Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C@H](CO)[C@@H](O)[C@H]1O.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].C(OC(=O)C)(=O)C.[Br:25]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:25][C:14]1[CH:13]=[CH:12][C:11]([NH2:16])=[C:10]([NH2:17])[CH:15]=1
Reactant: BrBr
Reactant: Nc1ccccc1N
Agent: O=S([O-])[O-]
Agent: OC[C@H]1OC[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1N
Temperature: 0 °C

Procedure:
A method for synthesizing a deoxyribofuranose compound having a structure represented by the above-mentioned formula (12) will be explained. The compound can be synthesized according to the scheme shown in FIG. 2. First, 4-bromo-phenylene diamine (compound 13) is synthesized. The synthesis can be conducted by a method disclosed in Japanese Laid-Open Patent Application Nos. 63-22091 and 63-179870. Specifically, o-phenylene diamine is added to acetic acid, and further mixed with acetic anhydride under cooling, and the resultant reaction mixture is heated. After cooling, a bromine solution in acetic acid is slowly added to the reaction mixture. Then, an acidic sodium sulfite solution dissolved in ice water is added into the reaction mixture. The resultant white precipitate is collected to obtain compound 13, 4-bromo-o-phenylene diamine. By reacting compound 13 and 1,2-bis(chlorodimethylsilyl)ethane, compound 14 of which two amino groups attached to the benzene ring are protected, can be obtained. By lithiating compound 14 by reacting with butyl lithium (n-BuLi), compound 15 can be obtained. Then, 2,3,5-tri-o-benzyl ribonolactone (compound 16) dissolved in THF (20 ml) is reacted with compound 15. The protecting groups of the amino groups on the benzene ring are removed by using trifluoroborane and triethylsilane to obtain compound 17. Compound 18 can be obtained by treating compound 17 with benzoyl chloride. Treatment of compound 18 with boron tribromide in dichloroethane to convert all benzyloxy groups at 2′, 3′ and 5′ positions of compound 18 to hydroxyl groups gives ribofuranose compound 11. Then compound 11 is reacted with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane so as to obtain compound 19 where 3′ and 5′ hydroxyl groups of the ribofuranose compound 11 are protected. The hydroxyl group at the 2′ position of compound 19 is reacted with p-trichlorothinoformate so as to obtain compound 20. Compound 20 is reacted with tributyltin hydride in the presence of a catalytic amount of azoisobutylonitrile (AIBN) to obtain compound 21. By reacting compound 21 with tetrabutyl ammonium fluoride in THF at room temperature to remove the protection group, a deoxyribonucleoside having a deoxyribofuranose ring represented by the above-mentioned formula 12, which does not have a hydroxyl group at the 2′ position, can be obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].O>Br.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Agent: Br
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Yield: 14.2 %

