Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:13][C:14]([C:23]4[N:27]=[CH:26][N:25]([CH:28]5[CH2:33][CH2:32][CH2:31][CH2:30][O:29]5)[N:24]=4)=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>COCCOC.O>[CH3:11][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[CH:7][N:6]2[C:8]=1[C:12]1[S:13][C:14]([C:23]2[N:27]=[CH:26][N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc2ccc(Br)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2ccc(-c3cnn(C)c3)cn2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 95 °C
Reaction time: 12 h
Yield: 40.8 %

Procedure:
To a suspension of 6-bromo-2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}imidazo[1,2-a]pyridine (157 mg, 0.3 mmol) obtained in Example 117-B(i) in DME (10 mL) and water (2 mL), were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (93.6 mg, 0.45 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (24.5 mg, 0.03 mmol) and cesium carbonate (293 mg, 0.9 mmol) under a nitrogen atmosphere, and the mixture was stirred at 95° C. for 12 h. The reaction mixture was allowed to cool to rt, and then were added water (40 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (40 mL) and then a 1:1 mixture of EtOAc and THF (60 mL×2), and the combined organic layers were dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with THF to give the title compound (64.0 mg, 41%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:32]([NH:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[S:33])=[C:18]([CH3:24])[CH:17]=1
Reactant: NN1CCCCC1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(NC(=S)NN4CCCCC4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 12.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 7 hr. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 14 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (9 mg, yield 12%).
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][CH2:5][NH2:6].CC1C=CC(S(O[CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:25]=3)[O:20]2)(=O)=O)=CC=1.FCCCN>>[F:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:25]=2)[O:20]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: NCCCF
Agent: Cl
Product: CS(=O)(=O)c1ccc2c(c1)OC(CNCCCF)CC2

Procedure:
3-fluoropropan-1-amine HCl-salt (0.178 g, 1.52 mmol) was basified on a SCX-3 ion exchange column (TEA/MeOH). [7-(methylsulfonyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.020 g, 0.0561 mmol) and 3-fluoropropan-1-amine (0.15 M in MeOH/TEA:4/1, 5 ml) was heated under microwave radiation at 120° C. for 1 h 20 min. MS m/z (rel. intensity, 70 eV) 301 (M+, 3), 131 (8), 91 (9), 90 (bp), 86 (18), 70 (18).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([O-])=[O:25])=[CH:22][N:21]=[C:20]([S:27][CH3:28])[N:19]=3)=[CH:13][C:12]=2[F:29])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[Na+].S(Cl)([Cl:33])=O.[F:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:37]=1[NH2:38].Cl>C1C=CC=CC=1.O>[ClH:33].[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:23]([C:24]([NH:38][C:37]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:36]=4[F:35])=[O:25])=[CH:22][N:21]=[C:20]([S:27][CH3:28])[N:19]=3)=[CH:13][C:12]=2[F:29])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: O=S(Cl)Cl
Reactant: Nc1ccc(F)cc1F
Reactant: CSc1ncc(C(=O)[O-])c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CSc1ncc(C(=O)Nc2ccc(F)cc2F)c(Nc2ccc(Oc3ccnc(C(N)=O)c3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a suspension of sodium 4-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-2-(methylthio)pyrimidine-5-carboxylate (2.94 g, 6.72 mmol) in benzene (75 mL) was added thionyl chloride (4.9 mL, 62 mmol) and the solution was refluxed for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was treated with benzene and again concentrated in vacuo to remove the residual thionyl chloride. The resulting solid was taken up in THF (75 mL) and was treated with 2,4-difluoroaniline (2.6 g, 20.2 mmol). After stirring overnight the mixture was acidified with dilute aqueous HCl, was diluted with water (400 mL), and filtered. The resulting solid was purified by repeated trituration with methanol or ethyl acetate to give the amide (1.69 g, 45%) as a solid. MS(ESI+) m/z 527 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][O:24]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc[nH]c2n1
Reactant: C1=COCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2ncn(C3CCCCO3)c2n1
Temperature: 70 °C
Reaction time: 6 h
Yield: 78.9 %

