Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH2:13][S:14][C:15](N)=[NH2+])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[C:22](=O)([O-])[O-].[K+].[K+].CO.[OH-].[K+]>C1(C)C=CC=CC=1.O>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[CH:19]=[CH:18][C:12]([CH2:13][S:14][CH2:15][CH3:22])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: NC(=[NH2+])SCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
S-(4-(4-chlorobenzoyl)benzyl)thiouronium bromide (3.3 g) and potassium carbonate (1.5 g) were dissolved in dimethylformnamide (20 ml). A methanol solution (10 ml) of potassium hydroxide (1.0 g) was added and stirred at room temperature for 30 minutes. To the reaction mixture, water (100 ml) and toluene (100 ml) were added. The organic layer was separated, and washed with water and an aqueous saturated sodium chloride solution, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent, the crude product was purified by silica gel column chromatography (developing solvent: ethyl acetaten:hexane=1:9) to obtain 4-chloro-4'-ethylmercaptomethylbenzophenone (1.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH:18][CH3:19].CC(C1C=C(C=CC=1O)C(C1C=CC=CC=1)=O)C=C>>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:17]=[CH:18][CH3:19]
Reactant: CC=CCBr
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: C=CC(C)c1cc(C(=O)c2ccccc2)ccc1O
Product: CC=CCOc1ccc(C(=O)c2ccccc2)cc1

Procedure:
4-crotyloxybenzophenone was prepared from 4-hydroxybenzophenone and crotyl bromide using the procedure of Example 23. Through Claisen rearrangement it was converted into 3-(α-methyl-allyl)-4-hydroxybenzophenone. The crude product (10.1 g) was acylated (procedure of Example 1) and purified by chromatography (40:60 hexane-methylene chloride on silica gel) to produce 12.25 g (91%) of oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].II.[Br:11]Br>C(Cl)(Cl)Cl>[Br:11][C:5]1[CH:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cn1cccc1C=O
Agent: II
Solvent: ClC(Cl)Cl
Product: Cn1cc(Br)cc1C=O
Temperature: -10 °C
Yield: 95.7 %

Procedure:
To a solution of 1-methyl-1H-pyrrole-2-carbaldehyde (1.09 g, 10.0 mmol) in 60 mL chloroform at −20° C. was added a single crystal of iodine. The mixture was stirred until homogeneous. Bromine (0.51 mL, 10.0 mmol) was added dropwise as a solution in 10 mL chloroform. The solution was stirred while warming from −20 to 0° C. over 1.5 h. Chloroform was removed in vacuo and the residue added to 5% sodium bisulfite solution to quench excess bromine/iodine. Saturated sodium bicarbonate was added until the pH of the mixture reached 7. Organics were extracted with ether (3×75 mL), dried over magnesium sulfate, filtered and concentrated to give crude 4-bromo-1-methyl-1H-pyrrole-2-carbaldehyde (1.80 g) as the major component of a mixture of starting aldehyde and dibromopyrrole. Used without further purification.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13]([NH:16][NH2:17])=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>C(O)C>[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13]([NH:16][N:17]=[CH:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:3]1
Reactant: O=Cc1cccnc1
Reactant: NNc1ncnc2cc(-c3ccsc3)sc12
Agent: Cl
Solvent: CCO
Product: C(=NNc1ncnc2cc(-c3ccsc3)sc12)c1cccnc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A suspension of (6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (222, 39 mg, 0.14 mmol) and 3-pyridinecarboxaldehyde (20 mg, 0.19 mmol) in ethanol (2 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration to yield 3-pyridinecarboxaldehyde(6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl)hydrazone (40 mg, 87% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([NH2:21])=[O:20])[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.CO>CS(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][CH:16]([C:19](=[O:20])[NH2:21])[CH2:15][CH2:14]2)=[N:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: NC(=O)C1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(N2CCC(C(N)=O)CC2)nc1
Temperature: 95 °C

