Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:10][C:9]=1[CH3:31])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Cl>CO.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:21])([F:20])[F:22])[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:32])=[C:9]([CH3:31])[CH:10]=3)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
In a solution of 2.6 g of methyl N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl]glycine (Compound of the present invention No. 5-128) synthesized similarly to Synthetic Example 5 in 10 ml of methanol, a solution of 1.0 g of potassium hydroxide in 10 ml of water was added with stirring at room temperature, and stirred at the same temperature for further 1 hour. After the completion of the reaction, 10 ml of 12N hydrochloric acid was added and extracted with ethyl acetate (50 ml×1), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.4 g of the aimed product as pale yellow resinous substance.
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:24]2[CH:29]=[CH:28][C:27]([O:30]COC)=[CH:26][CH:25]=2)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O.O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC=C(c1ccccc1)C(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC=C(c1ccccc1)C(C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of 3b (30 mg, 0.0632 mmol) in MeOH (1 ml) was added 3N HCl in AcOEt (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 h. A solution of NaHCO3 (139 mg) in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 8 (67%). 8: colorless powder; 1H-NMR (CD3OD) δ 1.53 (3H, dd, J=1.4, 6.8 Hz), 2.35 (6H, s), 2.77 (2H, t, J=5.4 Hz), 4.06 (2H, t, J=5.4 Hz), 4.64 (1H, brt), 5.53 (2H, dq, J=1.5, 6.8 Hz), 6.74 (2H, d, J=8.6 Hz), 6.85 (2H, d, J=9.2 Hz), 7.18-7.22 (5H, m), 7.27-7.32 (4H, m). HRMS calcd for C27H31N2O3 [M+H]+: 431.2335. Found: 431.2348.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11].[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[N+:43]([O-:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[C:35]([N+:43]([O-:45])=[O:44])[CH:36]=2)[C:17]=1[C:18]([OH:20])=[O:19])=[O:11]
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)csc1NC(=O)c1cc2ccccc2o1
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2csc(NC(=O)c3cc4ccccc4o3)c2C(=O)O)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 81.7 %

Procedure:
tert-butyl 2-(benzofuran-2-carbonylamino)-4-(trifluoromethylsulfonyloxy)thiophene-3-carboxylate (82, 50 mg, 0.102 mmol), 4-methyl-3-nitrophenylboronic acid (28 mg, 0.153 mmol), Tetrakis(triphenylphosphine)palladium(0) (1.0 mg, 0.001 mmol), and sodium carbonate (42 mg, 0.407 mmol), were combined in 2:1:1 ethanol, toluene and water the biphasic mixture was stirred vigorously in sealed vial at 70 C. After 2 hours, the mixture was filtered through Celite and the Celite rinsed with methylene chloride. The organic fraction of the filtrate was washed with water, dried with sodium sulfate, filtered, concentrated, triturated in methanol, centrifuged, decanted and the resulting solid was dried under vacuum and treated with a 1:1 mixture of methylene chloride and trifluoroacetic acid. After 4 hours the mixture was concentrated in vacuo, and the residue triturated in methylene chloride, centrifuged, decanted and dried under high vacuum to give 84 as a white powder (35.2 mg, 43%). 1H NMR (500 MHz, DMSO d6) δ=13.48 (br, 1H), 12.57 (br, 1H), 7.96 (s, 1H), 7.86 (m, 2H), 7.76 (d, 1H), 7.64 (d, 1H), 7.57 (t, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 2.55 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:18])([CH3:17])[C:8](=[O:16])[NH:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].CN(C)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.O.C(OCC)(=O)C>[CH3:15][O:14][C:12]([C:11]1[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])=[CH:3][CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:16])[C:7]([CH3:18])([CH3:17])[NH:6]2)=[O:13]
Reactant: COC(=O)c1c(Br)ccc2c1NC(=O)C(C)(C)N2
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2OC)ccc2c1NC(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 48 h
Yield: 53.3 %

