Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([NH:15][OH:16])=[NH:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:17](OC)(OC)OC.B(F)(F)F.CCOCC>CO>[O:16]1[CH:17]=[N:14][C:13]([C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:15]1
Reactant: COC(OC)OC
Reactant: N=C(NO)c1sc(N)nc1-c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Product: Nc1nc(-c2ccccc2)c(-c2ncon2)s1

Procedure:
2-Amino-N-hydroxy-4-phenyl-thiazole-5-carboxamidine (1.0 g, 4.3 mmol) was dissolved in methanol (20 mL), and trimethyl orthoformate (1.2 mL, 11 mmol) containing boron trifluoride etherate (0.2 mL, 1.6 mmol) was added End the mixture was heated at reflux for 3 h. The reaction mixture was cooled, and the solvent was removed under reduced pressure at 20° C. The residue was extracted with ethyl acetate, and the solution was washed with saturated aqueous NaHCO3 dried over sodium sulfate and evaporated. The crude product was purified by flash column chromatography, eluted with the gradient of 10-18% ethyl acetate in hexanes to get the product (the product was eluted by 18% ethyl acetate in hexanes). Yield: 0.1 g, 10%
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Product: O=S(=O)(c1ccc(OCC2CO2)cc1)c1oc2ccccc2c1-c1ccccc1

Procedure:
Reaction of 2-(4-hydroxyphenylsulfonyl)-3-phenylbenzofuran with epibromohydrin according to the procedure of Example 3 gives 2-[4-(2,3-epoxypropoxy)phenylsulfonyl]-3-phenylbenzofuran.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=4[CH3:24])=[N:13][NH:12][C:11](=[O:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.C(N(CC)CC)C>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>[C:31]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=4[CH3:24])=[N:13][NH:12][C:11](=[O:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1)(=[O:33])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(-c2n[nH]c(=O)c3[nH]c4cc(Br)ccc4c23)cccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(c1)[nH]c1c(=O)[nH]nc(-c3cccc([N+](=O)[O-])c3C)c12
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 109 %

Procedure:
A mixture of 7-bromo-1-(2-methyl-3-nitrophenyl)-3H-pyridazino [4,5-b]indol-4(5H)-one (2.00 g, 5.01 mmol), tributyl(1-ethoxyvinyl)stannane (4.06 mL, 12.02 mmol), dichlorobis(triphenylphosphine)-palladium(II) (0.422 g, 0.601 mmol), and triethylamine (0.908 mL, 6.51 mmol) in 1,4-Dioxane (100 mL) was heated at 95° C. for 24 hr. Upon cooling to room temperature, the mixture was filtered through CELITE®. The filtrate was concentrated under vacuum to dryness. To the residue was added THF (100 mL) and 1 N HCl solution (100 mL), and the mixture was stirred at 60° C. for 1.5 hr. It was concentrated under vacuum to a volume of 100 mL, neutralized with 1 N NaOH solution to pH 4-5, and extracted with ethyl acetate (3×150 mL). The combined, cloudy organic solution was concentrated under vacuum to dryness. To the residue was added hexane (100 mL), and the mixture was stirred at room temperature for 1 hr. The clear solution was decanted and the residue was repeated with this operation for two more times. The solid material was collected by suction filtration to give a crude product (1.98 g, 5.46 mmol, >100% yield) as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:29](=[O:30])[C:17]2[N:18]=[C:19]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[S:20][C:16]=2[C:15](=[O:31])[CH:14]=1>C(O)C>[CH3:10][N:5]([CH2:6][CH2:7][CH2:8][NH:9][C:13]1[C:29](=[O:30])[C:17]2[N:18]=[C:19]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])[S:20][C:16]=2[C:15](=[O:31])[CH:14]=1)[CH2:4][CH2:3][CH2:2][NH:1][C:13]1[C:29](=[O:30])[C:17]2[N:18]=[C:19]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])[S:20][C:16]=2[C:15](=[O:31])[CH:14]=1
Reactant: COC1=CC(=O)c2sc(C(=O)N3CCOCC3)nc2C1=O
Reactant: CN(CCCN)CCCN
Solvent: CCO
Product: CN(CCCNC1=CC(=O)c2sc(C(=O)N3CCOCC3)nc2C1=O)CCCNC1=CC(=O)c2sc(C(=O)N3CCOCC3)nc2C1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
