Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1.FC(F)(F)C1N=C[N:17]=C(O)C=1.N>C(#N)C>[NH2:17][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][N:3]=1
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Agent: N
Solvent: CC#N
Product: Nc1cc(C(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 98 %

Procedure:
To a stirred mixture of 4-chloro-6-trifluoromethylpyrimidine (prepared from 6-trifluoromethyl-4-pyrimidinol as described in U.S. Pat. No. 5,714,438) (17.14 g, 93.9 mmol) in acetonitrile (282 ml) was added 25% aqueous ammonia solution (564 ml) and the mixture was stirred at room temperature for 23 h. The mixture was extracted with ethyl acetate (3×1 l), and the combined extracts were dried (MgSO4) and evaporated in vacuo to leave 14.97 g (98%) of the title compound as a white solid: 1H NMR (360 MHz, DMSO-d6) δ 6.80 (1H, s), 7.52 (2H, br s), 8.49 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[NH2:9])[N:3]=1.[CH3:11][CH:12]1[CH2:17][C:16](=O)[CH2:15][CH2:14][NH:13]1>CCO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH3:10])[N:9]=[C:16]2[CH2:15][CH2:14][NH:13][CH:12]([CH3:11])[CH2:17]2)[N:3]=1
Reactant: CC1CC(=O)CCN1
Reactant: CN(N)c1cccc(Br)n1
Solvent: CCO
Product: CC1CC(=NN(C)c2cccc(Br)n2)CCN1
Yield: 100 %

Procedure:
2-Bromo-6-(1-methylhydrazinyl)pyridine (1.58 g, 7.80 mmol) and 2-methylpiperidin-4-one (975 mg, 8.63 mmol) were heated in EtOH (10 mL) at reflux for 16 h, and then the mixture was concentrated to provide the title compound as a white foam, carried forward crude assuming 100% yield: ESI MS m/z 282 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:33][CH2:34][CH2:35][O:36][CH3:37]>CS(C)=O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:16]=[CH:15][C:14]=2[CH3:20])[N:8]=1)=[O:5]
Reactant: COCCCBr
Reactant: Cc1ccc(O)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COCCCOc1ccc(C)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,6-difluoro-N-{1-[(5-hydroxy-2-methylphenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Intermediate 49)(82 mg, 0.239 mmol) in DMSO (1 ml) was added cesium carbonate (155 mg, 0.476 mmol) and then a solution of 1-bromo-3-(methyloxy)propane (45 mg, 0.294 mmol, Matrix Scientific) in DMSO (0.1 ml). The resulting red solution was stirred at ambient temperature under nitrogen overnight. The solution was filtered using a hydrophobic frit and diluted with methanol (0.9 ml). The mixture was purified by MDAP on a Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a luminous yellow gum (19.4 mg); LCMS (System 4) MH+=416, tRET=2.79 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[C@H:23]12[CH2:29][C@H:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:27]1[CH2:28][C@@H:23]2[CH2:29][C@H:26]1[CH2:25][N:24]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 194.7 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (400 mg, 1.32 mmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2,2,1]heptane-2-carboxylate (665 mg, 3.35 mmol), HATU (1.02 g, 2.68 mmol), and DI PEA (1.2 ml, 6.7 mmol) were dissolved in DMF (25 ml) and stirred at room temperature for 72 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product (1.23 g) as brown oil, used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH3:18].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:19][C:16]1[S:17][C:11]2[N:10]=[C:9]([CH3:18])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2sccc2c(=O)n1-c1ccccc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1nc2sc(Br)cc2c(=O)n1-c1ccccc1Cl
Yield: 78.2 %

Procedure:
In chloroform was dissolved 22.85 g of 3,4-dihydro-3-(2-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidine, and 19.5 g of N-bromosuccinimide and trace benzoyl peroxide were added to the solution. The mixture was refluxed for 10 hours. After the resulting crystals were removed from the reaction mixture, the solvent was distilled off. The residue was crystallized from hexane-ethyl acetate to give 22.95 g of 3,4-dihydro-6-bromo-3-(2-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidine, m.p. 164.5°-166.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][OH:10])[N:3]=1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC#N>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:10][CH2:9][CH2:8][N:4]2[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C)n(CCO)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCn2nc(C)cc2C)cc1
Yield: 46 %

Procedure:
A cooled (0° C.) mixture of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-ethanol (0.48 g, 3.4 mmol) and triethylamine (0.47 mL, 3.4 mmol) in MeCN (5 mL) was treated with 4-methylbenzenesulfonyl chloride (0.72 g, 3.8 mmol), after which the mixture was kept cool in a refrigerator for 2 days. The mixture was then concentrated in vacuo to give a residue which was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:1), to give 0.46 g (46%) of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1nc(-c2cccnc2)sc1N
Reaction time: 2 h

