Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl>CN1CCCC1=O>[C:2]1([O:1][CH:4]=[CH:5][C:6]2[CH:7]=[CH:8][C:13]([CH3:12])=[CH:14][CH:15]=2)[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)cccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(C=COc2cccc3c2C(=O)c2ccccc2C3=O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.1 mol of 1-hydroxyanthraquinone is dissolved hot in 100 ml of N-methylpyrrolidone in a 1 liter brown glass flask with a mechanical stirrer, thermometer and condenser. After the mixture has been cooled to room temperature, 0.1 mol of NaH suspension is added in portions. When the evolution of gas has ended, 0.11 mol of a mixture of 3- and 4-vinylbenzyl chloride is added and the mixture is stirred at 100° C. for 5 hours. Stirring is continued overnight at room temperature. 100 ml of 0.1 N HCl are then added and the suspension thus formed is extracted several times by shaking with methylene chloride. After the extract has been neutralised with sodium bicarbonate solution and dried with Na2SO4 and the methylene chloride has been stripped off, an oil remains, from which a yellow crystalline product is precipitated with water. Crude yield: 33.7 g (99% of theory). The crude product is purified by column chromatography with methylene chloride; yield of m-/p-methylstyryl 1-anthraquinonyl ether=58 % of theory, melting point: 88°-90° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C(OC(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)C.Cl.C1C[O:27][CH2:26]C1>C(OCC)(=O)C.O>[N:18]1[CH:17]=[CH:16][CH:21]=[CH:20][C:19]=1[C:26]([CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9])=[O:27]
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1cccnc1
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccn1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 55 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.66 g, 12 mmol) in 40 mL of THF was treated with NaH (60 percent, 2.4 g, 17 mmol). After the addition of Nicotinic acid ethyl ester (0.3 g, 20 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Pyridine-2-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g, 8 mmol) as red solid in 55% yield.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([O:17]C)=O)=[C:4]2[N:3]=1.[NH3:19]>>[SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([NH2:19])=[O:17])=[C:4]2[N:3]=1
Reactant: N
Reactant: COC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reaction time: 24 h

Procedure:
A solution of 1.80 g of methyl 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate in 800 ml of 25 percent aqueous ammonia was allowed to stand at 20° for 24 hours. The solution was concentrated to a small volume in a vacuum, made acidic with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated in a vacuum. The residual crystal slurry was treated with petroleum ether and filtered. There was obtained 5-mercapto-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([CH2:15][OH:16])[CH:14]=1.[ClH:22]>C(#N)C.[Cu](Cl)Cl>[Cl:22][C:9]1[CH:10]=[CH:11][C:12]([O:17][C:18]([F:21])([F:20])[F:19])=[C:13]([CH2:15][OH:16])[CH:14]=1
Reactant: Cl
Reactant: Nc1ccc(OC(F)(F)F)c(CO)c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: OCc1cc(Cl)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
t-Butyl nitrite (2.49 g, 24.2 mmol), copper (II) chloride (2.71 g, 20.2 mmol), and acetonitrile (100 mL) were added to a round-bottom flask. The resulting mixture was cooled to 0° C. (5-Amino-2-trifluoromethoxy-phenyl)-methanol (1.67 g, 8.1 mmol) in acetonitrile (10 mL) was slowly added to the reaction over a period of 5 min. The reaction was warmed up to room temperature and stirred overnight. The mixture was then poured into 20% HCl (100 mL) and extracted with ether (100 mL). The organic layer was washed with 20% HCl (100 mL) and dried over MgSO4. The ether was removed in vacuo and the residue was chromatographed with 4:1 hexanes:EtOAC to give 1.2 g (66%) of (5-chloro-2-trifluoromethoxy-phenyl)-methanol as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([O:17][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:11]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Yield: 122.9 %

