Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[N:5]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[N:4]([CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[C:3]1=[O:25]>C(O)C.[C].[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[C:2]([CH3:26])([CH3:1])[C:3](=[O:25])[N:4]2[CH:15]2[CH:16]3[CH2:24][CH:20]4[CH2:19][CH:18]([CH2:23][CH:22]2[CH2:21]4)[CH2:17]3)=[CH:7][CH:8]=1
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4,4-dimethyl-1-(4-nitrophenyl)-2-(adamantan-2-yl)-1,2-diazetidin-3-one (15.3 mg, 0.0430 mmol) prepared in Example 182 in ethanol (2 mL) was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere the resultant was stirred at room temperature for 20 minutes. The reaction solution was filtered using celite, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=1:1), and the title compound (14.2 m, quant.) was obtained as a colorless oil.
Reaction SMILES: [Na].[N+]([CH:5]([C@@H:7]1[C@@H:14]2[C@@H:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][C@H:8]1[CH3:16])[CH3:6])([O-])=O.[N+](=C)([O-])[O-:18].S(=O)(=O)(O)O>CO.O.C(O)(=O)C>[C:5]([C@@H:7]1[C@@H:14]2[C@@H:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][C@H:8]1[CH3:16])(=[O:18])[CH3:6]
Reactant: CC([C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1C)[N+](=O)[O-]
Reactant: C=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1C

Procedure:
Sodium (1.3 g) was dissolved in methanol (30 mL) and the solution added at 0° to a methanol (40 mL) solution of the crude, optically active (3aR,4S,5R,6aS)-4-(1-nitroethyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (10.0 g). This nitronate anion solution was added, 30 minutes later and at -30°, to a cold (-30°) solution of concentrated sulfuric acid (6 mL) in methanol (40 mL). The resulting mixture was processed as in Example III, including hydrolysis with acetic acid (8 mL) in water (30 mL) while stripping, to give 8.47 g (99%) of the crude, optically active (3aR,4S,-5R,6aS)-4-acetylhexahydro-5-methyl-2H-cyclopenta[b]furan-2-one as a yellow oil. This material was used directly in Example XIV.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[OH:25])[CH2:20][CH2:19]2)=[C:10]([O:40][CH3:41])[CH:9]=1)=[O:7])(=O)C.[OH-].[K+].[Cl-].[Na+]>C(O)C.O>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)([OH:25])[CH:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][O:14][C:11]3[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][OH:4])=[CH:9][C:10]=3[O:40][CH3:41])[CH2:23][CH2:22]2)=[CH:27][CH:28]=1
Reactant: COc1cc(C(=O)COC(C)=O)ccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 3.9 g (0.0069 mole) of 2-(acetyloxy)-1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone and 1.2 g (0.02 mole) of potassium hydroxide in 50 ml of 95% ethanol and 10 ml of water was heated at reflux under a nitrogen atmosphere for 4 hr. The solution was poured into 600 ml of ice-water and sodium chloride was added until a solid precipitated. The solid was collected by filtration and dried under vacuum to give the title compound. The compound is air sensitive and must be handled in an inert atmosphere.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1[CH2:29][CH2:28][S:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[O:18])=[CH:20][CH:21]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 50 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (100 mg, 0.32 mmol) obtained in Example 21 and thiomorpholine (0.035 ml, 0.35 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (65 mg, 0.16 mmol, yield 51%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:14]([CH3:29])=[C:13]([CH3:30])[N:12]=1.CCOC(C)=O>C(COC)OC>[CH3:30][C:13]1[C:14]([CH3:29])=[C:15]([NH:20][CH2:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])([CH3:24])[CH3:23])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