Procedure:
To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1 (M+1), 324.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[NH:28][C:27](=[O:41])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[NH:28][C:27](=[O:41])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NCc4ccc(F)cc4)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 65.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one as starting materials to give 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (44 mg, 65.1%) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](Br)[CH:3]=1.[S:10]1[C:14]([CH:15]=O)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2>>[S:10]1[C:14]([CH2:15][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[CH:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]1=2
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: O=Cc1cc2ccccc2s1
Product: Clc1cc(Br)cc(Cc2cc3ccccc3s2)c1

Procedure:
1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound.
Reaction SMILES: [I-].[Na+].CN1C(=O)COCC1=O.[CH3:12][CH2:13][O:14][C:15]([C:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16].O>C(#N)C>[CH:17]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:15]([O:14][CH2:13][CH3:12])=[O:16])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C(=O)OCC)C(=O)OCC
Agent: CN1C(=O)COCC1=O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)C(=O)OCC

Procedure:
Employing the apparatus and procedure described in EXAMPLE 3 above, the cathode compartment was charged with 100 milliliters of 0.3 molar sodium iodide in dry acetonitrile (dried as described in Procedure A, EXAMPLE 1 above), 2.6 grams (0.02 mole) of N-methyldiglycolimide, and 3.2 grams (0.01 mole of tetraethyl ethenetetracarboxylate and the anode compartment was charged with 30 milliliters of the 0.3 molar sodium iodide in dry acetonitrile solution. Electrolysis was conducted as described in Procedure A, EXAMPLE 1 above for 4.2 hours. Upon completion of the electrolysis, the cell was transferred to the dry box and the catholyte, containing precipitated material, was separated from the mercury pool. The solvent was evaporated in vacuo to leave a residue which was mixed with water. Evolution of gas immediately ensued and a portion of the solid material dissolved. The undissolved solid was collected by suction filtration to give a quantitative yield of tetraethyl ethane-1,1,-2,2,-tetracarboxylate. Evaporation of the filtrate in vacuo yielded 2.03 grams (52 percent) of sodium N-methyldiglycolimide-3-carboxylate.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][N:5]12.[BH4-].[Na+].[NH4+].[Cl-]>CO>[CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]=[C:4]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][N:5]12
Reactant: O=C1CCc2cc3ccccc3n2C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OC1CCc2cc3ccccc3n2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a cooled (0° C.) solution of 8,9-dihydropyrido[1,2-α]indol-7(6H)-one from Step 6 in MeOH (0.3 M) was added NaBH4 (1 equiv.) portionwise. After stirring for 1 h at 0° C., the reaction mixture was poured into an equal volume of saturated aqueous solution of NH4Cl and extracted (2×) with EtOAc. The combined organic layers were washed with brine, dried with MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (10:90 to 60:40) to give the title compound (98%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=O)=[O:8])=[CH:5][CH:4]=1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH:7]([OH:8])[CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]2[N:20]2[CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=1
Reactant: O=C1CCCCC1C(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1CNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: OC(c1ccc(C(F)(F)F)cc1)C1CCCCC1N1CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[4-(trifluoromethyl)benzoyl]cyclohexanone, 5.4 g, 0.02 mole, with 2.28 g, 0.04 mole of azetidine and 25 mg of p-toluenesulfonic acid in 50 ml of benzene was refluxed for 17 hr using a Soxhlet device containing 50 g of 3A molecular sieves. The resulting solution was evaporated, the residue was dissolved in 75 ml of ethanol and hydrogenated in the presence of 0.5 g of platinum dioxide (PtO2) at an initial pressure of 54 psig for 1.5 hr. The mixture was filtered, cooled in ice and treated with 5.4 g of sodium borohydride (NaBH4) and stirred at room temperature for 16 hr. The mixture was then evaporated, the residue taken up in a water/diethyl ether mixture, the ether extract being separated and washed with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. Trituration of the residue with diethyl ether gave 0.76 g (plus filtrate) of the N-[2-[[4-(trifluoromethyl)phenyl](hydroxy)methyl] cyclohexyl]azetidine as a colorless solid, mp 163°-165° C., which was raised to 167°-168° C. on recrystallization from methanol. The UV λmax(ε)216(9,550), 252(382), 258(442), 263(411), 258(307). The IR and Mass spectral analyses were consistent. The NMR (CDCl3) indicated that the product contained a mixture of two diastereoisomers. δ7.6-7.4(m,5H,aromatic) 5.1(m,1H, HC--O), 2.7(m,1H, CH--N), 2.2-1.9(m,3H, CH--C--O and C--CH2 --C of azetidine), 1.9-0.9(m,8H, CH2 's).
Reaction SMILES: C(O[N:5]=[C:6]([C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Br:15])=[CH:10][C:9]=1[OH:16])[CH3:7])(=O)C.CC(=O)OCC>C(Cl)Cl.CCCCCC>[Br:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[C:6]([CH3:7])=[N:5][O:16][C:9]=2[CH:10]=1
Reactant: CC(=O)ON=C(C)c1cc(C)c(Br)cc1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(C)noc2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
Neat 2-(4-bromo-2-hydroxy-5-methylphenyl)-1-azaprop-1-enyl acetate (103) (0.5 g, 1.748 mmol) was heated at 175° C. for 2 h then at 100° C. for 1 h. After cooling down to r.t., the dark brown solid was dissolved in DCM and subjected to silica gel flash chromatography (0-40% B, A: hexane; B: 50% EA in hexane) to give 6-bromo-3,5-dimethylbenz[d]isoxazole (104) (92 mg, yield: 23.3%; purity>95%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:20][OH:21])=[C:13]2[C:18]=1[N+:17]([O-:19])=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[N+:17]([O-:19])=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]([CH:20]=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cccc2c(CO)ccc(OCc3ccccc3)c21
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(OCc2ccccc2)c2c1ccc[n+]2[O-]
Reaction time: 1 h
Yield: 54.3 %

