Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][CH:7](Br)[CH3:8].[I-].[Na+].C(=O)=O.[NH3:19]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][CH:7]([NH2:19])[CH3:8]
Reactant: Cc1cc(C)cc(OCC(C)Br)c1
Reactant: N
Agent: O=C=O
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)cc(OCC(C)N)c1
Temperature: 130 °C
Reaction time: 7 h
Yield: 53.8 %

Procedure:
A 20 ml autoclave was charged with 4.20 g (17.3 mmol) of 1-(3,5-dimethylphenoxy)-2-bromopropane, 4 ml of methanol and 0.03 g of sodium iodide, and the autoclave was cooled in a dry ice.acetone bath. The pressure in the autoclave was reduced, and 7 g of liquid ammonia was added. The autoclave was allowed to stand until its temperature reached room temperature, and the mixture was continuously stirred at 130° C. for 7 hours to finish the reaction. After allowed to cool, the reaction mixture was post-treated in the same manner as in Example 26 to give 1.66 g of 1-(3,5-dimethylphenoxy)-2-aminopropane (yield 53.8%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.O[CH2:28][CH2:29][C@@H:30]1[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C.C(#N)C>[I:25][CH2:28][CH2:29][C@@H:30]1[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31]1
Reactant: CC1(C)OC[C@@H](CCO)O1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CC#N
Product: CC1(C)OC[C@@H](CCI)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 416.5 %

Procedure:
Triphenyl phosphine (5.94 g, 22.65 mmol) and imidazole (22.65 mmol) were dissolved in a mixed solution (120 ml) of diethyl ether-acetonitrile (3:1). Iodine (5.75 g, 22.65 mmol) was added thereto under cooling on ice and the mixture was stirred at room temperature for 30 minutes. The solution was cooled on ice again, (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (3.0 mmol, 20.59 mmol) was added thereto and the mixture was stirred at room temperature for 24 hours. A saturated sodium thiosulfate aqueous solution was added to the reaction solution under cooling on ice and stirred for a while, the solution was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3.20 g (61%) of the title compound in the form of a yellowish oily product.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: OCc1ccc(Br)cn1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Br)cn4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (66.8 mg) and triphenylphosphine (140 mg) in THF (6 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc to EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (25.2 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH2:9][N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:17])[CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[CH:20]2[CH2:24][CH2:25][CH:26]=[CH:27][CH:19]12>C(O)(=O)C>[Cl:1][C:2]1[C:8]([CH2:9][N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:13])=[CH:7][C:5]([N:6]2[C:21](=[O:22])[C:20]3[CH2:24][CH2:25][CH2:26][CH2:27][C:19]=3[C:18]2=[O:23])=[C:4]([F:17])[CH:3]=1
Reactant: CC(C)N(Cc1cc(N)c(F)cc1Cl)C(C)C
Reactant: O=C1OC(=O)C2CCC=CC12
Solvent: CC(=O)O
Product: CC(C)N(Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl)C(C)C
Yield: 6.6 %

Procedure:
By the method of Example 2, Step H, 0.50 g (0.0020 mole) of 4-chloro-2-fluoro-5-(diisopropylaminomethyl)aniline and 0.85 g (0.0056 mole) of tetrahydrophthalic anhydride in 20 ml of acetic acid were reacted yielding 0.052 g of N-[4-chloro-2-fluoro-5-(diisopropylaminomethyl)phenyl]-3,4,5,6-tetrahydrophthalimide. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1C(OCC)=O>Cl>[O:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2](=[O:1])[CH2:3]1
Reactant: CCOC(=O)c1oc2ccncc2c1O
Agent: Cl
Product: O=C1COc2ccncc21
Yield: 15.1 %

Procedure:
Ethyl 3-hydroxyfuro[3,2-c]pyridine-2-carboxylate (5.79 g, 27.9 mmol) was dissolved in 10% hydrochloric acid (50 mL), and heated under reflux for 40 h. The reaction mixture was evaporated to dryness. The residue was suspended in saturated sodium bicarbonate solution and extracted with chloroform 3 times. The chloroform extracts were combined, dried (MgSO4), filtered, and evaporated to give furo[3,2-c]pyridin-3(2H)-one (570 mg) as a light-brown oil. N,N-Diisopropylethylamine (616 mg, 4.77 mmol) was added slowly to a solution of furo[3,2-c]pyridin-3(2H)-one (560 mg, 4.14 mmol) in dry methylene chloride (25 mL) under nitrogen at −10° C. Then trifluoromethanesulfonic anhydride (1.40 g, 4.97 mmol) was added slowly. The mixture was allowed to warm to RT, and stirred for another 1 g. The reaction was quenched with water. The organic layer was washed with water, dried (MgSO4), filtered, and then the solvent was evaporated to give the sub-title compound as a brown oily residue (1.10 g), which was used without further purification for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)CC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(F)cc1C1CC(=O)C=C(N)C1

