Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH:5]([C:9](F)=[O:10])[C:6]([F:8])=[O:7])([F:4])[F:3].C=C=O>>[F-:1].[F:1][C:2]([C:5]([C:6]([F:8])=[O:7])=[C:9]=[O:10])([F:4])[F:3]
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Agent: C=C=O
Product: O=C=C(C(=O)F)C(F)(F)F
Product: [F-]
Yield: 15 %
Yield: 40 %

Procedure:
A mixture of 17.6 g (0.10 mol) of trifluoromethylmalonyl fluoride (containing ca. 5% of the ketene) and 24 g (0.3 mol) of SO3 was heated and crude distillate was redistilled to provide 11.9 g (40%) of pyrosulfuryl fluoride, bp 51°-54°C, and 2.4 g (15%) of trifluoromethylfluorocarbonylketene, bp 58°-59.5°C. Pyrosulfuryl fluoride was identified by comparison of bp, infrared spectrum and nmr spectrum with those reported for authentic samples. The ketene was shown in infrared to be the same as that prepared in Example 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)\[CH2:7][Br:17])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(Br)c1
Yield: 31.6 %

Procedure:
To a stirred mixture of (E)-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (5.80 g, 0.020 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (5.51 g, 0.031 mol) and benzoyl peroxide (500 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-bromo-phenoxy)-but-2-enoic acid ethyl ester (2.30 g, 31%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13](=[O:15])[CH3:14])[O:8][C:7](=[O:16])[CH:6]=[C:5]2[CH3:17].[Se]=[O:19]>C1(C)C=CC=C(C)C=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13](=[O:15])[CH3:14])[O:8][C:7](=[O:16])[CH:6]=[C:5]2[CH:17]=[O:19]
Reactant: O=[Se]
Reactant: CC(=O)Oc1cc2oc(=O)cc(C)c2cc1Br
Solvent: Cc1cccc(C)c1
Product: CC(=O)Oc1cc2oc(=O)cc(C=O)c2cc1Br
Yield: 67.7 %

Procedure:
A mixture of 404.9 mg (1.363 mmol) of compound 18, 239.2 mg (2.156 mmol) of selenium oxide in m-xylene (15 mL) was stirred under refluxed temperature for 21 hours. The reaction mixture was cooled and evaporated. Purification by column chromatography gave 287.0 mg (0.9226 mmol, 67.7% yield) of compound 19.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:24]([O:23][CH2:22][CH2:21][O:20][CH3:19])=[O:25])[N+:7]([O-:8])=[C:6]([NH:9][C:24]([O:23][CH2:22][CH2:21][O:20][CH3:19])=[O:25])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: COCCOC(=O)Cl
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCCOC)[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]-pyrimidine-3-oxide are stirred at 5° C. in 150 ml. of methylene chloride and 30 ml. of triethylamine and treated with 20 ml. of chloroformic acid 2-methoxyethyl ester. The mixture is stirred at room temperature for 4 hours, then washed with water and extracted with methylene chloride. The organic phases are evaporated under reduced pressure and the residue is recrystallized from diethyl ether, there being obtained bis(2-methoxyethyl) 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 126°-128° C.
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[CH:23]=[C:24]([CH3:25])[CH3:26])[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C=C(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)=CC(=O)N1CC(NC(=O)Nc2cccc(C(=O)O)c2)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Yield: 68.8 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(3-methyl-2-butenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (340 mg) was dissolved in methanol (16 ml), aqueous lithium hydroxide monohydrate (120 mg) solution (8 ml) and tetrahydrofuran (8 ml) were added, and the mixture was refluxed for 50 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 223 mg of the titled compound (Yield: 68.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(F)cc3F)c2O1)OCc1ccccc1
Yield: 80.5 %

Procedure:
Treatment of (±)-1-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.0 g, 6.72 mmol) with diisopropylethylamine (1.30 g, 10.07 mmol) followed by benzyl chloroformate (1.26 g, 7.37 mmol) generally according to the procedure described for Intermediate 12 gave 2.14 g (81%) of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 78-80° C.; Anal. calcd. for C23H19F2NO3: C, 69.87; H, 4.84; N, 3.54. Found: C, 69.76; H, 4.8; N, 3.35. Chiral HPLC separation of (±)-benzyl {[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=9.117 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (Rt=9.424 min, Chiralpak AD ethanol:hexane 1:1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].C(=O)([O-])[O-].[Ba+2].[CH3:12][O:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C@H:19]1[O:29][CH:23]([O:24]CCCC)[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32].[OH2:33]>CO>[CH3:12][O:13][CH2:14][CH2:15][CH2:16][N:17]([CH:18]([OH:33])[C@H:19]1[O:29][C@:23]([CH2:18][CH2:19][CH2:20][CH3:21])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:5](=[O:6])[NH:4][CH2:3][CH2:2][Cl:1]
Reactant: CCCCOC1O[C@H](CNCCCOC)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C=NCCCl
Reactant: O
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCCOC)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Yield: 32.2 %

