Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH2:33])[CH3:22].C(OC(C)C)(C)C>>[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH:33][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH3:22]
Reactant: CN(C)CC1CCCCN1CCCN
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Solvent: CC(C)OC(C)C
Product: CN(C)CC1CCCCN1CCCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 80 %

Procedure:
Prepared analogously to Example 2 from 5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3-[2-[(dimethylamino)methy]-piperidin-1-yl]propanamine in a yield of 80% of theory. Colourless crystals, m.p. 131°-133° C. (diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].[CH3:28][O-].C[O-].[Mg+2].CI.Cl.S(=O)(O)[O-].[Na+]>CS(C)=O.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH3:28])[C:12]=2[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[C:7]1=[O:23]
Reactant: C[O-]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Cl
Agent: O=S([O-])O
Agent: [Mg+2]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (0.1 g, 0.254 mmol) in dry DMSO (5 mL) was added magnesium methylate (1.097 mL of a 6-10% methanol solution, 0.792 mmol), and the reaction was heated to 60° C. for 0.5 hour. The reaction mixture was rotavapped to remove all of the MeOH. The heat gun was used to drive all MeOH from the bump bulb. The reaction was treated with methyl iodide (0.079 mL, 6.35 mmol) and allowed to stir at 60° C. overnight. LCMS showed trace starting material remaining and mostly N-alklated product formed (O-alkylated products minor). The reaction was diluted with 0.5 mL MeOH then 1 N HCl was added until a precipitate began to form. A 5 mL portion of 10% sodium bisulfite was added and the brown mixture turned green. Water was added and the mixture stirred for 1 hr, then the mixture was partitioned with chloroform 20 mL and 1 N HCl 20 mL. The organic layer was washed 2 times more with 1 N HCl and then with brine, dried over Na2SO4, filtered and evaporated to an oil. The residue was passed through a Gilson reverse phase column eluting from 95:5 to 5:95 to give an oil after concentration.
Reaction SMILES: F[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.O.[NH2:13][NH2:14].O.CCO>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:11][C:4]1[N:3]=[C:2]2[NH:13][N:14]=[C:8]([CH3:9])[C:7]2=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccc(F)nc1F
Reactant: NN
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2nc(F)ccc12
Reaction time: 1.5 h

Procedure:
To a stirred solution of 7.46 g (47.51 mmol) of 1-(2,6-difluoropyridin-3-yl)ethanone (37-2) in 50 mL of CH2Cl2 under nitrogen was added dropwise titanium (IV) isopropoxide. The resulting solution was stirred vigorously for 15 minutes before hydrazine hydrate (4.62 g, 95.0 mmol) was added slowly to form a thick slurry. The reaction mixture was stirred for 1 hour before the addition of 11 mL of H2O, and the resulting mixture stirred for 1.5 hours until completion as determined by LC/MS analysis. The solid matter was filtered off and the filterate was condensed to yield a white solid. EtOH (100 mL) was added to the crude intermediate and the mixture was heated to reflux for 6 hours. After the reaction was complete as determined by LC/MS analysis the solvent was removed to yield the desired product. No further purification was necessary. 1H NMR (CDCl3): 2.56 (s, 3H), 6.78 (d, 1H), 8.08 (t, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[H-].[Na+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([O:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=[C:4]([S:18][CH3:19])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2ccccc2Cl)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1nc(Nc2ccccc2Cl)c(C=O)c(Oc2ccccc2)n1
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a solution of 4-chloro-6-(2-chloro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (315 mg, 1 mmol) in 10 mL of anhyd DMSO was added NaH (50 mg, 1.2 mmol, 60% dispersion in mineral oil, 1.2 eq) followed by phenol (112 mg, 1.2 mmol, 1.2 eq). The reaction mixture was stirred for 1 h 23°, quenched with H2O (20 mL), Et2O (100 mL) was added and the layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4) filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to afford 120 mg (45% yield) of 4-(2-chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carbaldehyde. 1H-NMR δ 2.32 (s, 3H), 7.01-7.49 (m, 8H), 8.51 (d, 1H, J=7.2 Hz), 10.49 (s, 1H), 11.58 (br s, 1H). LC MS (m/e)=372 (MH+). Rt=2.94 min.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[C:16]1([C:3]2[C:2]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Temperature: 125 °C
Reaction time: 3 h
Yield: 104.4 %

