Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:17])=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]O)=[N:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([C:4]1[C:5]([O:17][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:33])([F:18])[F:32])=[CH:25][N:24]=2)=[C:6]([Cl:16])[CH:7]=[C:8]([O:10][CH2:11][CH:12]=[C:13]([Cl:15])[Cl:14])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1O
Reactant: OCCCCOc1ccc(C(F)(F)F)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cc(OCC=C(Cl)Cl)cc(Cl)c1OCCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of protective gas, 0.1 g of 3-acetyl-1-chloro-5-(3,3-dichloroprop-2-enyloxy)-2-hydroxybenzene, 0.08 g of 4-(5-trifluoromethylpyrid-2-yloxy)butan-1-ol and 0.093 g triphenylphosphine were dissolved in 2 ml of dry tetrahydrofuran (THF). With ice-bath cooling, 56 μl of diethyl azodicarboxylate were added dropwise. After about 30 minutes, the ice-bath was removed, and the mixture was stirred at room temperature for 15 hours. The mixture was then concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate and water. After shaking, the organic phase was isolated, dried and concentrated under reduced pressure. The crude product was purified chromatographically. Yield: 0.051 g (35%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(#N)C.[NH2:23][C:24]1[C:32]([CH3:33])=[CH:31][C:30]([Cl:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CS(Cl)(=O)=O>C(N(CC)CC)C>[Cl:34][C:30]1[CH:31]=[C:32]([CH3:33])[C:24]2[N:23]=[C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[O:14][C:26](=[O:27])[C:25]=2[CH:29]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
To a mixture of 1.0 g of 1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride and 10 ml of acetonitrile was added 0.60 g of 2-amino-5-chloro-3-methylbenzoic acid, and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture, 0.46 ml of triethylamine was added. After the mixture was stirred at room temperature for 20 minutes, 0.92 ml of triethylamine was further added thereto. After the mixture was stirred at room temperature for 20 minutes, 0.28 ml of methanesulfonyl chloride was added thereto and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.98 g of 6-chloro-2-[1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:38])([CH:33](OC)[O:34]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][C:9]([CH3:38])([CH:33]=[O:34])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(C)(CNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CN(c1cccc2cc(C(=O)NCC(C)(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxy-2-methylpropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g), Amberlyst (registered trade mark) 15 ion exchange resin (0.20 g), water (0.1 ml) and acetone (10 ml) was stirred overnight at room temperature. The insoluble substance was removed by filtration, and the filtrate was concentrated to give the title compound (0.83 g, yield 92%) as colorless crystals. melting point 149-150° C.
Reaction SMILES: C([CH:8]([C:37](=[O:39])[OH:38])[C@@H:9]([C:21]([CH:23]1[CH2:25][C:24]1([NH2:36])[C:26]([O:28][CH:29]1[CH:33]([CH3:34])[CH2:32][CH2:31][CH:30]1[CH3:35])=[O:27])=[O:22])[NH:10]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)C>[NH2:10][C@H:9]([C:21]([CH:23]1[CH2:25][C:24]1([NH2:36])[C:26]([O:28][CH:29]1[CH:33]([CH3:34])[CH2:32][CH2:31][CH:30]1[CH3:35])=[O:27])=[O:22])[CH2:8][C:37](=[O:38])[OH:39]
Reactant: CC1CCC(C)C1OC(=O)C1(N)CC1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CC1CCC(C)C1OC(=O)C1(N)CC1C(=O)[C@@H](N)CC(=O)O
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A mixture of compound 3 (0.31 g), 1,4-cyclohexadiene (0.46 g), 10% palladium-on-carbon (0.3 g) and 95% ethanol (10 ml) was placed in an ultrasonic bath for 10 minutes. The mixture was then filtered through Celite, and the solvent was evaporated to yield 130 mg of a colorless oil which solidified upon standing. This was purified by HPLC using a reverse phase C18 column, 60% methanol in water as eluent to yield the desired product as a white solid (72 mg, 40%). MP: 155.5°-157° C. FAB MS (m/z): 313 (M+H, 22%) 217 (87%), 102 (69%), 88 (100%).
Reaction SMILES: [H-].[K+].O1[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:8][S:9][CH2:10][S:11](=[O:13])[CH3:12].BrCCCCBr>C(Cl)Cl>[CH3:8][S:9][C:10]1([S:11](=[O:13])[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [K+]
Solvent: ClCCl
Solvent: BrCCCCBr
Product: CSC1(S(C)=O)CCCC1
Reaction time: 0.67 h