Procedure:
8-(Benzyloxy)-5-(hydroxymethyl)quinoline N-oxide (3) (0.5 g, 1.78 mmol) was added to a solution of pyridinium chlorochromate (0.42 g, 1.95 mmol) in methylene chloride (10 ml) and the solution was stirred for 1 h, then TLC indicated that the reaction was completed. The solution was then washed with water, dried over Na2SO4, and evaporated. The residue was passed through a short silica gel column using dichloromethane-methanol mixture (100:3) to elute the product. Evaporation gave a yellow solid (4) (0.27 g, 55%): mp 118°-121° C.; Rf 0.64 (chloroform-methanol, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].N.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[Cl:23])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1O
Agent: N
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 6-chloro-4-hydroxy-2-isopropyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 20 step A, 2 g, 7.15 mmol) and phosphorous oxychloride (10 ml) under nitrogen was refluxed for 1 h. After cooling the reaction mixture to room temperature, the mixture was poured onto ice cold water and the pH of the aqueous phase was adjusted to 7 with aqueous ammonia solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 5-10% EtOAc in hexane) to afford pure 4,6-dichloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (1.3 g, 61%) as pale yellow solid. LC-MS: 298 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(Oc2ccccc2)cc1N
Product: COc1ccc(Oc2ccccc2)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-phenoxyaniline (62 mg, 0.290 mmol) similar to Example 58 and isolated as a tan solid (46 mg, 54%). 1H NMR (CDCl3): 9.57 (dd, J=1.1, 2.3 Hz, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 8.42-8.38 (m, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.38-7.31 (m, 2H), 7.25-7.21 (m, 1H), 7.11 (t, J=1.2 Hz, 1H), 7.09-7.03 (m, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.82 (dd, J=2.7, 8.7 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][O:14][NH2:15])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.O=[C:19]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14]/[N:15]=[C:19](/[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CON)cc1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CCCCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxy)benzyloxyamine (3.10 g), ethyl 8-oxo-8-phenyloctanoate (6.32 g), acetic acid (2.07 ml), sodium acetate (1.98 g) and ethanol (80 ml) was heated under reflux for 20 hours. The reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (60 ml), tetrabutylammonium fluoride trihydrate (3.98 g) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (3.55 g, yield 77%) as a colorless oil from an ethyl acetate-hexane (2:7, v/v)-eluted fraction.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[NH:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>CN(C)C=O>[CH2:28]([N:12]([C:5]1[CH:6]=[C:7]([CH3:11])[C:8]([Cl:10])=[CH:9][C:4]=1[Br:3])[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N(Cc2ccccc2)C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(Br)cc1Cl
Temperature: 25 °C

Procedure:
Sodium hydride (193 mg, 8.06 mmol) was added to a stirred solution of tert-butyl 4-{[(2-bromo-4-chloro-5-methylphenyl)amino]carbonyl}piperidine-1-carboxylate 2-5 (2.90 g, 6.72 mmol) in N,N-dimethylformamide (40 mL) at approximately 0° C. The reaction mixture was warmed to ambient temperature and aged for 30 min. Benzyl bromide (1.20 mL, 10.1 mmol) was added and after 1 h, the reaction mixture was poured into aqueous 2 N hydrochloric acid and extracted with diethyl ether. The organic phase was washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (gradient elution; 0%-20% acetone/methylene chloride as eluent) afforded 2-6 as a white solid.