Procedure:
Potassium carbonate (6.5 g; 47 mmol) was added to a solution of 3,4-dihydroxybenzoic acid methyl ester (2.6 g; 15.7 mmol) and benzyl bromide (5.37 g; 31.4 mmol) in acetone (100 ml). The reaction mixture was refluxed for 12 hrs. After the removal of the solvent under reduced pressure, the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 3.36 g of 3,4-Dibenzyloxy benzoic acid methyl ester (Yield=86.6%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12](=[O:29])[N:11]([CH2:30][CH2:31][CH3:32])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]([C:37]1(C)[CH2:41][CH:40](S(C)(=O)=O)[CH2:39][N:38]1[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:36].[C:54]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:33][O:34][C:35]([CH:37]1[CH2:41][CH:40]([CH2:54][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:15]4[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12](=[O:29])[N:11]([CH2:30][CH2:31][CH3:32])[C:10]=4[N:9]=3)=[CH:6][CH:7]=2)[CH2:39][N:38]1[C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[O:36]
Reactant: O=C([O-])[O-]
Reactant: CCCn1c(=O)c2c(nc(-c3ccc(O)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Reactant: COC(=O)C1(C)CC(S(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3ccc(OCC4CC(C(=O)OC)N(C(=O)OC(C)(C)C)C4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 80 °C

Procedure:
A mixture of 8-(4-hydroxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6 dione (100 mg, 0.231 mmol), 4-methanesulfonyl methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (82 mg, 0.254 mmol) and K2CO3 (63 mg, 0.462 mmol) in DMF (8 ml) was heated at 80° C. for 3 hrs. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water, brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by column chromatography to offer 4-{4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-phenoxymethyl}-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (110 mg, 36%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH2:43])=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:33][C:34]1[C:35]([F:44])=[C:36]2[C:42]([NH:43][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:41][NH:40][C:37]2=[N:38][CH:39]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
2-Phenylacetic acid (592 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide (606 mg, 80.1% yield) was obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:7]=[CH:8][N:9]=2)[N:4]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][N:9]=[C:10]3[C:5]=2[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]3)=[N:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2nccc(-c3ccc(C)cn3)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nccc(-c3ccc(CBr)cn3)c2n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirred solution of 2-methoxy-8-(5-methylpyridin-2-yl)[1,5]naphthyridine (1.2 g, 4.78 mmole), in dry CCl4 (150 mL) at RT was added NBS (1.02 g, 5.73 mmole) and benzoylperoxide (0.12 g, 0.48 mmole). After 18 h at reflux, the reaction contents were cooled to RT and filtered through a scintered-glass funnel washing with CHCl3. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (1.12 g, 71%) as light yellow solid: (EtOAc): LC-MS (ES) m/e 330 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH3:27])=[CH:22][N:21]=1)[OH:19].O>CN(C)C=O>[CH2:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:18]([OH:19])[CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:21][CH:22]=1)[CH3:27]
Reactant: CCc1ccc(C(O)CBr)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Into a solution of 2.9 g (0.0234 mol) of 4-hydroxy benzaldehyde dissolved in 100 mL dimethylformamide, 8.94 g (0.063 mol) of potassium carbonate in 20 mL dimethylformamide was added in 10 min. followed by slow addition of 5 g (0.0213 mol) of 2-bromo-1-(5-ethyl-pyridin-2-yl)-ethanol dissolved in 1000 mL dimethylformamide. Reaction mixture was stirred for 1 hr. at 25 to 30° C., heated at 80 to 90° C. for 14 hr. and poured into excess of water at 25° C. Product was extracted with diethyl ether. Subsequent concentration in vacuo of the organic layer and purification as described earlier yielded 3.97 g (67.5%) of the desired product. m.p. 80° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([NH:36][S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])=[O:27])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Reactant: NS(=O)(=O)CCCCl
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCCl

Procedure:
Prepared by coupling 2e and 3-chloropropanesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (65%); 1H NMR (d6-DMSO) δ 11.83 (s, 1H), 7.54 (d, J=15.7 Hz, 1H), 7.34–7.09 (m, 10H), 6.87 (d, J=8.1 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.51 (d, J=15.7 Hz, 1H), 3.72 (t, J=6.4 Hz, 2H), 3.54 (t, J=6.4 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.08 (m, 4H); APcI m/z: 504 (M−H−).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]=[C:21]2[C:25](=[O:26])[O:24][NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1.CO>O1CCCC1.[C].[Pd]>[C:22]([CH:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:29][CH:28]=1)[C:25]([OH:26])=[O:24])(=[O:27])[NH2:23]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2C(=O)NOC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C(N)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 44.1 %

