Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:14]=3)[CH:10]=[C:9]([C:29]([F:32])([F:31])[F:30])[N:8]=2)[CH:6]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[F:28][C:25]([F:26])([F:27])[CH2:24][O:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:29]([F:31])([F:30])[F:32])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:37]4[CH:38]=[CH:39][C:34]([NH2:33])=[N:35][CH:36]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.54) (0.268 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.056 g, 20%). MS (ISP) 549.2 [(M+H)+]; mp 285° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)[OH:4].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:25][C:2]([F:1])([F:24])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:28]1[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=1)[N:19]=[CH:18]2)[OH:4]
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Reactant: c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cn1cc(C(O)(c2ccc3c(cnn3-c3cccnc3)c2)C(F)(F)F)c2ccccc21
Temperature: 25 °C
Yield: 23.7 %

Procedure:
A mixture of 70 mg (0.20 mmol) of 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol, 65 mg (1.97 mmol) of 3-pyridyl boronic acid ester, 55 mg (0.3 mmol) of copper acetate and 50 μL (0.62 mmol) of pyridine in dry dichloromethane was stirred at room temperature. Oxygen gas was bubbled into the solution for 5 minutes and the mixture was stirred in a sealed tube. The reaction was monitored by LC-MS indicating partial conversion to product at 3 hours. The mixture was stirred overnight for 18 hours and then diluted with brine and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and absorbed onto silica gel and first purified by Combiflash chromatography using a 0-80% EtOAc-hexanes gradient and then by preparative TLC using 20% EtOAc-hexanes. Crystallization from ether-hexanes to gave 20 mg (26%) of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[S:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([OH:24])(=[S:23])[CH3:22]>C(OCC)C>[C:21]([S:23][CH:14]([CH2:13][C:11](=[S:12])[C:10]1[CH:19]=[CH:20][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:24])[CH3:22]
Reactant: CC(O)=S
Reactant: COC(=O)C=CC(=S)c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)C(CC(=S)c1ccc(-c2ccccc2)cc1)SC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2.98 g of methyl 3-(4-phenylthiobenzoyl)acrylate in 30 ml of diethyl ether was added 0.8 ml of thioacetic acid, and the resulting mixture was stirred at room temperature for 5 hours. The reaction solution was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified by silica gel column chromatography (eluent: hexane-diethyl ether) to give 3.73 g of methyl 2-acetylthio-3-(4-phenylthiobenzoyl)propionate as an oil.
Reaction SMILES: NC1C=CC(Br)=CC=1C1C([C:15]([C:17]2[C:22]([C:23]3[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=3[NH2:30])=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=NC=CC=1.[BH4-].[Na+].C[OH:34]>>[NH2:30][C:24]1[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]=1[CH:22]([OH:34])[C:17]1[CH:15]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Nc1ccc(Br)cc1-c1cccnc1C(=O)c1ncccc1-c1cc(Br)ccc1N
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Nc1ccc(Br)cc1C(O)c1ccccn1
Reaction time: 0.5 h

Procedure:
In 100 ml of methanol was dissolved 10 g of 2-amino-5-bromophenyl-2-pyridylketone. To the solution was added 1.7 g of sodium borohydride and stirred for 30 minutes. The solvent methanol was evaporated off under reduced pressure. The residue was treated with an aqueous solution of hyrochloric acid. The decomposed residue was then neutralized with 200 ml of a sodium bicarbonate aqeous solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 2-amino-5-bromo-α-(2-pyridyl)benzyl alcohol (9.0 g) as prisms, m.p. 104°-105° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH:6]=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:34][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCCC1>[O:14]1[CH2:15][CH2:16][CH:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH2:34])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Brc1ccc2c(ccn2C2CCOCC2)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc2c(ccn2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
Compound 88 (140 mg, 0.500 mmol), tris(dibenzylideneacetone)dipalladium (0) (45.7 mg, 0.050 mmol) and anhydrous tetrahydrofuran (15 mL) were charged to a dry argon purged flask fitted with magnetic stir bar and condenser. A solution of tri-tert-butylphosphine (10 wt % in hexane, 202.3 mg, 0.100 mmol) is added followed by dropwise addition of a 1M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1.500 ml, 1.500 mmol) and mixture refluxed for a period of 45 minutes. The mixture was cooled to room temperature then to 0° C., quenched with 1M HCl (10 mL) and stirred for 15 minutes. The solution was diluted with ethyl acetate and conc. NH4OH added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (EtOAc: Hexanes, 7:3) to yield a pale brown solid 89 (96 mg, 88.8%). 1H NMR (DMSO-d6) δ 1.80-1.99 (m, 4H), 3.53 (dt, 2H, J=11.4, 2.9 Hz), 3.95-3.99 (m, 2H), 4.39-4.50 (m, 1H), 4.55 (brs, 2H), 6.14 (d, 1H, J=4.1 Hz), 6.52 (dd, 1H, J=8.8, 2.1 Hz), 6.68 (d, 1H, J=1.9 Hz), 7.23 (d, 1H, J=8.6 Hz), 7.27 (d, 1H, J=3.2 Hz); ESI-MS (m/z, %): 217 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]1[CH3:49].C(Cl)Cl.CO>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:41][CH2:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][N:44]3[CH3:49])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCCC1CCCl
