Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34])[CH3:36]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCCCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), diethylamine (29 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then 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 (27 mg, yield 41%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: NC(=O)c1ccccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccccc1Br
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.47 g (2.3 mmol) of 2-bromobenzamide and 0.34 g (2.7 mmol, 1.2 eq) of oxalyl chloride were added to 10 ml of 1,2-dichloroethane and then the mixture was stirred for 8 hours at 100° C. The reaction solution was cooled down to room temperature. The reaction solvent and excessive oxalyl chloride were removed by distillation under reduced pressure to obtain 2-bromobenzoyl isocyanate in an oily state. 10 ml of fresh 1,2-dichloroethane and 0.64 g (2.3 mmol) of 2-bromo-4-chloro-5-trifluoromethyl aniline were successively added thereto, reacted for 2 hours and filtered to obtain 0.25 g (Yield 22%) of the title compound as a solid.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][C:9]1[C:14]([C:15]2[C:24](=[O:25])[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[OH:26])=[CH:13][CH:12]=[C:11]([Cl:27])[N:10]=1.N1C=CC=CC=1>ClCCl>[Cl:8][C:9]1[C:14]([C:15]2[C:24](=[O:25])[NH:23][C:18]3=[N:19][CH:20]=[CH:21][N:22]=[C:17]3[C:16]=2[O:26][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([Cl:27])[N:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1c(-c2ccc(Cl)nc2Cl)c(=O)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pivaloyl chloride (0.096 ml) was added dropwise to a solution of 7-(2,6-dichloro-pyrid-3-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 1.6) (0.20 g) and pyridine (0.068 ml) in dichloromethane (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour and was then diluted with more dichloromethane. The organic phase was washed with aqueous sodium hydrogen carbonate (saturated) and brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 2:1) to give Compound No. A14 of Table A as a white solid (0.088 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[O:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1>CO.C1COCC1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[O:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1
Reactant: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1cc(-c2ccccc2O)on1
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide (0.142 g, 0.00026 mole) in a mixture of methanol (60 mL) and THF (10 mL) was added 10% Pd/C (0.05 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. The mixture was then filtered through celite, the celite was washed with methanol and the organic layers were concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate to afford 0.02 g (13%) of 5-(2-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.14 (M+1)+. 94.82%, 1H NMR (DMSO-d6): δ 10.8 (s, 1H), 8.7 (t, 1H), 7.81 (d, 1H), 7.38 (t, 1H), 7.25 (d, 1H), 7.0 (m, 4H), 6.8 (d, 1H), 6.6 (t, 1H), 4.9 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (s, 1H), 3.2 (m, 1H), 2.7 (m, 1H), 2.2 (m, 2H), 1.5 (m, 2H).
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:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27]>>[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][N:15]([CH2:22][C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[CH:26]=[O:27])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: O=Cc1cccc(CBr)c1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C=O)c3)C2=O)cn1
Yield: 35 %

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)benzaldehyde. Yield: 35%. 1H NMR (DMSO, 400 MHz): δ2.123 (s, 3H), 2.388 (s, 3H), 4.035 (s, 2H), 4.631 (s, 2H), 5.186 (s, 2H), 7.581 (m, 1H), 7.643 (m, 1H), 7.787 (m, 3H), 8.178 (s, H), 9.997 (s, H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.2 uM.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].N1C=CC=CC=1.[SH2:15]>C(N(CC)CC)C>[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]([NH2:7])=[S:15]
Reactant: CN(C)CCCC#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CN(C)CCCC(N)=S
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A reaction mixture was prepared containing 95.2 g. of 4-dimethylaminobutyronitrile, 134.3 g. of pyridine, 257.6 g. of triethylamine and 113 g. of H2S. The reaction mixture was placed in an autoclave and the autoclave shaken for about 16 hours at 55° C. The reaction mixture was then removed from the autoclave and the volatile constituents removed by evaporation in vacuo. The resulting residue comprising 4-dimethylaminothiobutyramide formed in the above reaction was digested with about 1.5 l. of boiling ethyl acetate. The mixture thus produced was filtered through cellulose (hyflo supercel). The filtrate was concentrated until crystals appeared. The crystals were separated by filtration and the separated crystals washed with ethyl acetate. Sixty grams of 4-dimethylaminothiobutyramide melting at about 77° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:13][CH2:12][C:11](=[O:19])[CH2:10]1.[CH3:20]OC(OC)OC>S(=O)(=O)(O)O.CO>[CH3:20][O:19][C:11]12[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16][CH2:17][OH:18])[CH:9]([CH2:10]1)[C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[O:1]2
Reactant: COC(OC)OC
Reactant: O=C1CC[C@@H](CCCO)[C@H](c2ccc(O)cc2O)C1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC12CCC(CCCO)C(C1)c1ccc(O)cc1O2
Yield: 82 %