Procedure:
2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purine (600 mg, 1.89 mmol) was dissolved in EtOAc (25 mL) under argon. After addition of 3,4-dihydro-2H-pyrane (172 μl, 1.89 mmol), trifluoro acetic acid anhydride (27 μl, 188 μmol), and trifluoro acetic acid (319 μl, 4.15 mmol), the reaction mixture was heated to 70° C. After 6 hours, 3,4-dihydro-2H-pyrane (1.44 mL, 15.7 mmol) was added. The reaction was then stirred for 22 hours at 70° C. and then cooled to room temperature. 500 mg of solid Na2CO3 was added and stirring continued for 10 minutes. The reaction mixture was diluted with EtOAc, the organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (40 g SiO2, heptane/EtOAc in a gradient from 9/1 to 2/3) to give the product as a foam (600 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(OCc2cc(F)ccc2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccc(OCc2cc(F)ccc2F)cc1
Reaction time: 3 h

Procedure:
To a solution of Ethyl 4-(4-(2,5-Difluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 16.51 g, 47.4 mmol) in abs ethanol (100 ml) was added 1N NaOH (40 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified with 1 M HCl and concentrated in vacuo. The crude mixture was taken in chloroform and washed with water. The aqueous layer was washed one more time with chloroform. The combined organic layers were dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7].S(Cl)(Cl)=O.[CH3:15]O>>[ClH:1].[CH3:15][N:4]([CH2:3][CH2:2][Cl:1])[C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]
Reactant: CO
Reactant: O=C(O)[C@H](CS)NCCCl
Solvent: O=S(Cl)Cl
Product: CN(CCCl)[C@@H](CS)C(=O)O
Product: Cl
Temperature: 0 °C
Yield: 76.1 %

Procedure:
39 g (0.21 mol) 2-chloroethyl cysteine was dissolved with 500 ml anhydrous methanol, and cooled with an ice bath. 80 ml (1.1 mol) thionyl chloride was slowly added dropwise to the solution in the ice bath. Thereafter, the reaction mixture was warmed and reacted at room temperature for 24 hours. After removing the solvent under reduced pressure, the reaction product was dissolved with anhydrous methanol (200 ml×2) and then evaporated to dryness, to remove redundant thionyl chloride. The obtained solid was recrystallized with 50 ml anhydrous methanol and 160 ml anhydrous ethyl ether, resulting in 37.5 g of a white crystal, yield 76.1%.
Reaction SMILES: [K].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[N:23]=[CH:24][S:25][CH:26]=1)=[O:12])([OH:4])=[O:3].O.Cl.[CH2:29]([NH:41][C:42]([NH2:44])=[NH:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)(C)C>[CH2:29]([NH:41][C:42]([NH2:44])=[NH2+:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[N:23]=[CH:24][S:25][CH:26]=1)=[O:12])([OH:4])=[O:3]
Reactant: CCCCCCCCCCCCNC(=N)N
Agent: Cl
Agent: O=C(O)CCCCCOC(=O)n1c(-c2cscn2)nc2ccccc21
Agent: [K]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCNC(N)=[NH2+]
Reaction time: 0.75 h