Procedure:
A solution of 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (3.0 g) and ammonium acetate (3.1 g) in ethanol (50 ml) was refluxed for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-amino-5-(5-fluoro-2-methylphenyl)cyclohexen-3-one, which was dissolved in ethanol (70 ml) and toluene (120 ml). To the mixture were added 3-oxobutylaldehydedimethylacetal (4.1 g) and powdery potassium hydroxide (0.57 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (0.14 g) 30 minutes later; powdery potassium hydroxide (0.14 g) and 3-oxobutylaldehydedimethylacetal (0.33 g) 1 hour later; and powdery potassium hydroxide (0.14 g) 1.5 hours later. Then, the mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was subjected to silica gel column (ethyl acetate-hexane) to give crystals, which were recrystallized from ethyl acetate-hexane to give 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.5 g).
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:10]2[C:11](=[O:31])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[N:20][CH:21]=3)[CH2:13][CH2:14][O:15][C:9]=2[N:8]=[CH:7][N:6]=1>O1CCOCC1.O>[NH2:4][C:5]1[C:10]2[C:11](=[O:31])[N:12]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([CH3:29])([CH3:30])[C:25]([OH:27])=[O:26])=[N:20][CH:21]=3)[CH2:13][CH2:14][O:15][C:9]=2[N:8]=[CH:7][N:6]=1
Reactant: COC(=O)C(C)(C)COc1ccc(N2CCOc3ncnc(N)c3C2=O)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(N2CCOc3ncnc(N)c3C2=O)cn1)C(=O)O
Temperature: 60 °C
Yield: 56 %

Procedure:
Lithium hydroxide monohydrate (16.4 mg, 0.39 mmol) was added at room temperature to a solution of methyl 3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-21 (50.4 mg, 0.13 mmol) in 1,4-dioxane (2.0 mL) and water (1.0 mL). The reaction mixture was heated at 60° C. for 2 h and then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give 3-(5-(4-amino-5-oxo-7,8-dihydropyrimido[5,4-f][1,4]oxazepin-6(5H)-yl)pyridin-2-yloxy)-2,2-dimethylpropanoic acid B-22 (27.0 mg, Yield=56%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 1.33 (s, 6H), 4.13 (m, 2H), 4.35 (s, 2H), 4.85 (m, 2H), 6.90 (d, J=8.83 Hz, 1H), 7.71 (d, J=8.83 Hz, 1H), 8.16 (s, 1H), 8.29 (s, 1H); MS (ESI) [M+1]+ 374.
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[CH2:7][CH:8]([P:17]([O:22]CC)([O:19]CC)=[O:18])[P:9]([O:14]CC)([O:11]CC)=[O:10])[CH2:2][CH2:3][CH3:4].B.CSC.Cl>C1COCC1>[CH2:1]([NH:5][CH2:6][CH2:7][CH:8]([P:17]([OH:22])(=[O:18])[OH:19])[P:9]([OH:14])(=[O:10])[OH:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCNCCC(P(=O)(O)O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 109 %

Procedure:
A solution of N-butyl-3,3-bis(diethoxyphosphinyl)propionamide (1.40 g, 3.5 mmol) in THF (9 mL) was cooled to 0° C., and borane-methyl sulfide (0.90 ml, 9.0 mmol) was added via syringe. The reaction was stirred at 0° C. for 5 minutes, then warmed to 65° C. for 3 hours. The reaction mixture was cooled to 0° C. and 6N HCl (6 ml) was added carefully. The solvent was removed in vacuo, and the residue was repeatedly concentrated from methanol (3×10 mL). The product was dissolved in 12N HCl and heated at reflux for 20 hours. After cooling, the volatile materials were removed under vacuum, the residue was dissolved in water (10 mL) and then concentrated to give 1.05 g of Compound No. 158 as a hygroscopic glass.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14](F)[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O-:21].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[C:14]([O:21][CH3:20])[N:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(Nc3cccc(Br)c3)ncnc2cn1