Procedure:
4-[4-[2-(5-Methyl-2-phenyl-4-oxazolyl)ethoxy]benzilidene]-3,5-isooxazolidinedione (11.5 g, 29.3 mmol) synthesized according to the method described in WO95/18125 was dissolved in tetrahydrofuran (220 ml). 5% Palladium carbon (1.15 g) was added and the mixture was vigorously stirred under a hydrogen atmosphere (normal pressure) at room temperature for 13.5 hr. To the reaction mixture was added methanol (150 ml), and the catalyst was removed by celite filtration. The solvent was evaporated and the residue was suspended in 2.5N aqueous sodium hydroxide solution (50 ml) and washed with ethyl acetate. To the obtained aqueous layer was added 1N hydrochloride (150 ml) and the precipitated white solid was collected by filtration. The solid was washed with water and dried to give the title compound (5.10 g, yield 44%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[N:18]([C:19](=[O:37])[N:20]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]C=C)[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH2:17][CH:16]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:19](=[O:37])[N:18]1[CH:14]([CH2:15][CH:16]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:17]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(OC(=O)c3ccc([N+](=O)[O-])cc3)CC1C(=O)N2

Procedure:
Compound 132 (406 mg, 0.6 mmol) was dissolved in DCE (250 ml) and degassed. Hoveyda-Grubbs Catalyst 2nd generation (26 mg, 0.042 mmol) was added and the solution was heated to reflux. After 3 h the solution was evaporated and used direct in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([OH:3])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C1COCC1.CN(C=O)C>[F:26][CH:27]1[CH2:32][CH2:31][N:30]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH2:29][CH2:28]1
Reactant: FC1CCNCC1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C(=O)N2CCC(F)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 4-carboxybenzenesulfonamide (2 g; 9.9 mmol; 1 eq) in THF 30 mL) at 0° C. is added 1,1′-carbonyldiimidazole (1.9 g; 11.9 mmol; 1.2 eq) in one portion and the mixture is stirred for 3 h at room temperature. 4-Fluoropiperidine (3.1 g; 29.8 mmol; 3 eq) in THF (3 mL) and DMF (10 mL) is added dropwise and the mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and a saturated solution of NaHCO3 is added to the colourless oil which precipitates. The solid is filtered off, washed with water and dried under vacuum to afford 2.6 g (91%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.87 (d, J=8.3, 2H), 7.58 (d, J=8.3, 2H), 7.37 (br s, 2H), 4.92 (d, J=48.2, 1H), 3.67 (br s, 2H), 3.25 (br s, 2H), 1.87 (m, HPLC (max plot) 99%; Rt 1.77 min. LC/MS: (ES+) 287.0; (ES−) 285.0
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].[I-].[Na+].C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:9][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: O=C(O)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Benzoic acid (2.44 g, 0.02 mole) and 2-chloro-N,N-dimethylacetamide (2.43 g, 0.02 mole) were dissolved in 10 ml of N,N-dimethylformamide. Sodium iodide (150, 2 mmol) and triethylamine (2.02 g, 0.02 mole) were added and the mixture was stirred at room temperature (20°-25° C.) overnight. After addition of 50 ml of water the reaction mixture was extracted twice with ethyl acetate. The combined extracts were washed with a diluted solution of sodium thiosulphate, a 2% aqueous solution of sodium bicarbonate, water, dried over anhydrous sodium sulphate and evaporated in vacuo. The residue was crystallized from ethanol-water to give 3.5 g (85%) of the title compound. Mp 81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]([CH3:9])[CH3:8])[N:3]=1.C(O)(=O)C.O=[C:15]1[CH2:20][CH2:19][CH2:18][S:17][CH:16]1[C:21](OCC)=[O:22]>CN(C)C=O>[CH3:8][N:7]([CH3:9])[C:4]1[N:3]=[C:2]2[NH:1][C:15]3[CH2:20][CH2:19][CH2:18][S:17][C:16]=3[C:21](=[O:22])[N:6]2[N:5]=1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: CN(C)c1n[nH]c(N)n1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CN(C)c1nc2[nH]c3c(c(=O)n2n1)SCCC3
Reaction time: 0.67 h
Yield: 65.3 %

