Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[N:10]=1.Br[C:19]1[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=[C:23]([Br:25])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:25][C:23]1[CH:24]=[C:19]([NH:1][C:2]2[S:3][C:4]3[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=3[N:10]=2)[C:20](=[O:27])[N:21]([CH3:26])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2nc3c(s2)CN(C(=O)OC(C)(C)C)CC3)c1=O
Temperature: 110 °C

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (600 mg, 2.35 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (942 mg, 3.53 mmol), Pd2(dba)3 (214 mg, 0.235 mmol), Xantphos (270.5 mg, 0.47 mmol), Cs2CO3 (1.53 g, 4.7 mmol), and dioxane (30 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 110° C. under N2 protection for 12 h. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with acetonitrile to afford 233a (600 mg, 54%) as yellow solid. MS-ESI: [M+H]+ 441.1
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)[CH3:2].[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:44])([F:43])[F:42])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1.BrCC>CN(C=O)C>[CH2:1]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:28]=[C:27]([CH2:29][CH2:30][C:31]4[C:36]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:35][CH:34]=[CH:33][N:32]=4)[C:26]([C:41]([F:42])([F:44])[F:43])=[CH:25][N:24]=3)=[CH:18][CH:17]=2)[CH2:11]1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCN1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)C1
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
N,N-Diisopropylethylamine (18.0 μL, 0.103 mmol) was added to a solution of 2-(2-(2-(2-((4-(Piperidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyridin-3-yl)acetamide (39) (17 mg, 0.034 mmol) in DMF (5 mL). The mixture was stirred for 5 min then bromoethane (4.0 μL, 0.051 mmol) was added and stirring was continued for 24 h at room temperature. A further portion of bromoethane (4.0 μL, 0.051 mmol) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. The volatiles were evaporated in vacuo and the residue partitioned between ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over Na2SO4. Filtration then removal of the solvent under reduced pressure afforded a beige solid which was purified by mass-directed preparative HPLC to afford the title compound (40) (6.2 mg, 36%) as a white solid; 1H NMR (400 MHz, d4-MeOH) δ 8.54 (s, 1H), 8.38 (dd, J=4.8, 1.5 Hz, 1H), 7.69-7.66 (m, 3H), 7.28-7.19 (m, 3H), 3.68 (s, 2H), 3.59-3.46 (m, 2H), 3.38-3.22 (m, partially obscured by d4-MeOH), 3.19-3.08 (m, 2H), 3.04-2.80 (m, 3H), 2.12-1.99 (m, 2H), 1.99-1.70 (m, 2H), 1.34 (t, J=7.3 Hz, 3H). LCMS Method C: rt=4.20 min, m/z=513.2 [M+H]+, 511.2 [M−H]−.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:48][OH:49].O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:33][CH2:32]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:18])[NH:48][OH:49])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: NO
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine (120 mg, 1.6 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile: water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (230 mg, 46%): mp, 191-193° C.; 1HNMR (CDCl3): δ 0.88-0.93 (m, 2H, cyclopropyl ring CH2), 1.09-1.12 (m, 2H, cyclopropyl ring CH2), 1.64-1.67 (m, 1H, cyclopropyl ring CH), 2.84-2.92 (m, 1H, CHHCO), 3.38-3.48 (m, 1H, CHHCO), 4.18 (d, J=18 Hz, 1H, CHHN), 4.36 (d, J=18 Hz, 1H, CHHN), 5.47-5.49 (m, 1H, CHN), 6.52 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 6.99 (d, J=8 Hz, 1H, Ar), 7.25-7.31 (m. 3H, Ar), 7.45 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 9.20 (broad, 1H, NHOH), 10.35 (s, 1H, NHCO); 13C NMR (DMSO): 30.82, 35.26, 38.47, 46.17, 47.50, 51.68, 112.50, 116.83, 117.01, 117.39, 117.66, 117.99, 120.56, 120.97, 121.73, 125.73, 133.41, 137.47, 138.38, 142.76, 146.83, 166.12, 168.68, 172.21, 179.98. Anal. Calcd. for C23H21F4N3O6: C, 54.02; H, 4.14; N, 8.22. Found: C, 53.89; H, 3.96; N, 8.22.
