Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[Si:14]([O:21][CH2:22][C:23]([CH3:26])([NH2:25])[CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[CH3:27]CN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11](=[O:13])[CH2:27][NH:25][C:23]([CH3:26])([CH3:24])[CH2:22][O:21][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NCC(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 30 °C
Yield: 59.2 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (2.5 g, 10.33 mmol), 1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-amine (2.52 g, 12.4 mmol), EDCI (1.97 g, 10.33 mmol), HOBt (2.8 g, 20.6 mmol) and DIPEA (2.7 g, 20.66 mmol) in dry DMF (30 mL) was heated to 30° C. for 16 hours. Then water (30 mL) was added, the formed precipitate was separated by filtration and the filter cake was washed with water (10 mL) and dried to afford 1-(2-bromo-5H-pyrrolo[3,2-b]pyrazin-7-yl)-2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-ylamino)ethanone (2.7 g, 61%) as a yellow solid. LCMS: (M+H)+=427.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH2:4][CH:3]1[CH2:12][C:13]([OH:15])=O.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:13](=[O:15])[CH2:12][CH:3]3[CH2:4][S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: O=C(O)CC1CSc2ccccc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CC2CSc3ccccc3C2=NN1c1ccc(Cl)cc1
Yield: 77.7 %

Procedure:
A mixture of 10 g of α-(2,3-dihydro-4-oxo-4H-1-benzothiopyran-3-yl)acetic acid, 12 g of 4-chlorophenyhydrazine hydrochloride and 5.5 g of sodium acetate in 200 ml of ethanol is refluxed under heating for 10 hours. The ethanol is distilled off under reduced pressure and to the residue is added 200 ml of acetic acid and the mixture is refluxed under heating for 10 hours. After the acetic acid is distilled off, the residue is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off under reduced pressure. To the precipitated crystals is added diisopropyl ether. The crystals are collected by filtration and recrystallized from acetic acid to give 11.5 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, melting at 146°-147° C., as colorless prisms.
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:3]1[O:4][C:5]2[C:10]([C:11](=[S:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: c1cc[nH]c1
Reactant: S=c1c(Br)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2ccc[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 50.4 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, pyrrole (134 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and the purified product was recrystallized from benzene/hexane to give the titled compound (57.5 mg; yield=54.0%) as ocher crystals. Melting point: 135°-136 ° C. 1H-NMR(CDCl3, δ ppm): 7.02 (s, H3), 8.51 (dd, H5), 7.56 (t, H6), 7.61-7.68 (m, H7), 7.61-7.68 (m, H8), 7.22 (hr. t, H2'), 6.44 (br. t, H3'), 6.44 (br. t, H4'), 7.22 (br. t, H5').
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[F:25]>CCOC(C)=O>[F:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Yield: 97.9 %

Procedure:
To a solution of 1-methylpiperazine (6.91 g, 69 mmol) and Et3N (6.98 g, 69 mmol) in EtOAc (60 mL) was added 1,2-difluoro-4-nitrobenzene (10.02 g, 63 mmol) dropwise with stirring and the mixture was stirred at rt overnight. The reaction mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a yellow solid (14.75 g, 98%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:7]=[CH:6][N:5]([CH3:8])[N:4]=1.[NH3:9]>>[ClH:1].[CH3:8][N:5]1[CH:6]=[N:7][C:3]([CH2:2][NH2:9])=[N:4]1
Reactant: Cn1cnc(CCl)n1
Reactant: N
Product: Cl
Product: Cn1cnc(CN)n1
Temperature: 80 °C
Yield: 92 %

Procedure:
A solution of 3-chloromethyl-1-methyl-1H-1,2,4-triazole (600 mg, 4.6 mmol) in aqueous ammonia (5 ml) was stirred and heated at 80° C. for 16 hours in a sealed tube. Upon cooling the volatiles were removed in vacuo (azeotroping with ethanol) to give the title compound (600 mg, 92%) as a colourless solid after drying under high vacuum. 1H NMR (250 MHz, d6-DMSO) δ 3.88 (3H, s), 4.04 (2H, s), 8.3 (3H, br s), 8.58 (1H, s).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](F)=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].O>C1COCC1>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:6][CH2:5][CH:4]([F:7])[F:3])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 122.5 %