Reactant: Oc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN1CCCCC1CCOc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Yield: 6.7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(4-hydroxybenzyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.500 g, 1.14 mmol) in DMF (5 ml) was added potassium carbonate (0.236 g, 1.7 mmol) and the resulting mixture allowed to stir for twenty minutes. To the reaction mixture was added 2-(2-chloroethyl)-N-methyl piperidine (0.271 g, 1.37 mmol). The reaction was allowed to stir overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by radial chromatography (100% CH2Cl2, then CH2Cl2/MeOH, 95:5) to yield the title compound (0.043 g, 7% yield): ES-MS (m/z) 565 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].OO.F[B-](F)(F)F.[H+].S([O-])([O-])=O.[Na+].[Na+]>O.C(#N)C.C1CCCCC1>[CH:12]1([O:15][N:3]2[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]2([CH3:11])[CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:9]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: O=C([O-])[O-]
Agent: F[B-](F)(F)F
Agent: O=S([O-])[O-]
Agent: OO
Solvent: O
Solvent: CC#N
Solvent: C1CCCCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Temperature: 56 °C
Reaction time: 8 h

Procedure:
A mixture of 5.21 g (33.1 mmol) of 2,2,6,6-tetramethylpiperidin-4-ol, 0.015 g (0.142 mmol) of anhydrous sodium carbonate, 15 ml of water, and 15 ml of acetonitrile is heated to 56° C. A solution of 6.5 g (96 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture over 1.5 hours while the temperature is brought to and maintained at 80° C. After the peroxide is added, the reaction mixture is heated at 80° C. for 3 hours, then cooled slowly to 50° C. over 1.75 hours. The mixture is kept at ambient temperature overnight. A solution of 0.184 g (0.662 mmol) of ferrous sulfate heptahydrate and 0.664 g (3.6 mmol) of 48% tetrafluoroboric acid in 2 ml of water is added to the reaction mixture, followed by 30 ml of cyclohexane and 24 ml of acetonitrile. The reaction mixture is heated to 50° C. A solution of 8.7 g (128 mmol) of 50% aqueous peroxide is added to the reaction mixture dropwise over 4.5 hours while the temperature is brought to and maintained at 62° C. After the peroxide is added, the reaction mixture is stirred at reflux for 1 hour. Upon cooling, residual peroxide is decomposed by the addition of aqueous sodium sulfite solution. Work-up with ethyl acetate and purification by flash chromatography afford 2.03 g (24% overall yield) of a white solid. GC analysis shows that the reaction product has a retention time identical to that of an authentic sample of the title compound.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:42])[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[C:35]([O:37]C(C)(C)C)=[O:36])=[O:29])[CH:22]=2)[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:35]([C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[C:28](=[O:29])[CH2:27][O:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:6]([OH:7])=[O:5])=[O:42])[CH:25]=[CH:24]2)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccc2cc(OCC(=O)N3CCC[C@@H]3C(=O)OC(C)(C)C)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CCCN1C(=O)COc1ccc2cc(OCC(=O)N3CCC[C@@H]3C(=O)O)ccc2c1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of 75 mg (0.13 mmol) (R)-1-[[6-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-naphthalen-2-yloxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 18 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 60 mg (98%) of the title compound as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH:5]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:23])[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([C:35](=[O:40])[C:36]([CH3:39])([CH3:37])[CH3:38])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:25]=2)[C:4]([OH:41])=[O:3])=[CH:8][CH:9]=1)=[O:23]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)c1cccc(N(CC(C)C)C(=O)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CN(C(=O)C(C)(C)C)c1cccc(C(Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)c1

Procedure:
Thus obtained 3-[4-(2,6-dichlorobenzoyl amino) phenyl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]phenyl}propionic acid ethyl ester (1.7 g, 2.8 mmol) was dissolved in a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL), and added with a 2 mol/L aqueous sodium hydroxide solution (15 mL, 30 mmol). The solvent was evaporated under reduced pressure, and the resultant residue was added with water to solubilize, and washed with diethyl ether. The separated aqueous phase was added with a 1 mol/L hydrochloric acid solution so as to adjust pH of the solution to as low as below 4. The solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure so as to remove the solvent, to thereby obtain 3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]phenyl}propionic acid (yield: 1.6 g, yield ratio: 99%) as a light-yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3C=O)[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:45])[CH2:24][CH:23]2[OH:36])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3O)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-formylphenyl)piperidin-3-ol (1.38 g, 2.8 mmol) obtained in Step 1 of