Reaction SMILES: [OH-].[K+].C1OC1C.[NH:7]1[CH:11]([C:12]([O-:14])=[O:13])[CH2:10][CH2:9][C:8]1=[O:15].[Na+]>O>[C:12]([CH2:11][NH:7][C:8](=[O:15])[CH:9]=[CH2:10])([OH:14])=[O:13]
Reactant: O=C1CCC(C(=O)[O-])N1
Agent: CC1CO1
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: C=CC(=O)NCC(=O)O
Yield: 292.6 %

Procedure:
100 g of 25 wt % polyacrylic acid aqueous solution and 2.5 g of N-carboxy methyl acrylamide were polymerized at 60° C. for 3 hours for partial crosslinking. Potassium hydroxide was added to neutralize the pH value to 7.0 and 40 g of T-P400(polymer of triol and propylene oxide, Union Carbide Co., U.S.A.) and 1 g of sodium 2-pyrrolidone-5-carboxylate were added. Deionized water was then added to the resultant product to adjust the solid content thereof to 35 wt %. The viscosity of the resultant solution was measured as 5500 to 6000 cps(30° C.). The resulting product was tested according to the procedures set forth in Example 1, and the test results are listed in Table 1.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[O:24][C:23]([C:25](O)=[O:26])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC1N=C(OC)N=C(OC)[N:31]=1.CN1CCOCC1.[OH-].[NH4+]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[O:24][C:23]([C:25]([NH2:31])=[O:26])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(C(=O)O)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(C(N)=O)o1
Reaction time: 2 h
Yield: 74214.1 %

Procedure:
To a room temperature suspension of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}-2-furoic acid (500 mg, 1.10 mmol) in THF (6.0 mL) was added 2-chloro-4,6 dimethoxy-1,3,5 triazine (307 mg, 1.75 mmol) and N-methyl morpholine (NMM, 184 mg, 1.82 mmol) sequentially. The resulting solution was matured for 2 hours and then a saturated aqueous solution of ammonium hydroxide (0.70 mL) was added. The resulting suspension was allowed to continue for 1 additional hour. The reaction mixture was diluted with 400 mL of brine and extracted with ethyl acetate (3×400 mL). The organic extracts were separated, Na2SO4 dried, and concentrated in vacuo and the resulting residue was subjected to SiO2 chromatography with ethyl acetate/hexanes/methanol (57:38:5) to provide the title compound (370 g, 74%). 1H NMR (300 MHz, d4-MeOH) δ 7.64 (app q, J=8.1 Hz, 1H), 7.10-7.00 (m, 3H), 6.53 (s, 1H), 6.52 (d, J=3.4 Hz, 1H), 5.43 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H); LC/MS C-18 column, tr=2.15 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 453 (M+H). ES-HRMS m/z 453.0249 (M+H calcd for C19H16BrF2N2O4 requires 453.0256).
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.C([O-])(=O)C.[Na+].[CH3:18][CH:19](C(=O)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH-].[K+].[Na+].[Cl-]>O.Cl.C(O)C>[CH3:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[NH:5][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18]2
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
15.4 g of NaNO2 in 4 ml of water are added, at 0° C., to 23.57 g of p-toluidine in 50 ml of HCl and 100 ml of water; after stiring for 20 minutes, 18.2 g of sodium acetate ate added. Separately, a mixture of 28.8 g of ethyl 2-methyl-3-oxobutyrate in 100 ml of ethanol is prepared, at 0° C, and is treated with 11.22 g of potassium hydroxide in20 ml of water and 200 g of crushed ice. The diazonium salt solution prepared above is added and the mixture is left stirring for 3 hours at 0° C. After leaving overnight in a refrigerator, it is poured onto saturated NaCl solution and is then extracted with EtOAc, dried over MgSO4 and concentrated. The residue is taken up in toluene, 16 g of para-toluenesulphonic acid are added and the mixture is refluxed overnight, eliminating the water using Dean-Stark apparatus. The reaction medium is chromatographed on silica, eluting with toluene, to give 12 g of the expected product: m.p.=133° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].O1CCCC1.C(O)(=O)C.[CH3:27][S:28][CH2:29][C:30](=O)[CH3:31]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][N:16]=[C:30]([CH3:31])[CH2:29][S:28][CH3:27])=[O:14])[CH3:2]