Procedure:
A mixture of 7-bromo-8-methoxycarbonyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 203 mg, 0.64 mmol), 2-methoxyphenylboronic acid (196 mg, 1.28 mmol), cessium carbonate (629 mg, 1.92 mmol) and bis(triphenylphosphine)palladium dichloride (II) (45.8 mg, 0.06 mmol) was suspended with anhydrous N,N-dimethylformamide (3 ml) and stirred at 80° C. for 2 days. After the mixture was cooled down, ethyl acetate (30 mL) and water (30 mL) were added thereto and the mixture was partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (116 mg) as a pale yellow amorphous product. (Yield 31%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>CS(C)=O.O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:12])[CH:7]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 60 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a solution of 2,4-dichloro-1-nitrobenzene (100 g, 0.52 mol) in DMSO (200 mL), aqueous solution of NaOH (41.6 g, 1.04 mol) in water (42 mL) was added and the resulting mixture was stirred 60° C. for 16 h. The mixture was allowed to cool to room temperature, poured to ice water, and then acidified with aqueous HCl (1M) to adjusted the pH to 3-4. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was used directly in the next step (80 g, 88% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C)[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br.CO.N.[Cl:48]CCl>>[ClH:48].[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2cccc(OC)c2)cc1
Reactant: ClCCl
Agent: BrB(Br)Br
Agent: N
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2cccc(O)c2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The 1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (1.196 g) obtained in Example 1 was dissolved in dichloromethane (24 ml), added with a solution of boron tribromide in dichloromethane (1.0 M, 8.8 ml) and stirred at room temperature for 2 hours. The reaction mixture was slowly added with methanol (6 ml) with ice cooling to quench the reaction and then added with 7.5 N aqueous ammonia (40 ml). The layers were separated, and the aqueous layer was extracted with dichloromethane (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (24 ml) and added with a solution of hydrochloric acid in methanol (8.8 ml), and then the solvent was evaporated under reduced pressure again. The residue was purified by LH-20 column chromatography (elution solvent: dichloromethane:methanol=1:1) to obtain 1.057 g of the title compound. Yield: 85%.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][CH2:11][C:5]=2[O:4][N:3]=1.[CH2:19](Br)[C:20]#[CH:21]>>[CH2:21]([O:1][C:2]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][CH2:11][C:5]=2[O:4][N:3]=1)[C:20]#[CH:19]
Reactant: CC(C)(C)OC(=O)N1CCCc2onc(O)c2C1
Reactant: C#CCBr
Product: C#CCOc1noc2c1CN(C(=O)OC(C)(C)C)CCC2
Yield: 58 %

Procedure:
The compound was synthezised from tert.butyl 3-hydroxy-5,6,7,8-tetrahydro-4H-isoxazolo [4,5-c]azepin-5-carboxylate (from Example 7) and 2-propynyl bromide, by the method described in Example 4. The title compound was isolated by using chromatography on silica gel (eluent: toluene-ethyl acetate (3:1)) in a yield of 58%. 1H NMR: δ4.83 (2 H, d), 4.20 (2 H, s), 3.60 (2 H, t), 2.83 (2 H, t), 2.52 (1 H, t), 1.86 (2 H, m), 1.43 (9 H, s).
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][NH:19][CH2:18]2>O1CCCC1.C(OCC)(=O)C>[CH:17]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][N:19]([C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9])[CH2:18]2
Reactant: C1CC2CCC1CNC2
Reactant: N#Cc1cccnc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccnc1N1CC2CCC(CC2)C1
Reaction time: 12 h

Procedure:
To a solution of 2-fluoro-3-cyanopyridine (0.4 g, 3.27 mmol) in 30 mL tetrahydrofuran was added triethylamine (0.66 g, 6.5 mmol) and 3-aza-bicyclo[3.2.2]nonane (0.5 g, 3.9 mmol). The reaction was held at 50° C. for 12 hours, cooled and diluted with 100 mL ethyl acetate. The organics were washed with water (2×50 mL), brine (1×50 mL), dried (MgSO4) and concentrated. Column chromatography (20% ethyl acetate/hexanes) gave the title compound as a solid. MS (ESI/NH3) m/z 126 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[CH:8]=[O:9].[H][H]>CO.[Ni]>[NH2:11][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH2:8][OH:9]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N)c(CO)c1

