Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(=O)CC(=O)CCCCC.C([N:19]1[CH:24]2[CH2:25][CH2:26][CH2:27][CH:20]1[C:21](=[O:40])[N:22]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=1)[C:23]2=[O:28])C1C=CC=CC=1.C(OCC)(=O)C>[Pd].C(O)C>[F:39][C:36]([F:37])([F:38])[O:35][C:32]1[CH:33]=[CH:34][C:29]([N:22]2[C:23](=[O:28])[CH:24]3[NH:19][CH:20]([CH2:27][CH2:26][CH2:25]3)[C:21]2=[O:40])=[CH:30][CH:31]=1
Reactant: O=C1C2CCCC(C(=O)N1c1ccc(OC(F)(F)F)cc1)N2Cc1ccccc1
Agent: [Pd]
Agent: CCCCCC(=O)CC(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1C2CCCC(N2)C(=O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h

Procedure:
3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo|3.3.1|nonane-2,4-dione: A mixture of 9-benzyl-3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione (120 mg, 0.3 mmol), 10% Pd/C (20 mg, 0.02 mmol Pd), ethyl acetate (8 mL), and ethanol (2 mL) were stirred vigorously under an atmosphere of H2. After 2 h, more ethanol (2 mL) was added. After an additional 16 h, the reaction was filtered through Celite and concentrated to give 3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-2,4-dione: MS (ESI): 315.4 (M+H).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[NH:8])=[CH:13][CH:12]=1
Reactant: N#Cc1ccccc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(NC(=N)c2ccccc2)cc1

Procedure:
The title compound was prepared from benzonitrile (3.705 g, 35.97 mmol) and 4-methylthioaniline (5.0 g, 35.97 mmol) by following the procedure described in preparation 1, (3.66 g, 42.1%, purity 99.8% by HPLC), mp 129-131° C. 1H-NMR (CDCl3):δ 2.49 (s, 3H), 4.84 (bs, 2H), 6.94-6.96 (d, 2H), 7.26-7.31 (m, 2H), 7.45-7.49 (m, 3H), 7.87-7.88 (d, 2H). MS m/z:243.2 (M+)
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]1[C:26]2[C:21](=[C:22]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[NH2:33])[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1>COC(O)C>[NH2:33][C:32]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH2:20][CH2:19][N:18]([C:2]1[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=1)[CH2:17]2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: Nc1ccncc1-c1cccc2c1CCNC2
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(cccc4-c4cnccc4N)C3)[nH]c(=O)c2cc1OC
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (0.076 g, 0.31 mmol) and 3-(1,2,3,4-tetrahydro-isoquinolin-5-yl)-pyridin-4-ylamine (0.075 g, 0.33 mmol) in methoxyethanol (5 mL) was heated to 95° C. with stirring for 18 h the volatiles were evaporated and the residue was purified by flash column eluting with 2% methanol in dichloromethane containing 0.2% of ammonium hydroxide to yield 2-[5-(4-amino-pyridin-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-6,7-dimethoxy-3H-quinazol-4-one 902. The product was converted to the hydrochloric acid salt, mp. >300° C., [M+H]+=430.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:25])[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:60][C:61]1[CH:65]=[C:64]([Sn](C)(C)C)[S:63][N:62]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:25][C:4]1[C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[CH:7]=[C:2]([C:64]2[S:63][N:62]=[C:61]([CH3:60])[CH:65]=2)[CH:3]=1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Reactant: COc1ccc2c(OCc3nnc4c(F)cc(Cl)cn34)ccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1ccc2c(OCc3nnc4c(F)cc(-c5cc(C)ns5)cn34)ccnc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
Dioxane (3.6 mL) was added to 4-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)-7-methoxyquinoline (175 mg, 488 μmol), X-Phos (32.6 mg, 68.3 μmol), 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol), palladium acetate (7.67 mg, 34.1 μmol). The flask was purged with argon and sealed. The reaction mixture was stirred at 80° C. for 2d. More X-Phos (32.6 mg, 68.3 μmol), palladium acetate (7.67 mg, 34.1 μmol) and 3-methyl-5-(trimethylstannyl)isothiazole (153 mg, 585 μmol) were added and stirring was continued at 80° C. overnight. The reaction mixture was cooled at RT, concentrated in vacuo and purified by MPLC(CH2Cl2/MeOH: 100/0 to 90/10). Further purification by MPLC (ISCO, EtOAc/MeOH:9/1, isocratic) afforded the title compound (105 mg, 51% yield). MS m/z=422.0 [M+H]+. Calc'd for C21H16FN5O2S: 421.46
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Br)[C:11]=1[CH2:12][O:13][C:14]([NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[O:15])[C:5]([O:7][CH3:8])=[O:6].C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I>[Br:1][C:2]1[C:11]2[CH2:12][O:13][C:14](=[O:15])[N:16]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: COC(=O)c1cc(Br)c(COC(=O)Nc2c(Cl)cccc2Cl)c(Br)c1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)OC2

