Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CC#N>[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([CH:4]([OH:5])[CH2:3][CH2:2][Cl:1])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)C(O)CCCl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To 3-chloro-1-propanol (5.02 mL, 60 mmole) in CH3CN (200 mL) was added, p-toluenesufonyl chloride (17 g, 90 mmole) and pyridine (7.3 mL, 90 mmole). The reaction mixture was stirred at room temperature for 12 hours under an argon atmosphere. 200 mL of saturated NaHCO3 (aq) was added and the stirring was continued for 15 minutes. The mixture was extracted several times with CH2Cl2. The combine CH2Cl2 layers were dried over Na2SO4, the Na2SO4 was filtered and the filtrate was evaporated to give 12.35 g (83.8%) of the title compound: TLC (Rf: 0.5; 20% EtOAc/Hexane), 1H NMR (CDCl3) δ 2.1 (m, 2 H, CH2), 2.5 (s, 3 H, CH3), 3.6 (t, 2 H, CH2), 4.2 (t, 2 H, CH2), 7.6 (d & d, 4 H, Ar). 13C NMR (CDCl3): δ 21.4 (CH3), 31.5 (CH2), 40.2 (CH2), 66.7 (CH2), 127.8 (Ar), 129.8 (Ar), 132.5 (Ar), 144.9 (Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([SH:19])[CH:13]=[CH:12]2.BrC1C=C2C(=CC=1)C=C(O)C=C2.[C:32](#[N:35])[CH:33]=[CH2:34].C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([S:19][CH2:34][CH2:33][C:32]#[N:35])[CH:13]=[CH:12]2
Reactant: C=CC#N
Reactant: Fc1ccc(-c2ccc3cc(S)ccc3c2)c(F)c1
Agent: Oc1ccc2cc(Br)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCCSc1ccc2cc(-c3ccc(F)cc3F)ccc2c1
Temperature: 50 °C

Procedure:
A mixture of 6-(2,4-difluorophenyl)-2-naphthyl hydrosulfide (prepared from 6-bromo-2-naphthol according to the methods of Example 1 Steps 1 and 2 and Example 2 Step 2, 7.3 g, 24.7 mmol), acrylonitrile (2.6 mL, 39.5 mmol) and triethylamine (370 μL) in tetrahydrofuran (50 mL) was heated to 50° C. under nitrogen for 1 hour. The solvent was removed in vacuo. The residue was triturated with isohexane to give 3-{[6-(2,4-difluorophenyl)-2-naphthyl]thio}propanenitrile (5.58 g). 1H NMR (500 MHz, CDCl3) δ 7.94 (1H, s), 7.90 (1H, s), 7.85 (2H, d, J=8.5 Hz), 7.66 (1H, d, J=8.3 Hz), 7.50 (2H, d, J=8.6 Hz), 7.00 (1H, dd, J=2.3, 8.6 Hz), 6.96 (1H, d, J=1.9 Hz), 3.24 (2H, t, J=7.2 Hz), 2.64 (2H, t, J=7.3 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.O.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH2:18][SH:19]>CN(C=O)C>[S:19]1[C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[C:18]1[C:17]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CS
Reactant: O=Cc1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cnccc2s1
Temperature: 45 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 4-chloropyridine-3-carboxaldehyde (D-1) (1.4 g, 10 mmol) dissolved in DMF (10 mL) and water (1 mL) were added K2CO3 (1.66 g, 12 mmol) and methyl thioglycolate (1.07 mL, 12 mmol) portion-wise. The reaction mixture was stirred at 45° C. overnight and then quenched with cold water. The flask was placed on ice to enhance precipitation. The precipitate was collected by filtration and air-dried to afford the title compound (1.23 g). MS (m/z): 194 (M+1)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:25])=[C:22]([CH3:36])[N:21]=[C:20](S(C)(=O)=O)[N:19]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:25])=[C:22]([CH3:36])[N:21]=[C:20]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:19]=2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
39.3 mg (0.0798 mmol) of phenol was dissolved in DMF. 16.7 mg (0.418 mmol) of sodium hydride (60% oily substance) was added at 0° C. and stirred at the same temperature for 30 minutes. 100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-methylsulfonyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was added at the same temperature and stirred heating to room temperature for 12 hours. After concentration under reduced pressure, the obtained residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[CH:14][C:13]=2[F:27])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:34]1[C:35]([CH3:45])=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][N:40]=[C:39]([Cl:44])[CH:38]=2)(=O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:44][C:39]1[CH:38]=[C:37]2[C:42]([CH:43]=[C:34]([C:16]3[CH:15]=[CH:14][C:13]([F:27])=[C:12]([NH:11][C:9]([NH:8][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:10])[CH:17]=3)[C:35]([CH3:45])=[N:36]2)=[CH:41][N:40]=1
Reactant: Cc1nc2cc(Cl)ncc2cc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(F)c(NC(=O)NC3CCCCCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(NC(=O)NC2CCCCCC2)c1
Temperature: 60 °C
Yield: 142.5 %