Procedure:
A quantity of 181.2 gm (1 mol) of 5-methoxy-2-nitrobenzaldehyde (prepared by methylation of 2-nitro-5-hydroxy-benzaldehyde with methyl iodide/potassium tert.-butoxide in dimethylsulfoxide) is dissolved in 1.8 liters of methanol, mixed with 50 gm of Raney nickel, and hydrogenated at ambient temperature and at 5 bar. After ten hours, the hydrogen uptake has ended. The catalyst is removed by suction filtration, and the methanol is distilled off.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:26])[C:6]3([F:16])[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2CCCC12F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: FC12CCCC1c1cc(Cl)ccc1NC2=S

Procedure:
A solution of 0.83 g (3.5 mmol) of 8-chloro-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 100 ml of THF is refluxed with 2.86 g (7.1 mmol) of Lawesson's reagent for 1.5 hours. Then, the reaction mixture is concentrated by evaporation, and the residue is purified by column chromatography on silica gel with hexane-ethyl acetate: 0.86 g of product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C1COCC1.CO>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(C(F)(F)F)cc4)c3C2=O)C(=O)N1
Yield: 76.5 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.6 g, 2.2 mmol) and 4-(trifluoromethyl)benzoyl chloride (1 g, 4.8 mmol) in THF (20 mL) was heated to reflux for 15 h. The solvent was removed in vacuo to give a solid. The solid was slurried in methanol (20 mL) for 2 h. The suspension was filtered and washed with ether (15 mL) then methanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-trifluoromethyl-benzamide as a white solid (750 mg, 77% yield): mp, 213–215° C.; 1H NMR (DMSO-d6) δ 2.05–2.10 (m, 1H, CHH), 2.49–2.65 (m, 2H, CH2), 2.83–2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.5 Hz, 1H, NCH), 7.72 (d, J=7.2 Hz, 1H, Ar), 7.90–8.02 (m, 3H, Ar), 8.16–8.19 (m, 2H, Ar), 8.49 (d, J=8.4 Hz, 1H, Ar), 10.58 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 118.88, 119.36, 119.32, 123.76 (q, JC-F=271 Hz); 125.99 (q, JC-F=3.6 Hz), 127.10 128.37, 131.54, 132.16 (q, JC-F=32 Hz), 136.00, 136.26, 13721, 164.05, 166.59, 167.65, 169.68, 172.73; Anal Calcd for C21H14N3O5F3: C, 56.64; H, 3.17; N, 9.44; F, 12.80. Found: C, 56.25; H3.05; N, 9.32; F, 12.69.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH2:11][OH:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([CH2:11][O:12][S:29]([CH3:28])(=[O:31])=[O:30])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(CO)(CC1CCCCC1)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(COS(C)(=O)=O)(CC1CCCCC1)C(=O)OCC
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of 2-cyclohexylmethyl-2-hydroxymethyl-malonic acid diethyl ester (1.31 g, 4.13 mmol) in methylene chloride (20 mL) and triethyl amine (1.16 mL, 8.00 mmol) was cooled to −40° C. A solution of methylsulfonyl chloride (0.402 mL, 5.2 mmol) in methylene chloride (4 mL) was added to the reaction mixture over 5 minutes. The reaction mixture was warmed to −10° C. over 1 hour and then poured into cold dilute aqueous HCl. The product was extracted with ethyl acetate, the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure to give 2-cyclohexylmethyl-2-methylsulfonyloxymethyl-malonic acid diethyl ester (1.505 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:27]=[C:26]([CH3:28])[N:25]([CH3:29])[N:24]=1>>[CH3:29][N:25]1[C:26]([CH3:28])=[CH:27][C:23]([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])=[N:24]1
Reactant: Cc1cc(CBr)nn1C
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cc(C)n(C)n3)C2=O)cn1
Yield: 22 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole. Yield: 22%. MS M+H calculated 384.1. found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 uM
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:21])[C:19]=1[OH:20])[CH:15]=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:15][C:14]2[CH:17]=[C:18]([CH3:21])[C:19]([OH:20])=[C:12]([CH3:11])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=CC(=O)c2ccc(Br)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4′-bromoacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:34]=[CH:33][C:23]([NH:24]C(=O)C2C=CC=CC=2)=[N:22][C:20]1=[O:21])(=O)C.[NH4+].[OH-].C(O)C>CO>[C@@H:6]1([N:19]2[CH:34]=[CH:33][C:23]([NH2:24])=[N:22][C:20]2=[O:21])[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In methanol (50 ml) is dissolved 2',3',5'-tri-O-acetyl-N4 -benzoylcytidine (0.53 g) followed by addition of concentrated NH4OH (5 ml) with stirring at 70° C. The mixture is stirred at 70° C. for 2.5 hours, at the end of which time ethanol is added. The mixture is allowed to stand at room temperature overnight to give colorless needles of cytidine. Yield 0.26 g (95.6%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.CC(=O)[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C.CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:17][C:18](=[O:20])[CH3:19]
Reactant: BrCCCCOCCc1ccccn1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)CCCCCOCCc1ccccn1
Yield: 83.3 %