Procedure:
2-Chloroethyl isocyanate (1.33 g) and barium carbonate (2.5 g) were added to a solution of n-butyl 6-(3-methoxy-n-propylamino)-6-deoxy-D-glucopyranoside 1/2 sulfate (3.64 g, 10.5 mmol) in a mixture of water (10 ml) and methanol (30 ml) at 0° to 5° C., and the mixture was heated under reflux on a water bath for 1 hour. The reaction mixture was then filtered while hot, to remove the insoluble barium salt. The filtrate was vacuum-concentrated and fractionated by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1) to separate the α- and β-form of products. The objective α- and β-form product fractions were each vacuum-concentrated at 25° C. and crystallized from aqueous isopropanol, giving 1.40 g of 3-(3-methoxy-n-propyl)-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-urea; yield 32.2%, m.p. 103°-105° C., [α]D20 +50.8° (C 1.0, methanol); and 1.32 g of 3-(3-methoxy-n-propyl)-3-(n-butyl β-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea; yield 30.4%, m.p. 109°-111° C., [α]D20 -4.7° (C 1.0, methanol).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1ccncc1B(O)O
Product: CCNC(=O)c1nnc2c(-c3cnccc3OC)cccc2c1N
Yield: 25.6 %

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide (70.0 mg, 0.237 mmol) and 4-methoxy-3-pyridine boronic acid (153.0 mg, 0.3439 mmol) according to Method A except that the extraction was carried out with methylene chloride rather than ethyl acetate and the flash column was eluted with a gradient of 10to 60% methanol in dichloromethane. The concentrated product was then recrystallized from chloroform (with a few drops of methanol) and hexanes to afford the title compound as a yellow solid (19.6 mg, 26% yield). 1H NMR (300.132 MHz, CDCl3) δ 8.58 (d, J=5.7 Hz, 1H), 8.52-8.43 (bm, 1H), 8.46 (s, 1H), 7.92 (app quintet, J=4.0 Hz, 1H), 7.74 (dd, J=4.9, 0.9 Hz, 2H), 6.96 (d, J=5.8 Hz, 1H), 3.78 (s, 3H), 3.53 (dq, J=5.8, 7.3, Hz, 2H), 1.27 (t, J=7.3 Hz, 3H). MS APCI, m/z=324 (M+H). HPLC 1.42 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=3)[C:9]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C(OC1C=C(C=[C:43]([N+:46]([O-])=O)C=1O)C=O)C.NC(N)=O.Cl>CCO>[CH2:26]([O:25][C:17]1[CH:16]=[C:15]([CH:10]2[C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:43]#[N:46])=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[NH:13][C:12](=[O:14])[NH:11]2)[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]=1[OH:24])[CH3:27]
Reactant: CCOc1cc(C2NC(=O)NC(c3ccc(Br)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: NC(N)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2C#N)cc([N+](=O)[O-])c1O
Yield: 29 %

Procedure:
A mixture of 2-(2-oxo-2-phenylethyl)benzonitrile (Intermediate 33) (100 mg, 0.45 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (87 mg, 0.41 mmol), urea (81 mg, 1.36 mmol), and concentrated HCl solution (0.03 mL, 0.41 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was concentrated, and purified by preparative HPLC to give Compound 70 (54.26 mg, yield 29%) as a yellow solid. 1H NMR (DMSO-d6 300 MHz): δ 10.24 (s, 1H), 8.91 (s, 1H), 7.61 (s, 1H), 7.51-7.44 (m, 2H), 7.31 (s, 1H), 7.24-7.16 (m, 4H), 7.13-7.08 (m, 3H), 5.37 (s, 1H), 3.99-3.93 (m, 2H), 1.31 (t, J=6.8 Hz, 3H); MS (ESI): m/z 456.8 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:8]2[CH:9]=[C:10]([CH2:13][C:14]([O:16][CH3:21])=[O:15])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]2[CH:17]=[CH:18][S:19][C:3]1=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2