Example 61 in 50 ml of chloroform, was added 486 mg of m-chloroperbenzoic acid (5.6 mmol). The reaction mixture was stirred for about 2 hours at room temperature. The resulting organic layer was washed with the solutions of sulfurous acid and sodium bicarbonate, dried on sodium sulfate. The resulting ester residue was dissolved in 100 ml of methanol and was added a drop of concentrated hydrochloride thereto. The reaction mixture was stirred for about 1 hour, was added sodium bicarbonate (0.5 g) thereto. The reaction mixture was concentrated. The resulting residue was purified with column chromatography to give 1.0 g of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[F:15])=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1c(F)ccc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1c(F)ccc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.7 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (6.0 g, 15.3 mmol), morpholine (13.3 mL, 153 mmol), copper(I) iodide (874 mg, 4.6 mmol), N,N-dimethylglycine hydrochloride (1.3 g, 9.2 mmol) and potassium carbonate (8.5 g, 61.2 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (4.8 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27FN2O3 (M+H)+: 399.48, observed: 399.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:16][O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.5 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde was dissolved in 20 ml N,N-dimethylformamide. 1.0 g of sodium hydride (60% oily) was added, followed by stirring at room temperature for 30 minutes. 1.8 ml methyl iodide was added dropwise thereinto, follwed by reacting for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 3.0 g of 2-methoxy-4-(trifluoromethyl)benzaldehyde as a colorless oil from fractions eluted with hexane-ethyl acetate (9:1).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:21])=[C:5]([C:18]([O-:20])=[O:19])[CH:6]([CH3:17])[C:7]=1[C:8]([O:10]CC(C#N)C#N)=[O:9]>CC(C)=O.[OH-].[Na+].O>[CH3:21][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]([CH3:17])[C:5]=1[C:18]([OH:20])=[O:19]
Reactant: CC1=C(C(=O)[O-])C(C)C(C(=O)OCC(C#N)C#N)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(C(=O)O)C(C)C(C(=O)O)=C(C)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
In 12 0 ml of acetone containing 240 ml of 1N sodium hydroxide was dissolved 12 . 7 g of the dicyanoethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate obtained in (1) above, and the solution was stirred at a room temperature for 2 hours. After the reaction, the reaction mixture was diluted with 240 ml of water and washed twice with dichloromethane. The separated aqueous layer was rendered acidic (pH=1-2) with concentrated hydrochloric acid under ice-cooling and stirred for 3 hours- The thus formed crystal was collected by suction filtration. The filtrate was dried under reduced pressure to yield 4.55 g (yield: 54%) of 1,4-dihydro- 2,4,6-trimethyl-3,5-pyridinedicarboxylic acid as a pale yellows powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:36][CH2:35][CH2:34][CH:33]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:35]4[O:36][CH2:32][CH2:33][CH:34]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C1=C(c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)OCC1
Yield: 72.2 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 5-(tributylstannyl)-2,3-dihydrofuran (250 mg, 0.70 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (10 ml) and heated at reflux under nitrogen for 2 hr (Procedure B). The solvent was removed from the cooled reaction under vacuum, and the residue was suspended in 1:1 iso-hexane/ethyl acetate and filtered. The solvent was removed from the filtrate under vacuum to give the product (140 mg, 72%) as a yellow solid; δH [2H6]-DMSO 9.88 (1H, b, NH), 8.62 (1H, s, 5-H), 8.50 (1H, s, 2-H), 8.05 (1H, d, 7-H), 7.67 (3H, m, 8-H, 2′-H, 6′-H), 7.55-7.29 (5H, m, 5×Ph-H), 7.03 (2H, m, 3′-H, 5′-H), 5.81 (1H, s, 3″-H), 5.12 (2H, s, PhCH2), 4.52 (2H, t, 5″-H2), 2.88 (2H, t, 4″-H2); m/z 396 (M+1)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18].O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:11][CH:12]=2)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(OC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In pyridine was dissolved 2 g of p-octyloxyphenol, and a solution of p-acetoxybenzoic acid chloride in chloroform was added dropwise to the thus-obtained solution and the mixture was stirred at room temperature for 3 hours. Water was added to the thus-obtained solution and the mixture was extracted with chloroform, and the extract was washed with a 0.5N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium chloride, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of sodium chloride in succession, followed by concentration. The concentrate was recrystallized from n-hexane to obtain 2.35 g of 4-octyloxyphenyl 4-acetoxybenzoate. The product was dissolved in a liquid mixture comprising tetrahydrofuran and methanol at a volume ratio of 10/1, 6.2 ml of a 1N aqueous solution of lithium hydroxide was added to the solution, the mixture was stirred at room temperature for 1 hour, and the mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then, the liquid was dehydrated on anhydrous magnesium sulfate and concentrated, and the concentrate was recrystallized from ethyl acetate to obtain 1.1 g of 4-octyloxyphenyl 4-hydroxybenzoate.