Procedure:
A solution of 1.22 g. (3.0 mmoles) of 1-(5-carboxypentyloxycarbonyl)-2-(4-thiazolyl)-benzimidazole potassium salt in 10 ml. of water is added gradually to a stirred solution of 3.3 mmoles of n-dodecylguanidine hydrochloride in 20 ml. of water containing isopropanol. The product precipitates immediately and is stirred for 45 minutes, filtered and washed with water, methanol and acetone affording 1.19 g. of 1-(5-carboxypentyloxycarbonyl)-2-(4-thiazolyl)-benzimidazole n-dodecylguanidinium salt,
Reaction SMILES: ClC1C=CC=CC=1.C([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:28])=[C:15]([NH:17][C:18](=[O:27])[CH:19]=[CH:20]C2C=CC=CC=2)[CH:16]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCC>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:28])=[C:15]2[C:16]=1[CH:20]=[CH:19][C:18](=[O:27])[NH:17]2
Reactant: CCOc1ccc(C)c(NC(=O)C=Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(O)c2ccc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Chlorobenzene (28.6 ml) was added to N-(5-ethoxy-2-methylphenyl)cinnamamide (3.9 g, 14.8 mmol). While stirring the mixture in a hot bath (125° C.), aluminum chloride (9.2 g, 69.0 mmol) was added to the mixture, followed by stirring for 30 minutes. After the mixture was cooled, it was poured into ice-water, to which n-hexane was added. Precipitated crystals were collected. The crystals were dissolved in chloroform-methanol (4:1). The solution was dried and condensed. The resultant residue was washed with chloroform, then dissolved in chloroform-methanol (4:1) again. The solution was condensed again. The residue was washed with chloroform and then dissolved in methanol. The resultant solution was treated with activated carbon. 2.4 g of 5-hydroxy-8-methylcarbostyril was obtained as colorless crystals (92.7%).
Reaction SMILES: Br[Si](C)(C)C.C([O:8][P:9]([C:14]1[C:15](=[O:29])[NH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][C:20]([S:24](=[O:27])(=[O:26])[NH2:25])=[C:19]([Cl:28])[CH:18]=2)(=[O:13])[O:10]CC)C>C(#N)C>[Cl:28][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([P:9](=[O:8])([OH:13])[OH:10])[C:15](=[O:29])[NH:16]2)=[CH:21][C:20]=1[S:24](=[O:26])(=[O:27])[NH2:25]
Reactant: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: NS(=O)(=O)c1cc2cc(P(=O)(O)O)c(=O)[nH]c2cc1Cl

Procedure:
3.33 ml (25.3 mmol) of bromotrimethylsilane are added to a suspension of the compound obtained in Step F (1.0 g, 2.53 mmol) in 30 ml of anhydrous acetonitrile. The batch is stirred at reflux for 1 hour and evaporated to dryness. The residue is dried in vacuole and is taken up in methanol. The suspension is stirred for 30 minutes, becoming thicker and thicker. After filtering off the white precipitate and rinsing with a little methanol and then ether, the title product is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[C:20]=1[C:21]([O:23]CC)=O.Cl.[C:30]([O:34][C:35](=[O:38])[CH2:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[C:20]=1[C:21]([NH:37][CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[O:23]
Reactant: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
DIPEA (0.05 mL, 276 μmol) was added to a stirred mixture of ethyl 5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroquinoline-6-carboxylate (24 mg, 92 μmol) and glycine tert-butyl ester hydrochloride (38 mg, 230 μmol) in 1,4-dioxane (3 mL). The reaction mixture was then stirred at 75° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the title compound as a crystalline white solid (15 mg, 47%). MS (m/z)=347 (M+H)+. Calculated for C18H22N2O5 346.4.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=[CH2:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=[CH2:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: C=Cc1cccc(-n2c(C)nc(CCCC)c(Cc3ccc(-c4ccccc4C#N)cc3)c2=O)c1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=Cc1cccc(-n2c(C)nc(CCCC)c(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2=O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogen carbonate (0.71 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(3-vinylphenyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.19 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.06 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.056 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.088 g, 40%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:16][CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=1
Reactant: Cn1c(CN2C(=O)c3ccccc3C2=O)nc(-c2ccncn2)cc1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1c(CN)nc(-c2ccncn2)cc1=O
Yield: 54.3 %