Reactant: CSCC(C)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN=C(C)CSC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a 200 ml volume four-necked flask, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazine ((12-1)-(11)-39) (6.44 g), tetrahydrofuran (72 ml), and acetic acid (1.65 g) were added under a nitrogen atmosphere. 1-methylsulfanyl-2-propanone (7-0-1) (3.12 g) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (30 ml), and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 7.17 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(8)-39).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][CH2:9][C:10]1([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.F[B-](F)(F)F.[H+].O>C(Cl)Cl>[CH3:1][O:8][CH2:9][C:10]1([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1C1(CO)Cc2ccccc2C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC1(N2C(=O)c3ccccc3C2=O)Cc2ccccc2C1
Reaction time: 0.33 h

Procedure:
(Trimethylsilyl)diazomethane (2 M hexanes, 0.51 ml, 1.03 mmol) is added dropwise to a cooled (0° C.) solution of 2-(2-hydroxymethylindan-2-yl)-isoindole-1,3-dione (0.150 g, 0.511 mmol) and fluoroboric acid (48% aqueous, 93.5 μl, 0.511 mmol) in CH2Cl2 (4 ml). The reaction is stirred for 20 minutes, then three further portions of (trimethylsilyl)diazomethane (2 M hexanes, 0.128 ml, 0.25 mmol; 64 μl, 0.12 mol; 64 μl, 0.12 mmol)) are made at 20 minute intervals. The reaction is stirred for a further 40 minutes after the final addition, poured into water and extracted with dichloromethane. The organic phase is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash chromatography (CH2Cl2 elution) to afford 2-(2-methoxymethylindan-2-yl)-isoindole-1,3-dione, MH+308.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(3-aminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (131 mg) and triethylamine (0.067 ml) in dichloromethane (3 ml) was added benzoyl chloride (0.056 ml). The mixture was stirred at room temperature for 30 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated, washed with brine, dried over magnesium sulfate and concentrated. The residue was crystallized from isopropyl ether to give 4-(3-benzoylaminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido-[2,3-b]pyrazine (110 mg).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1)([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.N1CCCCC1>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[C:4](\[N+:1]([O-:3])=[O:2])/[CH2:5][CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])CCC1OCCO1
Reactant: O=Cc1ccc(F)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])/C(=C\c1ccc(F)cc1)CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flask equipped with a Dean-Stark trap and a reflux condenser, a solution of 2-(2-nitro-ethyl)-[1,3]dioxolane (162.5 g, 1.1 mol) in toluene (1.2 L) was treated with 4-fluorobenzaldehyde (124 g, 1.0 mol) followed by piperidine (15 mL, 0.15 mol). The solution was heated at reflux under N2 for 16 h, then was cooled to rt and washed with water (2×300 mL) and satd. aq. NaCl (2×300 mL). Charcoal and MgSO4 were added, and the suspension was stirred for 1 h. Filtration and concentration of the filtrate provided the title compound, which was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): 8.15 (s, 1H), 7.70-7.65 (m, 2H), 7.18-7.10 (m, 2H), 5.23 (t, J=4.5, 1H), 4.10-3.80 (m, 4H), 3.26 (d, J=4.5, 2H). The (Z)-olefin geometry was confirmed by nuclear Overhauser effect (NOE) studies (Stott et al. J. Magn. Reson. 1997, 125, 302-324) with a mixing time of 0.8 sec. When proton at 8.15 ppm was selectively inverted, NOE was observed at 3.25 ppm and 7.65 ppm.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:19][CH2:18][CH2:17]2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1Br.[Li]CCCC.[Cl:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C1COCC1.O.C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:16]2[CH2:19][CH2:18][CH2:17]2)[N:5]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[C:28]1[CH:29]=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: C[Si](C)(C)CCOCn1c(C2CCC2)nc(Br)c1Br
Reactant: Clc1ncccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(C2CCC2)nc(Br)c1-c1ccnc(Cl)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 101.4 %

Procedure:
To a solution of 4,5-dibromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.43 g, 1.0 mmol) in THF (5 mL) at −78° C. under nitrogen was added n-BuLi (2.0 M in pentane, 0.68 mL, 1.36 mmol), dropwise over 5 minutes. After 40 minutes, a solution of 2-chloropyrimidine (0.17 g, 1.47 mmol) in THF (5 mL) was added dropwise over one minute. The reaction was stirred at −78° C. for 1 hour and LCMS indicated complete reaction. The reaction was slowly quenched with 1:1 water-THF solution (50 mL) from an addition funnel, keeping the temperature between −40° C. and −35° C. After 15 minutes of stirring, a solution of DDQ (0.36 g, 1.61 mmol) in THF (20 mL) was added slowly, and the mixture was stirred for 15 minutes under ice water cooling. Aqueous 2.0 N NaOH solution (12 mL) was then added followed by 1:1 water-THF solution (12 mL). The resulting mixture was partitioned with EtOAc and the layers separated. The organic layer was washed with water (2×), brine (2×), dried (Na2SO4), and concentrated to give a brown oil (0.45 g) as 4-(4-bromo-2-cyclobutyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine which was carried forward without further purification: LCMS (m/z) 443.1 (MH+), tR=1.27 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:28]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH2:14][N:28]3[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]3)=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCc1ncc(-c2ccc(Cl)c(Cl)c2)s1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(Cc2ncc(-c3ccc(Cl)c(Cl)c3)s2)c1
Reaction time: 0.5 h
Yield: 22.2 %

Procedure:
To a solution of the compound (260 mg, 1.00 mmol) obtained in Example 22a and triethylamine (0.21 mL, 1.50 mmol) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.093 mL, 1.20 mmol), and the mixture was stirred for 30 min. The reaction mixture was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL), ethyl 1H-pyrazole-4-carboxylate (140 mg, 1.00 mmol) and potassium carbonate (207 mg, 1.50 mmol) were added, and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was extracted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (85 mg, 22%) as colorless crystals.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:17])[CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.CCN(CC)CC.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:51][C@@H:52]([C@@H:57]([CH3:62])/[CH:58]=[CH:59]\[CH:60]=[CH2:61])[C@@H:53]([CH3:56])[CH:54]=[O:55])=[CH:46][CH:45]=1>C(Cl)Cl>[OH:55][C@@H:54]([C@H:53]([CH3:56])[C@@H:52]([O:51][CH2:50][C:47]1[CH:46]=[CH:45][C:44]([O:43][CH3:42])=[CH:49][CH:48]=1)[C@@H:57]([CH3:62])/[CH:58]=[CH:59]\[CH:60]=[CH2:61])[C@@H:15]([CH3:16])[C:14]([N:9]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:17]
Reactant: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)C=O
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A solution of (R)-4-benzyl-3-propionyl-2-oxazolidinone (2.18 g, 9.34 mmol) and methylene chloride (15 mL) is cooled to −20° C. (n-Bu)2BOTf (1.0 M in DCM, 8.7 mL, 8.7 mmol) is introduced dropwise. The reaction is allowed to warm to 0° C. NEt3 (1.15 9, 11.34 mmol) is added and the mixture is stirred at 0° C. for 1 h, then cooled to −78° C. A solution of (2R,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadienal (1.95 g, 6.77 mmol) in DCM (10 mL) is added dropwise at −70° C. for 10 min. After 1 h at −74° C., the mixture is warmed to 0° C. The reaction is quenched with pH 7 buffer (15 mL). The mixture is slowly treated with a solution of 30% H2O2 in MeOH (1:2, 15 mL) at 0° C., stirred for 40 min at room temperature, and concentrated. The residue is extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with saturated aqueous NaHCO3, brine, and concentrated. Flash chromatography gives the desired compound (3.4 g, 96.4%) as a clear oil.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([F:27])[C:15]=1[O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1)[CH:11]=O.[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH2:1])[CH:13]=[C:14]([F:27])[C:15]=1[O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1
Reactant: O=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (3.85 g, 10.77 mmol) and KOtBu (1.309 g, 11.67 mmol) in dry THF (50 mL), which was stirred at room temperature for 1 h under nitrogen, was added 3,5-difluoro-4-((2-(trifluoromethyl) pyrimidin-5-yl)oxy)benzaldehyde (2.73 g, 8.98 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was neutrilized with sat. NH4Cl. The aqueous phase was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (1.47 g, 4.86 mmol, 54.2% yield) as a yellow oil. LCMS: rt=3.72 min, [M+H+]=303