Procedure:
Ethyl-6-chloronicotinate (1.86 g, 10 mmol) and piperidine-4-carboxamide (1.54 g, 12 mmol) are dissolved in DMSO (7 ml). N,N-Diisopropylethylamine (2.1 ml, 12 mmol) is added and the reaction mixture is heated at 95° C. for 3 hours. Methanol (8 ml) is added as the reaction mixture cools to give a precipitate. The solid is collected, washed with water followed by diethyl ether, and dried in vacuo at 45° C. to yield the title compound as a white solid. MS (ES+) m/e 278 (MH+)
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O.[CH3:22][O-:23].[Na+].CO>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:2]([O:23][CH3:22])[C:3]2[N:10]=[C:8]([OH:9])[C:7]3[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)=[N:16][CH:17]=1
Reactant: NC(=O)c1ccccc1NC(=O)C(Br)c1ccc(F)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(c1ccc(F)cn1)c1nc(O)c2ccccc2n1
Temperature: 65 °C

Procedure:
To a 0.3 M solution of 2-(2-bromo-2-(5-fluoropyridin-2-yl)acetamido)benzamide in MeOH is added 25% sodium methoxide/MeOH (2 equiv) and the mixture is heated at 65° C. overnight or until the reaction is substantially complete. The mixture is concentrated under reduced pressure and the residue is purified by chromatography to afford 2-((5-fluoropyridin-2-yl)(methoxy)methyl)quinazolin-4-ol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]4[C:26]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO.O1CCOCC1>[C:27]1([C:26]2[N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]3=[N:19][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncccn4c3-c3ccccc3)cc2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4ncccn4c3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
To a mixture of crude {1-[4-(3-phenyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (390 mg) in DCM (0.9 mL) and methanol (0.57 mL) was added a solution of 4 M hydrogen chloride in dioxane (1.77 mL) and the mixture was stirred overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted three times with a mixture of DCM/methanol. The combined organic phases were washed with brine, dried and concentrated in vacuo to give the crude title compound as a yellow oil. Purification was achieved by chromatography [amino phase silica; gradient elution: hexane to EtOAc], followed by trituration with diisopropylether at 0° C. to give the title compound (21.9 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1I>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=[CH:26][C:21]=1[F:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(F)c(I)c1
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C#Cc1cc(S(C)(=O)=O)ccc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
A suspension of (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46; 200 mg; 0.78 mmol), 1-fluoro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 77; 233 mg; 0.78 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloro palladium(II) (34 mg; 0.05 mmol) and cuprous iodide (9 mg; 0.05 mmol) was degassed during 2 minutes under nitrogen then anhydrous THF (3 ml) and TEA (215 μl; 1.55 mmol) were added and the reaction mixture was stirred at 70° C. for 16 hours. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc to give the title compound (260 mg, 78%) as a yellow sticky solid.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[C:25]([O:27]C(C)(C)C)=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:32][CH3:33])[C:25]([OH:27])=[O:26])[C:5]1=[O:34])[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)C(=O)O)C1=O
Reaction time: 3 h

Procedure:
To a solution of 320 mg (0.64 mmol) of tert-butyl (2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate (Example 1, Step G) in DCM (3184 μL) was added trifluoroacetic acid (2453 μL, 31.8 mmol) at 0° C. After being stirred at 25 C. for 3 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure 3-times to provide the title compound as a pale yellow foam which was used in the subsequent reaction without further purification.
Reaction SMILES: Cl[C@:2]1([O:9][C@@H:8]([CH3:10])[C@@:6]([O:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])([OH:7])[C@@H:5]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:4]1)O.C1C=CC=CC=1.[Hg](C#N)C#N>O1CCOCC1>[F:23][C:20]([F:21])([F:22])[C:19]([NH:18][C@@H:5]1[C@:6]([O:11][C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])([OH:7])[C@H:8]([CH3:10])[O:9][CH:2]=[CH:4]1)=[O:24]
Reactant: C[C@@H]1O[C@](O)(Cl)C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)OC(=O)C(F)(F)F
Agent: N#C[Hg]C#N
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: C[C@@H]1OC=C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)OC(=O)C(F)(F)F
Yield: 93.9 %

