil, 48.3 mg, 1.208 mmol) was added, and the mixture was stirred 5 minutes at 0° C. and then 5 minutes at RT. 4-(2-Chloroethyl)morpholine hydrochloride (123 mg, 0.659 mmol) was added, and the mixture was stirred at RT for overnight. Additional NaH (43.93 mg, 1.098 mmol) was added over 4 days with stirring at RT. The reaction was quenched with water and brine and extracted with Et2O and twice with EtOAc. The combined organic layers were dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was purified by silica gel cartridge using as eluent:DCM to DCM/EtOAc 2:8 to give tert-butyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzyl(methyl)carbamate (114 mg, 0.249 mmol, 45.4% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[CH3:32][NH:33][CH3:34].O>C(#N)C>[CH3:32][N:33]([CH3:34])[C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:14])([F:16])[F:15])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29]
Reactant: CNC
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitrobenzamide (5.0 g, 11 mmol) (prepared according to WO 05/073165) in acetonitrile (100 ml) was added a solution of N,N-dimethylamine in water (40% by weight) (3.55 ml, 28 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. Then the reaction mixture was concentrated and the residue purified by chromatography over silica gel (eluent: ethyl acetate) to give 4-dimethylamino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitrobenzamide (5.3 g, 100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27]C(OC(C)(C)C)=O)[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[ClH:37]>O1CCOCC1>[ClH:37].[CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH2:27])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl ester 46 (0.4 g) was dissolved in 4M HCl in 1,4-dioxane (10 mL). The solution was stirred at rt for 16 h before being concentrated in vacuo to yield a brown solid, 0.38 g, 100%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([S:25]([NH:28][CH3:29])(=[O:27])=[O:26])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:30][CH3:31].Br[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:33]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([S:25]([NH:28][CH3:29])(=[O:26])=[O:27])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:30][CH3:31])([CH3:35])[CH3:34]
Reactant: CC(C)Br
Reactant: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(O)c(OC)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(OCC(F)(F)F)c(Nc2ncnc3cc(OC(C)C)c(OC)cc23)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
A solution of 3-{[7-hydroxy-6-(methyloxy)-4-quinazolinyl]amino}-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzenesulfonamide (170 mg, 0.37 mmol) in DMF (5 mL) was treated with 2-bromopropane (181 mg, 1.48 mmol) and K2CO3 (154 mg, 1.11 mmol) and stirred at 60° C. for 16 hours before being poured into water. The precipitate that formed was collected by filtration, washed with MeOH, and dried to give 3-(7-isopropoxy-6-methoxy-quinazolin-4-ylamino)-N-methyl-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonamide (80 mg, 43%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.C1C(=O)N([Cl:40])C(=O)C1>>[Cl:40][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:32]=[CH:31][C:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 37.9 %

Procedure:
Following General Procedure 1H, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (200 mg, 0.43 mmol) was reacted with NCS (68 mg, 0.52 mmol) to afford the desired product (79 mg, 38%) as a brown solid. ESI MS m/z 485 [C25H25ClN2O4S+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[NH4+].[Cl-].CCOCC>C1COCC1>[CH3:1][C@H:2]1[C@@:7]([C:14]2[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=2)([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc([C@]2(O)OCC(C)(C)N[C@H]2C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A solution of morpholin-2-one 15 (270 mg, 1.88 mmol) in anhydrous THF (1.9 mL) was cooled to −78° C. and treated with p-tolylmagnesium bromide (1.2 equiv., 2.26 mmol, 2.26 mL, 1 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. for 1.5 h, saturated aqueous solution of NH4Cl (30 mL) was added to the reaction vessel, and the mixture was allowed to warm to room temperature. Ether (30 mL) was added to the reaction flask, the organic layer was separated. The aqueous phase was extracted with ether (twice). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to give 271 mg (41%) of 4j as a yellow foam: [α]22D +21.2° (c 0.9, CHCl3); 1H NMR (CDCl3) δ 7.47 (d, 2H, J=8.2 Hz), 7.16 (d, 2H, J=8.0 Hz), 3.85 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.2 Hz), 3.20-3.07 (m, 1H), 2.35 (s, 3H), 1.39 (s, 3H), 1.08 (s, 3H), 0.81 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 129.6, 128.60, 128.49, 125.9, 103.2, 96.2, 69.4, 53.9, 53.4, 49.6, 27.3, 22.8, 16.5; LCMS (ESI) m/z 236.3 [(M+H)+, M=C14H21NO2].
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[F:29][C:30]1([F:37])[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[F:29][C:30]1([F:37])[CH2:35][CH2:34][CH:33]([NH:36][CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: NC1CCC(F)(F)CC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCC(F)(F)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 4,4-difluorocyclohexanamine via General Procedure E to give 15.4 mg of 294 following reverse phase purification. MS (Q1) 497.2 (M)+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][C:4]=1[O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.C(O)(=O)C.[CH3:32][C:33]([CH3:35])=O.C([BH3-])#N.[Na+]>CO>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][NH:9][C:10]2=[O:13])=[CH:5][C:4]=1[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:33]([CH3:35])[CH3:32])[CH2:17][CH2:16]1
Reactant: CC(C)=O
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)c(Cl)cc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)N1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.6 %

Procedure:
64 mg (0.23 mmol) of 7-chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one-hydro-chloride (54) were dissolved in 5 mL of methanol. 41.4 mg (0.41 mmol) of triethyl amine were added and the mixture stirred at room temperature for 10 minutes. After adding freshly dried molecular sieves, 122.4 mg (2.04 mmol) acetic acid, 26.7 mg (0.46 mmol) of acetone and 43.3 mg (0.69 mmol) of sodium cyanoborohydride, the reaction mixture was refluxed for 8 h. After the addition of 2 equivalents acetone and 2 equivalents of sodium cyanoborohydride at room temperature, the reaction was refluxed for another 2 h to complete conversion. For working up, the mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane, washed twice with 2 N NaOH and water and dried over MgSO4. After evaporation of the solvent and purification by preparative HPLC, 13 mg of the title compound were obtained as trifluoroacetate. Rt=0.96 min (Method B). Detected mass: 321.1/323.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)c1ccc(F)cc1Br
Reactant: OB(O)c1cc(F)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(=O)c1ccc(F)cc1-c1cc(F)ccc1F
Yield: 27.2 %

Procedure:
The title compound was prepared from 2,5-difluorophenylboronic acid (2.0 g, 12.7 mmol), tetrabutylammonium bromide (3.71 g, 11.5 mmol), potassium carbonate (4.78 g, 34.6 mmol), 2′-bromo-4′-fluoroacetophenone (2.5 g, 11.5 mmol), and palladium acetate (259 mg, 1.15 mmol) according to the procedure and in the same manner as described in Example 105, step a. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 10%-30% methyl tert-butyl ether in hexane, to afford the desired compound (784 mg, 27%) as a clear yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: Nc1ccncc1C=O
Reactant: COc1cccc(F)c1CCC#N
Product: COc1cccc(F)c1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-aminonicotinaldehyde and 3-(2-methoxy-6-fluorophenyl)propionitrile.