51 μl (0.32 mmol; 0.5 equivalent) of N-(3-aminopropyl)-N-methylpropane-1,3-diamine is added to 200 mg (0.65 mmol) of 5-methoxy-2-(morpholin-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione in solution in 15 ml of ethanol. The reaction mixture is maintained under stirring at 85° C. for 2 hours, then the solvent is evaporated off under reduced pressure and the expected product is purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 95/5) then recrystallized from a mixture of acetone and ethyl ether and 110 mg (yield=24%) of 5.5′-[(methylimino)bis(propane-3,1-diylimino)]bis[2-(morpholin-4-ylcarbonyl)-1,3-benzothiazole-4,7-dione] is obtained in the form of a red powder. Melting point=207-208° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:22])[C:7]([OH:21])=[CH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:4].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C=O)C>C1COCC1>[CH2:3]([O:5][C:6](=[O:22])[C:7]([OH:21])=[CH:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:12]=1)=[O:10])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)=CC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a suspension of 0.88 g (22 mmol) of sodium hydride (60% dispersion in mineral oil) in THF (50 ml) was added under ice-cooling, 2.94 g (10 mmol) of 4-(5-chloroindol-3-yl)-2-hydroxy-4-oxo-2-butenoic acid ethyl ester prepared in Example 1 (1). After stirring for 15 min at room temperature, to the mixture was added dropwise a solution of 2.12 g (12 mmol) of benzenesulfonyl chloride in THF (20 ml). After stirring for 2 hours at room temperature, to the mixture was added DMF (8 ml). After stirring for additional 30 min, the reaction mixture was poured into ice-water containing 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried. The solvent was concentrated and the residue was crystallized from ether to give crude crystal, which was washed with ether to give 3.75 of the titled compound. Yield: 87%. Subsequent recrystallization from ethyl acetate afforded the pure ester, melted at. 156-157° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(#N)C>S(Cl)(Cl)=O>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: c1ccc(C2CCCN2)nc1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCCC1c1ccccn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.075 g, 0.39 mmol) was suspended in thionyl chloride (1 mL) and the mixture heated at 60° C. for 1 hour. The mixture was cooled and concentrated by evaporation, azeotroping with toluene (×3). 2-Pyrrolidin-2-yl-pyridine (0.173 g, 1.17 mmol) and acetonitrile (1.5 mL) were added and the reaction mixture stirred for 30 minutes and then the solvent was removed by evaporation. The crude material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were evaporated, azeotroping with methanol (×3), to give the title compound as a foam (0.025 g). LCMS m/z 325.18 [M+H]+ R.T.=5.07 min (Analytical Method 2).
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH2:24]([O:31][C:32]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:33]=1[C:34]1[C:35]([CH2:57][O:58][CH3:59])=[C:36]([CH:55]=O)[N:37]=[CH:38][C:39]=1[N:40]2[S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:24]([O:31][C:32]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:33]=1[C:34]1[C:35]([CH2:57][O:58][CH3:59])=[C:36]([CH:55]=[CH2:2])[N:37]=[CH:38][C:39]=1[N:40]2[S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:46])=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCc1c(C=O)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Yield: 0 %

Procedure:
1.0 g of methyltriphenylphosphoniumbromide+sodium amide (condition-ylide) in 8 ml of absolute tetrahydrofuran is stirred at room temperature under argon for 15 minutes. To it is added 500 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-beta-carboline-3-carbaldehyde and the reaction mixture is refluxed for 4 hours. After evaporation of the solvent, the residue is chromatographed over silica gel with cyclohexane/acetic acid=8+2 as eluant. 0.153 mg of 5-benzyloxy-4-methoxymethyl-9-tosyl-3-vinyl-beta-carboline with a melting point of 141°-143° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([O:22][CH2:21][C@@H:13]1[C@@H:14]2[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:12]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Yield: 100 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (1.000 g, 0.003060 mol), pyridine (495.1 μL, 0.006121 mol), 4-dimethylaminopyridine (0.0748 g, 0.000612 mol) and acetic anhydride (577.5 μL, 0.006121 mol) were stirred in methylene chloride (20 mL) at room temperature for 1 h. The solution was diluted with Methylene chloride, extracted with HCl 1N, dried over NA2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/DCM 0% to 25%) to obtain the product (1.129 g, 84%) as