Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][S:7]([C:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[S:12][C:11]=1[C:19]([O:21]C)=O)(=[O:9])=[O:8])=[O:4]>O1CCCC1>[OH:21][C:19]1[C:11]2[S:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:10]=2[S:7](=[O:9])(=[O:8])[NH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CNS(=O)(=O)c1cc(C(F)(F)F)sc1C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)c2sc(C(F)(F)F)cc2S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 82.8 g of methyl 3-[(methoxycarbonylmethyl)sulfamoyl]-5-trifluoromethyl-thiopene-2-carboxylate in 1.7 l of absolute tetrahydrofuran is cooled to 3° and treated portionwise at this temperature for 20 minutes with a total of 62.9 g of potassium tert.butylate. Thereafter, the cooling bath is removed, the viscous red paste is stirred at room temperature for 2 hours and then as much tetrahydrofuran as possible is distilled off in vacuo at a maximum temperature of 30°. The powdery residue is taken up in 1.4 l of ice-water, treated with 10 g of active carbon while stirring and suction filtered over siliceous earth. The filtrate is adjusted to pH 2-3 with about 185 ml of 3N hydrochloric acid at a maximum temperature of 5°. The mixture is stirred for 0.5 hour, whereupon the crude product which initially separates in the form of an oil crystallizes (after the addition of ether). The precipitated crude product is removed by filtration under suction, washed neutral with water, dried at 50° overnight in vacuo and recrystallized from methanol. 4-Hydroxy-3-methoxycarbonyl-6-trifluoromethyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide of melting point 168°-170° is obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CCC1=Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC1CNCCC1Cc1ccccc1
Yield: 108.6 %

Procedure:
A solution of 2.7 g of 1-benzyl-4-benzylidene-3-methyl-piperidine and 2 g of 20% palladium hydroxide on carbon in 125 mL of ethanol was shaken 3 days under 55 psi of hydrogen. The catalyst was filtered off and the solution concentrated to give 2 g of a mixture of cis and trans-4-benzyl-3-methyl-piperidine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 79 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.45 (s, 3H), 3.60-3.80 (m, 4H), 3.80-4.05 (m, 4H), 4.13 (s, 3H), 6.52 (t, J=4.5 Hz, 1H), 7.00-7.69 (m, 4H), 8.32 (d, J=4.5 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:37][N:38]([CH3:43])[CH:39]1[CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH:39]([N:38]([CH3:43])[CH3:37])[CH2:40]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C)C1CNC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CC(N(C)C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30.0 mg, 0.058 mmol) and 3-(dimethylamino)azetidine dihydrochloride (30.2 mg. 0.174 mmol) in 1,4-dioxane (1 mL) was added triethylamine (58.8 mg, 81.0 μL, 0.581 mmol). The reaction mixture was heated at 50° C. for 1 h. Upon completion of the reaction, the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C30H35ClN5O3S (M+H+): 580.2; Found: 580.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([CH:9]([CH2:15][CH:16]=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[C:5]([CH3:20])[CH:4]=1)#[N:2].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([O:29][CH3:30])[CH:23]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CCO>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]2[C:6]2[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:20])=[C:24]([O:29][CH3:30])[CH:23]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: CCOC(=O)C(CC=O)C(=O)c1ccc(C#N)cc1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)c1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C#N)cc1C
Temperature: 50 °C

