Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@:2]([C@@H:6]([CH2:8]O)[OH:7])(O)[CH2:3][OH:4].C[C:11]1[C:12](=[O:16])[O:13]CC=1>CCOCC>[C:12]([O-:16])(=[O:13])[CH3:11].[CH3:8][C:6]([CH2:2][C:3]([OH:13])=[O:4])=[O:7]
Reactant: C[C@](O)(CO)[C@H](O)CO
Reactant: CC1=CCOC1=O
Solvent: CCOCC
Product: CC(=O)CC(=O)O
Product: CC(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
2-C-Methyl-D-erythritol with a ca 80% e.e. was synthesized according to a Duvold, et al. (1997) Tetrahedron Lett 38:4769–4772 and Duvold, et al. (1997) Tetrahedron Lett 38:6181–6184) adapted to the production of larger amounts. A solution of 3-methyl-2(5H)-furanone (200 mg, 2 mmol) in dry ether (20 ml) was added at 0° C. over a period of 15 min to a stirred suspension of LiAIH4 (46 mg, 1.2 mmol) in dry ether (20 ml) under argon. The reaction mixture was stirred at 0° C. for further 2 h. A saturated solution of NH4CI (2 ml) was slowly added until the excess of LiAIH4 was destroyed. After acidification with a 1M HCl solution until all aluminum salts were dissolved, the aqueous phase was extracted with ethyl acetate (6×20 ml). The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After removal of the solvent under reduced pressure, the crude diol (177 mg) dissolved in methylene chloride (20 ml) was directly acetylated for 15 min with a mixture of acetic anhydride/triethylamine (2:3, v/v, 1 ml) in presence of catalytic amounts of dimethylaminopyridine (12 mg). Solvent and excess or reagents were evaporated under reduced pressure. Flash column chromatography (Still et al., 1978) (hexanelethyl acetate, 4:1, v/v) afforded pure diacetate (330 mg, 86%). Enantioselective dihydroxylation of diacetate (300 mg, 1.6 mmol) was performed by stirring at 0° C. in terbutanol/water (1:1, v/v, 6 ml) in the presence of the chiral osmylation reagent AD-mix-b (2.5 g) and CH3SO2NH2 (152 mg, 1.6 mmol). After 24 hours, the reaction was quenched with solid Na2SO3 and additional stirring for 30 minutes. Repeated extraction with ethyl acetate (6×20 ml) and flash chromatography (ethyl acetate) afforded a mixture only containing 2-C-methyl-D-erythritol diacetates (resulting from partial intramolecular transesterifications) (312 mg, 88% yield). Quantitative deacetylation was performed overnight at room temperature in the presence of basic Amberlyst A-26 (OH— form) (150 mg for 1 mmol) in methanol (30 ml) (Reed et al., 1981) Filtration of the resin and evaporation of the solvent directly afforded pure 2-C-methyl-D-erythritol (1 90 mg, 75% overall yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.Cl.[CH3:14][C:15]1([NH:21][C:22](=[O:24])[CH3:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>[I-].[K+].CN(C)C=O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:18]2[CH2:19][CH2:20][C:15]([NH:21][C:22](=[O:24])[CH3:23])([CH3:14])[CH2:16][CH2:17]2)=[CH:7][CH:8]=1
Reactant: CC(=O)NC1(C)CCNCC1
Reactant: Fc1ccc(OCCCCl)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1(C)CCN(CCCOc2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 39.6 %

Procedure:
A mixture of 35.84 g of 1-(3-chloropropoxy)-4-fluorobenzene, 33 g of N-(4-methyl-4-piperidinyl)acetamide monohydrochloride, 54 ml of N,N-diethylethanamine, 0.1 g of potassium iodide and 1000 ml of N,N-dimethylformamide was stirred and heated for 1.5 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was taken up in a sodium carbonate solution in water and the product was extracted with dichloromethane. The extract was washed successively twice with water, twice with a sodium carbonate solution in water and again with water, dried, filtered and evaporated. The residue was purified by column chromatography (CHCl3 : CH3OH 95:5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 50° C., yielding 20.93 g of N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]acetamide; mp. 103.4° C. (interm. 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=C)=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2].C[N+]1([O-])CC[O:31]CC1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:31])=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:7]=1)=[O:5])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1c(C(=O)OCC)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C=O