A 250 mL-round bottom flask was charged with NaH (60% oil dispersion, 534 mg, 13.3 mmol) under N2. The NaH was washed with three portions of hexanes and dried under a stream of N2. Dimethoxyethane (10 mL) was then added to the flask followed by phenol (1.25 g, 13.3 mmol). After stirring for 10 min, a solution of N-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.80 g, 8.89 mmol) in 15 mL of dimethoxyethane was added to the reaction mixture, dropwise, via cannula. The reaction mixture was then heated to reflux for 24 h. The cooled solution was then treated with 100 mL of EtOAc and washed successively with H2O, 1% Na2CO3 solution (2×), H2O and brine. The organic portion was dried with Na2SO4 and concentrated to give a brown oil. Column chromatography (SiO2, 50% EtOAc/hexanes) gave N-{2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.40 g) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23]C3CCCCO3)=[CH:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(CCOC3CCCCO3)cc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OCCc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.1 %

Procedure:
A solution of 78 g (197 mmol) of (RS)-1-benzyl-4-[4-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl]-piperidin-4-ol in 400 ml of methanol was treated with 470 ml of 2N hydrochloric acid and stirred at room temperature for 5 hours. For the working-up, the reaction solution was poured into 1500 ml of saturated sodium hydrogen carbonate solution and subsequently extracted three times with 1000 ml of ethyl acetate each time. The combined organic phases were dried over sodium sulphate and evaporated under reduced pressure. For purification of the crude substance, a flash chromatography on silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent was carried out. There were obtained 51.6 g (84% of theory) of 1-benzyl-4-[4-(2-hydroxy-ethyl)-phenyl]-piperidin-4-ol as a yellowish solid; MS: 312 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
Using procedure 4, 4-bromobenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 141-143° C.
Reaction SMILES: O[C:2]1([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[C:3]1[C:20]([O:22]CC)=[O:21].BrC1C=CC(OC)=CC=1.[Mg].COC1C=CC([Mg]Br)=CC=1.C1OC2C=CC(C3C4C(=CC=CC=4)C(=O)C=3C(OCC)=O)=CC=2O1>CCOCC.C1COCC1>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]([C:11]3[CH:16]=[CH:15][C:14]4[O:17][CH2:18][O:19][C:13]=4[CH:12]=3)[CH:3]2[C:20]([OH:22])=[O:21])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(OC)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Ethyl (1RS)-1-Hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9: 1 Et2O/ THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10 : 1 Et2O/ THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/ hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[NH:18]1[CH:22]=[CH:21][C:20](B(O)O)=[N:19]1.C([O-])(=O)C.[K+].O>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:22]3[CH:21]=[CH:20][NH:19][N:18]=3)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Brc1cc2c(-c3cc[nH]n3)nn(C3CCCCO3)c2cn1
Temperature: 100 °C
Yield: 44.1 %

Procedure:
A microwave reaction vial was charged with 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (408.03 mg, 1.0 mmol), 1H-pyrazol-3-ylboronic acid (117.49 mg, 1.05 mmol), 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (81.66 mg, 0.1 mmol), 1.00 M of Potassium acetate in Water (1.5 mL, 1.5 mmol), 1.00 M of Sodium carbonate in Water (1.5 mL, 1.5 mmol), and Acetonitrile (3 mL). The reaction mixture was heated under microwave at 100° C. for 20 minutes. Added another 2 equivalents of 1H-pyrazol-3-ylboronic acid and continue heated under microwave at 100° C. for 20 minutes. The same procedure was repeated 2 more times. The mixture was concentrated and the residue was purified on silica eluted with 0 to 100% Ethyl acetate in Heptane to afford 5-bromo-3-(1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as an off-white solid (153.7 mg, 44%).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:35]1([NH2:38])[CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[CH:35]1([NH:38][C:32]([C:29]2[CH:30]=[N:31][C:26]([C:24]3[NH:25][C:21]([CH:13]([C:10]4[CH:11]=[CH:12][C:7]([S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:5])=[O:6])=[CH:8][CH:9]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)=[O:34])[CH2:37][CH2:36]1