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) and piperazine (77.4 mg, 0.90 mmol, 2.00 equiv) in DMSO (8 mL) was placed in a 20-mL sealed tube, stirred for 3 hrs at 125° C. in an oil bath, and then quenched by the addition of 50 mL of water. The resulting solution was extracted with 6×50 mL of dichloromethane, the organic layers combined and dried over anhydrous sodium sulfate, and the solution filtered to remove solids. Concentration under vacuum yielded 160 mg (91%) of methyl 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1([F:40])[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:30][C:31]1([F:40])[CH2:36][CH2:35][CH:34]([C:37]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:38])[CH2:33][CH2:32]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1CCC(F)(F)CC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
To a stirred mixture of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.205 g, 0.74 mmol), DIEA (0.14 mL, 0.81 mmol), and 4,4-difluoro-cyclohexanecarboxylic acid (0.13 g, 0.81 mmol) in DMF (4 mL) was added HATU (0.31 g, 0.81 mmol). The reaction mixture was continued to stir for 2 h, quenched with H2O, and extracted with DCM (3×). The organic extracts were dried over Na2SO4, concentrated and purified by ISCO (20% EtOAc/hexanes) to give the white solid. MS (ESI, positive ion) m/z: 424 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]([CH:15]([C:21]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22]1)[CH2:16][CH2:17][CH2:18][S:19][CH3:20])[CH3:14]>ClCCl.Cl>[CH3:12][N:13]([CH:15]([C:21]1([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:24][CH2:23][CH2:22]1)[CH2:16][CH2:17][CH2:18][S:19]([CH3:20])=[O:9])[CH3:14]
Reactant: CSCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(CCCS(C)=O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of m-chloroperbenzoic acid (1.75 g) in dichloromethane (50 ml) was added over 30 minutes to a stirred solution of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-4-methylthiobutylamine (2.4 g prepared in a similar manner to that described in Example 187) in dichloromethane (50 ml) at 0° C. The mixture was stirred at 0° C. for 11/2 hours and then kept at <5° C. overnight. The resulting solution was washed with 2N sodium hydroxide solution then brine and then dried and evaporated to give an oil which was treated with petroleum ether (b.p. 40°-60° C.). The resulting mixture was filtered and the filtrate evaporated to give a residue which was dissolved in 2N hydrochloric acid. The solution was washed with ether, basified and extracted with ether. The extracts were dried and evaporated to give N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-4-methylsulphinylbutylamine as an oil the boiling point of which was not determined.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9](=[O:12])[C:8]2[CH2:7][CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:5][CH2:4][C:3]1=2.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([C:13]([O:15][CH3:16])=[O:14])[CH2:7]2
Reactant: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCc2c(O)ccc(O)c2C1
Yield: 102.5 %