Reaction time: 3.5 h

Procedure:
A solution of 5-(4-chlorophenyl)-1-(2-chlorophenyl)-4-vinyl-1H-pyrazole-3-carboxylic acid ethyl ester I-1b (2.9 g, 7.5 mmol), osmium tetroxide (8 mg, 0.08 mmol) and N-methylmorpholine-N-oxide (1.1 g, 8.2 mmol) in dioxane (24 ml)/water (6 ml) was stirred at ambient temperature for 18 hours, then sodium periodate (16 g, 75 mmol) was added and stirring was continued for 3.5 hours. The thick slurry was diluted with ethyl acetate (100 ml), filtered and solids washed 2× with ethyl acetate. The combined filtrates were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a solid mass. The solids were slurried in hot hexanes (30 ml), cooled, filtered and dried in vacuo to afford the title compound (I-1c) as a tan solid, 2.2 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)c1
Yield: 87 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 3.28 (s, 4H), 3.80 (s, 6H), 4.13 (s, 4H), 6.45-6.58 (m, 3H), 7.01 (s, 1H), 7.17-7.23 (m, 2H), 7.37-7.70 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.[OH-].[Na+:36]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:19][CH:20]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[C:6]([C:4]([O-:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:23])[CH3:22].[Na+:36]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)[O-])n3-c2ccc([N+](=O)[O-])cc2)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc([N+](=O)[O-])cc1

Procedure:
5-(4-tert-Butylphenyl)-1-(4-nitrophenyl)indole-2-carboxylic acid ethyl ester was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 1-bromo-4-nitrobenzene. This ester (207 mg, 0.47 mmol) was dissolved in dioxane (2 mL) to which aqueous NaOH (1M, 1 mL) was added. The mixture was heated using microwave irradiation at 120° C. for 15 min and allowed to cool. The precipitate was filtered off, washed with water and recrystallised from EtOH/EtOAc to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[C:15]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CN(C)c1nc(Cl)cc(Cl)n1
Reactant: NCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1nc(Cl)cc(NCc2ccccc2F)n1

Procedure:
Analogously to Example 12, 13.9 g (110 mmol) of 2-fluorobenzylamine, 21.3 g (110 mmol) of 4,6-dichloro-2-(N,N-dimethylamino)-pyrimidine and 11.5 g (114 mmol) of triethylamine are dissolved in 300 ml of absolute ethanol and the mixture is heated under reflux for 48 hours. After the ethanol has been removed by distillation, water is added to the residue, the product is filtered off with suction and recrystallisation from cyclohexane yields 4-chloro-2-(N,N-dimethylamino)-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 71°-73°.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24](O)=[O:25])[CH:21]=[CH:20][S:19]2)[CH:2]([CH3:4])[CH3:3].[F:27][C:28]([F:36])([F:35])[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:14]=[CH:15]/[C:16]1[N:17]=[C:18]2[N:22]([C:23]=1[C:24]([NH:34][C:31]1[S:32][CH:33]=[C:29]([C:28]([F:36])([F:35])[F:27])[N:30]=1)=[O:25])[CH:21]=[CH:20][S:19]2)[CH:2]([CH3:3])[CH3:4]
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)C
