Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:34][C@@H:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH:26]3[OH:35])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: OC(CN[C@@H]1c2ccccc2CC1O)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, (1S, 2R)-(−)-cis-1-amino-2-indanol, and ethanol, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=435.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][N:24]2C(=O)C3C(=CC=CC=3)C2=O)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[OH-].[NH4+:36]>ClC(Cl)C>[NH2:24][O:23][CH2:22][CH2:21][CH2:20][CH2:19][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:36])[C:8]=2[N:18]=[C:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCON1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCON
Yield: 30.9 %

Procedure:
A mixture of 2-[4-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]-1H-isoindole-1,3(2H)-dione (8.92 g, 19.5 mmol) in dichloroethane (100 mL) was shaken vigorously until it became homogeneous. With vigorous stirring, ammonium hydroxide (100 mL) andp-toluenesulfonyl chloride (4.45 g, 23.4 mmol) were added sequentially. The reaction was stirred overnight at room temperature. The product was present as a white precipitate, which was isolated by filtration to provide 1.97 g of 1-[4-(aminooxy)butyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][C:12]2[CH:13]=[C:14]([CH3:28])[C:15]3[CH:19]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:18][B:17]([OH:26])[C:16]=3[CH:27]=2)=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH2:24]([O:23][C:21]([CH2:20][CH:19]1[O:18][B:17]([OH:26])[C:16]2[CH:27]=[C:12]([O:11][C:8]3[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=3)[CH:13]=[C:14]([CH3:28])[C:15]1=2)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=O)OC)cn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=O)O)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of 5-(3-ethoxycarbonylmethyl-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-pyrazine-2-carboxylic acid methyl ester (2.15 g, 11.3 mmol) in THF (42 mL) was added LiOH (0.47 g, 22.6 mmol) in water (21 mL). The mixture was stirred at room temperature for 1 h and acidified by 1N HCl to pH 3. The mixture was extracted by ethyl acetate, and the organic layer was washed with water and brine, dried from Na2SO4 and concentrated. The residue was purified by column chromatography (silica, DCM/MeOH=9:1) affording the title compound (1.9 g, 92%) as a white solid. 1H NMR (CDCl3) δ 8.96 (s, 1H), 8.42 (s, 1H), 7.31 (d, 1H), 7.03 (d, 1H), 5.68 (dd, 1H), 4.10 (q, 2H), 3.11 (dd, 1H), 2.43 (m, 1H), 2.40 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([NH:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)[CH3:18]>>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([N:19]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)[CH2:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(C(=O)OCC)cc1
Reactant: O=C(O)c1sccc1OCc1ccccc1
Product: CCOC(=O)c1ccc(N(CC)C(=O)c2sccc2OCc2ccccc2)cc1

Procedure:
3-Benzyloxy-2-thienylcarboxylic acid was converted to the corresponding acid chloride which was reacted with ethyl 4-ethylaminobenzoate using a similar method to that of Example 4 to give ethyl 4-[N-(3-benzyloxy-2-thienoyl)-N-ethylamino]benzoate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH:10]([C:21]([OH:23])=[O:22])[CH2:9]1>CO.C(O)(C(F)(F)F)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:13]2[CH2:8][CH2:9][C@H:10]([C:21]([O:23][CH3:1])=[O:22])[CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1

Procedure:
Trimethylsilyldiazomethane (15.71 ml, 31.4 mmol) was slowly added into a solution of (e)-4-(4-chlorophenyl)cyclohexanecarboxylic acid (3 g, 12.57 mmol) in MeOH (75 mL) at room temperature. LCMS indicated complete conversion in 1 hr. Added a few drops of TFA to quench the reaction. Volatiles were removed under reduced pressure. The resulting pot residue was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 20%). Related fractions were pooled and evaporated to afford a white solid as the titled compound. LCMS calc.=252.09. found=253.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](Cl)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(N2CCOCC2)c1[N+](=O)[O-]
Temperature: 115 °C
Yield: 46.6 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (12 g, 34 mmol) in DMSO (50 mL) was added morpholine (3.6 g, 41 mmol) followed by N,N-diisopropylethylamine (8.9 g, 69 mmol). The mixture was heated at 110-120° C. for 4 hours, then cooled to ambient temperature, quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine (2×30 mL), dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 6.3 g (46% yield) of N-(5-chloropyridin-2-yl)-2-nitro-3-(morpholin-4-yl)-5-chlorobenzamide; NMR (CDCl3) 8.2 (m, 1), 7.7 (m, 1), 7.2-7.4 (m, 3), 3.8 (m, 4), 3.0 (m, 4) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:46][CH3:47])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12])=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:45])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:2].Cl>O1CCOCC1>[CH2:46]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([OH:18])=[O:17])=[O:12])=[C:6]([C:26]2[CH:31]=[C:30]([C:32](=[O:45])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=3)[CH:29]=[CH:28][N:27]=2)[CH:5]=1)[CH3:47]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoate was added 4M HCl in dioxane (25 mL). The mixture was stirred at room temperature for 3 hours, concentrated to give a light yellow solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:22])[CH:16]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccccc2Cl)c1
Yield: 70.8 %