Reactant: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1CC1)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carboxylic acid (0.168 g) in N,N-dimethylformamide (5 mL) were added cyclopropylamine (0.036 mL), triethylamine (0.146 mL), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (102 mg) and 1-hydroxybenzotriazole (81 mg), and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=30:70-100:30, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.106 g, yield 58%) as colorless crystals. MS: 520 (MH+). melting point 134-136° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
Pyridinium p-toluenesulfonate (7.65 g, 30.45 mmol) was added to a clear solution of methyl 3-hydroxypropanoate (63.4 g, 609.00 mmol) and 3,4-dihydro-2H-pyran (78 mL, 852.60 mmol) in dichloromethane (650 mL) at room temperature under nitrogen to give a cloudy solution. This was allowed to stir at room temperature overnight. The reaction mixture was washed with water (250 mL) and brine (250 mL) before drying (MgSO4) and evaporating to an oil. This crude product was purified by flash silica chromatography, elution gradient 15 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 3-(tetrahydro-2H-pyran-2-yloxy)propanoate (67.7 g, 59.0%) as a colourless oil: 1H NMR Spectrum: (CDCl3) 1.47 (4H, dddd), 1.55-1.84 (2H, m), 2.55 (2H, t), 3.33-3.53 (1H, m), 3.53-3.7 (4H, m), 3.78 (1H, ddd), 3.93 (1H, dt), 4.42-4.72 (1H, m); Mass Spectrum [MH]+=189.
Reaction SMILES: [CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8]S[C:5]=2[CH2:4][CH2:3]1.[O:12]1C2CCCC(=O)C=2C=C1>>[CH3:1][CH:2]1[C:10](=[O:11])[C:6]2[CH:7]=[CH:8][O:12][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C1CCCc2occc21
Reactant: CC1CCc2sccc2C1=O
Product: CC1CCc2occc2C1=O

Procedure:
Following the procedure for the preparation of 5-methyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.24, 1.95, 2.25, 2.55, 2.93, 6.68, 7.33; MS (EI) m/z (rel. intensity) 150 (M+, 54), 150 (54), 121 (10), 109 (8), 108 (99), 86 (26), 84 (39), 80 (56), 52 (19), 51 (26), 50 (7). HRMS (FAB) calcd for C9H10O2+H 151.0759, found 151.0760. Anal. Calcd for C9H10O2: C, 71.98; H, 6.71. Found: C, 71.55; H, 6.74; N, 0.19.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cccc(F)c1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4cccc(F)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(3-fluorophenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:28])=[CH:4][CH2:5][CH2:6][C:7]([CH3:27])=[CH:8][CH2:9][CH2:10][C:11]([CH3:26])=[CH:12][CH:13]=[C:14]([CH:23]([CH3:25])[CH3:24])[CH:15]([O:18][Si](C)(C)C)[C:16]#[N:17].Cl>O1CCCC1>[Cl:1][CH2:2][C:3]([CH3:28])=[CH:4][CH2:5][CH2:6][C:7]([CH3:27])=[CH:8][CH2:9][CH2:10][C:11]([CH3:26])=[CH:12][CH:13]=[C:14]([CH:23]([CH3:24])[CH3:25])[CH:15]([OH:18])[C:16]#[N:17]
Reactant: CC(=CCCC(C)=CCCC(C)=CC=C(C(C)C)C(C#N)O[Si](C)(C)C)CCl
Agent: Cl
Solvent: C1CCOC1
Product: CC(=CCCC(C)=CCCC(C)=CC=C(C(C)C)C(O)C#N)CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 15-chloro-3-(1-methylethyl)-6,10, 14-trimethyl-2-trimethylsiloxy-3,5,9,13-pentadecatetraenenitrile (58 mg, 0.14 mmol) prepared in Reference Example 5 in tetrahydrofuran (2 ml) cooled at 0° C. is slowly added 1N hydrochloric acid (0.5 ml). After stirring at this temperature for 10 minutes, to the mixture is added a saturated saline solution (5 ml) and the mixture is extracted with ether (10 ml ×2). The organic layer is washed with a saturated saline solution (5 ml) and dried over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the resulting residue is purified by silica gel column chromatography (n-hexane/ethyl acetate=10:1) to give 15-chloro-2-hydroxy-3-(1-methylethyl)-6,10,14-trimethyl-3,5,9,13-pentadecatetraenenitrile (38 mg, 75%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH:30]([O:29][CH3:28])[CH3:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: COC(C)CC(=O)O
Agent: Cl
Product: COC(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (84 mg, 78%), MS (ISP) m/z=431.5 [(M+H)+], mp 168.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (RS)-3-methoxybutanoic acid.