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)c1OCC(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 2 (150 mg, 0.403 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (79 mg, 0.484 mmol) in the presence of EDCI hydrochloride (154 mg, 0.807 mmol) and DMAP (73 mg, 0.605 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 10 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.3 Hz, 6H), 1.98-2.04 (m, 2H), 3.65-3.71 (m, 2H), 3.81 (s, 3H), 6.97-7.03 (m, 1H), 7.07-7.14 (m, 1H), 7.30-7.36 (m, 1H), 7.42-7.52 (m, 2H), 7.83 (d, J=16.2 Hz, 1H), 7.97-8.07 (m, 2H), 13.00 (br s, 1H); APCI-MS (m/z) 523.12 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.Cl.O.[NH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>>[O:27]=[C:24]1[CH2:25][CH2:26][N:21]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH2:22][CH2:23]1
Reactant: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: O=C1CCN(S(=O)(=O)c2ccc(CC3SC(=O)NC3=O)cc2)CC1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-benzene-sulfonylchloride (J. Med. Chem. 1992, 35, 1853) and 4-piperidone monohydrate hydrochloride according to the procedure of Intermediate 22 as a white solid; 1H NMR (300 MHz, DMSO-d6) □ 2.40-2.50 (m, 4 H), 3.20-3.40 (m, 5 H), 3.50 (dd, J=14.1, 4.7 Hz, 1 H), 5.00 (dd, J=10.4, 4.7 Hz, 1 H), 7.56 (d, J=8.4 Hz, 2 H), 7.76 (d, J=8.4 Hz, 2 H), 12.09 (s, 1 H); MS (ES) m/z: 368.9 (M++H); HRMS Calcd. for C15H16N2O5S2(M++H): 368.0501. Found: 368.0481. Anal. Calcd. for C15H16N2O5S2: C, 48.90; H, 4.38; N, 7.60. Found: C,48.63; H, 4.35; N, 7.38.
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[Br:14]Br.N>CO.C(Cl)Cl>[CH2:1]([N:4]1[C:8]2[C:9]([Br:14])=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCn1cnc2ccc(N)cc21
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCn1cnc2ccc(N)c(Br)c21
Yield: 37 %

Procedure:
To a solution of 3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10 ml of ACOH was added solution of Br2 in ACOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.40 g (1.6 mmol, 37%) of the product.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([S:9](Cl)(=[O:11])=[O:10])[CH2:5][CH2:4]1.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O.O1CCOCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][O:25][CH:26]2[CH2:31][CH2:30][N:29]([S:9]([N:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)(=[O:11])=[O:10])[CH2:28][CH2:27]2)=[O:23])=[CH:17][CH:16]=1
Reactant: CN1CCN(S(=O)(=O)Cl)CC1
Reactant: O=C(NOC1CCNCC1)Nc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(S(=O)(=O)N2CCC(ONC(=O)Nc3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
4-Methylpiperazine-1-sulfonyl chloride hydrochloride (227 mg, 0.966 mmol) was added at room temperature to a solution of 1-(4-fluorophenyl)-3-(piperidin-4-yloxy)urea hydrochloride (140 mg, 0.483 mmol) and K2CO3 (200 mg, 1.45 mmol) in H2O-dioxane (1:1, 4 ml), and the whole was stirred at room temperature for 18 hours. The reaction was quenched with K2CO3 (200 mg) in H2O (10 ml), extracted with ethyl acetate (20 ml×3). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (chloroform/methanol: 90/10) to give 1-(4-fluorophenyl)-3-(1-(4-methylpiperazin-1-ylsulfonyl)piperidin-4-yloxy)urea (139 mg, 69%) as pale yellow amorphous: LCMS: 416 [M+1]+. 1H NMR (DMSO-d6) δ: 1.72 (m, 2H), 1.93 (m, 2H), 2.19 (s, 3H), 2.35 (m, 4H), 3.01-3.13 (m, 6H), 3.45 (m, 2H), 3.85 (m, 1H), 7.11 (m, 2H), 7.55 (m, 2H), 8.68 (s, 1H), 9.45 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=3)=[C:20]([OH:22])[CH:21]=1)=[N:5][CH:6]=[N:7]2.I[CH2:35][CH2:36][CH3:37].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[C:4]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=3)=[C:20]([O:22][CH2:35][CH2:36][CH3:37])[CH:21]=1)=[N:5][CH:6]=[N:7]2
Reactant: Oc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cc(CCNc2ncnc3c(F)ccc(F)c23)ccc1Oc1cc(C(F)(F)F)ccn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