Procedure:
To a solution of 800 mg of 1-chloro-2,3,6-trideoxy-3-trifluoroacetamido-4-trifluoroacetoxy-alpha-L-lyxohexopyranose (I)* in 25 ml of a 4:1 (by volume) mixture of benzene and dioxane there were added 500 mg of Hg(CN)2. The resulting suspension was heated under reflux for 3 1/2 hours. After cooling, the reaction mixture was filtered to give a clear solution, which was then evaporated to a residue. The residue was extracted with benzene and, upon evaporation of the benzene solution, there were obtained 650 mg of 1,2,3,6-tetradeoxy-3-trifluoroacetamido-4-trifluoroacetoxy-L-lyxo-hex-1-enopyranose (II) in crystalline form melting at 73°-74° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:5][CH:6]=[CH2:7])[CH2:3][OH:4].[CH3:9][C:10]1([CH3:19])[C:14]([CH3:16])([CH3:15])[O:13][B:12](C=C)[O:11]1>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:1][C:2]([CH3:8])([CH2:5]/[CH:6]=[CH:7]/[B:12]1[O:13][C:14]([CH3:16])([CH3:15])[C:10]([CH3:19])([CH3:9])[O:11]1)[CH2:3][OH:4]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: C=CCC(C)(C)CO
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC(C)(CO)C/C=C/B1OC(C)(C)C(C)(C)O1
Temperature: 40 °C

Procedure:
To a solution of 2,2-dimethylpent-4-en-1-ol (4.9 g, 42.9 mmol) in DCM (500 mL) is added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (22 mL, 128 mmol) and Grubbs catalyst (3.53 g, 4.29 mmol), and the mixture is heated at 40° C. for 18 h. The mixture is concentrated and washed with sat. NaHCO3 and purified to give the title compound as a greenish crystalline.
Reaction SMILES: Cl[C:2]([O:5][C:6](=[O:12])[O:7][C:8](Cl)(Cl)Cl)(Cl)Cl.[N:13]1[CH:18]=CC=C[CH:14]=1.[O:19]1[CH2:23]CC[CH2:20]1>>[C:6](=[O:12])([O:7][CH2:8][CH2:14][NH:13][CH3:18])[O:5][CH2:2][CH2:20][O:19][CH3:23]
Reactant: c1ccncc1
Reactant: C1CCOC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CNCCOC(=O)OCCOC
Reaction time: 0.17 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.59 g) in tetrahydrofuran (20 mL) was added dropwise a solution of pyridine (0.49 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 10 minutes under ice-cooling, and 2-methoxyethyl 2-(methylamino)ethyl carbonate hydrochlride (1.07 g) obtained in Reference Synthetic Example 18 was added. A solution of triethylamine (0.84 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2 N hydrocloric acid (20 mL), and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (20 mL). To the solution were added (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.85 g), triethylamine (1.05 mL) and 4-dimethylaminopyridine (0.061 g), and stirred at 60° C. for 6 hrs, and then at room temperature for 8 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated saline (50 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate). The purified material was crystallized from ethyl acetate-diethyl ether, and further recrystallized from ethyl acetate-diisopropyl ether to give title compound as colorless solid (1.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[CH:14]=1)[C:5]2=O.O.[NH2:25][NH2:26]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][F:22])[CH:14]=3)=[CH:7][NH:26][N:25]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2cccc(OCCF)c2)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2cccc(OCCF)c2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-[3-(2-fluoro-ethoxy)-phenyl]-7-hydroxy-chromen-4-one (0.2 g, 0.6 mmol), hydrazine hydrate (2.5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give an oil which was purified by column chromatography to give 4-Chloro-6-{4-[3-(2-fluoro-ethoxy)-phenyl]-1H-pyrazol-3-yl}-benzene-1,3-diol as an off white solid (0.12 g, 57.3%); Rf 0.5 cf SM 0.85 ethyl acetate/hexane (80/20).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][O:13]C(=O)[N:15]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[C:18]([C:35]([F:38])([F:37])[F:36])[CH:17]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[C:42](B(O)O)[CH:41]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[N:40][C:49]6[C:44]([CH:43]=5)=[CH:45][CH:46]=[CH:47][CH:48]=6)[CH:3]=4)[N:8]=[CH:7][C:6]=3[CH2:12][OH:13])=[CH:17][C:18]=2[C:35]([F:38])([F:36])[F:37])[CH2:23][CH2:24]1)=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C(=O)OCc4cnc5ccc(Cl)cc5c43)cc2C(F)(F)F)CC1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(CO)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a solution of tert-butyl 4-(4-(9-chloro-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)-yl)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (56 mg, 0.1 mmol) and quinolin-3-ylboronic acid (25 mg, 0.15 mmol) in 1,4-dioxane (1 mL) at room temperature was added bischloroditriphenyl phosphine palladium (4 mg, 0.005 mmol), tert-butyl Xphos (4 mg, 0.01 mmol), and Na2CO3(0.3 mL, 0.3 mmol). The resultant solution was heated to 100° C. for 4 h and then allowed to cool to room temperature, filtered through celite, and washed with EtOAc (3×10 mL). After removal of solvent in vacuo, the residue was purified by flash column chromatography to afford the title compound (35 mg, 55%). LC-MS: (M+H)=630.30
Reaction SMILES: [O:1]=[C:2]([NH:7][C@H:8]([C:26]([OH:28])=O)[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:3][CH2:4][CH2:5][CH3:6].[O:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[O:35][NH2:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[O:28]=[C:26]([NH:36][O:35][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][O:29]1)[CH:8]([NH:7][C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: NOC1CCCCO1
Reactant: CCCCC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCCCC(=O)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 58.6 %