Procedure:
2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.051 g (70%) of 2′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[Cl:9][C:10]1[N:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:19][C:18]2([CH3:30])[CH3:29])[N:11]=1>O.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=[C:12]([N:17]2[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:19][C:18]2([CH3:30])[CH3:29])[N:11]=1
Reactant: C1COCCN1
Reactant: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(Cl)n1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC2(CC(C)(C)N1c1nc(Cl)nc(N3CCOCC3)n1)OCCO2
Reaction time: 1.5 h

Procedure:
3.8 g of morpholine and, 15 minutes later, a solution of 1.7 g of NaOH in 5 ml of water are added to a solution of 30 g of 2,4-dichloro-6-(4,4-ethylenedioxy-2,2,6,6-tetramethylpiperidin-1-yl)-1,3,5-triazine (product from Example 17) in 100 ml of toluene. The mixture is then warmed to 6020 and after 45 minutes a further 3.8 g of morpholine and 1.7 g of NaOH in 5 ml of water are added. After a further 1.5 hours, the reaction has ended. After cooling and adding 200 ml of toluene, the phases are separated. The organic phase is dried over Na2SO4 and evaporated. Recrystallizing from acetonitrile leads to the compound of the above structure which melts at 154°-156° (white powder).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>CN(C)C=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccn2)ccc1C=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
In 53 mL of N,N-dimethylformamide were dissolved 8.00 g (52.6 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 14.5 g (105 mmol) of potassium carbonate, and 9.06 g (55.2 mmol) of 2-chloromethylpyridine hydrochloride and the solution was stirred at 50° C. for 4 hours. To the reaction mixture, 260 mL of water was added at room temperature and the precipitated crystal was separated by filtration. The crystal was washed with water and dried under reduced pressure to give 11.5 g (82% yield) of the title compound as a pale grey-brown powder with the following properties.
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1SC#N)(=O)C.[NH3:13].C([S:16][C:17]1[CH:22]=CC=CN=1)#N.C[Li]>O1CCCC1>[CH3:22][C:17]1[S:16][N:13]=[C:5]2[C:6]=1[N:7]=[CH:8][CH:9]=[CH:4]2
Reactant: CC(=O)c1ccncc1SC#N
Reactant: N#CSc1ccccn1
Reactant: N
Agent: [Li]C
Solvent: C1CCOC1
Product: Cc1snc2cccnc12

