Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:18])=[O:17])=[C:9]([O:29][CH2:30][O:31][CH3:32])[CH:8]=1)(=O)=O.C([O-])(=O)C.[K+].Br[C:41]1[CH:46]=[C:45]([F:47])[C:44]([F:48])=[C:43]([F:49])[CH:42]=1.[PH2](=O)[O-].[K+]>O.C(OCC)(=O)C.O1CCOCC1>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([O:27][CH3:28])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:41]3[CH:46]=[C:45]([F:47])[C:44]([F:48])=[C:43]([F:49])[CH:42]=3)=[CH:8][C:9]=2[O:29][CH2:30][O:31][CH3:32])(=[O:18])=[O:17])[CH:24]=1)#[N:26]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: COCOc1cc(OS(=O)(=O)C(F)(F)F)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: CC(=O)[O-]
Agent: O=[PH2][O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COCOc1cc(-c2cc(F)c(F)c(F)c2)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 80 °C
Reaction time: 15 h
Yield: 104.6 %

Procedure:
A mixture of 10.0 g of 4-[2-(5-cyano-2-methoxy-benzenesulfonylamino)ethyl]-3-methoxymethoxyphenyl trifluoromethanesulfonate, 5.33 g of bis(pinacoloto)diboron, 467 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex, 317 mg of 1,1′-bis-(diphenylphosphino)ferrocenepalladium(II), 5.61 g of potassium acetate, and 113 mL of 1,4-dioxane was stirred under an argon atmosphere at 80° C. for 15 hours. To the reaction mixture were added 4.02 g of 1-bromo-3,4,5-trifluorobenzene, 467 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex, 12.14 g of potassium phosphinate, and 40 mL of 1,4-dioxane. The mixture was stirred under argon atmosphere at 80° C. for 24 hours, and ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate-hexane) to give 10.09 g of 5-cyano-2-methoxy-N-[2-(3′,4′,5′-trifluoro-3-methoxymethoxybiphenyl-4-yl)ethyl]-benzenesulfonamide.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.BrC1C=CC(F)=C(OC)C=1.CON(C)[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>O1CCCC1>[F:10][C:3]1[CH:2]=[CH:7][C:6]([C:24]([C:25]([F:28])([F:27])[F:26])=[O:29])=[CH:5][C:4]=1[O:8][CH3:9]
Reactant: COc1cccc(Br)c1F
Reactant: CON(C)C(=O)C(F)(F)F
Agent: COc1cc(Br)ccc1F
Solvent: C1CCOC1
Product: COc1cc(C(=O)C(F)(F)F)ccc1F

Procedure:
Trifluoromethyl 4-fluoro-3-phenoxyphenyl ketone may be prepared using the following procedure. Bromination of 2-fluoroanisole yields a mixture of bromo-2-fluoroanisole isomers from which 5-bromo-2-fluoroanisole is isolated. The Grignard reagent of 5-bromo-2-fluoroanisole is then prepared and is in turn reacted with N-methoxy-N-methyl-2,2,2-trifluoroacetamide in tetrahydrofuran, yielding trifluoromethyl 4-fluoro-3-methoxyphenyl ketone. This ketone is protected by formation of the corresponding ketal, which is in turn treated with trimethylsilyl iodide, sodium hydroxide, bromobenzene, and acid, yielding trifluoromethyl (4-fluoro-3-phenoxyphenyl) ketone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].[CH3:25][N:26]1[CH:30]=[C:29]([Sn](CCCC)(CCCC)CCCC)[CH:28]=[N:27]1.O.Cl>CN(C=O)C.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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:29]1[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3cnn(C)c3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 53.7 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 1-methyl-4-tributylstannanyl-1H-pyrazole (0.1 mL, 0.31 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., water and EtOAc were added. 1 M HCl was added until pH was about 4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (50% EtOAc/CH2Cl2, then 100% EtOAc+1% AcOH) to give 44 mg of the title compound. MS: (+) m/z 391.29 (M+1).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.ClC1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: Cc1ccc(Cl)nn1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2cc(CO)c(C)o2)nn1
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (2.4 g), 3-chloro-6-methylpyridazine (1.5 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (0.44 g, 31%) as a yellow crystal.