Procedure:
To the solution of 6.35 g (0.05 mole) of 5-amino-3-dimethylamino-1H-1,2,4-triazole, 2.5 ml of acetic acid and 12.5 ml of dimethylformamide, 9.4 g (0.05 mole) of ethyl 3-oxo-3,4,5,6-tetrahydro-2H-thiopyrane-2-carboxylate are added and the reaction mixture is boiled for 40 minutes. The precipitated product is filtered off from the hot solution, then washed with acetic acid and i-propanol and recrystallized from dimethylformamide. Thus 8.2 g (65.2%) of 2-dimethylamino-5,7,8,9-tetrahydrothiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine-5(10H)-one are obtained. M.p.: higher than 350° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23]C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([O:36][CH:37]([O:39][NH:40][C:41]([C:43]1[S:47][C:46]2[CH:48]=[C:49]([CH:52]=O)[CH:50]=[CH:51][C:45]=2[CH:44]=1)=[O:42])[CH3:38])[CH:33]([CH3:35])[CH3:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[C@@H:7]([NH:14][CH2:15][CH:16]1[CH2:17][CH2:18][CH:19]([CH2:22][NH:23][CH2:52][C:49]2[CH:50]=[CH:51][C:45]3[CH:44]=[C:43]([C:41](=[O:42])[NH:40][O:39][CH:37]([O:36][CH2:32][CH:33]([CH3:34])[CH3:35])[CH3:38])[S:47][C:46]=3[CH:48]=2)[CH2:20][CH2:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Reactant: CC(C)(C)OC(=O)NCC1CCC(CN[C@H](C(=O)OC(C)(C)C)c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)COC(C)ONC(=O)c1cc2ccc(CNCC3CCC(CN[C@H](C(=O)OC(C)(C)C)c4ccccc4)CC3)cc2s1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
(S)-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexylmethyl]-amino}-phenyl-acetic acid tert-butyl ester (290 mg, 0.9 mmol) and 6-formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (Scheme 7) (255 mg, 0.8 mmol) were stirred in DCE (8 ml) for 30 min. Acetic acid (4 ul, 0.08 mmol) and sodium triacetoxyborohydride (504 mg, 2.4 mmol) were added and the reaction mixture was stirred at r.t. for 1 h30. DCM (5 ml) and a saturated solution of NaHCO3 (10 ml) were added and phases were separated. The aqueous phase was extracted with EtOAc (15 ml). The organics were dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product (543 mg) was purified on column chromatography (5 to 10% MeOH in DCM) to yield the expected pure product (172 mg, 34% yield). LCMS purity 100%, m/z 638 [M++H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.O=P(Cl)(Cl)[Cl:20].[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[Na+]>ClCCl.O.C(OCC)C>[Cl:23]([O-:27])(=[O:26])(=[O:25])=[O:24].[Cl:20][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[CH:4][CH:3]=[N+:2]([CH3:17])[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: C[N+](C)=CC=C(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]-2-propen-1-one (may be prepared as described in Intermediate 2) (1.49 g, 6.13 mmol) in dichloromethane (DCM) (6 ml) was cooled in an ice-water bath before the dropwise addition of POCl3 (0.571 ml, 6.13 mmol). The ice-water bath was removed and the reaction mixture stirred at room temperature for 3 hours. The solvent was removed under vacuum to yield a solid. To the solid was then added to an ice-cold solution of sodium perchlorate (3.75 g, 30.6 mmol) in water (8 mL) and diethyl ether (2 mL). The resulting suspension was stirred in an ice-water bath for 20 minutes. The solid was then collected by filtration, washed with ice-cold water (4 mL), dried by suction for 40 minutes then dried overnight under vacuum to yield the title compound as a solid (2.39 g.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Reaction time: 1.5 h

Procedure:
Kojic acid, 42.6 g, was dissolved in 350 ml of dimethylformamide and 82.8 g of anhydrous potassium carbonate and 55 g of p-methoxybenzyl chloride were added to the solution. The reaction was carried out at 70° to 75° C. for 1.5 hours.