Procedure:
0.30 g of 10% palladium-on-carbon catalyst was added to a solution of 4.0 g (0.018 mol) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in 180 ml of methanol and the mixture was shaken under one atmosphere of hydrogen until hydrogen uptake ceased (429 ml, 18 minutes). The mixture was filtered and the filtrate was evaporated to yield 4.1 g (100%) of methyl rac-5,8-dihydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate in the form of a white crystalline solid of melting point 135°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>>[CH3:19][N:20]([CH3:27])[CH2:21][CH2:22][CH2:23][C:24]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:25]
Reactant: CN(C)CCCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)CCCN(C)C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and 4-dimethylamino-butyryl chloride the title compound was obtained as a light yellow solid (10%), MS: m/e=379 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([C:13]3[O:17][C:16]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[O:19])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8]([C:13]3[O:17][C:16]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[N:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[O:19])=[CH:15][CH:14]=3)[C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1ccc(C(=O)Nc3cnccc3N3CCN(C(=O)OC(C)(C)C)CC3)o1)C2
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)N(c1ccc(C(=O)Nc3cnccc3N3CCNCC3)o1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The Example 1 compound, tert-butyl 4-(3-(5-(6-methoxy-1-oxoisoindolin-2-yl)furan-2-carboxamido)pyridin-4-yl)piperazine-1-carboxylate (1.5) (0.1 mmol) was cooled to 0° C. in 1 mL of dioxane and was added to 4N HCl in dioxane (1 mL) and stirred at room temperature for 30 min. Dioxane was removed under vacuo, redissolved in water-acetonitrile and freezed and lyophilized to obtain 5-(6-methoxy-1-oxoisoindolin-2-yl)-N-(4-(piperazin-1-yl)pyridin-3-yl)furan-2-carboxamide (Example 1) as white powder. HPLC-MS tR=0.75 min (UV254 nm); Mass calculated for formula C23H23N5O4, 433.18, observed LCMS m/z 434.20 (M+H)
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH3:40])[CH:36]([NH:41][CH3:42])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>O>[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37]([CH3:40])[CH:36]([N:41]([CH3:42])[C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CNC1CN(Cc2ccccc2)CCC1C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CN(Cc5ccccc5)CCC4C)ncnc32)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 106 %

Procedure:
4-Chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (2 g, 6.37 mmol, 2.00 equiv.) and potassium carbonate (2.7 g, 19.4 mmol, 6.00 equiv.) were added to a solution of (1-benzyl-4-methyl-piperidin-3-yl)-methyl-amine (700 mg, 2.89 mmol, 1.00 equiv.) in water (30 mL). The solution was stirred at about 100° C. for about 16 hours, and then was cooled to ambient temperature. Following standard extractive workup with ethyl acetate (3×100 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum (1:1)) to give the title product as a light yellow solid (1.5 g; yield=96%). 1H NMR (300 MHz, CDCl3) δ: 8.36 (s, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.45 (d, J=4.2 Hz, 1H), 7.20-7.42 (m, 7H), 6.75 (d, J=4.2 Hz, 1H), 5.05-5.20 (m, 1H), 3.40-3.65 (m, 5H), 2.70-2.92 (m, 2H), 2.50-2.70 (m, 1H), 2.42 (s, 3H), 2.23-2.42 (m, 1H), 2.10-2.23 (m, 1H), 1.55-1.75 (m, 2H), 0.92 (d, J=6.9 Hz, 3H). LC-MS: m/z=490 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(NCC(F)(F)F)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccc(N2CCN(C(C(=O)NCC(F)(F)F)c3ccccc3)CC2)cc1
Yield: 70.8 %

Procedure:
A mixture of intermediate (3) (0.0054 mole) in methanol (150 ml) was hydrogenated with Pd/C 10% (1 g) as a catalyst in the presence of a 4% thiophene solution (1 ml). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 1.5 g of (±)-4-(4-aminophenyl)-α-phenyl-N-(2,2,2-trifluoroethyl)-1-piperazineacetamide (intermediate 4, melting point 136° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:13]/[C:12]([C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[OH:1])=[O:14]
Reactant: CC(=O)c1cc(C(F)(F)F)ccc1O
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1O
Temperature: 110 °C