Procedure:
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (2.2 g) was stirred in 20 ml of 57% hydrobromic acid at 100°-110° C. for 2 hours. To the reaction mixture was then added 80 ml of water and the mixture was allowed to stand. The resulting syrupy precipitate was dissolved in 50 ml of ethyl acetate and washed with water. The ethyl acetate layer was evaporated to dryness and the residue was purified by column chromatography using 50 g of silica gel. The desired fractions were combined and crystallized from acetone-diethyl ether to give 0.3 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 190°-193° C. (decompn.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]([C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH2:30](Cl)CCl.CN(C1C=CC=CN=1)C>ClCCl>[C:21]([O:20][C:18]([NH:17][C@H:15]1[CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]([C:25]([O:27][CH3:30])=[O:26])[CH2:14]1)=[O:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis (+/−)-1-(benzyloxycarbonyl)-5-(tert-butoxycarbonylamino)piperidine-3-carboxylic acid (1.0 eq), methanol (20 eq.) and EDC (1.3 eq) in dichloromethane at a concentration of 0.25 M at 0*C was added dimethylaminopyridine (0.1 eq). After stirring for 48 hours as the reaction was allowed to warm to rt the volatiles were removed in vacuo. Upon addition of ethyl actetate and washing with H2O (3×), 1N HCl, NaHCO3(sat.) and brine, the solution was dried over MgSO4, filtered, concentrated and purified by column chromatography (25% ethyl acetate/hexanes) to yield cis (+/−)-1-benzyl 3-methyl 5-(tert-butoxycarbonylamino)piperidine-1,3-dicarboxylate. LCMS (m/z): 293.1 (MH-Boc+); LC Rt=4.09 min
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C(N(CC)CC)C.[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:1][CH:2]1[N:7]([C:40]([CH:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][N:28]=[CH:33][CH:32]=3)[CH2:39][CH2:38]2)=[O:41])[CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:3]1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
3-Methyl-1-(2-naphthylsulphonyl)piperazine (1.8 g) and triethylamine (3.18 ml) were added in turn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 89:10:1 mixture of ethyl acetate; methanol and ammonia as eluent. The material so obtained was triturated under diethyl ether to give 3-methyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-yl-carbonyl]piperazine (32% yield);
Reaction SMILES: [CH2:1]([O:19][C@@H:20]1[C@H:24]([OH:25])[C@@H:23]([CH2:26][OH:27])[O:22][C@H:21]1[N:28]1[C:38]2[N:37]=[C:35]([NH2:36])[NH:34][C:32](=[O:33])[C:31]=2[N:30]=[CH:29]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[Si](Cl)(C)C.[C:44](Cl)(=[O:48])[CH:45]([CH3:47])[CH3:46].[OH-].[NH4+]>N1C=CC=CC=1.O>[C:44]([NH:36][C:35]1[NH:34][C:32](=[O:33])[C:31]2[N:30]=[CH:29][N:28]([C:38]=2[N:37]=1)[C@@H:21]1[O:22][C@H:23]([CH2:26][OH:27])[C@@H:24]([OH:25])[C@H:20]1[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:48])[CH:45]([CH3:47])[CH3:46]
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)C(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
2′-O-Octadecylguanosine (1.9 g) in pyridine (150 ml) was cooled in an ice bath, and treated with trimethylsilyl chloride (2 g, 5 eq) and isobutyryl chloride (2 g, 5 eq). The reaction mixture was stirred for 4 hours, during which time it was allowed to warm to room temperature. The solution was cooled, water added (10 mL) and stirred for an additional 30 minutes. Concentrated ammonium hydroxide (10 mL) was added and the solution concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 3% MeOH/EtOAc) to yield 1.2 g of product. 1H NMR (DMSO-d6) δ 0.85 (t, 3, CH3), 1.15 (m, 38, O—CH2CH2(CH2)16 and CH(CH3)2), 2.77 (m, 1, CH(CH3)2), 4.25 (m, 2, 2′H, 3′H), 5.08 (t, 1, 5′-OH), 5.12 (d, 1, 3′-OH) , 5.87 (d, 1, 1′-H) , 8.27 (s, 1, 8-H), 11.68 (s, 1, NH2) and 12.08 (s, 1, NH2). Anal. Calcd. for C32H55N5O6: C, 63.47; H, 9.09; N, 11.57. Found: C, 63.53; H, 9.20; N, 11.52.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To acetone 40 mL solution of 4-bromo-2-nitrobenzoic acid 4.0 g were added potassium carbonate 3.4 g and dimethylsulfate 2.3 mL at room temperature, and it was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution,1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give methyl 4-bromo-2-nitrobenzoate 4.1 g of white solid.
Reaction SMILES: [Na].Cl.[C:3]([NH2:6])(=[NH:5])[CH3:4].[F:7][CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10]>>[CH3:4][C:3]1[N:6]=[C:14]([OH:15])[C:8]([F:7])=[C:9]([OH:10])[N:5]=1
Reactant: CCOC(=O)C(F)C(=O)OCC
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Product: Cc1nc(O)c(F)c(O)n1
Temperature: 23 °C
Reaction time: 0.08 h

Procedure:
According to the procedure of J. Chem. Soc. 1959, 3286, a solution of 0.92 g (40 mmol) of sodium metal dissolved in 20 mL of methaol was treated with 2.08 g (22 mmol) of acetamidine hydrochloride. After 5 minutes, to this stirred mixture was added 3.6 g (20 mmol) of diethyl fluoromalonate. The reaction mixture was heated to reflux for 18 hours, cooled to 23° C., and then concentrated in vacuo. The residue was dissolved in water, neutralized with aqueous 3N HCl (6 mL), and chilled. A precipitate which formed was isolated by filtration and triturated with a 1:1 mixture of diethyl ether/ethyl acetate. The resulting crude product (1.36 g, 47%) was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=2)=[N:17]1.[C:29]([CH:31]1[CH2:33][CH2:32]1)#[CH:30].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[NH:19][C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:30]#[C:29][CH:31]3[CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[N:17]1
Reactant: C#CC1CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC4CC4)cc3)[nH]c2=O)c1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 56.8 %