Procedure:
Potassium hydride (940 mg) was suspended in 15 ml. of tetrahydrofuran, and with ice cooling, 1.320g of formaldehyde dimethyl mercaptal S-oxide was added. With ice-cooling, the mixture was stirred for 40 minutes, and then 2.410 g of 1.4-dibromobutane was added. The mixture was stirred for 1 hour with ice cooling, and then for 19 hours at room temperature. Methylene chloride (70ml) was added, and the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (silica gel, eluted with CH2Cl2, 25% AcOEt-CH2Cl2, AcOEt, and MeOH) to afford 1.509 g of cyclopentanone dimethyl mercaptal S-oxide as a colorless oily substance. Furthermore, 208 mg of formaldehyde dimethyl mercaptal S-oxide was obtained from the MeOH fraction. The yield was 80%. The physical properties were as follows:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:18]=[C:17]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23](=[O:30])[NH:22][N:21]=3)[CH:16]=[CH:15][C:14]=2[F:31])[C:6]1=[O:32].CO.[NH3:36]>>[F:31][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[NH:22][N:21]=2)=[CH:18][C:13]=1[N:7]1[C:8](=[O:12])[C:9]([CH3:11])([CH3:10])[N:5]([CH2:4][C:3]([NH2:36])=[O:2])[C:6]1=[O:32]
Reactant: N
Reactant: COC(=O)CN1C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1(C)C
Solvent: CO
Product: CC1(C)C(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)N1CC(N)=O
Temperature: 60 °C

Procedure:
{3-[2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-phenyl]-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl}-acetic acid methyl ester (0.025 g, 0.055 mmol) was dissolved in solution of 7N ammonia in methanol (3 ml, 21 mmol) and heated in a sealed tube at 60° C. for 18 hours. The resultant solution was concentrated in vacuo and submitted for preparative HPLC purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([F:9])[CH:3]=1.N(OCCC(C)C)=O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Product: Fc1cc(Cl)ccc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-chloro-2-fluoro-aniline (1.0 mL, 0.0090 mol) in benzene (50 mL) at room temperature under nitrogen was added in one portion neat iso-amyl nitrite (1.7 mL, 0.014 mol), and the mixture was slowly heated until gas evolution was observed (˜70° C.). The heat source was removed and the solution allowed to cool. After 10 minutes at room temperature, the mixture was heated to reflux, refluxed 2 hours and cooled. The solution was rotary evaporated to ˜3 mL and filtered through silica gel (100 g), eluting with hexanes. Fractions containing product were rotary evaporated, and the residue was rechromatographed on silica gel (50 g) eluting with n-hexane (20×50 mL) followed by n-hexane-diethyl ether (9:1, 10×50 mL) to give 0.875 g of 4-chloro-2-fluoro-biphenyl as a clear colorless oil; proton nuclear magnetic resonance spectroscopy (1H-NMR) (CDCl3): δ 7.36-7.53 (m, 6H), 7.18-7.22 (m, 2H).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([SH:11])[CH2:7][CH2:6]1.Cl[CH2:13][C:14](=[O:16])[CH3:15]>O1CCCC1>[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([S:11][CH2:13][C:14](=[O:16])[CH3:15])[CH2:7][CH2:6]1
Reactant: CN1CCC(S)CC1
Reactant: CC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CSC1CCN(C)CC1
Reaction time: 24 h

Procedure:
Sodium methylate (5.9 g) is added in portions to a solution of 1-methylpiperidine-4-thiol (14 g) in anhydrous tetrahydrofuran (100 ml) at room temperature. After 2 hours at this temperature, chloroacetone (8.8 ml) is added dropwise. After 24 hours, the precipitate is filtered off and the filtrate is concentrated and chromatographed on silica gel (eluent: ethyl acetate, then ethanol) to give 1-methyl-4-[(2-oxopropyl)thio]piperidine (11.5 g) in the form of an oil.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39](O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1CCCCC1>C(Cl)Cl.C(OCC)(=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OC(C)(C)C)CC1)OS(=O)(=O)C(F)(F)F

Procedure:
0.85 ml of pyridine and 0.56 ml of trifluoromethanesulfonic acid anhydride were added, in that order, to a solution of 1.0 g of ethyl 6-(1-t-butoxycarbonyl-4-piperidyl)-2-hydroxyhexanoate in 10 ml of anhydrous methylene chloride, whilst cooling on an ice-salt bath, and the mixture was then stirred for 30 minuites. At the end of this time, 20 ml of a 1:1 by volume mixture of cyclohexane and ethyl acetate were added to the reaction mixture, the solution was poured onto a short column packed with silica gel, and eluted with a 1:1 volume mixture of cyclohexane and ethyl acetate. The fraction containing the title compound was concentrated by evaporation under reduced pressure, to give 0.50 g of the title compound as a syrupy substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Br)ccc1Br
Product: O=C(Cl)c1cc(Br)ccc1Br