an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][OH:19])[C:9]=2[CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@H:15]1[C:14]1[C:9]2[CH2:8][CH2:7][O:6][C:10]=2[CH:11]=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@@H]1c1cccc2c1CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Methane sulfonyl chloride (6.5 mmol) was added dropwise to a solution of (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methanol (5.0 mmol) and triethylamine (7.5 mmol) in 50 mL of CH2Cl2 at 0° C. The resulting mixture was allowed to warm to RT and stirred for 2 h. The crude reaction mixture was then diluted with CH2Cl2 (50 mL) and washed sequentially with water (2×50 mL), saturated aqueous sodium bicarbonate solution (2×50 mL) and then brine (1×50 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 1.38 g of the desired product as an oil (quantitative yield).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:30]=[CH:31][CH:32]=1)[C:24]([N:26]([CH3:29])OC)=O)#[N:20]>C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([C:18]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:18][C:29]3=[N:26][C:24]=2[C:23]2[CH:22]=[C:21]([CH:32]=[CH:31][CH:30]=2)[C:19]#[N:20])[CH:15]=[CH:14][N:13]=1
Reactant: CON(C)C(=O)c1cccc(C#N)c1
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M in THF, 36.0 mL, 36.0 mmol) was added to 100 mL of THF and cooled to −78° C. 2-Chloro-4-methylpyrimidine (3.07 g, 23.9 mmol) in 20 mL of THF was added dropwise over 10 minutes. The addition funnel was rinsed with 10 mL of THF. The reaction was stirred 20 minutes, and 3-cyano-N-methyl-N-(methyloxy)benzamide (see Organic Lett. 2006, 8, 4843-4846) (5.00 g, 26.3 mmol) in 25 mL of THF was added dropwise over 10 minutes. The addition funnel was rinsed with 10 mL of THF. The reaction was stirred for one hour and allowed to warm to 0° C. The reaction was quenched with saturated ammonium chloride solution and poured into H2O and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford the product contaminated with 3-cyano-N-methyl-N-(methyloxy)benzamide. The mixture was triturated with 30% EtOAc in hexanes, filtered, and the solid washed with 30% EtOAc in hexanes followed by hexanes. The yellow solid was collected to provide 1.56 g (25%) of the title compound as an approximately 1:1 mixture of ketone and enol tautomers. 1H NMR (400 MHz, DMSO-d6) δ [Enol tautomer] 13.45 (s, 1H), 6.70 (s, 1H); [Ketone tautomer]-4.72 (s, 2H); [Aromatic protons] 8.72 (d, J=5.1 Hz, 1H), 8.62 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.70 (t, J=7.9 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.33 (d, J=5.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1>C(OCC)(=O)C.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:31])([F:32])[F:30])=[CH:12][N:11]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I5) (0.358 g, 0.572 mmol) in ethyl acetate (25 mL) and dimethylformamide (5 mL) was added 10% Pd/C (0.200 g). The mixture was evacuated and backfilled three times with hydrogen gas then stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a plug of Celite, washing with ethyl acetate then the filtrate was evaporated in vacuo and dried under high vacuum to give the title compound (I6) (0.360 g, 100%) as a viscous yellow oil; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9 H), 3.00-3.20 (m, 8 H), 3.59 (t, 4 H, J=4.8 Hz), 3.67 (s, 3 H), 3.75 (s, 2 H), 3.90 (s, 3 H), 6.55-6.57 (m, 2 H), 7.19-7.26 (m, 4 H), 7.75 (s, 1 H), 8.26 (d, 1 H, J=9.4 Hz) and 8.50 (s, 1 H). LCMS Method B: rt 6.55 min; m/z 630.5 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4].Br[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:33]=[CH:32][S:31][CH:30]=1.C(OCC)C>O1CCCC1>[CH2:3]([N:5]([CH2:16][C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH2:26]/[CH:27]=[CH:28]/[C:29]2[CH:33]=[CH:32][S:31][CH:30]=2)[CH:20]=[CH:19][N:18]=1)[CH2:6]/[CH:7]=[CH:8]/[C:9]#[C:10][C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[CH3:4]
Reactant: BrC/C=C/c1ccsc1
Reactant: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(CO)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(C/C=C/C#CC(C)(C)OC)Cc1cc(COC/C=C/c2ccsc2)ccn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