Procedure:
Treatment of 4-(3-bromoanilino)-6-fluoropyrido[3,4-d]pyrimidine (see a previous experimental) at 100° C. in a pressure vessel with sodium methoxide in methanol gives 4-(3-bromoanilino)-6-methoxypyrido[3,4-d]pyrimidine. 1H NMR (DMSO) δ 9.93 (1H, s), 8.94 (1H, s), 8.61 (1H, s), 8.26 (1H, brs), 7.94 (1H, brd, J=7.6 Hz), 7.88 (1H, s), 7.43-7.32 (2H, m), 4.01 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:10][C:8]([F:9])([F:11])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)Oc1ccccc1

Procedure:
According to the procedure described in Example 113B, 2-amino-4-trifluoromethylpyridine (462 mg, 2.85 mmoles) was dissolved in 20 ml of tetrahydrofuran. To this solution was added potassium carbonate (511 mgs, 3.7 mmoles) followed by phenyl chloroformate (521 mgs, 3.33 mmoles). The mixture was concentrated and purified according to the procedure in in Example 138 to afford phenyl 4-(trifluoromethyl)pyridin-2-ylcarbamate. 1H NMR (300 MHz, CDCl3) δ 9.53 (s, 1H), 8.56 (m, 1H), 8.38 (s, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m, 2H), 6.8 (m, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([CH2:10][NH:11][C:12]([C:14]2[C:19](=[O:20])[C:18](Br)=[C:17]([CH3:22])[N:16]([CH:23]([CH3:25])[CH3:24])[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][CH:27]([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[CH3:1][S:2]([C:5]1[S:9][C:8]([CH2:10][NH:11][C:12]([C:14]2[C:19](=[O:20])[C:18]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH:27]([F:37])[F:26])[CH:33]=3)=[C:17]([CH3:22])[N:16]([CH:23]([CH3:25])[CH3:24])[CH:15]=2)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1cccc(C(F)F)c1
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)s2)cn1C(C)C
Product: Cc1c(-c2cccc(C(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)s2)cn1C(C)C

Procedure:
Example 40 is prepared following the procedure for Example 24.1, substituting preparation 24 with preparation 39a and replacing 3-(trifluoromethyl)phenylboronic acid with 3-(difluoromethyl)phenylboronic acid. ESI mass spectrum: [M+H]+=495; Retention time HPLC: 0.82 min (Z011_S03).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[CH:11]=[C:7]([C:8]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:9])[CH:6]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCCO)c1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)N3CCOCC3)cc2OCCO)c1

Procedure:
In analogy to Example 121, by coupling 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with morpholine there was obtained N-[3-(2-hydroxy-ethoxy)-2-(3-methoxy-phenoxy)-5-(morpholine-4-carbonyl)-phenyl]-4-methylsulphanyl-benzenesulphonamide.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49]C1C=CC=CC=1CS(Cl)(=O)=O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:48]=1[Cl:49])(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 86 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 6, Example 1) was added [(2-chlorophenyl)-methyl]sulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 86% yield.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:4]=2[O:3]1.[OH-].[K+].O1CCCC1.CO>C(OCC)(=O)C.O>[S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[O:3]1
Reactant: COC(=O)c1ccc2[nH]c(=S)oc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc2[nH]c(=S)oc2c1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Methyl 2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxylate (Example 92A, 470 mg, 2.25 mmol) and potassium hydroxide (1.26 g, 22.5 mmol) were combined in a 11.6 mL mixture of tetrahydrofuran, methanol, and water (10:1:1) and stirred at 45° C. for three hours. The reaction mixture was diluted with ethyl acetate, washed with a 1 N aqueous solution of hydrochloric acid, dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound. MS (ESI−) m/z 193.8 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH:13]([CH3:19])[CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(C)(C)C.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:48]([O:56][CH2:57][CH3:58])(=[O:55])[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51]>>[CH2:57]([O:56][C:48](=[O:55])[CH:49]([C:16](=[O:17])[CH:15]=[CH:14][CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([C:2]([F:24])([F:25])[F:1])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1)[CH3:19])[C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH3:58]
Reactant: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Product: CCOC(=O)C(C(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OCC
Yield: 87 %