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([NH:22][N+:23]([O-:25])=[O:24])=[NH:21])=[CH:14][N:13]=1.CCCCCC>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH3:26])[C:20]([N:21]=[CH:4][N:5]([CH3:7])[CH3:6])=[N:22][N+:23]([O-:25])=[O:24])=[CH:14][N:13]=1
Reactant: CCOC(OCC)N(C)C
Reactant: CN(Cc1ccc(Cl)nc1)C(=N)N[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CN(C)C=NC(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 130 °C

Procedure:
Variant a): 1.5 g of N,N-dimethylformamide-diethyl-acetal are added to 2.43 g of N-(2-chloropyrid-5-ylmethyl)-N-methyl-N'-nitroguanidine in 75 ml of dioxane. The mixture is heated at 130° C. for 45 minutes and is then freed of solvent using a rotary evaporator. The crude product is chromatographed over silica gel using first ethyl acetate and then ethyl acetate/ethanol (5:1). A viscous oil is formed which, after the addition of hexane, yields crystals of the desired product (m.p.: 85°-89° C.).
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:67]1([CH2:73][CH2:74][CH2:75][NH2:76])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O1CCCC1.C(OCC)(=O)C>[C:67]1([CH2:73][CH2:74][CH2:75][NH:76][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Nα-benzyl-Nδ-Boc-Nα-methylornithine (300 mg), diisopropylethylamine (326 μl), and anhydrous tetrahydrofuran (4 ml) was treated with PyBop (585 mg) at 0° C. for 10 min., followed by the addition of a solution of 3-phenylpropylamine (147 μl) in anhydrous tetrahydrofuran (2 ml). The resulting solution was stirred at ambient temperature for 4 hrs. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by chromatography over silica gel (hexane/ethyl acetate) to give Nα-benzyl-Nδ-Boc-Nα-methylornithine 3-phenylpropylamide (370 mg): 1H NMR (400 MHz, CDCl3) δ1.43 (s, 9H), 1.6-1.9 (m, 6H), 2.2 (s, 3H), 2.65 (t, J=6.2 Hz, 2H), 3.0-3.4 (m, 5H), 3.64 (s, 2H), 4.8 (s, 1H), and 7.1-7.5 (m, 10H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[CH:6]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:11][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][N:7]=[CH:6]1
Reactant: OCCCN1C=NCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCN1C=NCC1
Yield: 61.5 %

Procedure:
A solution of 1-(3-hydroxypropyl)-4,5-dihydroimidazole (1.0 g, 3.65 mmol) in tetrahydrofuran (15 ml) was reacted with carbon tetrabromide (1.43 g, 5.47 mmol) and triphenylphosphine (1.43 g, 5.47 mmol) at ambient temperature for 18 hours. Solvent evaporation in vacuo and purification by flash chromatography on silica gel, eluting with 10% methanol in dichloromethane, yielded 1-(3-bromopropyl)-4,5-dihydroimidazole (429 mg, 35% yield) as a white solid:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17](O)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:28][N:29]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([S:23][CH2:24][CH2:25][CH2:26][OH:27])([CH3:22])[CH3:21])[C:17]([NH:29][OH:28])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)SCCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)NO)C(C)(C)SCCCO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanoic acid (500 mg, 1.2 mmol) in dimethylformamide (10 mL) was added N-hydroxybenzotriazole (194 mg, 1.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (322 mg, 1.68 mmol) followed by N-methylmorpholine (0.198 mL, 1.8 mmol) and the resulting mixture was stirred for 1 h at room temperature. A 50% aqueous solution of hydroxylamine (0.367 mL, 6 mmol) was added and the mixture was stirred for 15 h at room temperature. The solvent was removed and the product was partitioned between ethyl acetate and water. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, brine, and dried over anhydrous sodium sulfate. Removal of the solvent gave (2S)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-[(3-hydroxypropyl)sulfanyl]-3-methylbutanamide, which was triturated with hexanes to obtain 130 mg (25%) of the pure product; HRMS (C18H26N2O6S2)(M+H);
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2].Br[CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH:12]1[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][CH2:28][S:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:16][CH2:17]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2]
Reactant: Fc1ccc(SCCCBr)cc1