Procedure:
To a solution of Intermediate C (2.5 g, 9.2 mmol) and 4-chloro-2-methoxyaniline (1.8 g, 9.2 mmol) in anhydrous EtOH (20 mL) was added PPTS (0.46 g, 0.18 mmol), and the reaction mixture was heated at 50° C. for six hours. Followed work-up procedure described in Step 1, Scheme 1 to give the desired compound, which was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:11]#[N:12].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:11]#[N:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(O)cc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Caesium carbonate (2.41 g, 7.4 mmol) was added to a solution of 3,5-dihydroxy benzonitrile (1.0 g, 7.4 mmol) in dimethylformamide (5 ml) at room temperature and the mixture stirred for 10 minutes. Benzyl bromide (0.880 ml, 7.4 mmol) was added dropwise and the mixture heated at 80° C. for 30 minutes. The solvent was removed in vacuo, the residue treated with water (10 ml), acidified with aqueous hydrochloric acid (2M) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with water (2×10 ml), brine (10 ml), dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/pentane (20:80 to 50:50) to afford the title compound as a white solid in 26% yield, 445 mg.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](/[C:8](=[CH:14]/[N:15](C)C)/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.Cl.[O:24]1[CH2:30][CH:29]([NH:31]N)[CH2:28][O:27][CH2:26][CH2:25]1>C(#N)C.O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[N:31]([CH:29]3[CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:30]3)[N:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: NNC1COCCOC1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of (Z)-ethyl 2-(4-bromo-2-nitrobenzoyl)-3-(dimethylamino)acrylate (642 mg) in acetonitrile (8 mL) was added a solution of (1,4-dioxepan-6-yl)hydrazine hydrochloride (341 mg) obtained in Preparation Example 16 in water (2 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and further stirred at 50° C. for 9.5 hours. The reaction mixture was returned to room temperature and partitioned by adding ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were sequentially washed with the saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/heptane, 20 to 33%) to give the title compound (408 mg).
Reaction SMILES: [CH2:1]([S:17](Cl)(=[O:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:21][N:22]([CH3:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30]>O1CCCC1>[CH3:31][N:22]([CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][S:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:19])=[O:18]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: CN(C)CCCCCCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)NCCCCCCCN(C)C
Yield: 33.6 %

Procedure:
650 mg (2 meq) of hexadecanesulfonylchloride are added dropwise to 744 mg (4 meq) of 7-dimethylaminoheptylamine stirring in tetrahydrofuran at 0° C. The reaction mixture is evaporated under reduced pressure (<30° C.) dried in vacuo, and chromatographed on silica gel in the system CH2Cl2 :CH3OH:NH4OH (65:25:4) and fractions 47-52 having Rf 0.9 on TLC S.G. CH2Cl2 :CH3OH:NH4OH are combined, evaporated under reduced pressure <30° C. and dried in vacuo to yield 300 mg of title compound having a m.p. of 56°-57.5° C. uncorr.
Reaction SMILES: IC.[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1.[C:39]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:21][C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([O:29][CH3:39])=[C:24]([CH3:30])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:35]=[CH:36][CH:37]=[CH:38][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c(O)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](Cc1cc(C)c(OC)c(C)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
19 μL (0.30 mmol) iodomethane were added to a solution of 100 mg (0.20 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-methoxycarbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 2 mL DMF and the mixture was stirred for 15 min at RT. Then 131 mg (0.40 mmol) Cs2CO3 was added and the reaction solution was heated to 50° C. for 3 h. The precipitate was filtered, the filtrate was evaporated down to 1 mL down and combined with 3 mL water. The precipitate was suction filtered, dried and further reacted without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][CH:30]=2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.Cl>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: Brc1ccc(-c2cnco2)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Temperature: 98 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
To a 25 mL pressure resistant vial which contained a solution of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (147 mg, 0.5 mmol) and 5-(4-bromo-phenyl)-oxazole (170 mg, 0.75 mmol) in anhydrous dioxane (4 mL) were added cesium carbonate (300 mg, 1.5 mmol) and N,N-dimethylglycine.HCl (25 mg, 0.66 mmol) at rt. The reaction mixture was flushed with argon and Copper (I) iodide (14 mg, 0.06 mmol) was added. The vial was sealed and the reaction mixture was stirred at 98° C. for 72 h. After cooling to rt, the mixture was poured onto 50 mL ice-water solution and this solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL) and dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford title product (145 mg, 65%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1>N1C=CC=CC=1>[C:1]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H]1CCC[C@@H](N)C1
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CCC[C@@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Acetic anhydride (1.20 ml, 12.7 mmol) was added to a stirred solution of cis-methyl 3-aminocyclohexanecarboxylate (0.40 g, 2.54 mmol) in pyridine (10 ml) under an atmosphere of argon and stirred for 3 h at room temperature. The excess pyridine was removed under vacuo and the resulting residue was partitioned between DCM and saturated sodium bicarbonate solution. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuo to afford cis-methyl 3-acetamidocyclohexanecarboxylate (350 mg, 69.0%) as a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:43](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]5[CH2:40][CH2:39][N:38]([CH3:43])[CH2:37][CH2:36]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)ncnc2cc1OCC1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.8 %