Procedure:
To a solution of methyl 3,5-dibromo-4-[({[(2,6-dichlorophenyl)amino]carbonyl}oxy)methyl]benzoate (1 g, 1.96 mmol, 1 eq) in DMF (20 mL) was added CuI (411 mg, 2.16 mmol, 1.1 eq) and diisopropylethylamine (0.51 mL, 2.95 mmol, 1.5 eq). Degassed the reaction flask with argon and placed in a 140° C. oil bath. After 2.5 h the reaction was cooled. The mixture was filtered to remove inorganics. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and washed with water. The aqueous layer was back-extracted 2× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with Et2O leaving 283 mg of solid methyl 5-bromo-1-(2,6-dichlorophenyl)-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-7-carboxylate. The supernatant was further purified by flash column chromatography on silica gel eluting with 2:1 CH2Cl2/hexanes giving an additional 309 mg of not quite pure product. Mass spectrum (ESI) 430.0 (M+1); 432.0 (M+3), 434.0 (M+5).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:27])[CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=S)Nc1ccc(Oc2ccccc2)cc1
Temperature: 120 °C
Yield: 86.6 %

Procedure:
To a solution of N-(4-phenoxy-phenyl)-acetamide (1.20 g, 5.28 mmol) in 10 ml of toluene was added Lawesson's reagent (1.50 g, 3.70 mmol). The reaction mixture was heated at 120° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (0.78 g, 60.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1>C1COCC1.C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitro-benzamide (2 g, 7.2 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney Ni (0.2 g) and the mixture was placed under hydrogen (4.1 bar) in a high pressure apparatus. After shaking overnight, the mixture was filter d and concentrated in vacuo and purified by flash chromatography to give 1.5 g (83%) of an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>ClCCl>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26]
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of N,N-dimethyl-1,3-diaminopropane (0.92 g) and triethylamine (0.95 mL) in dichloromethane (10 mL) was added 2-nitrobenzenesulfonyl chloride (1 g), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (1.26 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCCCOc1ccc2ccccc2c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCOc1ccc2ccccc2c1

Procedure:
1-Chloro-8-(2-naphthyloxy)octane (4.75 g) and potassium phthalimide (4.2 g) were heated in dimethylformamide (25 ml) at 120° for 4 hours. The solution was then cooled, added to water, and extracted with methylene chloride. The extracts were then dried and evaporated to afford N-[8-(2-naphthyloxy)octyl]phthalimide as a gum. This material was refluxed for 16 hours in ethanol (150 ml) containing 85% aqueous hydrazine hydrate (3 ml). The solution was cooled and water (450 ml) and 10% aqueous potassium hydroxide (50 ml) were added. The resultant solution was extracted with hexane; the extract was dried and evaporated to afford the title compound as an oil (hydrochloride mp 169°-170°).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH2:14][CH:15]=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]1=[O:17].OC1C=C2C(=CC=1)N(C)C(=O)C=C2.[NH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][N:37]=[CH:36]1.[BH4-].[Na+]>CO.O>[N:35]1([CH2:34][CH2:33][CH2:32][NH:31][CH2:15][CH2:14][CH2:13][O:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:17])[CH:4]=[CH:5]3)[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: Cn1c(=O)ccc2cc(OCCC=O)ccc21
Reactant: NCCCn1ccnc1
Agent: Cn1c(=O)ccc2cc(O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cn1c(=O)ccc2cc(OCCCNCCCn3ccnc3)ccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 11.2 %