Procedure:
One proceeds in an analogous manner to the process disclosed in Example 4 by reacting 4-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-2-pentenoic acid at first with 12 g of pivaloyl chloride and thereafter with diethyl-ethoxy-magnesium malonate prepared from 17.6 g of diethyl malonate. The reaction mixture is worked up. 43 g of the viscous oily desired compound are obtained which turns to a faint yellow crystalline product on standing. Mp.: 52°-55° C., yield 87%.
Reaction SMILES: Cl[C:2]1C=CC(C(C2C3C(=C(CSC)C=CC=3)NC=2)(C2CC2)CC)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:38]2[C:46]3[C:41](=[C:42]([CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)([CH:35]2[CH2:37][CH2:36]2)[CH3:34])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:38]2[C:46]3[C:41](=[C:42]([CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH3:2])=[CH:29][CH:28]=1
Reactant: CCC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Product: CCC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 116 mg (0.31 mmol) of the compound from Example 191 in analogy to the synthesis of the compound from Example 209. 98 mg (78% of theory) of the target compound were obtained.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:29]=2[CH:28]=1.C(N(CC)CC)C>CCO>[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[CH:9]=[C:8]([C:10]5[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=5)[C:7]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=5)=[N:6]4)[CH2:36][CH2:35]3)[C:29]=2[CH:28]=1
Reactant: Cn1c(=O)n(C2CCNCC2)c2cc(Cl)ccc21
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(=O)n(C2CCN(CC(O)Cn3cc(-c4ccncc4)c(-c4ccc(C(F)(F)F)cc4)n3)CC2)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 21.6 %

Procedure:
To a solution of 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (68 mg, 0.197 mmol) and 5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027 mL, 0.197 mmol). The reaction mixture was heated at 80° C. overnight, concentrated, and purified by column chromatography (silica, 2-10% MeOH/CH2Cl2) to afford the title compound (0.026 g, 22%). MS (electrospray): exact mass calculated for C31H30ClF3N6O2, 611.2 [M+H]+. m/z found, 611.2. 1H NMR (400 MHz, CDCl3): 8.59 (br s, 2H), 8.20 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2, 1.8 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz, 1H), 4.31 (d, J=14.2, 6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H), 3.18-3.33 (m, 2H), 3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t, J=12.4 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:13][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7]1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc([N+](=O)[O-])n(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
Into a round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (3.00 g, 17.5 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL). Potassium carbonate (4.84 g, 35.0 mmol, 2.00 equiv) and CH3I (2.98 g, 21.0 mmol, 1.20 equiv) were added at 0° C. The resulting solution was stirred for 2 h at 40° C. in an oil bath. After cooling to ambient temperature, the solids were removed by filtration followed by the addition of 120 mL of ice water. The mixture was extracted with 3×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from ether. This resulted in 1.10 g (34%) of methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid. m/z (ES+) 186 (M+H)+. 1H-NMR, (300 MHz, DMSO-d6, ppm): ˜7.57 (s, 1H), 4.22 (s, 3H), 3.91 (s, 3H). The filtrate was concentrated under vacuum and the crude product (2 g) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (10% CH3CN up to 56.5% in 10 min); Detector, uv 254 nm. The fractions containing pure compound were combined and concentrated to yield 470 mg (15%) of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate as a white solid. m/z (ES+) 186 (M+H)+. 1H-NMR, (300 MHz, DMSO-d6, ppm): □□ 7.64 (1H, s), 4.24 (3H, s), 3.87 (3H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH:36]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:29][C:28]=2[CH:56]([CH3:58])[CH3:57])=[O:25])[C:6]1=[O:59])[CH2:2][CH2:3][CH3:4]>C(O)C.[C].[Pd]>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:30]([NH2:36])=[CH:29][C:28]=2[CH:56]([CH3:58])[CH3:57])=[O:25])[C:6]1=[O:59])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Agent: [Pd]
Solvent: CCO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Yield: 86.2 %

Procedure:
A suspension of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-4-tritylaminophenyl)urea (273 mg, 0.348 mmol), a 10% palladium carbon (56 mg) in ethanol is stirred under hydrogen atmosphere at room temperature for 8 hours. The mixture is filtered on celite, and the solvent is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give the title compound (165 mg, 0.30 mmol) as crystals.