Reaction SMILES: CN1CCCC1=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]=[C:30]=[O:31])[CH:23]=1>O>[F:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[CH2:28][NH:29][C:30](=[O:31])[NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=NCc1cccc(F)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NCc2cccc(F)c2)n1

Procedure:
An N-methylpyrrolidinone (5 mL) solution of ethyl 2-(2-aminothiazol-4-yl)-2-oxoacetate (commercial, 1.00 g, 5.0 mmol) and 1-fluoro-3-(isocyanatomethyl)benzene (831 mg, 5.5 mmol) was heated in a microwave reactor at 120 C for 30 minutes. Upon cooling, water (50 mL) was added with vigorous stiffing. Filtration of the precipitate afforded ethyl 2-(2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)-2-oxoacetate. M/Z 352 (M+H)+. The filtrate was dissolved in EtOH (100 mL) then hydroxylamine hydrochloride (700 mg, 10 mmol) and sodium acetate (1.07 g, 13 mmol) were added to the mix. The solution was stirred at 75 C for 4 hours and filtered while hot. Evaporation of the mixture and Flash chromatography afforded ethyl 2-(2-(3-(3-fluorobenzyl)ureido)thiazol-4-yl)-2-(hydroxyimino)acetate as a mixture of isomers. M/Z 367 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26][CH3:27])(=[O:4])[CH2:2][CH3:3].C([O-])(O)=[O:29].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26]([CH3:27])=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C([O-])O
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 4 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(2-methylthioethyloxy)quinoline (0.10 g, 0.26 mmol) was dissolved in methylene chloride (5 ml). NaHCO3 (45 mg) in H2O (5 ml) was added. The mixture was cooled to 4° C. A solution of 71% m-CPBA (0.062 g, 0.25 mmol) in methylene chloride (5 ml) was added dropwise. After stirring for 1 h at 2°-4° C., the organic layer was washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; CH2Cl2 :EtOH 90:10) gave 50 mg (48%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[C:8](=[O:19])[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][CH2:21][O:22][CH3:23])[CH2:11][CH2:10][NH:9][C:8](=[O:19])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)C(=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CCOC)CCNC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
4-(2-Methoxy-ethyl)-2-oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8.7 g) dissolved in dichloromethane (300 ml) under an argon atmosphere was treated with trifluoroacetic acid (60.32 g, 39.11 ml) and stirred for 3 hours at RT. The reaction mixture was then concentrated in vacuo, the residue dissolved in AcOEt, which was then washed with 3M aqueous NaOH, brine and dried over magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (acetone/CH2Cl2, gradient 0 to 10%) to give the desired product as light brown viscous oil (1.49 g). MS (ESI): 230.13 (MH+).
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])/[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21]O>>[CH:1]1(/[CH:7]=[C:8](\[CH2:12][P:13]([OH:19])([CH2:15][CH:16]([CH3:17])[CH3:18])=[O:14])/[C:9]([O:11][CH3:21])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)CP(=O)(O)C/C(=C\C1CCCCC1)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)/C(=C/C1CCCCC1)CP(=O)(O)CC(C)C

Procedure:
(Z)-3-cyclohexyl-2-(hydroxyisobutylphosphinoyl)methylpropenoic acid was treated in a similar manner as in Example 52 except that HCl-methanol was used instead of HCl-ethanol used in Example 52. The captioned compound was obtained as a colorless oil.