Procedure:
A solution of 1.5 g. (5.68 mmole) of trans-3-(2,4-dihydroxyphenyl)-4-(3-hydroxypropyl)cyclohexanone in 40 ml. methanol, 6 ml. trimethylorthoformate and 7 drops of concentrated sulfuric acid was stirred at 0° C. for 45 minutes. The reaction was quenched by the addition of excess solid sodium bicarbonate and then evaporated on a rotovapor. The residue was diluted with 300 ml. saturated sodium bicarbonate-300 ml. ether. The ether extract was dried over magnesium sulfate and evaporated. The crude product was purified via column chromatography on 150 g. of silica gel eluted in 15 ml. fractions with ether to yield 1.29 g. (82%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:53].CCCCCC>C1COCC1>[Br:53][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1C[C@@H](Br)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methyl-4-hydroxypyrrolidine (910 mg, 2.0 mmol) and Ph3P (628 mg, 2.4 mmol) in THF (20 ml) was added CBr4 (993 mg, 3.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hr. n-Hexane (40 ml) was added thereto. The resulting solid was filtered off, and dried in vacuo. The residue was purified by column chromatography on silica gel with n-hexane to n-hexane-EtOAc (3:2, v/v) as eluent to give cis-4-bromo-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methylpyrrolidine (1.0 g, quant.) as a pale yellow oil. 1H-NMR (CDCl3) δ1.06 (s, 9H), 1.31 and 1.45 (each s, 9H), 2.63 (m, 2H), 3.49 (m, 1H), 3.89-4.14 (m, 5H), 7.35-7.42 (m, 6H), 7.64-7.66 (,4Hm).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:8])=[CH:5][CH:4]=1>C(Cl)Cl.C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:8])=[CH:17][CH:18]=1)=[O:1]
Reactant: O=C(Nc1ccccc1O)c1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
4-Hydroxymethyl-N-(2-hydroxyphenyl)-benzamide from above (0.56 g, 2.3 mmol) was dissolved in CH2Cl2 (12 mL) and THF (12 mL), treated with activated MnO2 (2.0 g, 23 mmol) and stirred at room temperature overnight. The mixture was filtered through celite, the cake washed with CH2Cl2 and the solvent from the eluent removed under reduced pressure. Purification of the crude by column chromatography on silica gel (5% MeOH/CH2Cl2) gave 4-formyl-N-(2-hydroxyphenyl)-benzamide (0.05 g, 10%). 1H NMR (CDCl3) δ 6.95 (t, 1H, J=7.8 Hz), 7.05 (d, 1H, J=7.8 Hz), 7.16 (t, 1H, J=7.8 Hz), 7.42 (d, 1H, J=7.8 Hz), 8.04 (m, 5H), 8.33 (br, 1H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:32][CH3:33])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH2:30])=[O:29])=[C:24]([F:31])[CH:23]=2)[C:15]([O:32][CH3:33])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1ccc(C(N)=O)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (13 mg, 0.065 mmol), 3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide (20 mg, 0.06 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C22H21ClFN6O2 (M+H)+: m/z=455.1. found: 455.0.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]=[CH:15][CH2:16][N:17]([CH:24]3[CH2:26][CH2:25]3)C(=O)C(F)(F)F)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([O:12][CH2:13][CH:14]=[CH:15][CH2:16][NH:17][CH:24]3[CH2:26][CH2:25]3)=[CH:10][CH:9]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(OCC=CCN(C(=O)C(F)(F)F)C2CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)c1ccc(OCC=CCNC2CC2)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 11.5 g of N-[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-N-cyclopropyl-2,2,2-trifluoroacetamide in 150 ml of methanol and 50 ml of tetrahydrofuran is treated with 5 ml of 20% aqueous potassium hydroxide solution while cooling with ice. The mixture is brought to room temperature and stirred for one hour, concentrated under reduced pressure and the residue is treated with 100 ml of water. The phases are separated and the inorganic phase is extracted with methylene chloride. The organic extracts are washed with saturated sodium chloride solution, dried and evaporated. After purification of the residue over silica gel with ethyl acetate-hexane-triethylamine (50/49/1) there are obtained 7.0 g of (4-bromo-phenyl)-[4-(4-cyclopropylamino-but-2-enyloxy)-phenyl]-methanone, MS: m/e 386 (M+H+, 1Br),
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:1]([O:4][N:5]=[C:6]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:7]([O:9][CH:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON=C(C(=O)O)c1nsc(N)n1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1nsc(N)n1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To a solution of 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (10 g) in tetrahydrofuran (230 ml) was added portionwise diphenyldiazomethane (12.76 g) under cooling in an ice bath and stirring and the mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure until an crystallization began and stood overnight at room temperature. The precipitates were collected by filtration, washed with ethyl acetate and dried to give diphenylmethyl 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (5.41 g), mp. 175° to 180° C. (dec.). The filtrate and the washings were combined and evaporated to dryness. The residue was crystallized from methylene chloride-diethyl ether (4:1) to give further crops of the object compound (6.7 g), which was recrystallized from acetonitrile.
Reaction SMILES: O[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)(C)C.[C].[Pd]>[CH2:2]1[CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)C1CCCCC1