Procedure:
To a solution of N-(4-chloro-3-(4,5-dihydro-3-(4-iodophenyl)-5-oxo-1,2,4-triazol-1-yl)benzyl)pivalamide (Intermediate-95, 0.100 g, 0.196 mmol) in DMSO (3.0 mL), ethynylcyclopropane (0.035 g, 0.530 mmol), TBAF (0.150 g, 0.574) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were added and the reaction mass was stirred at 80° C. for 5-6 h. After completion of the reaction, the reaction mass was quenched with water and extracted with DCM and concentrated to afford 0.050 g of the desired title product. 1H NMR (300 MHz, DMSO d6): δ 0.76-0.91 (m, 2H), 0.91-0.92 (m, 2H), 1.11 (s, 9H), 1.57 (m, 1H), 4.28 (br d, 2H), 7.31-7.34 (br d, 1H), 7.42 (br s, 1H), 7.47-7.50 (br m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 8.18 (s, 1H), 12.58 (s, 1H); MS (m/z): 449.52 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -15 °C
Yield: 91.6 %

Procedure:
To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (200 g, 1.07 mol) and triethylamine (167 g, 1.63 mol) in toluene (700 mL) at -20 to -30° C. was added methanesulfonyl chloride (156 g, 1.36 mol) drop-wise while maintaining the temperature at -10 to -20° C. The solution was warmed to ambient temperature and allowed to stir. The reaction solution was sampled hourly and analyzed by HPLC to establish completion of the reaction. Upon completion of the reaction, the suspension was filtered to remove the triethylamine hydrochloride. The filtrate was washed with ˜600 mL of dilute aqueous sodium bicarbonate solution. The organic layer was dried and concentrated under reduced pressure to give 2 as a viscous oil (260 g, 92%) which is used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.27 (m, 1 H), 3.44-3.76 (m, 4H), 3.05 (s, 3H), 2.26 (m, 1H), 2.15 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.Cl>CN(C=O)C.N1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:2]=2[CH:3]=1)=[O:6]
Reactant: C#Cc1ccc(OC)cc1
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of Methyl 3-Iodo-4-hydroxybenzoate (0.7 g, 2.5 mmol), 4-Methoxyphenylacetylene (0.33 g, 2.5 mmol), Pd(Cl)2(PPh3)2 (0.05 g) and CuI (0.03 g) in DMF/Piperidine (20 ml) was heated at 60° C. After 2 hr, the reaction was cooled and poured into 2N HCl. The aqueous layer was extracted with EtOAc and then separated, dried, concentrated to give a solid. The solid was triturated with MeOH, filtered to give 142 (0.5 g, 71%): Mp=157-159° C.; 1H NMR (CDCl3) δ 8.28 (d, 1 H, J=1.3 Hz), 7.97 (dd, 1 H, J=8.5 Hz, 1.7 Hz), 7.82-7.79 (m, 2 H), 7.51 (d, 1 H, 8.5 Hz), 6.99 (d, 2 H, J=8.3 Hz), 6.93 (d, 1 H, J=0.9 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H); MS 283 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Reactant: CN1CCNCC1
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C)CC3)cc21
Yield: 30 %

Procedure:
A mixture of 1-ethyl-6,7-dichloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 2.86 g (0.01 mole), N-methylpiperazine 10 g (0.1 mole) and 15 ml water was heated in a sealed tube at 125°-130° C. (inner temperature) for 19 hours. After cooling, the reaction mixture was evaporated under vacuum and acidified with acetic acid. Insoluble matters were filtered off and the filtrate was neutralized with an aqueous solutiong of NaOH to pH 7, extracted with CHCl3, dried with anhydrous Na2SO4, and the solvent was distilled off. The residue was recrystallized from a mixed solvent of CHCl3 and benzene to give 1.05 g (30%) of 1-ethyl-6-chloro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. Colorless needles.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].Cl.[N+:6]([C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH2:14][CH2:15][NH2:16])=[C:11]([CH3:19])[CH:10]=1)([O-:8])=[O:7]>O>[N+:6]([C:9]1[CH:18]=[CH:17][C:12]([NH:13][CH2:14][CH2:15][NH:16][C:2]([NH2:1])=[O:3])=[C:11]([CH3:19])[CH:10]=1)([O-:8])=[O:7]
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCN
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1NCCNC(N)=O
Yield: 80.6 %

Procedure:
24.3 g (0.3 mole) of potassium isocyanate in solution in 75 cm3 of water is added to 57.9g (0.25 mole) of 4-nitro-2-methyl-N-(β-aminoethyl) aniline monohydrochloride in 235 cm3 of water at 60°. After keeping the reaction mixture for 15 minutes in a boiling water bath, drying yields 48 g of 4-nitro-2-methyl-N-(β-ureido-ethyl)aniline which, after recrystallization in acetic acid, melts at 186° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.Cl.[NH2:15][OH:16].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[N:15][OH:16]
Reactant: COc1cccc2c1CCCC2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc2c1CCCC2=NO
Yield: 79.5 %

