Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:13])[NH:8][C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>COCCOC>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:13])[N:8]([CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cnc(C)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(C)n(CC(=O)C(C)(C)C)c1=O
Temperature: 25 °C

Procedure:
To a suspension of 5-ethoxycarbonyl-2-methylpyrimid-4-one (2.7 g, 14.75 mmol.) in DME (20 ml), tetrabutylammonium fluoride (22 ml, 22.0 mmol.) was added. The solution was stirred at room temperature until solids dissolved, then 1-bromopinacolone (2.2 ml, 1.1 eq., 16.22 mmol) was added. The solution was stirred overnight and concentrated to a brown oil. The crude mixture was purified by silica gel column chromatography (hexane/ethyl acetate, 100/0 to 0/100). A less polar O-alkylated by-product was eluted first (1.8 g) and then the desired N-alkylated product (1.1 g); MS (281, M+H)+. NMR (CDCl3, δ): 8.57 (1H, s) , 5.06(1H, s), 4.35(2H, q), 2.42 (3H, s), 1.34 (3H, t), 1.30 (9H,s).
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[C:28]([C:31]1[CH:52]=[CH:51][C:34]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]([N+:48]([O-])=O)[CH:43]=[CH:44][C:45]=2[C:46]#[N:47])=[C:33]([CH2:53][CH2:54][CH3:55])[C:32]=1[OH:56])(=[O:30])[CH3:29]>>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=2)[NH2:19])=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[C:28]([C:31]1[CH:52]=[CH:51][C:34]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]([CH:43]=[CH:44][C:45]=2[C:46]#[N:47])[NH2:48])=[C:33]([CH2:53][CH2:54][CH3:55])[C:32]=1[OH:56])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCCCOc2cccc([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCOc2cc([N+](=O)[O-])ccc2C#N)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2cc(N)ccc2C#N)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCOc2cccc(N)c2)ccc(C(C)=O)c1O

Procedure:
In analogous manner, starting from 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-nitrobenzene and from 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propyloxy]-4-cyano-nitrobenzene, there are obtained 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-aniline having a melting point of 76°-77° (ether/petroleum ether) and 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propyloxy]-4-cyano-aniline.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[N:6]([CH:14]=[C:15]([C:17]([O:19]CC)=[O:18])[N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].O.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:5]2[N:6]([CH:14]=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1cn2c(n1)c(OCC)nc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1nc2ccccc2n2cc(C(=O)O)nc12
Reaction time: 8 h

Procedure:
A suspension of 0.5 g of the product of Step B, 50 ml of water, 15 ml of ethanol and 8 ml of 1 N sodium hydroxide solution was stirred overnight to obtain a clear colorless solution which was acidified with concentrated hydrochloric acid. The mixture was filtered to obtain 4-ethoxy-imidazo-[1,2-a]-quinoxaline-2-carboxylic acid melting at 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:16]([SH:17])=[N:15][CH:14]=[N:13][C:12]=2[N:18]=1.[CH2:19](N(CC)CC)C.CI>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][C:11]2[C:16]([S:17][CH3:19])=[N:15][CH:14]=[N:13][C:12]=2[N:18]=1
Reactant: Sc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CI
Product: CSc1ncnc2nc(-c3c(Cl)cccc3Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a solution of 2-(2,6-dichlorophenyl)thiazolo[4,5-d]pyrimidine-7-thiol (1.29 g, 4.1 mmol) and triethylamine (1.66 g, 16.4 mmol) in ethanol (20 mL) was added methyl iodide (2.32 g, 16.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with 0-20% EtOAc/hexane gradient to give the desired compound as a white solid (0.59 g, 44% yield). 1H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 7.49-7.47 (M, 2H), 7.45-7.40 (m, 1H), 2.81 (s, 3H). LCMS (ESI) m/z: 328.9 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]#[N:18])[S:11]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([NH:20][OH:21])=[NH:18])[S:11]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C#N)sc2nc(-c3ccc(F)cc3)cn12
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c(C(=N)NO)sc2nc(-c3ccc(F)cc3)cn12
Yield: 63 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile (example 20, 140 mg, 0.54 mmol), hydroxylamine hydrochloride (226.9 mg, 3.26 mmol) and triethylamine (529 μl, 3.8 mmol) were stirred in 10 ml of isopropanol at 90° C. for 2 hours. The solvent was removed in vacuo and water was added. The solid was filtered, washed with diluted hydrochloric acid and water and was dried. Yield: 63%. MS: M+H+=291.15.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH2:26]Cl)[O:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][C:36](C)=[O:37]>>[CH2:35]1[O:28][C:21]2([C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:25][O:24][C:23]([CH2:26][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:10])=[O:11])=[CH:6][CH:7]=3)=[CH:22]2)[O:37][CH2:36]1
Reactant: CC(C)=O
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: O=c1cc(CCl)occ1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)Cc1ccc(OCC2=CC3(OCCO3)C(OCc3ccccc3)=CO2)cc1