Procedure:
Sparge a suspension of 1-cycloheptyl-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.420 g, 1.116 mmol), 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (0.438 g, 1.339 mmol) and K2CO3 (0.463 g, 3.35 mmol) in dioxane (4 mL) and H2O (1 mL) with Ar, add Pd(PPh3)4 (0.064 g, 0.056 mmol) and heat at 60° C. for 3 h. Concentrate the mixture to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (679 mg, 61%) as a white solid. MS(ESI) m/z: 427.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:13])=[O:11])=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: O=C(Cl)Cc1ccc(Br)cc1

Procedure:
4-Bromophenylacetyl chloride is prepared according to the method described in Example 8 using 4-bromophenylacetic acid (2.75 g, 12.8 mmol) to give an oil which is dissolved in chloroform (10 mL). This solution is refluxed for 19 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (2.25 g, 12.2 mmol) in chloroform (10 mL) under nitrogen. The solvent is removed in vacuo, and the residue is treated as in Example 13 to give the crude free ester, which is then dissolved in 1M hydrochloric acid (70 mL). Sodium chloride (14 g) is added to the solution which is then extracted with chloroform (60 mL then 2×40 mL). The combined extracts are dried over sodium sulfate and the solvent removed in vacuo. The residue is recrystallised from hot ethyl acetate/methanol to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[OH:28].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cc(Br)ccc2c1Br
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4cc(Br)ccc4c3Br)c2cc1OC
Temperature: 150 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (223 mg), 1,6-dibromo-2-naphthol (910 mg), and 4-dimethylaminopyridine (366 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 150° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-[(1,6-dibromo-2-naphthyl)oxy]-6,7-dimethoxyquinoline (326 mg, yield 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[CH:22]3[CH2:23][CH2:24][CH:18]2[CH2:19][O:20][CH2:21]3)[N:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH2:31][CH2:32][O:33][CH2:34][CH:35]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[O:33]1[CH2:32][CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[CH:22]4[CH2:23][CH2:24][CH:18]3[CH2:19][O:20][CH2:21]4)[N:3]=2)[CH2:35][CH2:34]1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3C4CCC3COC4)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc(C3=CCOCC3)nc(N3C4CCC3COC4)n2)cc1
Temperature: 100 °C
Yield: 85.6 %

Procedure:
A microwave vial was charged with 8-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.440 g, 1.27 mmoles). Toluene (6 mL) was then added and the solution was sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.088 g, 0.076 mmol) and tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.567 g, 1.52 mmol) were added. The vial was sealed and heated to 100° C. for 40 minutes via microwave. Additional tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (0.283 g, 0.76 mmoles) and tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol) were added and the suspension was heated to 110° C. by microwave for additional 90 minutes. The suspension was then cooled to room temperature and filtered through Celite™. The filter cake was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 0-2% methanol in methylene chloride, to provide 8-(4-(3,6-dihydro-2H-pyran-4-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.430 g, 86%) as a light yellow solid. HRMS 396.1666 (M+H, calc.), 396.1668 (M+H, obs.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[O:12]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:12]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[CH:5]3)=[O:27])=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccc2ncccc2c1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Nc1ccc2ncccc2c1