Procedure:
One mole of 4-hyroxybenzoic acid was reacted with two moles of hydrogen in the presence of 5% palladium-carbon catlyst. This reaction was carried out in isopropyl alcohol at a temperature of 130°-140° C. and a hydrogen pressure of 20-40 kg/cm2 (gauge). After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to recover the solvent. The resulting residue was recrystallized from a mixture of benzene and hexane to obtain cyclohexane-4-carboxylic acid. This product had a melting point of 67.0°-68.0° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:8][C:7]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:6]1.[Li+].[OH-].Cl>O1CCOCC1.O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.3 %

Procedure:
30.8 g of (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid methyl ester was dissolved in 250 mL dioxane and a solution of 2.4 g LiOH in 250 mL of water was added. The mixture was stirred for 24 h at RT. The mixture was acidified with HCl-solution. The precipitate was filtered to give 29 g of the desired product. Rt: 1.28 min (method B), (M+H)+: 316
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:16])[CH:10]=1)[CH3:8])=[CH2:5].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>C(Cl)Cl>[CH3:18][C:2]([CH3:17])([CH3:1])[CH2:3][C:4]([NH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:22]([CH:21]=[CH2:20])(=[O:24])=[O:23])=[C:11]([I:16])[CH:10]=1)[CH3:8])=[CH2:5]
Reactant: C=C(CC(C)(C)C)NC(C)c1ccc(N)c(I)c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CS(=O)(=O)Nc1ccc(C(C)NC(=C)CC(C)(C)C)cc1I
Temperature: 0 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
4-{1-[1-(2,2-Dimethylpropyl)vinylamino]ethyl}-2-iodophenylamine (218.1 mg, 0.65 mmol) was dissolved in methylene chloride. The reaction mixture was cooled down to 0° C. 2-Chloroethane sulfonyl chloride (3 eq, 1.95 mmol, 203.64 μl) and Pyridine (3 eq, 1.95 mmol, 157.71 μl) were added into mixture. The reaction mixture was stirred for 48 hrs. After confirming the completion of the synthesis, a reaction solvent was removed in vacuo. A residue was extracted with methylene chloride. A combined organic layer was washed with H2O and brine, dried over NaSO4, and concentrated in vacuo. The residue was purified with column chromatography (n-Hx:EA=3:1) to yield title compound (104.9 mg, 78%) as a brownish solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][S:8]([NH2:11])(=[O:10])=[O:9].Cl[C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1>>[CH2:12]([C:3]([CH2:14][CH3:15])([CH2:4][CH2:5][CH2:6][CH2:7][S:8](=[O:9])(=[O:10])[NH2:11])[CH2:2][O:1][C:17]1[C:18]([CH3:26])=[CH:19][C:20]2[N:21]([N:23]=[CH:24][N:25]=2)[N:22]=1)[CH3:13]
Reactant: CCC(CC)(CO)CCCCS(N)(=O)=O
Reactant: Cc1cc2ncnn2nc1Cl
Product: CCC(CC)(CCCCS(N)(=O)=O)COc1nn2ncnc2cc1C

Procedure:
Using 6-hydroxy-5,5-diethyl-1-hexanesulfonamide and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction was conducted as in Example 5 to produce the title compound. m.p. 132°-133° C.