Procedure:
To a solution of 5.3 g (15.26 mmol) of 2-(1-Methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-ylmethyl)-isoindole-1,3-dione in 40 ml of ethanol was added 2.37 mL (76.30 mmol) of hydrazine hydrate and the resulting mixture was heated under reflux for 3 h. The mixture was filtered and the solid obtained was triturated with dichloromethane for 24 h, filtered, and the resulting filtrates were evaporated to dryness, the residue was triturated with diethyl ether and filtered to give 1.8 g of pure compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH2:12][N:13]=[N+]=[N-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[CH2:12][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NCc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc(OCc2ccccc2)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Benzyloxybenzyl azide, as described above in Step A, (5.0 g, 20.9 mmol) was dissolved in dry THF (100 mL) and the solution was cooled to −70° C. Lithium aluminum hydride (31.4 mL of a 1.0 M solution in THF, 31.4 mmol) was added dropwise, then the reaction mixture was warmed to 0° C. and stirred for 30 min. The reaction was quenched with EtOAc (1.2 mL), then water (1.2 mL), then 15% NaOH (1.2 mL), and finally water (3.6 mL). The resulting mixture was filtered, concentrated under reduced pressure and purified by flash column chromatography on silica, eluting with CH2Cl2-3% MeOH −0.3% NH40H, to yield the titled product as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].[Cl:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:17][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:16])[CH2:6][CH2:7][N:8]2[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)N1CCC(=O)c2c1ccc(O)c2Cl
Yield: 91.5 %

Procedure:
A solution of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.643 g) and N-chlorosuccinimide (1.068 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 18 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was recrystallized from chloroform to give 5-chloro-6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.74 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH3:10].C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.[OH-].[Na+]>C1COCC1>[CH3:10][S:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[B:16]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: CSc1cc(F)ccc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1cc(F)ccc1B(O)O
Temperature: -78 °C
Yield: 83.1 %

Procedure:
Dissolve 1-bromo-4-fluoro-2-methylsulfanyl-benzene (22 g, 99.6 mmol) in dry THF (500 mL) and cool to −78° C. under nitrogen. Add butyl lithium (2.5M in hexanes, 48 mL, 120 mmol) slowly and stir for 10 minutes after complete addition. Add trimethyl borate (22 mL, 200 mmol) and warm to room temperature. Pour into 0.1 M NaOH and extract with ether. Acidify the aqueous layer to pH 2 with concentrated HCl. Extract with ether, rry the organic layer with sodium sulfate, filter and concentrate in vacuo to yield 15.4 g (83%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:16]=2[C:17]([Cl:27])=[N:18][CH:19]=[N:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:34]([NH2:35])=[C:33]2[O:36][CH2:37][O:38][C:32]2=[CH:31][CH:30]=1>>[ClH:27].[ClH:28].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:16]=2[C:17]([NH:35][C:34]2[C:29]([Cl:28])=[CH:30][CH:31]=[C:32]4[O:38][CH2:37][O:36][C:33]=24)=[N:18][CH:19]=[N:20]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(Cl)ncnc2c1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Product: Cl
Yield: 151.4 %

Procedure:
Using an analogous procedure to that also described in the portion of Example 31 that is concerned with the preparation of starting materials, 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-chloro-7-methoxyquinazoline (0.14 g) and 6-chloro-2,3-methylenedioxyaniline (0.064 g) were reacted to give 5-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(6-chloro-2,3-methylenedioxyanilino)-7-methoxyquinazoline dihydrochloride (0.17 g); NMR Spectrum: (DMSOd6) 1.42 (s, 9H), 1.8–2.0 (m, 2H), 2.0–2.15 (m, 2H), 3.0–3.2 (m, 2H), 3.85–3.95 (m, 2H), 3.99 (s, 3H), 5.1 (m, 1H), 6.96 (d, 1H), 7.05 (d, 1H), 7.12 (s, 1H), 7.15 (d, 1H), 8.78 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 529 and 531.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20]([O:22]CC)=[O:21])[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:20]([OH:22])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.8 %

Procedure:
To a solution of ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 150 mg, 0.44 mmol) in MeOH (0.7 mL) and THF (1.7 mL) was added LiOH (13 mg, 0.54 mmol) in H2O (1.7 mL). The reaction was stirred for 14 h at ambient temperature. The crude reaction mixture was concentrated to dryness under reduced pressure. 10% HCl (aq.) (6.0 mL) was added, and the precipitate was collected and dried under high pressure to afford the title compound as a white solid (106 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.25 (s, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.63 (s, 1H), 7.58-7.41 (m, 4H), 5.37 (s, 2H). [M+H]=314.2.