Procedure:
Prepared from 6-aminoquinoline and 4-phenoxyphenyl isocyanate. m/z (ES+) 356 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([C:11]=1C(O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]2[C:25]([O:27][C:28](=O)[C:18]=2[CH:17]=1)=[O:26].ClC1C=CC(Cl)=CC=1Cl>>[OH:1][C:2]1[C:3]([CH:15]2[C:25](=[O:26])[C:19]3[C:18](=[CH:17][CH:16]=[C:21]([C:22]([OH:24])=[O:23])[CH:20]=3)[C:28]2=[O:27])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: O=C(O)c1ccc2c(c1)C(=O)C(c1nc3ccccc3cc1O)C2=O
Temperature: 25 °C
Yield: 48 %

Procedure:
To a 250-mL round-bottom-flask, 3-hydroxy-2-methylquinoline-4-carboxylic acid (4.0 g, 0.02 mol), 1,2,4-benzenetricarboxylic anhydride (3.8 g, 0.02 mol) and 1,2,4-trichlorobenzene were added and the mixture was refluxed for 2 hours under nitrogen. After the mixture was cooled to room temperature, a yellow precipitate formed and was collected by filtration. The solid was washed with methanol, refluxed with water and collected by hot filtration to give 2-(3-hydroxy-quinolin-2-yl)-1,3-dioxo-indan-5-carboxylic acid as yellow powder (3.2 g, 0.009) in 48% yield. m.p.>350°. UV-Vis (DMSO) λmax: 424 (32,200), 442 (39,600). In order to convert the acid form into the corresponding tetrabutyl ammonium salt, 2 g of the acid was suspended in methanol (100 mL) and tetrabutyl ammonium hydroxide (1.0 M, 6.0 mL) was added slowly. Because the deprotonation of the first proton (carboxylic acid proton) of the yellow dye does not change its absorption spectrum while the deprotonation of the second proton (hydroxy group) shifts its absorption significantly, the addition of base can be followed easily by UV-Vis spectroscopy. After most of the yellow solid went into the solution, the mixture was filtered and the filtrate was collected. The solvent was removed under vacuum and the resulting residue was washed with ether to give the title compound (3.2 g). UV-Vis (CH2Cl2) λmax: 424 (32,400), 442 (40,000).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])=[O:3].[Cl:16][C:17]1[C:18]([OH:26])=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH:20]=O.O>CN(C)C=O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[S:15])[NH:13][N:14]=[CH:20][C:19]2[CH:22]=[C:23]([Cl:25])[CH:24]=[C:17]([Cl:16])[C:18]=2[OH:26])=[CH:9][CH:10]=1)([OH:4])=[O:3]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(NC(=S)NN=Cc2cc(Cl)cc(Cl)c2O)cc1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
Concentrated aqueous hydrochloric acid (1 mL) was added to a stirred solution of 4-(4-carboxyphenyl)-3-thiosemicarbazide (213 mg, 1.00 mmol) and 3,5-dichloro-2-hydroxybenzaldehyde (198 mg, 1.04 mmol) in dimethylformamide (20 mL). The mixture was stirred for 18 h, water was added and the precipitate filtered, washed (water) and dried to give the title compound (212 mg, 55%) as a solid. MS (ES−) m/e 382, 384 [M−H]-.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+:19]([O-])=O)[CH:11]=2)=[N:7][CH:8]=1.[CH3:24][P:25](=[O:29])([CH2:27]N)[CH3:26]>C1(C)C=CC=CC=1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:8][N:7]=2)=[CH:11][C:12]=1[NH:19][CH2:24][P:25](=[O:29])([CH3:27])[CH3:26])([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1[N+](=O)[O-]
Reactant: CP(C)(=O)CN
Solvent: Cc1ccccc1
Product: CP(C)(=O)CNc1cc(Oc2ccc(C(F)(F)F)cn2)ccc1[N+](=O)[O-]