Procedure:
17.7 g (0.1 mole) of commercial 5-methoxy-1-tetralone (from Aldrich), 18.4 g (0.26 mole) of hydroxylamine hydrochloride and 22.6 g of sodium bicarbonate (0.26 mole), in 450 ml of methanol and 80 ml of water, are refluxed for 36 hours. The solvent is then removed on a rotary evaporator, the residue is thoroughly stirred with water and the precipitate is filtered off, dried and recrystallized from toluene. 15.2 g of 5-methoxy-tetralone-1-oxime (79.6% yield), of melting point 158°-159° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The procedure was adapted from that reported in J. Med. Chem. 1976, 19, 1072. 6-Methylpyrimidine-2,4(1H,3H)-dione (7.0 g, 55.56 mmol) was added to concentrated sulfuric acid (26 mL) cooled in ice at such a rate that the internal temperature did not exceed 40°. To this mixture fuming nitric acid (5.2 mL) was added dropwise whilst maintaining the temperature below 15°. The cooling bath was removed and the mixture was stirred at room temperature for 30 min then dumped into 100 ml of crushed ice. After stirring for 10 min the solid was collected and washed with cold water then dried in vacuo over phosphorus pentoxide. A yellow-green solid of 6-methyl-5-nitropyrimidine-2,4(1H,3H)-dione was obtained (7.92 g, 83%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=O>[Pd]>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Pd]
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 2.5 h

Procedure:
By using 27.0 g of the thus prepared catalyst (0.1% by weight based on glucose, calculated as palladium metal), an aqueous solution of glucose was oxidized at a temperature of 30° ± 3° C and a pH of 10.0 in the same manner as described in Example 1 except that air was used instead of the oxygen gas used in Example 1. The reaction was completed in 2.5 hours and a colorless transparent liquid was obtained. The content of gluconic acid in the solid obtained by concentration of the liquid was 98.0 wt.% and the saccharide residual ratio was 1.2 wt.%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7]O.[CH2:9]([NH2:16])[CH2:10][S:11]S(O)(=O)=O>>[CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:11][CH2:10][CH2:9][NH2:16]
Reactant: Cc1nc[nH]c1CO
Reactant: NCCSS(=O)(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 70.1 %

Procedure:
In the same manner as in Example 1 (i), 2.8 g of 4-methyl-5-hydroxymethylimidazole (free base) is reacted with 4.3 g of 2-aminoethanethiolsulfuric acid, yielding 3.0 g of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole as an oily product (yield: 72.0%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCO.Cl>[Cl:13][C:4]1[CH:3]=[C:2]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccccc1
Temperature: 80 °C
Yield: 41 %

Procedure:
Ethyl 4,6-dichloronicotinate (10.0 g, 45.44 mmol) in EtOH (100 mL) was stirred till a clear solution was obtained followed by addition of aniline (3.90 mL, 43.17 mmol) and 10 drops of conc. HCl. The resulting solution was heated to 80° C. for 2-3 h. The reaction mass was cooled to room temperature, poured onto ice-cold water and then extracted with EtOAc (3×250 mL). The combined organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was then purified over silica gel (100-200 M, 2% EtOAc-hexane) to obtain the desired product ii (4.90 g, 39%). 1H-NMR (400 MHz, DMSO-d6): δ 9.72 (br s, 1H), 8.66 (s, 1H), 7.28-7.49 (m, 5H), 6.77 (s, 1H), 4.35 (q, J=7.20 Hz, 2H), 1.34 (t, J=7.20 Hz, 3H). [M+H]+ m/z=277.17.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:13](Cl)/[CH:14]=[CH:15]/[CH2:16]Cl>CO>[CH:14]([CH:15]1[CH2:16][C:5]1([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])=[CH2:13]
Reactant: ClC/C=C/CCl
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CC1CC1(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
Sodium methoxide (108.02 g, 2.0 moles) 25% in MeOH was added in 40 minutes to dimethyl malonate (132.12 g, 1.0 mole), 1,4-dichlorobutene-2 (150 g, 1.2 moles), and 50 mL MeOH and allowed to stir at ambient temperature overnight. The mixture was vacuum filtered, neutralized with concentrated HCl to 3.5-4.0 pH, and filtered a second time. Solvent was then removed under vacuum to give 194.8 g of light yellow crude product. Vacuum distillation (55°/0.25 mm-72°/0.4 mm) with 0.064 g of hydroquinone added gave 142.5 g of product (77.4% yield) and 30.4 g of residue.