11.6 mg of 60% oily sodium hydride was suspended in 0.5 ml of tetrahydrofuran at 0 ° C., under a nitrogen atmosphere, and a tetrahydrofuran solution( 2 ml) of 87.5 mg of (E)-N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-4-hydroxymethyl-2-pyridylmethylamine was added dropwise. The mixture was stirred for 20 minutes, and a tetrahydrofuran solution (1 ml) of 50 mg of (E)-3-bromo-1-(3-thienyl)-1-propene was added dropwise. The mixture was stirred overnight at room temperature, and then ice water and ethyl ether were added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography [silica gel column, chloroform→chloroform/methanol=20/1] to give 56 mg (yield 46%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][C:21](=[O:25])[NH:22]3)=[CH:17][CH:16]=2)[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]2[C:32]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[N:33][O:34][C:30]=2[CH:29]=1>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:32]1[C:31]2[CH:46]=[CH:47][C:28]([NH:27][C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:24]=[C:23]5[C:18]([CH:19]=[CH:20][C:21](=[O:25])[NH:22]5)=[CH:17][CH:16]=4)[C:10]3=[O:26])=[CH:29][C:30]=2[O:34][N:33]=1
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3ccc(=O)[nH]c3c2)C1=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1)[C@H]1OCCN(c2ccc3ccc(=O)[nH]c3c2)C1=O

Procedure:
According to the Step 15-1 in the synthetic method for Example aa15, (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]acetic acid (compound aa7-4) and 6-amino-3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(1R)-2-[[3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-7-yl)morpholin-2-yl]ethyl]acetate (compound ap2-1), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.37 g, 10.17 mmol) was dissolved in DMF (100 mL). The solution was then heated to 80° C. N-Chlorosuccinimide (1.49 g, 11.1 mmol) was added at 80° C. under Argon gas. After two hours of continuous stirring, the reaction was checked by TLC and LCMS, and found to be incomplete. An additional aliquot of NCS (0.5 g, 3.7 mmol) was added, bringing the reaction to completion after 1.5 hours. While stirring, a portion of water (200 mL) was added to force the product to precipitate out of solution. After the precipitation was complete, the flask containing the solid was cooled in an ice water bath for 10 minutes. The solid was then filtered under vacuum and rinsed with water, yielding 2.4 g (89%) of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. This material was used in the next step without purification. LCMS m/z (%)=267 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.41 (dd, J1=8 Hz, J2=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J=12 Hz, 1H), 3.97 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: ClCc1cccnc1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCc1cccnc1
Yield: 18 %

Procedure:
Using an analogous procedure to that described in Example 32, 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-chloromethylpyridine, hydrochloride salt to give 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-pyridylmethoxy)quinazoline in 18% yield; NMR Spectrum: 3.93 (s, 3H), 5.28 (s, 2H), 7.16 (s, 1H), 7.4 (m, 2H), 7.75 (m, 1H), 7.95 (m, 1H), 8.1 (m, 2H), 8.4 (s, 1H), 8.6 (m, 1H), 8.75 (m, 1H); Elemental Analysis: Found C, 61.0; H, 3.9; N, 13.5; C21H16ClFN4O2 requires C, 61.4; H, 3.9; N, 13.6%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:23][CH:22]=2)[C:18](O)=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:37][N:38]1C2C=CC=CC=2N=N1.NO>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]([CH3:16])[CH:17]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:33])[O:34][CH2:35][CH3:36])=[CH:25][CH:26]=2)[C:18]([NH:38][OH:37])=[O:19])(=[O:14])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Agent: NO
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OCCCNC(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino}(4-{3-[(ethoxycarbonyl)amino]propoxy]phenyl)acetic acid (0.35 g, 0.67 mmol) and 1-(3-dimethyl aminopropyl)3-ethyl carbodiimide (0.2 g, 1.01 mmol) in DMF (8 ml), 1-hydroxybenzotriazole (0.13 g, 0.95 mmol) was added and the reaction was stirred at room temperature for 2 h. Hydroxylamine (0.23 ml. of 50% in water, 3.71 mmol) was added and the reaction was stirred overnight. After evaporating the solvent, the residue was extracted with ethyl acetate and water, the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The residue was purified with preparative TLC plates (eluting with ethyl acetate:methanol (85:15) to provide 0.1 g of ethyl 3-{4-[1-[{[4-(2-butynyloxy)phenyl]sulfonyl}-(methyl)amino]-2-(hydroxyamino)-2-oxoethyl]phenoxy}propylcarbamate as a yellow solid. mp 60-62° C. Electrospray Mass Spec 532 (M+H)+.