Procedure:
By the general method of Part C of Example 1, the reaction of 50.0 g (0.1786 mol) 2,5-dibromobenzoic acid with 150 mL thionyl chloride gave after distillation 40 g of 2,5-dibromobenzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH3:17])=O)[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][CH2:9][CH2:10][CH2:11][CH2:12][NH:14][CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNC(=O)CCCOCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCNCCCCOCc1ccccc1
Temperature: 45 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To an ice-cold, stirred mixture of 4-(benzyloxy)-N-propylbutanamide (2.59 g, 11.0 mmol) in THF (8 mL) is added lithium aluminum hydride (0.54 g, 14.3 mmol). The reaction mixture is heated to 40-50 degrees C. for 5 hours. The cooled reaction mixture is quenched with water (0.5 mL), sodium hydroxide (2 N, 1.0 mL), and saline (0.5 mL) then diluted with ether (30 mL). The precipitate that formed is filtered off, and the ether phase dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give N-[4-(benzyloxy)butyl]-N-propylamine (2.41 g), APCI-MS (m/z): 222 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[N:18][C:19](Cl)=[N:20]3)=[C:15]([O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[O:38][CH2:39][O:40][C:33]=12>N.C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]5[O:38][CH2:39][O:40][C:33]=45)=[N:18][CH:19]=[N:20]3)=[C:15]([O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CCOc2cc(OC3CCOCC3)c3cnc(Cl)nc3c2)CC1
Reactant: Nc1ccnc2c1OCO2
Agent: N
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOc2cc(OC3CCOCC3)c3c(Nc4ccnc5c4OCO5)ncnc3c2)CC1
Yield: 53 %

Procedure:
Using an analogous procedure to that described in Example 1, 7-[2-(4-acetylpiperazin-1-yl)ethoxy]chloro-5-tetrahydropyran-4-yloxyquinazoline (0.113 g) was reacted with 4-amino-2,3-methylenedioxypyridine (0.036 g). The reaction mixture was quenched with glacial acetic acid (0.031 g) and diluted with methanol. The mixture was evaporated and the residue was purified by column chromatography on a C18 reversed phase silica column (Waters Symmetry column, 5 microns silica, 20 mm diameter, 100 mm length) using a decreasingly polar mixture of water and acetonitrile (containing 1% acetic acid) as eluent. The material so obtained was diluted with a 7M methanolic ammonia solution. The mixture was evaporated and the material so obtained was dissolved in methylene chloride. The solution was dried over magnesium sulphate and evaporated to give the title compound as a foam in 53% yield; NMR Spectrum: (CDCl3) 2.02 (m, 2H), 2.1 (s, 3H), 2.22 (m, 2H), 2.6 (m, 4H), 2.9 (m, 2H), 3.51 (m, 2H), 3.6 (m, 2H), 3.66 (m, 2H), 4.1 (m, 2H), 4.25 (m, 2H), 4.73 (m, 1H), 6.13 (s, 2H), 6.59 (s, 1H), 6.9 (s, 1H), 7.7 (d, 1H), 8.36 (d, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 537.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH3:18]
Reactant: Oc1cc(F)ccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-bromo-5-fluorophenol (5.0 g) in DMF (30 mL) was added potassium carbonate (10.8 g) and iodoethane (6.12 g). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and hexane (3:1). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 5.06 g of the title compound as a crude product, that was used for the next step without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl.[F:11][C:12]1([F:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN1C(=O)CCC1>CCOC(C)=O>[F:11][C:12]1([F:18])[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: Cc1nc(Cl)ncc1F
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1nc(N2CCC(F)(F)CC2)ncc1F
Temperature: 120 °C