Procedure:
3-(1-Methyl-2-oxo-1,2-dihydroquinolin-6-yloxy)propionaldehyde (127.5 mg) prepared from 6-hydroxy-1-methylquinolin-2(1H)-one and N-(3-aminopropyl)imidazole (82.9 mg) were added to methanol (10 ml). The mixture was stirred at room temperature for 7 hours. The mixture was cooled to 0° C., and sodium borohydride(31.4 mg) was added thereto. The mixture was further stirred at room temperature overnight. Water was added to the reaction mixture and methanol was distilled off under reduced pressure. The residue was subjected to extraction using dichloromethane. The organic layer was washed with saturated saline, dried with anhydrous sodium sulfate, and was condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol=10:0→4:1). The purified product was condensed under reduced pressure to give the title compound(21 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C@H:8]([C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])[NH2:9])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C@H:8]([C:10]([S:13][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:12])[CH3:11])[NH:9][C:35](=[O:37])[CH3:36])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CNC(=O)[C@@H](N)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)[C@@H](NC(C)=O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To the solution of S-trityl-L-penicillamylglycine ethyl ester (C-2) (3.7 g) in dichloromethane (50 ml) were added acetyl chloride (0.66 ml) and triethylamine (0.88 ml) at 0° C. The mixture was stirred at the same temperature for 15 minutes and then ice water was added. The organic layer was washed with an aqueous potassium hydrogensulfate solution, water, an aqueous sodium hydrogencarbonate solution, water and saturated saline, in this order, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was subjected to silica gel column chromatography, to give N-acetyl-S-trityl-L-penicillamylglycine ethyl ester (3.5 g).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7]C[CH:5]1[CH2:4]C(=O)[O:2]2.[H-].C([Al+]C[CH:17]([CH3:19])[CH3:18])C(C)C>C1(C)C=CC=CC=1>[CH3:4][CH2:5][CH:1]([OH:2])[CH2:8][CH2:7][CH2:19][CH2:17][CH3:18]
Reactant: O=C1CC2CCCC2O1
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCCC(O)CC

Procedure:
The compound (52) (12.1 g) was reduced with diisobutylaluminum hydride (1.5M, 65.1 ml) in toluene (500 ml) at -78° C. and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (53). Yield: 11.1 g (91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)=[O:4].C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>O>[N:20]([C:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[OH:15])=[O:21]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2c(N=O)c(O)ccc2c1
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
202.0 g (1.0 mol) of 6-methoxycarbonyl-β-naphthol were suspended in 1120 ml of 90%-strength acetic acid, nitrosated with 182 g (1.05 mol) of 40%-strength sodium nitrite solution at 0°-5° C. in the course of 2.5 hours and then stirring was continued at room temperature for 45 minutes. The suspension obtained was made up to 3 l with water, the solid was filtered off by suction and washed with water until neutral. After drying, 228.1 g (99.7%) of crude 1-nitroso-6-methoxycarbonyl-β-naphthol were obtained.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[C:29]([F:30])=[C:28]([F:31])[C:14]3[N:15]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[CH3:27])[CH2:16][O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=O)=C(F)C(F)=C(F)C=1F.C1COCC1.Cl.CN.[CH:44]([N:47](CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:44][NH:47][C:9]([C:11]1[C:29]([F:30])=[C:28]([F:31])[C:14]2[N:15]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[CH3:27])[CH2:16][O:17][C:18](=[O:19])[C:13]=2[CH:12]=1)=[O:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c(F)c21
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(c(F)c1F)N(c1ccc(I)cc1C)COC2=O
Reaction time: 17 h
Yield: 76.8 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid (0.3 g, 0.67 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.127 mL, 0.74 mmol) and pyridine (0.60 mL, 0.74 mmol). After stirring for 4 hours the reaction mixture is diluted with ethyl acetate and washed 3 times with 1.0 M HCl solution, 3 times with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester as a dark orange oil (0.34 g, 83.1%). To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester (0.33 g, 0.54 mmol) in freshly distilled THF (10 mL) is added methylamine hydrochloride (0.037 g, 0.54 mmol) and N,N-diisopropylethylamine (0.019 mL, 1.08 mmol). After stirring for 17 hours, the reaction mixture was diluted with ethyl acetate and washed 2 times with water and 2 times with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide as a yellow solid (0.19 g, 76.9%); mp 219–223° C.; 1NMR (400 MHz; DMSO-d6) 8.40 (s, 1H), 8.06 (d, 1H, J=6.8), 7.74 (s, 1H), 7.50 (d, 1H, J=8.4), 6.87 (d, 1H, J=8.0), 5.61 (s, 2H), 2.76 (d, 3H, J=4.4), 2.25 (s, 3H); MS(APCI)m+1=459; Anal.calcd/found for C17H13F2IN2O3 C 45.00/45.39, H 3.01/3.16, N 6.05/5.88.
Reaction SMILES: [C:1]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.C(Cl)(Cl)Cl>C(O)C>[C:1]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2CCC1Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: c1ccc(NC2CCc3ccccc3C2)cc1
Temperature: -10 °C
Yield: 80 %