Procedure:
A mixture of 4-hydroxyphenylpropan-2-one, ethylene ketal (3.88 g), 5-benzyloxy-2-chloromethyl-4H-pyran-4-one (5.0 g) and potassium carbonate 3.5 g) in acetone, was heated under reflux for 18 h. The reaction mixture was cooled, filtered and the solvent removed in vacuo. The residue was dissolved in ethyl acetate, washed with 2N-sodium hydroxide solution (1×50 ml), water (2×50 ml), dried (magnesium sulphate), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica using chloroform as eluent, followed by crystallisation from acetone to give 2-(4-acetonylphenoxymethyl)-5-benzyloxy-4H-pyran-4-one ethylene ketal, (5.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[N:11][N:12]([CH3:17])[C:13]=1[CH:14]=[N:15][OH:16].O.[NH2:26]O.CCOC(C)=O>C(OC(=O)C)(=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:10]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)=[N:11][N:12]([CH3:17])[C:13]=1/[C:14](=[N:15]/[OH:16])/[NH2:26]
Reactant: NO
Reactant: Cn1nc(-c2ccc(O)cc2)c(-c2c(F)cccc2F)c1C=NO
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cn1nc(-c2ccc(O)cc2)c(-c2c(F)cccc2F)c1/C(N)=N/O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
To 4-(2,6-difluorophenyl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime (30.0 mg, 0.09 mmol) in acetic anhydride (1 mL) was irradiated in the microwave for 20 min 1.5 ml water was added and the mixture was stirred at rt for 3 h, extracted with DCM, filtered through a phase separator and concentrated. The raw product was dissolved in DMSO (1 mL) and neutral hydroxylamine solution (50 wt % in water, 0.12 mL, 1.96 mmol) was added. The mixture was stirred in the microwave at 130° C. for 10 min. EtOAc and water were added and the phases were separated. The mixture was purified on preparative HPLC to give (Z)-4-(2,6-difluorophenyl)-N′-hydroxy-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carboximidamide (5.2 mg, 0.016 mmol, 18%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 345.11 (M+H), 343.26 (M−H); 1H NMR (MeOD, 500 MHz): 7.37 (m, 1H), 7.15 (m, 2H), 6.96 (m, 2H), 6.65 (m, 2H) and 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]12([C:18](Cl)=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([NH:7][C:18]([C:8]23[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]2)[CH2:9]3)=[O:19])=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C