Procedure:
0.6 g 60% NaH was added in portions to a solution of 1.23 g 2,2-difluoroethanol in 20 ml THF and stirred at room temperature for 15 minutes. 2.02 g (3-Chloro-4-fluoro-phenyl)-(7-fluoro-6-nitro-quinazoline-4-yl)-amine was added as a solid and the mixture was heated to 65° C. for 1 hour, then cooled to room temperature. Water was added and the THF was removed under vacuum. The mixture was sonicated and the resulting solids collected by filtration and dried under vacuum overnight to give 2.93 g of crude (3-Chloro-4-fluoro-phenyl)-[7-(2,2-difluoro-ethoxy)-6-nitro-quinazolin-4-yl]-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[S:16][CH:15]=2)[N:11]([CH3:27])[N:10]=1.[H-].[Na+].I[CH2:31][CH2:32][CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=3)[S:16][CH:15]=2)[N:11]([CH3:27])[N:10]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(O)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2scc(-c3nc(-c4c(F)cccc4Cl)nn3C)c2C)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 114.3 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-5-[5-(4-hydroxyphenyl)-4-methylthien-3-yl]-1-methyl-1H-1,2,4-triazole (97 mg, 0.2 mmol) in dry THF (2 mL) was cooled to −3° C. and treated with sodium hydride (95% suspension in mineral oil, 9 mg, 0.4 mmol). After stirring for 5 minutes, iodopropane (62 mg, 0.4 mmol) was added and the reaction was allowed to stir at room temperature for 16 hours. An additional batch of sodium hydride (9 mg, 0.4 mmol) and iodopropane (62 mg, 0.4 mmol) was added and the reaction heated to 45° C. After dilution with water (5 mL), the product was extracted with ether (3×5 mL). The combined ethereal extracts were washed with water (2×5 mL) and brine (10 mL), dried over magnesium sulphate and concentrated. Column chromatography gave the product (101 mg, 93%) as a colorless glass: 1H NMR (CDCl3) δ 7.49 (s, 1H), 7.27-7.41 (m, 4H), 7.12 (t, 1H), 6.98 (d, 2H), 4.04 (s, 3H), 3.99 (t, 2H), 2.32 (s, 3H), 1.85 (m, 2H), 1.08 (t, 3H); EI/MS 441 m/e (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12](=[CH:15]NC2C=CC=CC=2)[C:13]#[N:14])[CH:2]=1.[NH2:23][C:24]([NH2:26])=[NH:25]>>[NH2:25][C:24]1[N:26]=[C:13]([NH2:14])[C:12]([CH2:11][C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][N:23]=1
Reactant: N#CC(=CNc1ccccc1)Cc1cnc2ccccc2c1
Reactant: N=C(N)N
Product: Nc1ncc(Cc2cnc3ccccc3c2)c(N)n1
Yield: 87 %

Procedure:
2-(3-Quinolylmethyl)-3-anilinoacrylonitrile (6.38 g) was treated with guanidine in the manner of Example 5B. There was isolated 4.90 g (87%) of 2,4-diamino-5-(3-quinolylmethyl)pyrimidine which was recrystallized from methyl cellosolve with the aid of decolorizing charcoal; m.p. 279°-282° C. (dec). Anal. Calcd. for C14H13N5 : C, 66.92; H, 5.21; N, 27.87. Found: C, 66.57; H, 5.36; N, 27.54.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([NH2:21])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]>ClCCl>[BrH:1].[Br:1][CH2:2][C:3]([NH:21][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[C:7]([Cl:6])[CH:8]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Solvent: ClCCl
Product: Br
Product: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl

Procedure:
A solution of 1.86 mL (21.00 mmol) of bromoacetylbromide in 10 mL of dichloromethane was added dropwise to a solution of 5.00 g (21.00 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine. in 100 mL of dichloromethane at 0° C. and the mixture was stirred for 20 minutes at 0° C. The precipitate formed was filtered off, washed with dichloromethane and MTBE and dried i. vac. at 40° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]#[C:19][CH3:20])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]3)=[N:11][C:10]=2[N:9]([CH3:35])[C:7]1=[O:8])=[O:4].[OH-].[K+]>O1CCCC1.CO>[C:3]([CH2:5][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]#[C:19][CH3:20])[C:12]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]3)=[N:11][C:10]=2[N:9]([CH3:35])[C:7]1=[O:8])([OH:4])=[O:2]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)OC)c(=O)n2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)O)c(=O)n2C