Procedure:
Scheme I-19 depicts the preparation of isothiazolobenzene or isothiazolopyridine glyoxylic acid derivatives which may be employed to prepare compounds of formula I. 3-methyl isothiazolopyridines can be prepared as depicted in step a by using methodology as described in Taurins, A.; Khouw, V. T. Can. J. Chem. 1973, 51(11), 1741-1748. For example Isothiazolo[3,4-b]pyridine was synthesized from 2-aminonicotinonitrile in three steps: by the reaction with NH3 and H2S to produce 2-aminothionicotinamide; oxidative cyclization with H2O2 to give 3-amino-isothiazolo[3,4-b]pyridine, followed by diazotization and reduction with hypophosphorous acid. 3-Aminoisothiazolo[4,3-b]pyridine was prepared in a similar way from 3-aminopicolinonitrile via 3-aminothiopicolinamide. Isothiazolo[5,4-b]pyridine was synthesized from 2-chloronicotinonitrile in three steps: reduction with HCO2H in the presence of Raney Nickel to obtain 2-chloronicotinaldehyde; transformation of the latter into 2-thiocyanonicotinaldehyde; and cyclization with NH3 to obtain isothiazolo[5,4-b]pyridine. 3-Methylizothiazolo[5,4-c]pyridine was prepared by cyclization of 4-acetyl-3-thiocyanopyridine with NH3. Alternatively, the 3-methylisothiazolopyridines may be prepared as described in Chimichi, S.; Giomi, D.; Tedeschi, P. Synth. Commun. 1993, 23(1), 73-78 in a single step procedure by treating a cyanomercaptopyridine with methyllithium in an appropriate solvent such as tetrahydrofuran to provide the 3-methylisothiazolopyridine derivative. As described previously for Scheme I-18 the methyl group may be converted to the bromide with N-bromosuccinimide as shown in step b. Bromide displacement with cyanide, as shown in step c, followed by hydrolysis and esterification, as shown in step d, provides the methyl ester. Oxidation of the methyl ester to the oxalate can then be carried out as depicted in step e. The oxidation can be carried out in one step with selenium dioxide to provide the oxalate. Alternatively, the methyl ester can be treated with a strong base such as lithium bistrimethylsilyl amide in tetrahydrofuran at reduced temperature followed by camphorsulfonyl oxaziridine to provide the corresponding α-hydroxy ester which may be oxidized with the Dess-Martin reagent in order to obtain the oxalate. The oxalate may then be hydrolyzed under standard conditions as depicted by step f to provide the oxalic acid derivative. The oxalic acid derivative may then be coupled to an appropriate piperazine derivative to provide a compound of Formula I.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:10][NH:11][C:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20]I)[N:19]=1)=[O:13].[CH3:26][C:27]1[C:31]([S:32]([O-:34])=[O:33])=[C:30]([CH3:35])[O:29][N:28]=1.[Na+]>O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:10][NH:11][C:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][S:32]([C:31]2[C:27]([CH3:26])=[N:28][O:29][C:30]=2[CH3:35])(=[O:34])=[O:33])[N:19]=1)=[O:13]
Reactant: Cc1noc(C)c1S(=O)[O-]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1S(=O)(=O)Cc1csc(NC(=O)NCc2ccc(Cl)c(Cl)c2)n1

Procedure:
A DMF (0.30 mL) solution of Intermediate 6: 1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (45 mg, 0.10 mmol) and sodium 3,5-dimethylisoxazole-4-sulfinate (56 mg, 0.2 mmol, ˜60% pure) was stirred for an hour. The mixture was diluted with water and extracted with EtOAc. The organics were washed with brine, dried and evaporated to a residue that was purified by chromatography (silica gel) to afford the title compound. 1H NMR (400 MHz, CDCl3): 9.80 (1H, br), 7.39 (m, 2H), 7.15 (dd, 1H), 6.77 (s, 1H), 4.42 (d, 2H), 4.37 (s, 2H), 2.37 (s, 3H), 2.22 (s, 3H). MS (ES+): M/Z 475 (M+H).
Reaction SMILES: [C:1](O[K])(C)(C)C.[CH3:7][O:8][C:9]1[CH:10]=[N:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:19]=O)[C:17]=2[N:18]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[CH3:7][O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17](=[C:16]([CH:19]=[CH2:1])[CH:15]=[CH:14][CH:13]=2)[N:18]=1
Reactant: CC(C)(C)O[K]
Reactant: COc1cnc2cccc(C=O)c2n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1cccc2ncc(OC)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A suspension of methyltriphenylphosphonium bromide (22.78 g) in THF (200 mL) was treated with tBuOK (7.15 g) and further stirred at rt for 1 h. The mixture was cooled to 0° C. and treated with a solution of 3-methoxy-5-quinoxalinecarboxaldehyde (10.0 g; prepared according to WO 2006/021448) in THF (100 mL). The mixture was further stirred at rt for 3 h, diluted with ether and washed with water and an aq. sat. NH4Cl solution. The org. phase was dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from ether and the crystals were filtered off. The mother liquor was purified by CC (Hex/EA 1:1), affording a light orange solid (8.70 g; 88% yield).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([OH:33])[C:24]=2[CH2:34][CH2:35][CH3:36])[C:8]=1[CH2:37][CH2:38][CH3:39])C.[OH-].[Na+]>CO>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:40])=[O:3])=[C:8]([CH2:37][CH2:38][CH3:39])[C:9]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([C:30](=[O:32])[CH3:31])=[C:25]([OH:33])[C:24]=1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14]
Reactant: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCC(=O)O)c1CCC
Yield: 80.8 %