Reactant: CCc1c(C2CCNCC2)c2ccc(F)cc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C2CCN(CCCSc3ccc(F)cc3)CC2)c2ccc(F)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A mixture of 2-ethyl-6-fluoro-1-phenyl-3-piperidin-4-yl-1H-indole (70 mg, TFA salt), 1-(3-Bromo-propylsulfanyl)-4-fluoro-benzene (44 mg), potassium iodide (5 mg) and potassium carbonate (55 mg) in DMF (3 ml) is heated at 80° C. for 3 h, and allowed to cool to r.t. overnight. Ethyl acetate (50 ml) and water (25 ml) are added and the organic phase is washed with water, dried and concentrated in vacuo. The crude product is purified by flash chromatography (98:2 CH2Cl2:MeOH) to give 50 mg pure product (64%) as brown solid.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:3]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([F:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanesulphonyl chloride (1.5 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3a-f, triethylamine (4.35 ml) and dry dichloromethane (100 ml) at ambient temperature and the resultant solution stirred for 5 minutes then kept at ambient temperature overnight. Further ethanesulphonyl chloride (0.2 ml) was added and the solution stirred at ambient temperature for 4 hours and then kept at this temperature for 3 days. The mixture was filtered and the filtrate was washed with water (2×150 ml). The dichloromethane solution was dried over magnesium sulphate and the solvent evaporated to give a residue which was crystallised from industrial methylated spirit (100 ml). The solid was triturated with diethyl ether (100 ml) and then water (500 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydro-quinol-3-yl ethanesulphonate, m.p. 154°-156.5°.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:11][C:4]=2[NH:3]1.[OH-].[Na+].O.C(O)(=O)C>CCO>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]([CH3:18])[C:13]([OH:15])=[O:14])=[CH:11][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)c1ccc2c(c1)NC(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2c(c1)NC(=O)CO2
Temperature: 50 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Ethyl 2-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]oxazin-6-yl)propanoate (63 mg, 0.253 mmol) in 90% aq. EtOH (4.5 mL) was added sodium hydroxide (50 mg, 1.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours at 50° C. and cooled to room temperature. The mixture was added water (20 mL) and acidified with acetic acid. The mixture was extracted with methylene chloride. The organic layer was dried with MgSO4 and filtered. The filtrate was concentrated in vacuo. white solid (m.p. 191-193° C.), yield: 95%,
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1.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>[NH:42]1[CH:41]=[C:40]([C:27]2[CH:26]=[C:25]([O:24][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([N:11]4[CH2:15][CH2:14][N:13]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[C:12]4=[O:22])=[O:10])=[C:5]([F:23])[CH:4]=3)[CH:30]=[CH:29][N:28]=2)[CH:44]=[N:43]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F)N1CCN(C2CCOCC2)C1=O
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: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(Cl)c(Oc2ccnc(-c3cn[nH]c3)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of Example C8 (0.200 g, 0.426 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.124 g, 0.639 mmol) and K2CO3 (0.177 g, 1.279 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.025 g, 0.021 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (160 mg, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 10.91 (d, J=2.7 Hz, 1 H), 8.40 (1H, d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.33 (s, 1 H), 8.04 (s, 1 H), 7.57 (d, J=11.2 Hz, 1 H), 7.30 (d, J=2.5 Hz, 1 H), 6.61 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.77 (m, 5 H), 3.47 (t, J=8.2 Hz, 2 H), 3.37 (t, J=11.8 Hz, 2 H), 1.75-1.64 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: 501.1 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][OH:25])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(Cl)[Cl:34]>>[ClH:34].[NH2:7][CH:8]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:24][OH:25])=[O:26])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1
Reactant: ClCCl
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Product: CN(C)C(=O)C(N)Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The hydroxamate 12 (0.8 g) was dissolved in CH2Cl2 (25 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 13 as a white amorphous solid (0.34 g,). 1H NMR (DMSO-d6): 11.20 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.52 (m, 1H), 2.92-3.05 (m, 1H), 2.76 (s, 3H), 2.71 (s, 3H). LCMS: Obsd 344.0, calcd 343.48.