Procedure:
4,10-Dihydro-10-oxothieno[3,2-c] [1] benzoxepin-8-acetic acid, 25.5 g, synthesized according to the method of D. E. Aultz, et al. [J. Med. Chem., 20, 456 (1977)] and 0.9 g of p-toluenesulfonic acid monohydrate were heated under reflux for 3 hours in 600 ml of methanol. The solvent was distilled off under reduced pressure and the resulting residue was extracted with 500 ml of ethyl acetate. After washing in sequence with saturated sodium bicarbonate aqueous solution and then with saturated sodium chloride aqueous solution, the extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=3:1) to give 24.9 g of methyl 4,10-dihydro-10-oxothieno[3,2-c] [1] benzoxepin-8-acetate as light yellow solids.
Reaction SMILES: C1(=O)C2C(=CC=CC=2)CC1.Br[CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14](=[O:22])[CH2:13]1.C(N(CC)CC)C>O1CCCC1>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([CH:12]=[CH:13][C:14]2=[O:22])=[CH:19][CH:18]=1
Reactant: O=C1CC(Br)c2ccc(Cl)cc21
Agent: O=C1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1C=Cc2ccc(Cl)cc21

Procedure:
Further exemplary methods of synthesis include conversion of indanone A to intermediate C via treatment of 3-bromo-6-chloro-indan-1-one (A; for references on this material, see: Bøgesø EP 35363 A1 19810909 and Kehler, Juhl, Püschl, WO 2008025361; each herein incorporated by reference in its entirety) with a base such as triethylamine in a solvent such as tetrahydrofuran at ambient temperature (Scheme 1). Removal of the precipitated amine hydrobromide salt by filtration and concentration of the filtrate will afford 6-chloro-inden-1-one (B). This material can be reacted with phenyl-d5-boronic acid in the presence of approximately 1 equivalent of a base such as triethylamine and a catalytic amount of a 1:1 mixture of [Rh(ndb)2]BF4 (bis(norbornadiene)rhodium(I) tetrafluoroborate) and racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) in a suitable solvent (e.g. approximately 10:1 solvent mixture of 1,4-dioxane and water) under an atmosphere of argon at elevated temperature (e.g. about 100° C.). Work-up will afford racemic 6-chloro-3-phenyl-d5-indan-1-one (C).
Reaction SMILES: [CH3:1][OH:2].[Na].[NH2:4][C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1.O>C(Cl)(Cl)Cl>[NH2:4][C:5]1[CH:10]=[C:9]([O:2][CH3:1])[N:8]=[C:7]([CH2:12][CH2:13][CH3:14])[N:6]=1
Reactant: CO
Reactant: CCCc1nc(N)cc(Cl)n1
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1nc(N)cc(OC)n1

Procedure:
To a mixture of 25 ml of methanol and 1.1 g (0.048 mole) of sodium was added 5.1 g (0.030 mole) of 4-amino-6-chloro-2-(n-propyl)pyrimidine, and the resulting mixture was heated at reflux for four days. The mixture was allowed to cool to about 20° C., at which time water and chloroform were added thereto. The layers were separated, and the aqueous layer was extracted with additional chloroform. The organic layers were combined, dried over magnesium sulfate, and evaporated to provide a residue. The residue was recrystallized from cyclohexane with treatment with decolorizing charcoal to provide white solid 4-amino-6-methoxy-2-(n-propyl)pyrimidine, m.p. 97°-99° C. The structural assignment was supported by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23]O)[C:19](=[O:25])[CH:18]([CH2:26][C:27](O)=[O:28])[S:17]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:32])=O.CN(C)C=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[C:12]([C:9]1[CH:8]=[C:7]([CH:16]2[N:20]([CH2:21][CH2:22][CH2:23][Cl:32])[C:19](=[O:25])[CH:18]([CH2:26][C:27]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:28])[S:17]2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: O=S(Cl)Cl
Reactant: C1CCNC1
Reactant: CC(C)(C)c1cc(C2SC(CC(=O)O)C(=O)N2CCCO)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C2SC(CC(=O)N3CCCC3)C(=O)N2CCCCl)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a suspension of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-hydroxypropyl)-5-carboxymethyl-1,3-thiazolidin-4-one (0.61 g) obtained in Reference Example 41 in dichloromethane (20 ml) were added thionyl chloride (0.38 g) and a catalytic amount of dimethylformamide, and the mixture was refluxed for 2 hours. After allowing to cool, the mixture was added dropwise to a solution of pyrrolidine (1.02 g) in dichloromethane (20 ml) under cooling with ice, and stirred at that temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice-water and extracted with chloroform. The organic layer was washed successively with 1N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 97:3) and then recrystallized from chloroform/n-hexane to yield 0.65 g (92%) of the title compound as colorless crystals. mp 193-194° C. NMR (CDCl3) (200 MHz) δ: 1.43 (18H, s), 1.4-2.2 (6H, m), 2.5-3.1 (2H, m), 3.2-3.7 (8H, m), 4.2-4.5 (1H, m), 5.29 (1H, s), 5.53 (1H, s), 7.08 (2H, s)
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][CH2:9][CH2:10][OH:11].[NH2:12][C:13]1[CH:41]=[CH:40][C:16]2[NH:17][C:18]([C:23]3[C:24](=[O:39])[N:25]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C:26]4[C:31]([C:32]=3[OH:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:19][S:20](=[O:22])(=[O:21])[C:15]=2[CH:14]=1.C(N(CC)CC)C.Cl>ClCCl>[OH:33][C:32]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:34][CH2:35][CH:36]([CH3:37])[CH3:38])[C:24](=[O:39])[C:23]=1[C:18]1[NH:17][C:16]2[CH:40]=[CH:41][C:13]([NH:12][S:2]([NH:5][C:6](=[O:7])[O:11][CH2:10][CH2:9][Cl:8])(=[O:4])=[O:3])=[CH:14][C:15]=2[S:20](=[O:21])(=[O:22])[N:19]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: OCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCCCl)ccc3N2)c(O)c2cccnc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.1 %