Procedure:
A mixture of 2-[2-[(4-bromobutyl)oxy]ethyl]pyridine (6.2 g), 2,4-pentanedione (3.61 g), potassium carbonate (4.75 g) and potassium iodide (3.95 g) in ethanol (125 ml) was stirred and heated overnight under reflux. The solids were removed by filtration and the filtrate evaporated to leave a dark brown semi-solid. Addition of ether (200 ml) and filtration of the solid produced a brown solution which was evaporated to give a brown oil (4.71 g). Purification by FCC eluting with ether-hexane (1:1→3:1) gave the title compound as a pale yellow oil (1.93 g).
Reaction SMILES: [Cl:1][C:2]([F:18])([F:17])[C:3]([C:6]1[NH:11][C:10](=[O:12])[C:9]([C:13]([O:15]C)=O)=[CH:8][CH:7]=1)([F:5])[F:4].Cl.[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]([F:18])([F:17])[C:3]([C:6]1[NH:11][C:10](=[O:12])[C:9]([C:13]([NH:22][CH2:20][CH3:21])=[O:15])=[CH:8][CH:7]=1)([F:4])[F:5]
Reactant: COC(=O)c1ccc(C(F)(F)C(F)(F)Cl)[nH]c1=O
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1ccc(C(F)(F)C(F)(F)Cl)[nH]c1=O

Procedure:
At room temperature, 300 mg (1.04 mmol) of methyl 6-(2-chloro-1,1,2,2-tetrafluoroethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate were stirred in 5 ml of aqueous ethylamine solution (70%) for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 310 mg (98% of theory) of the product.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]1[CH:16]=[CH:15][C:11](C(Cl)=O)=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].NC1C=CC=CC=1.Cl>O1CCCC1>[N+:17]([C:9]1[CH:10]=[CH:11][CH:15]=[CH:16][CH:8]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
0.87 mL (10.8 mmole) of pyridine and 956 mg (4.35 mmoles) of 4-chloro-3-nitrobenzoylchloride were added to a 30 mL tetrahydrofuran solution of 1.0 g (3.6 mmoles) of aniline compound (1B-18) and the mixture was stirred for one hour at room temperature. To the reaction solution was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was slurry washed with ethyl acetate-hexane, yielding 1.41 g (a yield of 85 percent) of nitrobenzene compound (1B-19).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])C.[CH3:5][CH:6]([O-])C.CC([O-])C.CC([O-])C.[Al+3].[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>O>[CH:5](=[C:3]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:1][OH:4])[CH3:6]
Reactant: CC(C)O
Reactant: Cc1ccccc1
Reactant: CC(C)[O-]
Agent: [Al+3]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC=C(CO)c1ccccc1
Temperature: 80 °C

Procedure:
Into a 3 liter reaction vessel equipped with stirrer, reflux condenser, thermometer and heating mantle are placed 2000 grams of isopropyl alcohol and 75 grams of aluminum triisopropylate. The resulting mixture is heated to reflux and while refluxing, over a period of 1.5 hours, 500 grams of the aldehyde having the structure: ##STR72## is added slowly to the reaction mass. At the end of the feed period of the aldehyde, solvent is commenced to be stripped at the ratio of 3:1 to a pot temperature of 130° C. The stripping takes place over a period of 5.5 hours. At the end of the 5.5 hour period, the reaction mass is cooled to 80° C. and 500 ml toluene and 150 grams of 50% aqueous sodium hydroxide and 150 grams of water is added to the reaction mass. The reaction mass is refluxed for a period of one hour and then cooled to room temperature.