Procedure:
To a solution of 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-(piperidin-4-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (82.5 mg, 0.15 mmol) in 1,2-dichloroethane/N,N′-dimethylacetamide (1.3 mL, 3:1) was added 37% formaldehyde (24 mL, 0.3 mmol) and acetic acid (10 μL, 0.18 mmol). The mixture was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (48 mg, 0.23 mmol) was added in portions and the resulting mixture stirred at room temperature for 2h. Ethyl acetate and 1N sodium hydroxide were added to the mixture, the organic layer was separated and the water phase extracted three times. The organics were combined, dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) to afford 1-(3-tert-butylisoxazol-5-yl)-3-(3-(6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yloxy)phenyl)urea (57 mg, 68%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.75 (bs, 1H), 9.21 (bs, 1H), 8.55 (s, 1H), 7.57 (d, 2H), 7.37-7.26 (m, 3H), 6.96 (d, 1H), 6.47 (s, 1H), 4.07-3.99 (m, 5H), 2.83-2.79 (m. 2H), 2.17 (s, 3H), 1.93-1.76 (m, 5H), 1.39-1.35 (m, 2H), 1.27 (s, 9H); LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1[CH:20]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(=[CH:41][C:42]([O:44][CH3:45])=[O:43])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1/[CH:20]=[CH:41]/[C:42]([O:44][CH3:45])=[O:43])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H](c2cccnc2)[C@@H]1C=O
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 9.75 g (0.0292 mol) of (2S,3S,4S)-4-(t-butyldimethylsilyloxy)2-(3-pyridyl)tetrahydrofuran-3-carboxaldehyde in 120 ml of methylene chloride is added 9.75 g (0.0292 mol) of methyl (triphenylphosphoranylidene)acetate, the mixture is stirred at room temperature overnight and evaporated. The residue is triturated with ether to precipitate out most of the triphenylphosphine oxide, filtered and washed with ether. The filtrates are evaporated and the residue is purified by flash chromatography from silica gel (5×9 cm2) using methylene chloride-ethyl acetate (1:1) as eluent to give 6.77 g of methyl (E)-(2S,3S,4S)-3-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]-2-propenoate with elemental analysis: C, 62.67; H, 8.12; N, 3.86 (theory: C, 62.78, H, 8.04; N, 3.85) and optical rotation [α]D 25=+26.77 (8.9 mg/ml methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][CH:7]=[C:6]2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][N:8]=1
Reactant: COc1ccc2c(O)ncc(N3CCOCC3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(N3CCOCC3)c2c1
Yield: 18 %

Procedure:
A solution of 6-methoxy-4-morpholinoisoquinolin-1-ol (0.33 g, 1.268 mmol) in POCl3 (5 ml) was refluxed for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (10% ethyl acetate in pet ether) to get desired compound (0.065 g, 18%) as oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.18-8.16 (d, J=8 Hz 1H), 7.94 (s, 1H), 7.45-7.40 (m, 2H), 3.98 (s, 3H), 3.88-3.86 (m, 4H), 3.09-3.07 (m, 4H); MS: MS m/z 279.1 (M++1).
Reaction SMILES: [K].[Cl:2][C:3]1[C:4](=[O:29])[N:5]([C:19]2[C:26]([OH:27])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18].I[CH3:31]>CN(C)C=O>[Cl:2][C:3]1[C:4](=[O:29])[N:5]([C:19]2[C:26]([O:27][CH3:31])=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18]
Reactant: CI
Reactant: N#Cc1cc(O)c(-n2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(F)c1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1cc(C#N)cc(F)c1-n1ccc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reaction time: 2 h