Procedure:
A 5 mL microwave vial was charged with 2-chloro-5-fluoro-4-methylpyrimidine (JOC 2004, 69, 3943-3949) (0.19 g, 1.3 mmol), 4,4-difluoropiperidine hydrochloride (1.0 g, 6.5 mmol) and NMP (2.6 mL). The mixture was heated in a microwave oven at 120° C. for 24 hours then cooled to ambient temperature. The mixture was then diluted with EtOAc, washed with water (3×), and brine. The organic extract was concentrated and purified by chromatography (silica gel, 0-5% EtOAc/hexanes gradient) to afford the title compound. MS (ESI) m/z: 232.4 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[CH2:27]([NH2:30])[CH:28]=[CH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([NH:11][C@H:12]([C:17]([NH:30][CH:27]=[CH:28][CH3:29])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C=CCN
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC=CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Cbz-leucine (3.0 g, 11.3 mmol) was dissolved in DMF (50 ml), then NMM (1.3 g, 12.4 mmol) was added, followed by allyl amine (0.65 g, 0.85 mmol), and HBTU (4.3 g, 11.3 mmol) and the reaction was stirred overnight at RT. The reaction was diluted with water, extracted with EtOAc, dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 40% EtOAc: hexanes): MS(ES) M+H+=305.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][NH:28][C:27]=1[C:33]([OH:35])=O.[NH2:36][CH2:37][C:38]1[C:39]([F:55])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:49]#[N:50])[C:41]([Cl:44])=[CH:42][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][NH:28][C:27]=1[C:33]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([C:49]#[N:50])[CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:39]=1[F:55])=[O:35]
Reactant: O=Cc1c[nH]c(C(=O)O)c1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cc(C=O)c3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-4-formyl-1H-pyrrole-2-carboxylic acid (0.028 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). The solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc, followed by washing the organic layer with a 15% Na2CO3 solution and drying over MgSO4. The solid was filtered off, and the solvent was evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to give an orange film which was triturated in acetone to afford the title compound (0.014 g, 18%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.66 (br. s., 1H), 9.75 (s, 1H), 8.27 (t, 1H), 7.77-7.82 (m, 1H), 7.73 (s, 1H), 7.46-7.51 (m, 2H), 7.44 (t, 1H), 7.36 (t, 1H), 4.54 (d, 2H). LCMS: m/z=464.3 (M−1).
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[S:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(N(CC)C(C)C)(C)C>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([S:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[O:9][N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)no4)c3)c2cc1OC
Temperature: 50 °C
Yield: 55 %

Procedure:
Using the procedure described in Example 159B, a mixture of phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate described in Example 159A (0.158 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) were heated at 50° C. for 5 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea as solid (0.114 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.10 (s, 1H), 8.70 (s, 1H), 7.85 (s, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 7.34 (m, 3H), 6.22 (s, 1H), 4.70 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.28 (s, 3H); LC-MS (ESI) m/z 516 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][C:14]2[CH:22]=[CH:21][C:17]3[NH:18][CH:19]=[N:20][C:16]=3[CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1OCC[O:9]1.[OH-].[Na+]>CC(C)=O.O.C(OCC)(=O)C>[NH:18]1[C:17]2[CH:21]=[CH:22][C:14]([O:13][C:4]3[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[CH:3]=3)=[CH:15][C:16]=2[N:20]=[CH:19]1
Reactant: Clc1cc(Oc2ccc3[nH]cnc3c2)ccc1C1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1ccc(Oc2ccc3[nH]cnc3c2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-{[3-Chloro-4-(1,3-dioxolan-2-yl)phenyl]oxy}-1H-benzimidazole (1.41 g) was dissolved in approximately 15 mL of acetone and heated at reflux over 3 days with 25 mg of p-tosic acid. An additional 50 mg of p-tosic acid was added and the reaction was heated at 80 degrees Centigrade for an additional 6 hours. The reaction was allowed to cool to room temperature, diluted with water and ethyl acetate, made basic with 10 N NaOH and extracted twice with ethyl acetate. The organic layer was washed with brine and 1N NaOH, dried over MgSO4 and concentrated. The residue was dissolved and stirred in neat trifluoroacetic acid overnight. The reaction was concentrated and purified by silica gel column chromatography (0-10% gradient of methanolic 2N NH3/CH2Cl2). The fractions were concentrated and the residue was purified by preparative HPLC to give 4-(1H-benzimidazol-5-yloxy)-2-chlorobenzaldehyde, which was ultimately used to prepare Examples Nos. 73 and 74.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])=[O:5]
Reactant: CC(C)C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(NC(=O)C(C)C)cc1Cl
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-(2'-methylpropionamido)benzoyl chloride from the preceding reaction in dry THF (10 ml) was added dropwise with stirring over 10-15 minutes to a solution of diethylamine (1.46 g) in dry THF (10 ml), at 0°-5° C. After stirring at 0°-10° C. the reaction mixture was stood overnight at room temperature, poured into cold water and extracted with ethyl acetate. This extract was dried and evaporated to give a viscous gum which crystallised slowly and was then recrystallised from ethyl acetate to give 2-chloro-4-(2'-methylpropionamido)-N,N-diethylbenzamide as white crystals (0.507 g).