Procedure:
A solution of 0.945 g (0.0016 mole) of [4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid ethyl ester in 50 ml of methanol and 8.2 ml (0.0082 mole) of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed in vacuo and the pH of the residue was adjusted to 2.0. The product was extracted with methylene chloride and the dried (magnesium sulfate) extract was concentrated in vacuo. The residue was crystallized from ether-hexane to give 0.710 g (79% yield) of [4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid, melting point 77°-80°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:31]=[CH:30][CH:29]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:14][C:15]([OH:17])=O)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:31]=[CH:30][CH:29]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:14][C:15]([NH:45][OH:46])=[O:17])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 48.2 %

Procedure:
3-(3-Acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (1.14 g, 7.03 mmol) and hydroxylamine hydrochloride (651 mg, 9.37 mmol) in tetrahydrofuran (10 mL) to afford 3-(3-acetoamidophthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.0 g, 48% yield): mp, 117.0–119.0° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 2.19 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.98 (q, J=7.0 Hz, 2H, CH2), 5.65 (t, J=7.8 Hz, 1H, NCH), 6.87–6.95 (m, 2H, Ar), 6.99 (br s, 1H, Ar), 7.54 (d, J=6.9 Hz, 1H, Ar), 7.77 (t, J=7.45 Hz, 1H, Ar), 8.41–8.47 (m, 1H, Ar), 8.80 (br s, 1H, OH), 9.71 (s, 1H, NH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 24.69, 34.20, 44.09, 60.04, 65.48, 73.79, 121.78, 122.43, 126.69, 127.97, 129.64, 135.83, 141.00, 141.44, 145.75,146.38, 157.70, 158.59, 175.97, 177.13, 178.19, 179.22; Anal Calcd for C22H23N3O7+0.3 H2O: C, 59.14; H, 5.32; N, 9.40. Found: C, 59.32; H, 5.33; N, 9.02.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:21])=[C:14]([CH:22]([CH3:24])[CH3:23])[CH:13]=1)[CH3:4].[S:26](Cl)(=[O:29])(=[O:28])[NH2:27]>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:21][S:26](=[O:29])(=[O:28])[NH2:27])=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:17]=1)[CH3:4]
Reactant: CCOC(=O)CCCCCc1cc(C(C)C)c(O)c(C(C)C)c1
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCc1cc(C(C)C)c(OS(N)(=O)=O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.257 g, 6.4 mmol) was added to 6-(4-hydroxy-3,5-diisopropyl-phenyl)-hexanoic acid ethyl ester (1.46 g, 5.0 mmol) in dimethylformamide (20 mL) at 0° C. over about 3 minutes. The cooling bath was removed, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to zero degrees and sulfamoyl chloride (1.18 g, 10.3 mmol) was added over ~ 3 minutes. The reaction mixture was stirred 1.5 hours at zero degrees and was quenched by adding saturated aqueous sodium bicarbonate solution. The mixture is diluted with diethyl ether (300 mL) and water (100 mL). The organic layer is washed with water (3×100 mL), brine, dried over magnesium sulfate, filtered, and concentrated to an oil. The oil is chromatographed on silica gel using 4:1 hexanes/ethyl acetate as eluant. The title compound is obtained as a light yellow oil, 1.29 g. CI Mass Spectrum: [M+H+ ]+ =400.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[C:18]([CH2:20][OH:21])=[CH:17][CH:16]=[CH:15]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=NN=N1.[CH2:27]([O:30][P:31]([O:39][CH2:40][CH:41]=[CH2:42])N(C(C)C)C(C)C)[CH:28]=[CH2:29].C([O:47]O)(C)(C)C>>[P:31]([O:21][CH2:20][C:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:15]=[CH:16][CH:17]=1)([O:30][CH2:27][CH:28]=[CH2:29])([O:39][CH2:40][CH:41]=[CH2:42])=[O:47]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc2cccc(CO)c12
Reactant: CC(C)(C)OO
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Agent: c1nnn[nH]1
Product: C=CCOP(=O)(OCC=C)OCc1cccc2cccc(CO[Si](C)(C)C(C)(C)C)c12
Yield: 81 %

Procedure:
According to a similar procedure to that described in Example 1-(10), [8-[(tert-butyldimethylsilyl)oxymethyl]-1-naphthyl]methanol (described in Aust. J. Chem., 49, 793 (1996); 4.04 g, 13.4 mmol), tetrazole (2.34 g, 33.4 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 3.93 g, 16.0 mmol), and tert-butyl hydroperoxide (80% di-tert-butyl peroxide solution; Merck; 1.8 g, 16 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction, an oily residue. The residue was subjected to chromatography on a silica gel (120 g) column (eluent; ethyl acetate:hexane=1:5˜1:2) to afford the title compound (5.02 g, 81% yield) as a colorless oil.