Procedure:
2.37 grams (0.01 mol.) of 2-phenylaminotetralone (formula I: R = phenyl) are refluxed during 6 hours in 50 ml of ethanol, in the presence of one equivalent of tosylhydrazine. After the removal of the alcohol, 100 ml of alcohol-free chloroform are added to the residue (crude tosylhydrazone). After cooling to -10°C, 0.011 mol. of catecholborane are added and the reaction is allowed to take place during 30 minutes. 0.03 mol. of trihydrated sodium acetate are then added so as to initiate the decompositon of the intermediate addition product and the mixture is refluxed during 1 hour. After cooling, 100 ml of water are added and the pH is adjusted at 13. The obtained 2-phenylaminotetraline (yield: 80%) is extracted by means of chloroform and converted into hydrochloride. Melting point: 193° - 196°C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[Br:11][C:12]1[N:17]=[C:16]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[Br:11][C:12]1[N:17]=[C:16]([CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[CH:1]=[O:3])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(CNCc2cccc(Br)n2)c(OC)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: COc1ccc(CN(C=O)Cc2cccc(Br)n2)c(OC)c1
Temperature: 55 °C
Reaction time: 0.75 h

Procedure:
To acetic anhydride (0.703 mL) was added dropwise formic acid (0.349 mL) under ice-cooling, and the mixture was stirred at 55° C. for 45 min. The mixture was allowed to be cooled to room temperature, and tetrahydrofuran (10 mL) was added thereto. A solution of 1-(6-bromopyridin-2-yl)-N-(2,4-dimethoxybenzyl)methanamine obtained in Reference Example 19 (930 mg) in tetrahydrofuran (10 mL) was added dropwise thereto over 3 min under ice-cooling, and the reaction mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, the obtained colorless oil was subjected to azeotropy with toluene, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (932 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a flame dried round bottom flask 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G, 2.0 g, 7.93 mmol) was dissolved in anhydrous THF (50 ml) and 3,4,5,6,-tetrahydro-2(H)-pyrimidinone (DMPU) (11.5 ml, 95.16 mmol) was added, under argon atmosphere. The reaction was then cooled to −20° C. and a solution of t-butyl magnesium chloride (16 ml, 31.7 mmol) (2 M in Et2O) was added dropwise and stirred at −20° C. for 2 h and at ambient temperature for 1 h, under argon atmosphere. The reaction was quenched at 0° C. with saturated ammonium chloride solution (20 ml) and extracted with EtOAc (2×50 ml). The combined extract was washed with water (20 ml), brine (20 ml) and dried over MgSO4. The solvent was evaporated under reduced pressure to afford a yellow oil. To this yellow oil were added MeOH (50 ml) and p-tolylsulfonic acid (100 mg). The resultant reaction solution was heated in an oil bath (60° C.) for 3 h. The reaction was cooled and quenched with water (20 ml), extracted with EtOAc (2×50 ml). The combined extract was washed with saturated NaHCO3 (20 ml), water (20 ml), brine (20 ml), and dried over MgSO4. The solvent was concentrated in vacuo and the title compound was obtained as a colorless oil after purification by flash chromatography (silica, hexane).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: Oc1ccc(S)cc1
Product: O=C(Sc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A PPE (polyphosphate ester) solution (7 mL) was added to a mixture of 4-hydroxybenzoic acid (552 mg, 4 mmol) and 4-mercaptophenol (554 mg, 4.4 mmol). After stirring for 16 h, the solvents were removed by evaporation and the residue was purified by column chromatography (hexane-EtOAc 7:1 to 1:1). 4-Hydroxy-thiobenzoic acid S-(4-hydroxy-phenyl)ester (240 mg, 24%) was obtained as a white solid. MS (ES) m/z: 247.04 (M+1), 167.03, and 122.55. 13C-NMR (DMSO-d6): δ 188.24, 162.85, 158.82, 135.87, 129.59, 127.10, 116.33, 115.72, and 115.34.