Reaction SMILES: [OH-].[Na+].C1(C[O:10][C:11]([C:13]2([NH:19][C:20]([C:22]3[S:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH:26]=3)=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])C=CC=CC=1.CCOCC>O1CCCC1>[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH:26]=[C:22]1[C:20]([NH:19][C:13]1([C:11]([OH:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:21]
Reactant: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2s1
Yield: 83.8 %

Procedure:
42 ml of 2N aqueous sodium hydroxide solution was added to a solution of 10 g (24 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid phenylmethyl ester in 20 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 days. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid, and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 6.1 g (80%) of the title compound.
Reaction SMILES: CO[C:3]1[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1.C([O-])(=O)C.[NH4+:33]>O1CCCC1>[NH2:33][C:3]1[N:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1
Reactant: CCOC(=O)C1=C(C)N=C(OC)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N=C(N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.9 %

Procedure:
A solution of 2-methoxy-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (3.78 g, 9.66 mmoles of crude from previous reaction) in anhydrous tetrahydrofuran (20 ml) was cooled to 0° C. (ice bath) and a slow stream of ammonia gas was bubbled through it for approximately 5 minutes. Solid ammonium acetate (385 mg, 5.0 mmoles) was added and the reaction flask was tightly stoppered and allowed to stir at room temperature for 72 hours. A light yellow solid precipitated out of the reaction. Excess ammonia and tetrahydrofuran were evaporated and the residue was dissolved in methylene chloride. The insoluble material (ammonium acetate) was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography (30% ethyl acetate in dichloromethane). The desired product was crystallized from dichloromethane-isopropyl ether to provide 2.03 g of the title compound as a yellow solid, melting point 166°-168° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:22]=[C:21]([Cl:23])[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][C:6]=1[C:7]([N:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH3:10])=[O:8].[CH3:36][S:37](Cl)(=[O:39])=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:23][C:21]1[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])=[CH:19][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH3:10])=[O:8])=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:22]=1
Reactant: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N(C)C(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-amino-ethoxy)-4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide (30 mg, 0.06 mmol) in DCM (1 mL), methanesulfonylchloride (7 μL, 0.09 mmol) and DIPEA (16 μL, 0.09 mmol) were added. The mixture was stirred at rt overnight, concentrated, diluted with 1 mL MeOH and purified by prep HPLC yielding 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(2-methanesulfonylamino-ethoxy)-N-(2-methoxy-phenyl)-N-methyl-benzamide 48-1. MS: 583.0 (M+H)+, tR=7.61 min (method 2).