Procedure:
Prepared by saponifying 1-methoxycarbonylmethyl-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine with 4 N potassium hydroxide solution in a mixture of tetrahydrofuran and methanol (5:1) at ambient temperature.
Reaction SMILES: CN(C)C=O.[C:6]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)(=O)[CH3:7].[Br-].[CH2:16]([O:23][C:24]([CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[N:12]1[CH:13]=[CH:14][C:9]([C:6]([CH3:7])=[CH:26][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:25])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccncc1
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=CC(=O)OCc1ccccc1)c1ccncc1
Temperature: 70 °C
Yield: 42.4 %

Procedure:
N,N-Dimethylformamide (33 ml) was added to a mixture of 4-acetylpyridine (2.00 g, 16.5 mmol) and (benzyloxycarbonyl)methyltriphenylphosphonium bromide (8.94 g, 18.2 mmol), and the whole was stirred under ice-cooling. Potassium carbonate (9.12 g, 66.0 mmol) was added thereto, the external temperature was raised to 70° C., and the whole was stirred overnight. The reaction mixture was diluted with diethyl ether (100 ml), and the whole was washed with water (100 ml, twice) and saturated brine (50 ml) successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.77 g (42%: mixture of E form and Z form) of benzyl 3-(4-pyridyl)-2-butenoate as a pale yellow oily matter.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][C:10]=3[CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li+].[OH-].Cl.C(OCC)(=O)C>C1COCC1.C(O)C>[CH3:1][O:2][C:3]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][C:10]=3[CH:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cccc(C2Oc3cccc(OC)c3-c3ccc(CS(N)(=O)=O)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cccc2c1-c1ccc(CS(N)(=O)=O)cc1C(c1cccc(C(=O)O)c1)O2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of Example 51 (0.34 g, 0.76 mmol) in THF (5 mL) and ethanol (5 mL) was treated with a solution of 10% LiOH (5 mL), stirred at room temperature for 20 hours, and poured into a mixture of ice, 1M HCl (50 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated to provide the desired product.(0.26 g, 80%) as a white solid MS (ESI(−)Q1MS) m/z 424 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=1)=[O:7].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([NH:17][C:16](=[O:28])[C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:11]=3)=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(OC)c(OC)c4)c3)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 3,4-dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide (50.0 mg, 0.12 mmol) in 1 mL of DMF. To the mixture was added methyl bromoacetate (0.02 mL, 0.20 mmol) and K2CO3 (50 mg, 0.36 mmol). The mixture was stirred at room temperature overnight. LC-MS indicated the desired product. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-95% CH3CN/H2O) to give 37 mg (7-{3-[(3,4-dimethoxy-benzoylamino)-methyl]-benzoylamino}-3,4-dihydro-1H-isoquinolin-2-yl)-acetic acid methyl ester. MS, electrospray 590.6 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=3)[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[C:4]([Cl:29])[CH:3]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+].COCCOC>CCOC(C)=O.O>[Cl:29][C:4]1[CH:3]=[C:2]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH:39]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([C:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)[N:10]=[C:9]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2cn(-c3ccc(Br)cc3Cl)c(-c3ccccc3Cl)n2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(-n3cc(-c4cc(C(F)(F)F)on4)nc3-c3ccccc3Cl)c(Cl)c2)c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 52.7 %

Procedure:
To an 8 mL glass vial was added 3-(1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)-5-(trifluoromethyl)isoxazole (120 mg, 236 μmol), 3-methylsulfonylphenyl boronic acid (52 mg, 260 μmol), PdCl2dppf (20 mg, 10 mol %), K2CO3 (100 mg, 708 μmol), 1,2-dimethoxyethane (6 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 80° C. for 2.5 hrs. The reaction solution was diluted with EtOAc (30 mL) and filtered through a celite padded Buchner funnel to remove spent Pd. The filtrate was transferred to a separatory funnel and washed with aq NH4Cl (40 mL) and aq NaCl (40 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 12 g SiO2 column using a mobile phase gradient of 5% EtOAc to 100% EtOAc to afford 72 mg (53% yield) of the title compound. MS (ESI) 578.0, 580.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 8.13 (d, J=8 Hz, 1H), 8.08 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.71-7.79 (m, 2H), 7.69 (d, J=7 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.48 (m, 1H), 7.36-7.42 (m, 2H), 3.34 (s, 3H) ppm; 19F NMR (400 MHz, DMSO-d6) 6-81.9 ppm.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]=O.Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(O)(C)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:19][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccccc12
Reactant: C1COCCN1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CCN1CCOCC1)c1c(-c2ccccc2)oc2ccccc12