Procedure:
A solution of 4.97 g of (5-trifluoromethyl-2-pyridyloxy)-3,4-dinitrobenzene in 15 ml of toluene is refluxed, and 3.21 g of melted P,P-dimethyl-aminomethylphosphine oxide are added dropwise. The mixture is refluxed for a further 2 hours, nitrous gases being evolved at the start. The brown solution is subsequently concentrated by evaporation, and the residue is recrystallised from 50 ml of ethyl acetate to thus obtain 4.10 g (70% of theory) of N-[2-nitro-5-(5-trifluoromethyl-2-pyridyloxy)-phenyl]-P,P-dimethyl-aminomethylphosphine oxide in the form of yellow crystals, m.p. 158°-160° C.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:47]=[CH:48][CH:49]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:27][C:28]([C:30]2[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=2)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:29])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([CH:44]=[CH:45][CH:46]=3)[CH2:33][S:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:29])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:47]=[CH:48][CH:49]=[C:3]([C:2]([F:51])([F:1])[F:50])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)phenyl)carbamoyl)-benzylthio)propanoate (600 mg, 0.84 mmol, 1.00 equiv) in dichloromethane (20 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2.5 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 96.2 mg (15%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.92 (s, 1H), 9.51 (t, J=11.7 Hz, 1H), 8.95 (d, J=5.4 Hz, 1H), 8.28 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.82 (d, J=5.4 Hz, 2H), 7.73 (t, J=12.3 Hz, 2H), 7.55 (m, 5H), 6.96 (d, J=2.4 Hz, 1H), 6.76 (m, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 3.33 (s, 4H), 2.62 (m, 2H), 2.50 (m, 2H), 1.99 (s, 4H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: FC(S([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])(=O)=O)(F)F.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:19]([O:18][C:13](=[O:17])[C:14]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:16])[CH3:20]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)C(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of trimethylsilyl trifluoromethylsulfonate (9.52 mL, 52.5 mmol) in anhydrous methylene chloride (10 mL) was added to a stirred ice-cooled solution of ethyl pyruvate (5.56 mL, 50 mmol) and diisopropylethyl amine (9.6 mL, 55 mmol) in anhydrous methylene chloride (100 mL) over a period of 15 minutes. The reaction was stirred on ice for 1.5 hours and then at room temperature for 3 hours. The solvent was evaporated at room temperature and the residue treated with anhydrous pentane (200 mL) and cooled in ice. The precipitated solid was filtered off. The filtrate was collected and the pentane evaporated to give 2-trimethylsilanyloxyacrylic acid ethyl ester as a light brown liquid (90% yield). The crude product was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.Br[CH2:39][C:40]([NH2:42])=[O:41]>C(Cl)Cl>[C:40]([CH2:39][N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:23][CH3:24])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=2[F:28])[CH2:18][CH2:19]1)(=[O:41])[NH2:42]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: NC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DCM (10 ml), and diisopropylethylamine (45 μl, 0.26 mmol) was added. 2-Bromoacetamide (36 mg, 0.26 mmol) was added, and the solution stirred for 16 hours at ambient temperature. The solvent was evaporated, and the residue purified by chromatography, eluting with 0 to 3% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the residue crystallised from acetonitrile to give the product as a white crystalline solid (48 mg, 60%); 1H NMR: 1.70-1.84 (m, 2H), 1.98-2.09 (m, 2H), 2.38 (m, 2H), 2.70-2.80 (m, 2H), 2.89 (s, 2H), 3.92 (s, 3H), 4.54 (m, 1H), 7.08 (br. s, 2H), 7.20 (s, 1H), 7.26 (ddd, 1H), 7.47 (ddd, 1H), 7.51 (ddd, 1H), 7.80 (s, 1H), 8.35 (s, 1H), 9.53 (s, 1H); Mass Spectrum: 460.5, 462.4.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1)c1ccccc1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
A mixture of 6-(4-hydroxypiperidino)carbostyril (0.25 g), benzoyl chloride (0.17 g) and dry pyridine (2 mL) was heated for 3 hours at 100° C. The reaction mixture was cooled and water (about 25 mL) and sodium bicarbonate (1 g) were added. The mixture was chilled in ice and stirred. The resulting solid was removed by filtration, washed with water and dried to give crude 6-(4-benzoyloxypiperidino)-2(1H)-quinolinone (0.25 g). Recrystallization twice from ethyl acetate gave 6-(4-benzoyloxypiperidino)-2(1H)-quinolinone (0.18 g); m.p. 212°-215° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2c(n1)CCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2c(n1)CCCC2

Procedure:
A solution of 2-chloro-5,6,7,8-tetrahydroquinoline (3.69 g, 22 mmol) and vinyl tributyl tin (7.7 mL, 33 mmol) in toluene (60 mL) was treated with Pd(PPh3)4 (2.5 g, 2.2 mmol) and heated to reflux overnight. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 20% EtOAc in hexanes) to afford the title compound as a colorless oil. LRMS m/z (M+H) 160.2 found, 160.1 required.