Procedure:
A solution of chlorosulfonyl isocyanate (33 mg, 0.23 mmol) in dichloromethane (8 mL) was cooled to 0° C. and 2-chloroethanol (18.8 mg, 0.23 mmol) was added dropwise. The mixture was stirred at 0° C. for 90 minutes followed by the addition of a solution containing the product of Example 205 (100 mg, 0.23 mmol) and triethylamine (71 mg, 0.70 mmol) in dichloromethane (2 mL). The mixture was stirred for 24 hrs at 25° C. then partititioned between dichloromethane (25 mL) and 1N aqueous hydrochloric acid (20 mL). The resulting organic layer was separated and dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (96 mg, 67%). MS (ESI−) m/z 611 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.69 (m, 1 H) 3.78 (m, 2 H) 4.32 (m, 2 H) 4.49 (m, 2 H) 7.51 (m, 2 H) 7.63 (s, 1 H) 7.77 (d, J=9.19 Hz, 1 H) 8.56 (dd, J=7.72, 1.10 Hz, 1 H) 8.90 (dd, J=4.41, 1.47 Hz, 1 H) 11.15 (s, 1 H) 12.26 (s, 1 H) 14.10 (s, 1 H).
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[C:14]([CH3:36])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([OH:35])=O)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>C1COCC1>[OH:1][C@@H:2]([C:13]1[C:14]([CH3:36])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:35])[CH2:31][CH2:32]3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1-(4′-{4-[(S)-1-Hydroxy-2-((R)-1-phenyl-ethoxy)-ethyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.022 g, 0.044 mmol) was dissolved in THF (3 mL) and carbonyldiimidazole (0.022 g, 0.14 mmol) was added. After 1.5 hours an additional portion of carbonyldiimidazole (0.011 g) was added. The reaction stirred for 40 minutes then carbonyldiimidazole (0.044 g) was added. The reaction stirred overnight then carbonyldiimidazole (0.044 g) was added and the reaction was heated to 50° C. After heating for 3 hours, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.100 mL, 0.67 mmol) and methanesulfonamide (0.050 g, 0.53 mmol) were added and the reaction was heated to 100° C. The reaction was monitored by analytical LCMS and when it was complete it was cooled and purified on preparatory HPLC to afford the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(C1C=C(O)C(C(C)(C)C)=CC=1O)(C)(C)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C(C)C(=O)OCCO
Agent: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of 2,5-di-t-butylhydroquinone (polymerization inhibitor) were added. The mixture was heated to keep about 130° C. for 3 hours in nitrogen atmosphere with distilling 23.5 ml (0.40. mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 64.8 g (yield 52.4%) of 2-ethoxalyloxyethyl methacrylate (bp 95°-125 ° C./0.3 mmHg).
Reaction SMILES: [OH-:1].[Na+:2].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]2[C:10](=[O:21])[O:11][C:12](=[O:20])[C:13]=2[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:5][CH2:4]1>O1CCOCC1>[O:3]1[CH2:8][CH2:7][CH:6](/[C:9](=[C:13](\[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)/[C:12]([O-:11])=[O:20])/[C:10]([O-:21])=[O:1])[CH2:5][CH2:4]1.[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: O=C1OC(=O)C(C2CCOCC2)=C1C1CCOCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C([O-])/C(=C(\C(=O)[O-])C1CCOCC1)C1CCOCC1
Reaction time: 24 h
Yield: 94.8 %

Procedure:
A 1 M NaOH (4.5 ml, 4.5 mmol) was added to a solution of 3,4-bis(tetrahydro-2H-pyran-4-yl)furan-2,5-dione (600 mg, 2.25 mmol) in 1,4-dioxane (4.5 ml) at room temperature, and the mixture was stirred for 24 hr. The reaction mixture was concentrated, and the residue was dried in vacuo to give the title compound as a colorless solid (0.7 g, quantitative).