To a solution of 5-[2-(5,8-difluoroquinazolin-4-ylamino)-ethyl]-2-(4-trifluoromethylpyridin-2-yloxy)-phenol (0.462 g, 0.5 mmol) in DMSO (5 mL) was added 1-iodopropane (0.204 g, 1.2 mmol) and K2CO3 (0.207 g, 1.5 mmol). The reaction mixture was stirred at 50° C. overnight and then at 70° C. for another 24 h. After cooling to room temperature, the mixture was poured into water and the gum-like material was separated via suction filtration and washed with water. The gum-like product then was partitioned between CH2Cl2 and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo, and the product was purified by preparative reverse phase HPLC to give 0.161 g (32%) of (5,8-difluoroquinazolin-4-yl)-{2-[3-propoxy-4-(4-trifluoromethylpyridin-2-yloxy)-phenyl]-ethyl}-amine as a brown gum; MS m/z 504. 1H NMR (CDCl3): δ 8.68 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 7.33 (m, 1H), 7.08-7.15 (m, 3H), 6.87-7.03 (m, 3H), 6.70-6.83 (br, 1H), 3.89-3.97 (m, 2H), 3.80-3.86 (m, 2H), 3.02 (t, J=6.9 Hz, 2H), 1.51 (m, 2H), 0.66 (t, J=7.2 Hz, 3H). LC/MS: 506.10 (M++1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:9]=[CH:8][S:7][N:6]=1)[CH:2]=[CH2:3].[F:10][S:11]([O:14][CH3:15])(=[O:13])=[O:12]>>[F:10][S:11]([O-:14])(=[O:13])=[O:12].[CH2:1]([O:4][C:5]1[CH:9]=[CH:8][S:7][N+:6]=1[CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccsn1
Reactant: COS(=O)(=O)F
Product: C=CCOc1ccs[n+]1C
Product: O=S(=O)([O-])F
Yield: 89 %

Procedure:
3-Allyloxyisothiazole (4.0 g, 0.028 mol) and 5 ml methyl fluorosulfonate were heated at 60° for 45 min. After cooling, the solid was washed with ether to yield 6.5 g (89%) of 3-allyloxy-2-methylisothiazolium fluorosulfonate, mp 50°-53°. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: CC1C=CC(S(OC[CH2:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[C:17]([S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[CH:18][NH:19]3)(=O)=O)=CC=1.[CH2:33]([NH:35][CH3:36])[CH3:34].[CH2:37]1COCC1>[OH-].[Na+]>[CH2:33]([N:35]([CH3:37])[CH2:36][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[CH:18][NH:19]2)[CH3:34]
Reactant: CCNC
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2cccc3[nH]cc(S(=O)(=O)c4ccccc4)c23)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCN(C)CCCc1cccc2[nH]cc(S(=O)(=O)c3ccccc3)c12
Temperature: 65 °C
Yield: 100 %

Procedure:
To a solution of 3-[3-(phenylsulfonyl)-1H-indol-4-yl]propyl 4-methylbenzenesulfonate (0.21 g, 0.447 mmol) in anhydrous THF (5 mL) was added N-ethylmethylamine (0.77 mL, 8.944 mmol) and the reaction mixture heated to 65° C. in a sealed vessel for 16 hours. The cooled reaction mixture was then diluted with 1 N aqueous NaOH (50 mL) and the resulting milky suspension extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford N-ethyl-N-methyl-3-[3-(phenylsulfonyl)-1H-indol-4-yl]propan-1-amine as a cream solid (0.16 g, 100%). The product was dissolved in absolute ethanol (10 mL), 1.25 N HCl in ethanol (0.47 mL, 0.583 mmol, 1.3 equivalents) added, the mixture stirred for 15 min and then concentrated in vacuo to afford a yellow syrup. The product was crystallized from ethanol (5 mL) to give the title compound as white needles (0.121 g, 69%). MS (ES+) m/z 356.9 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43]N=1)C.O>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)CCCCCCCCCCCCC>[C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:25][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][O:24][CH2:41][CH2:46][CH2:45][CH2:44][CH2:43][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:6][CH2:7][CH2:28][CH3:29])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(O)CO)cc1)C(=O)OC(C)(C)C
Reactant: CN(C)c1ccccn1
Agent: CCCCCCCCCCCCCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCOCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of (4-(6,7-dihydroxy-4-thiaheptanoylamino)benzoyl)glutamic acid di-t-butyl ester as obtained in Reference Example 6 (50 mg) in chloroform (1 ml), triethylarnine (0.258 ml), myristyl chloride (0.196 ml) and dimethylaminopyridine (1 mg) were added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (76 mg, yield 85%) as a wax-like substance.