Procedure:
A mixture of 5-bromothiazol-2-amine (3.0 g, 11.5 mmol), adamantane-1-carbonyl chloride (2.74 g, 13.8 mmol), triethylamine (3.2 mL, 23 mmol) and 4-di(methylamino)pyridine (1.1 g) in tetrahydrofuran (100 mL) was heated at 80° C. for 48 hours. The mixture was cooled to ambient temperature, concentrated, diluted with water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexanes) afforded the title compound. MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:34])[C:15]([C:17]1[O:18][C:19]3[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=3[C:21]=1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:16])=[CH:7]2.Br[CH2:36][C:37]([O:39][CH3:40])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][O:12][C:11]1[CH:10]=[CH:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([CH2:13][N:14]([CH3:34])[C:15]([C:17]3[O:18][C:19]4[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=4[C:21]=3[CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:16])[CH:7]=2)[C:2]=1[Br:1]
Reactant: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1oc2ccccc2c1CCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2cc(CN(C)C(=O)c3oc4ccccc4c3CCc3ccccc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 3-phenylethyl-benzofuran-2-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide, prepared in step 4 of Example 45, methyl bromoacetate (260 μL, 2.75 mmol) and potassium carbonate (1.58 g, 11.96 mmol) in 25 mL of DMF was stirred under nitrogen at room temperature 16 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give (1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (1.29 g, 96%) as a light brown foam, MS m/z: 586 [M+H]+.
Reaction SMILES: NC(C)(C)[CH2:3][OH:4].[C:7]([C:10]1[CH:18]=[CH:17][C:13](C(O)=O)=[CH:12][CH:11]=1)(=O)[CH3:8].C(Cl)C[Cl:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:3]([Cl:21])(=[O:4])[CH2:8][CH2:7][C:10]1[CH:11]=[CH:12][CH:13]=[CH:17][CH:18]=1
Reactant: ClCCCl
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(N)CO
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
A mixture of 2-amino-2-methyl-1-propanol (4 ml, 42 mmol), CH2Cl2 (200 mL), 4-acetyl benzoic acid (1, 6.9 g, 42 mmol), EDC (1-(3-dimethylaminopropyl)-3-eythylcarbodiimide HCl, 12.1 g, 63 mmol), HOBT (N-hydroxybenzotriazole H2O, 6.4 g, 42 mmol), and Hunig's base (diisopropylethylamime, 22 mL, 126 mmol) was stirred at room temperature for 18 hours. Upon completion (TLC, LC/MS) the reaction mixture was concentrated, and the resulting residue was diluted with EtOAc (50 mL) and washed with NaHCO3 (2×40 mL) and brine (40 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated. The crude material was purified by flash column chromatography (4:1:1 hexanes:EtOAc:CH2Cl2; 1:1:1 hexanes:EtOAc:CH2Cl2; 1:1 EtOAc:CH2Cl2) to remove bisacylated material. Alcohol 2 was obtained in 54% yield (5.36 g).
Reaction SMILES: O1CCOCC1.[C:7]1([C@H:17]([N:19]([CH2:27][C@@H:28]2[C@@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:31][NH:30][CH2:29]2)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:48]=[CH:49][C:50]=1[NH:51][C:52](OC1C=CC([N+]([O-])=O)=CC=1)=[O:53])[C:44]([O:46][CH3:47])=[O:45]>C(N(CC)CC)C>[C:22]([O:21][C:20]([N:19]([CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:31][N:30]([C:52]([NH:51][C:50]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=2[O:40][CH3:39])=[O:53])[CH2:29]1)[C@@H:17]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:18])=[O:26])([CH3:24])([CH3:25])[CH3:23]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A 1,4-dioxane solution of 250 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed, under ice-cooling, with 0.13 ml of triethylamine and 250 mg of methyl 3-methoxy-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate and stirred overnight at 80° C. The solvent was evaporated under a reduced pressure, and the residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 245 mg of methyl 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)-3-methoxybenzoate as a colorless amorphous substance.
Reaction SMILES: C([O-])(O)=O.[Na+].C[C@@H](N)[C@H]1O[C@H]([O:14][C@H:15]2[C@H:20](O)[C@@H:19]([O:22][C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H:18](N)[CH2:17][C@@H:16]2N)[C@H](N)CC1.C[C@@H](NC)[C@H]1O[C@H](O[C@H:47]2[C@H:52](O)[C@@H:51]([O:54][C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H:50](N)[CH2:49][C@@H:48]2N)[C@H](N)CC1.[CH3:71][C@@:72]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O>>[C:17]1([CH:71]=[CH:72][C:48]2[CH:47]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)[CH:16]=[C:15]([OH:14])[CH:20]=[C:19]([OH:22])[CH:18]=1
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Reaction time: 1 h

Procedure:
Cultures of African green monkey kidney cells (Vero) cells, obtained from the American Type Culture Collection, Rockville, Md., were grown to confluence in Medium 199 supplemented with 5% fetal bovine serum, 0.075% NaHCO3, and 50 μg/ml gentamycin sulfate in 25 cm2 tissue culture flasks. Cells were infected with pseudorabies virus at a multiplicity of infection (moi) of one and incubated at room temperature for one hour to allow for virus attachment to and penetration of the cell. Under these conditions, approximately half of the cells are infected with virus. Thereafter, the cultures were rinsed three time with media and incubated in medium containing resveratrol at a final concentration of 50 μg/ml. Stock solutions of the resveratrol, obtained from Sigma Chemical Co, St. Louis, Mo. were prepared in 100% ethanol and diluted to the final concentration in tissue culture media. The maximum concentration of alcohol in the medium was 0.5%. Controls were treated identically, but were incubated without resveratrol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:26]1([C:32]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=4[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:24][CH3:25])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OC(=O)N4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (intermediate 4) (86 mg), morpholine-4-carbonyl chloride (114 mg), and potassium carbonate (175 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (17 mg, yield 15%).
Reaction SMILES: COCCS[CH2:6][CH2:7]OC.[BH3:10].[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>ClCCl>[CH2:11]([B:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:6][CH3:7])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COCCSCCOC
Reactant: C=CCCCCCC
Reactant: B
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCB(CCCCCCCC)CCCCCCCC
Reaction time: 0.08 h