Procedure:
The potassium salt of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-1(2H)-yl]-3-fluoro-5-hydroxybenzonitrile (from Step 1) (273 mg, 0.614 mmol) was stirred in 5 ml anhydrous dimethylformamide under nitrogen. Iodomethane (93 mg, 0.66 mmol) was added, and stirring continued for 2 hr. The mixture was diluted to 50 ml with ice-cold water, and the white precipitate collected by filtration. The precipitate was washed thrice with water, sucked dry under a blanket of nitrogen, and dried further in vacuo overnight (242 mg, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 7.73 (m, 2H), 7.65 (m, 2H), 7.34 (dt, J=9.90, 2.39 Hz, 1H), 7.17 (dt, J=8.75, 2.47 Hz, 1H), 6.75 (d, J=7.97 Hz, 1H), 5.37 (s, 2H), 3.84 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ−109.24 (quintet, J=7.85 Hz, 1F), −113.54 (quartet, J=9.83 Hz, 1F), −118.33 (d, J=7.77 Hz, 1F). LC/MS tr=5.40 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50° C.) ES-MS m/z 421 (M+H). ES-HRMS m/z 421.0522 (M+H calcd for C20H13ClF3N2O3 requires 421.0561).
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:15]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:26])[NH:18][C:17]([CH3:27])=[C:16]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:11][CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[C:10]([CH:15]2[C:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:17]([CH3:27])[NH:18][C:19]([CH3:26])=[C:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ncccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ncccc1O
Yield: 111.9 %

Procedure:
Diethyl 1,4-dihydro-4-(3-benzyloxypyridyl)-2,6-dimethyl-3,5-pyridine dicarboxylate (7.0 grams; 0.016 mole) was hydrogenated in three batches using 1.2 grams of 10% Palladium on carbon. Material was dissolved in 300 ml ethanol and over a period of two hours there was a drop of 44 psi. The reaction mixtures were vacuum filtered through celite and the filtrate concentrated to approximately half the volume. Crystals formed on standing were filtered and collected. Recrystallization from acetonitrile yielded 6.2 grams of yellow crystals, m.p. 238°-239° C.
Reaction SMILES: C[O:2]C1C=CC(C=CC(O)=O)=CC=1.[CH:14]1([N:20]=[C:21]=[N:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.NCCC[Si](OC)(OC)OC>>[CH:23]1([NH:22][C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CO[Si](CCCN)(OC)OC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
30 g of p-methoxycinnamic acid and 35.1 g of dicyclohexylcarbodiimide were added to a 1 L round 3-necked flask equipped with a dropping funnel and a cooler, 600 mL of toluene newly distilled from sodium ketyl was added thereto, and the resultant mixture was refluxed to yield a homogeneous solution. After about 30 minutes, 37.5 g of 3-aminopropyltrimethoxysilane was dropped over 30 minutes through the dropping funnel. The resultant reaction mixture was refluxed for 4 hours, and then toluene was removed by vacuum distillation without contacting with moisture. Dicyclohexyl urea formed in a remaining solution was removed by filtration to yield a product. The resultant product was determined using FT-IR and thin layer chromatography (TLC). Yield of the resultant product is about 40 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:18]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[C:18]([NH:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[CH:25]5)=[N:17][CH:16]=[N:15][C:14]=3[CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: Clc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-chlorobenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 8.86 (s, 1H), 7.58 (m, 9H), 7.21 (d, 1H), 6.50 (s, 1H). M.P. 190-210° C.; LC-MS: 377 (MH+); HPLC RT: 5.32 minutes.