Procedure:
To a solution of the title compound of Example 11e (690 mg, 1.64 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (192 mg, 1.64 mmol) in anhydrous THF (40 mL), cooled to zero degrees C., was added EDC (330 mg, 1.72 mmol) and HOBT (264 mg, 1.72 mmol). After stirring at zero degrees C. for 5 hours and at room temperature for 18 hours, the solution was concentrated. The residue was dissolved into EtOAc (50 mL) and washed with 1M KHSO4 (2×50 mL), saturated NaHCO3 (2×50 mL), and brine (1×50 mL) and dried over Na2SO4. Purification by chromatography (1:1 EtOAc/hexane) yielded the title compound as a colorless oil (500 mg, 59%): Anal. Calcd. for C25H32N2O6S2: C, 57.67; H, 6.19; N, 5.38. Found: C, 57.48; H, 6.37; N, 5.11.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.O>CC(C)=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:26][CH:25]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and 4-fluorobenzyl bromide (26.1 g) were refluxed in acetone (150 ml) with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum. The resulting residue, with water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 ml) added thereto, was refluxed with stirring for 2 hours. The reaction mixture, with water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained solid was recrystallized (from n-hexane/ethanol), thereby yielding 30.8 g of the aimed compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH2:12])=[O:11]>S(=O)(=O)(O)O.O>[C:1]([NH:12][C:10](=[O:11])[CH:9]([Cl:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)C(Cl)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NC(=O)C(Cl)c1ccccc1

Procedure:
To a solution of one drop of concentrated sulfuric acid in 5 ml. of acetic anhydride was added 2 g. of the amide of Step A above, and the reaction mixture was heated on a steam bath for 1.5 hours. The resulting yellow solution was stirred with ice and water and 2.1 g. of precipitate was soon collected. The precipitate was dissolved in about 15 ml. of dichloromethane, after which petroleum ether was carefully added to near the cloud point. Short white needles of precipitate formed to give a yield of 1.9 g. having an m.p. of 101°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:18]=1[C:19](Cl)=[O:20]>C1(C)C=CC=CC=1.ClCCl>[CH2:13]([C:7]1([C:5]2[O:4][N:3]=[C:2]([NH:1][C:19](=[O:20])[C:18]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:17]=3[O:16][CH3:15])[CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:14]
Reactant: CCC1(c2cc(N)no2)CCCCC1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC1(c2cc(NC(=O)c3c(OC)cccc3OC)no2)CCCCC1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of 14 g of 3-amino-5-(1-ethylcyclohexyl)isoxazole and 14.4 g of 2,6-dimethoxybenzoyl chloride in 100 ml of toluene was heated to reflux and stirred for eighteen hours. The reaction mixture then was cooled to room temperature and the solvent was removed by evaporation under reduced pressure to provide a solid. The solid was dissolved in 200 ml of dichloromethane, washed with dilute sodium hyroxide and with brine, dried, and the solvent was removed by evaporation. The product was crystallized from dichloromethane and diethyl ether to provide 15.5 g of N-[5-(1-ethylcyclohexyl)-3-isoxazolyl]-2,6-dimethoxybenzamide. M.P. 179°-181° C. Yield 60%.