Reaction SMILES: Cl[O-].[Na+].[OH:4][N:5]=[CH:6][CH2:7][O:8][CH:9]([C:13]1([CH3:16])[CH2:15][CH2:14]1)[CH2:10][CH:11]=[CH2:12].C(N(CC)CC)C>ClCCl.O>[CH3:16][C:13]1([C@@H:9]2[O:8][CH2:7][C:6]3=[N:5][O:4][CH2:12][C@@H:11]3[CH2:10]2)[CH2:15][CH2:14]1
Reactant: C=CCC(OCC=NO)C1(C)CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1([C@H]2C[C@H]3CON=C3CO2)CC1

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 65 mL, 51 mmol) was added drop-wise over 24 minutes to a solution of N-hydroxy-2-{[1-(1-methylcyclopropyl)but-3-en-1-yl]oxy}ethanimine (C55) (6.54 g, 36 mmol) and triethylamine (280 mg, 2.7 mmol) in dichloromethane (64 mL) that was immersed in a room temperature water bath. The rate of addition was adjusted to maintain the internal temperature of the reaction between 19.5° C. and 22.8° C. After completion of the addition, the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo (300 mbar, 40° C.). Silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) provided the product as a white solid. Yield: 3.84 g, 21.2 mmol, 57%. The indicated relative stereochemistry of compound C56 was assigned based on nuclear Overhauser enhancement studies, which revealed an interaction between the methine protons on carbons 3a and 5. LCMS m/z 182 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 4.73 (d, J=13.2 Hz, 1H), 4.64 (dd, J=10.4, 8.0 Hz, 1H), 4.14 (d, J=14.1 Hz, 1H), 3.81 (dd, J=11.6, 8.0 Hz, 1H), 3.44-3.39 (m, 1H), 2.82 (d, J=12.8 Hz, 1H), 2.21-2.15 (m, 1H), 1.76 (q, J=11.9 Hz, 1H), 1.05 (s, 3H), 0.55-0.51 (m, 1H), 0.44-0.41 (m, 2H), 0.40-0.39 (m, 1H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[OH-].[K+]>>[C:1]([OH:6])(=[O:7])[CH2:2][CH2:3][C:4]([OH:9])=[O:5].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]
Reactant: O=C1CCC(=O)O1
Agent: COCCOCCOCCO
Agent: [K+]
Agent: [OH-]
Product: O=C(O)CCC(=O)O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
In a 3-L flask equipped with a stirrer, a thermometer and a dehydration tube, 500 g of succinic anhydride, 2,463 g of triethylene glycol monomethyl ether and 9.5 g of paratoluenesulfonic acid monohydrate were charged and the mixture was reacted under reduced pressure of 4 to 10.7 kPa at 110° C. for 15 hours, while blowing nitrogen (500 mL/minute) into the space. The acid value of the reaction solution was 1.6 (KOH mg/g). To the reaction solution, 27 g of an adsorbent Kyoward 500SH (manufactured by Kyowa Chemical Industry Co., Ltd.) was added, stirred at 80° C. at 2.7 kPa for 45 minutes, and filtered. Thereafter, triethylene glycol monomethyl ether was distilled off at a liquid temperature of 115 to 200° C. at a pressure of 0.03 kPa. After cooling to 80° C., the residual liquid was filtered under reduced pressure, to give a diester of succinic acid and triethylene glycol monomethyl ether as a filtrate. The resultant diester had an acid value of 0.2 (KOH mg/g), a saponification value of 276 (KOH mg/g), a hydroxyl value of 1 or less (KOH mg/g) and a hue of APHA200.