Procedure:
A mixture of 23.6 grams of 2-phenyl-3- acetylbenzofuran, 70 milliliters of isopropanol, 4.2 grams of paraformaldehyde, and 17.3 grams of morpholine hydrochloride were heated under reflux at the boiling point for 12 hours, after which the solvent was evaporated therefrom under vacuum and the residue was triturated with dilute hydrochloric acid and the hydrochloride of the compound named in the heading of this example, which separated in the form of crystals therefrom, was separated from the mixture by suction filtration and dried. In this manner, 23.8 grams of the specified hydrochloride, which had a melting point of 177°-179°C, was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30]>C1COCC1.CN(C=O)C>[OH:26][C@@H:25]([CH2:27][N:29]([CH3:30])[CH3:28])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CNC
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@@H](O)CN(C)C
Temperature: 75 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of (2S)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 297), and dimethylamine (0.42 ml of a 2M solution in THF, 0.84 mmol) in DMF (5 ml) was stirred at 75° C. for 3 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by trituration with methanol to give (2S)-7-(2-hydroxy-3-dimethylaminopropoxy)-4-(indol-5-yloxy)-6-methoxyquinazoline (100 mg, 85%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]=1.CCN(CC)CC.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C1=CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2=CCCC2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
In a sealed tube is added 4-iodobenzoic acid (5.0 g, 20.16 mmol), cyclopentene (17.8 mL, 2101.6 mmol), Et3N (8.4 mL, 60.48 mmol) in toluene (100 mL). It is purged with N2 for 15 min. Pd(OAc)2 (0.23 g, 1.01 mmol) and P(o-Tol)3 (0.61 g, 2.01 mmol) are added. The reaction is stirred at 120° C. overnight. It is diluted with EtOAc, washed with 1M HCl, H2O, and brine. Purification of the crude material by chromatography gives the title compound (2.63 g, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:10][CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])([CH3:12])[CH3:11])=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (0.95 g, 5.0 mmol) and diisopropylethylamine (0.87 mL, 5.0 mmol) in DCM (25 mL) was added 4-methoxybenzoyl chloride (0.69 mL, 5.0 mmol) at room temperature and the mixture was stirred for 4 h. The reaction mixture was partitioned between DCM and 50% brine solution. The organic layer was separated, dried with Na2SO4, filtered and concentrated. The residue was dissolved in ethyl acetate and washed with 0.5 M hydrochloric acid. The organic layer was separated, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate in heptane (0-25%) to give the title compound (0.55 g, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.09-7.90 (m, 2 H), 7.04-6.81 (m, 2 H), 4.65 (br s, 1 H), 4.35 (s, 2H), 3.88 (s, 3 H), 1.44 (s, 9 H), 1.40 (s, 6 H). m/z (APCI+) for C17H25NO5 224.1 (M-tBuCO2—+H)+.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]#[CH:29])[CH:22]=3)=[CH:15][C:14]=2[C:31]([F:34])([F:33])[F:32])[CH2:8][CH2:7]1)([CH3:4])=[O:3].Br[C:36]1[CH:45]=[N:44][C:43]2[NH:42][C:41](=[O:46])CO[C:38]=2[CH:37]=1.N#N.C(N(CC)C(C)C)(C)C.C[CH2:59][O:60]C(C)=O>[Cu]I.O.CN(C=O)C>[CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]#[C:29][C:36]4[CH:45]=[N:44][C:43]5[NH:42][C:41](=[O:46])[O:60][CH2:59][C:38]=5[CH:37]=4)[CH:22]=3)=[CH:15][C:14]=2[C:31]([F:34])([F:32])[F:33])[CH2:8][CH2:7]1)([CH3:4])=[O:3]
Reactant: O=C1COc2cc(Br)cnc2N1
Reactant: CCOC(C)=O
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)ccc1C
Agent: [Cu]I
Agent: N#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2c(c1)COC(=O)N2
Temperature: 80 °C
Reaction time: 24 h

Procedure:
N-[4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-3-ethynyl-4-methylbenzamide (0.22 mmol), 7-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (45.8 mg, 0.2 mmol), Pd[(PPh3)]4 (11.6 mg, 0.01 mmol). CuI (2.9 mg, 0.015 mmol) is placed in a vial capped with rubber septa. This vial is subjected to 3 cycles of vacuum-refilling with N2. To this mixture is added anhydrous N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) and DMF (1.0 mL). The resulting solution is stirred at 80° C. for 24 h. After the reaction mixture is cooled, water and EtOAc are added to facilitate the extraction. The combined organic layers are dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue is purified on a silica gel column (eluent: 10% MeOH in CH2Cl2, MeOH is pre-saturated with NH3 gas).