Procedure:
Borane bis(2-methoxyethyl) sulfide (5.0 ml, 30 mmol) was dissolved in dichloromethane (30 ml) and 1-octene (10.10 g, 90 mmol) was added dropwise with cooling to keep the temperature at 20°-25° C. The reaction was complete in 5 min as indicated by 11B NMR. The solution was vigorously stirred with water (10×20 ml), dried over magnesium sulfate and the solvent was removed under vacuum. 1H NMR spectrum showed the sulfide present. Diethyl ether (20 ml) was added, followed by 5% sodium hypochlorite solution (40 ml) and the mixture was stirred keeping the temperature at 20°-25° C. After 1 h, the organic phase was separated, washed with water (3×20 ml) and dried over magnesium sulfate. Ether was removed under vacuum to give trioctylborane, 9.84 g, 94%, 11B NMR, δ, 86 ppm. 1H NMR did not indicate bis(2-methoxyethyl)sulfide. Tetrahydrofuran (30 ml) was added, followed by 3M sodium hydroxide (10 ml, 30 mmol) and 30% hydrogen peroxide (10 ml, 100 mmol). The mixture was stirred for 2 h at room temperature and then 1 hour at 40° C., saturated with potassium carbonate, the organic layer was separated and the aqueous layer was extracted with diethyl ether (2×30 ml). The extracts were combined with the THF solution, dried over magnesium sulfate and octanol was isolated by distillation, 10.60 g, 90.5%, bp 99°-100° C./20 mm Hg. GC analysis (Carbowax 20 M) showed 1-octanol (94%) and 2-octanol (6%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][C:3]=1[O:18][CH3:19].C([O-])([O-])=O.[K+].[K+].Cl[C:27]1[N:32]=[C:31]([Cl:33])[C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1>O1CCOCC1>[Cl:33][C:31]1[C:30]([C:34]([F:36])([F:35])[F:37])=[CH:29][N:28]=[C:27]([NH:1][C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])=[CH:4][C:3]=2[O:18][CH3:19])[N:32]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 130 °C

Procedure:
Benzyl 4-amino-3-methoxybenzoate (1.92 g, 6.8 mmol) and K2CO3 (2.38 g, 17 mmol) are suspended in 4 mL dioxane and then mixed with 2,4-dichloro-5-trifluoromethylpyrimidine (1.48 mL, 6.8 mmol). The suspension is then refluxed for 100 min with stirring in the oil bath (approx. 130° C.). Once the reaction has ended the reaction mixture is filtered, the filtrate is concentrated by rotary evaporation and purified by normal-phase column chromatography. The product-containing fractions of A-3a (HPLC-MS: tRet.=1.94 min; MS (m-H)−=436) are combined and concentrated by rotary evaporation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[F:21][C:22](I)([F:24])[F:23]>[Cu].CN(C)C=O>[F:21][C:22]([F:24])([F:23])[C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: FC(F)(F)I
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(Br)c1
Agent: [Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
To a solution of 0.01 moles of ethyl 3-bromo-4-cyclohexylphenylglyoxylate in 50 ml. of dimethylformamide is added 0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. The reaction is shaken in a sealed tube for 5 hours at 140° C., cooled, and then filtered and evaporated in vacuo. 200 ml. of water is added to the residue and extracted with ether. The ether extract is dried, evaporated to dryness and distilled to obtain ethyl 3-trifluoromethyl-4-cyclohexylphenylglyoxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH:28]=1>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:27]1[CH:28]=[C:23]([CH2:22][N:11]2[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:24]=[C:25]([C:36]([O:38][CH3:39])=[O:37])[CH:26]=1
Reactant: COC(=O)c1cc(CBr)cc(-c2ccccc2Cl)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: COC(=O)c1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc(-c2ccccc2Cl)c1

Procedure:
Analogously to the preparation of Example 139, 248 mg (0.81 mmol) of the compound from Example 5A were reacted with 274 mg (0.81 mmol) of the compound from Example 112A. This gave 271 mg (59% of theory) of the target compound.