Reaction SMILES: [CH:1]12[C:10](=O)[O:9][C:7](=O)[CH:2]1CC=C[CH2:6]2.[Pd:12]([Cl:14])[Cl:13].[C:15](#[N:17])[CH3:16]>CN(C)C=O>[Pd:12]([Cl:14])[Cl:13].[CH2:10]([O:9][CH:7]=[CH2:2])[CH:1]([CH3:6])[CH3:15].[Pd:12]([Cl:14])[Cl:13].[C:15](#[N:17])[CH3:16].[CH:7]([O:9][CH2:10][CH:1]([CH3:6])[CH3:15])=[CH2:2]
Reactant: O=C1OC(=O)C2CC=CCC12
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=COCC(C)C

Procedure:
4-cyclohexene-1,2-dicarboxylic acid anhydride is dissolved in three times its quantity of dimethyl formamide. Its equimolar quantity of acetonitrile palladium dichloride is added at 40° C. in the course of 2 hours. Dimethyl formamide and acetonitrile are distilled off at 45° C./25 mbar. A brownish solid with a melting point of 53°-54° C. is obtained in a 90% yield. Isobutylvinyl ether palladium dichloride is obtained in analogous manner from acetonitrile palladium dichloride and isobutyl vinyl ether, melting point 57°-60° C.
Reaction SMILES: CCCC.[C:5]1(C)[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:12]([OH:14])=[O:13].[O:32]=O.C[C:35](CC)=[O:36]>C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:35]([C:11]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:12]([OH:14])=[O:13])([OH:36])=[O:32]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Reactant: O=O
Reactant: CCC(C)=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CCCC
Product: CCCCCCCCCCCCCCCCC(C(=O)O)(C(=O)O)c1ccccc1
Yield: 47.9 %

Procedure:
The oxidation procedure of Example I was repeated except that only 40 gms cobalt (II) acetate was employed. Also, for this reaction 40 gms methylethyl ketone and 72 gms butane were charged to the reactor. Eighty percent conversion of the tolylstearic acid was achieved after only four hours reaction (105° C. and 350 psig O2). Carboxyphenylstearic acid was obtained in 47.9% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH2:30])[CH2:28][C:27]([CH3:32])([CH3:31])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1.CCN(CC)CC.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[OH-].[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C@H:29]([NH:30][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:28][C:27]([CH3:32])([CH3:31])[O:26][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:16][C:15]=2[Cl:25])=[CH:4][CH:3]=1
Reactant: CC1(C)C[C@@H](N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4cn[nH]c4)cc3Cl)nc2O1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC1(C)C[C@@H](NC(=O)c2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(-c4cn[nH]c4)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step B (35.6 mg, 0.08 mmol) and NEt3 (43 μL, 0.31 mmol) in 10 mL of CH2Cl2 was added benzoyl chloride (20 μL, 0.17 mmol). After stirring at rt for 1 h, 2.0 mL of CH3OH and 100 μL of 5.0 N NaOH was added to the reaction mixture. After stirring for 30 min, the reaction mixture was partitioned between EtOAc (20 mL) and saturated aq NaHCO3 (20 mL). The organic layer was separated and washed with brine (20 mL). After the phases separated, the organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40+S cartridge using 7:3 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.50 (s, 3H), 1.56 (s, 3H), 1.96 (t, J=12.4, 1H), 2.36 (dd, J=6.4, 13.2, 1H), 5.73 (m, 2H), 6.61 (d, J=8.7, 1H), 7.02 (d, J=8.5, 2H), 7.13 (d, J=8.5, 2H), 7.14-7.55 (m, 6H), 7.72-7.83 (m, 5H).