Procedure:
1-[2-Hydroxy-5-(trifluoromethyl)phenyl]ethanone, (Preparation 860, 7.0 g, 0.0343 mol) was taken in dimethylformamide dimethylacetal (18.2 mL, 0.137 mol) at room temperature and then heated at 110° C. for 30 min. The reaction mixture was concentrated in vacuo and the crude product was crystallised from 2-propanol to give the title compound as bright yellow solid (6.4 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[Br:11][N:9]1[C:10]2[NH:1][CH2:2][CH2:3][CH2:4][C:5]=2[CH:6]=[CH:7][CH2:8]1
Reactant: c1cnc2c(c1)CCCN2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: BrN1CC=CC2=C1NCCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.6730 g (5.02 mmol) 32 in 20 mL glacial acetic acid was added 1.0701 g (6.01 mmol) N-bromosuccinimide. After 16 h at 65° C., the reaction mixture was cooled to room temperature and poured onto 50 mL ice water. This was brought to pH 11 with K2CO3 and extracted with 4×100 mL CHCl3. The combined CHCl3 extracts were washed with 100 mL brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (50×115 mm silica gel, linear gradient 2-5% (10% NH4H:MeOH):CH2Cl2) yielded 33. 1H NMR (CDCl3, 400 MHz) δ 8.175 (s, 1H, ArH); 7.877 (s, 1H, ArH); 3.458-3.423 (m, 2H, CH2); 2.725 (t, 2H, J=6.26 Hz, CH2); 1.970-1.911 (m, 2H, CH2); MS (Electrospray): m/z 212.9, 214.8 (M+H, 79Br, 81Br).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])=[O:3].[OH-].[K+].S(OC)(O[CH3:41])(=O)=O.C1COCC1>C(OCC)(=O)C.CCCCCC.O>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[O:34][CH3:41])=[O:3]
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CCC)cccc1OCC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CCC)cccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 41 (134 mg), potassium hydroxide (18 mg) and dimethyl sulfate (53 mg) were added to 2.0 ml of THF and the reaction mixture was stirred at room temperature overnight. Water (10 ml) was added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to give an oil. Chromatography of the oil on silica gel with 50/50 ethyl acetate/hexane as eluant gave the product as a colorless gum.
Reaction SMILES: S(=O)(=O)(O)O.[OH2:6].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1>[O-2].[Cr+6].[O-2].[O-2].CC(C)=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:6])=[O:17])=[CH:12][CH:11]=1)=[O:18]
Reactant: O
Reactant: COC(=O)c1ccc(CO)cc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over 1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol) and water (925 ml) at 0°. The resulting solution was added dropwise over 1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g, 0.564 mol) and acetone (4.6 l) at 0°. The reaction mixture was allowed to warm to room temperature and stirred overnight. The supernatant was decanted before the black tar-like residue was extracted with acetone. The decanted supernatant and acetone extracts were combined and concentrated under vacuum to leave a dark brown residue which was triturated with cold water (4 liter). The precipitate which formed was collected, washed three times with water (1 liter), and dried to give 94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29].I[C:34]1[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([O:41][CH3:42])[C:35]=1[CH3:43].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>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>[F:1][C:2]1[CH:7]=[C:6]([C:34]2[C:39]([CH3:40])=[CH:38][N:37]=[C:36]([O:41][CH3:42])[C:35]=2[CH3:43])[C:5]([F:17])=[CH:4][C:3]=1[C:18]1[N:22]([C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[N:21]=[CH:20][C:19]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: COc1ncc(C)c(I)c1C
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(B2OC(C)(C)C(C)(C)O2)cc1F
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1cc(F)c(-c2c(C)cnc(OC)c2C)cc1F
Temperature: 25 °C

Procedure:
Ethyl 5-(4-bromo-2,5-difluorophenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate obtained in Preparation Example 11-1 (4.31 g), bis(pinacolato)diboron (3.27 g), potassium acetate (3.16 g) and Pd(dppf)Cl2-DCM complex (439 mg) were added to DMF (41.6 mL), and the mixture was stirred at 95° C. in a nitrogen atmosphere. After two hours, the reaction mixture was stirred at 105° C. for four hours. The reaction mixture was cooled to room temperature and filtered through Celite™. The filtrate was concentrated under reduced pressure, brine and ethyl acetate were added to the residue, and the mixture was then stirred at room temperature for five minutes. The mixture was filtered again through Celite™, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered through Celite™. The filtrate was concentrated. The residue was purified by silica gel chromatography (n-heptane/ethyl acetate, 20% to 30% to 80%) to give ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (2.95 g). The resulting ethyl 5-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1((S)-tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxylate (900 mg), 4-iodo-2-methoxy-3,5-dimethylpyridine obtained in Preparation Example 29(3) (634 mg), Pd(PPh3)4 (116 mg) and cesium carbonate (1.96 g) were added to a mixed solvent of 1,4-dioxane (9.3 mL) and water (3.1 mL), and the mixture was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and partitioned by adding ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, first time: 15% to 36% to 47%, second time: 10% to 30% to 35%) to give the title compound (280 mg).