Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:11]=[O:12].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:11]=[O:12]
Reactant: O=Cc1ccc(OCCc2ccccc2)c(O)c1
Reactant: ClCc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCc2ccccc2)c(OCc2ccccn2)c1
Reaction time: 8 h
Yield: 88.8 %

Procedure:
Cesium carbonate (800 mg, 2.5 mmol, 2 eq) was added to a stirred solution of 3-hydroxy-4-(2-phenylethoxy)-benzaldehyde (300 mg, 1.24 mmol, 1 eq), 2-picolyl chloride (210 mg, 1.3 mmol, 1.05 eq) and tetra-n-butylammonium iodide (460 mg, 1.24 mmol, 1 eq) in N,N-dimethylformamide (10 mL). The solution was stirred overnight, then concentrated in vacuo. The residue was azeotroped with water (2×10 mL), toluene (2×10 mL) and then purified by chromatography on silica gel. Elution with petroleum ether:ethyl acetate (1:1) gave the product as a white powder (367 mg, 89%). 1H NMR (CDCl3) δ 9.75 (s, 1H, O═C—H), 8.55 (d, 1H, J 4.9 Hz, pyH), 7.66 (ddd, 1H, J 7.5, 7.5 and 1.9 Hz, PyH), 7.47 (d, 1H, J 7.5 Hz, ArH), 5.22 (s, 2H, OCH2Py), 4.27 (t, 2H, J 7.2 Hz, OCH2CH2Ph), 3.15 (t, 2H, J 7.2 Hz, OCH2CH2Ph).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:15])=O>>[C:1]([Cl:15])(=[O:12])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC=CCC(=O)O
Reactant: O=S(Cl)Cl
Product: CCCCCCC=CCC(=O)Cl

Procedure:
The 3-decenoic acid was converted to its corresponding acyl chloride (3-decenoyl chloride) by reaction with thionyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[N:14]#[C:15][NH2:16]>C(O)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:16][C:15]#[N:14])([O-:3])=[O:2]
Reactant: N#CN
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: N#CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
It is known, from J. pract. Chem. [2] 110 (1925) 300, to react 2,4-dinitrochlorobenzene with a large excess of cyanamide in aqueous ethanol to give 2,4-dinitrophenylcyanamide and to precipitate the latter by means of hydrochloric acid. When this precipitate is heated together with alcoholic hydrochloric acid, 2,4-dinitrophenylurea is obtained therefrom.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]3[N:27]=[CH:28][C:29]4[N:35]([CH3:36])[C:34](=[O:37])[C:33]([F:39])([F:38])[CH2:32][N:31]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:30]=4[N:45]=3)=[C:21]([O:46][CH3:47])[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:40]1([N:31]2[CH2:32][C:33]([F:38])([F:39])[C:34](=[O:37])[N:35]([CH3:36])[C:29]3[CH:28]=[N:27][C:26]([NH:25][C:22]4[CH:23]=[CH:24][C:19]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[O:48])=[CH:20][C:21]=4[O:46][CH3:47])=[N:45][C:30]2=3)[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COc1cc(C(=O)NCCCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NCCCN2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of 0.0245 g (0.035 mmole) of 4-{3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (I-94), 2.25 mL of dichloromethane and 0.25 mL of trifluoroacetic acid was stirred for 2 hours and then concentrated under reduced pressure. The residue was diluted with methanol and neutralized with 1.0 M sodium hydroxide at 0 degrees. The methanol solution was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 1:99-90:10) to give 0.0162 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-piperazin-1-yl-propyl)-benzamide (I-95).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[CH2:14]([O:13][C:9](=[O:12])[CH2:10][CH2:11][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:15]
Reactant: Oc1cccc(Br)c1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCOc1cccc(Br)c1

Procedure:
A solution of 3-bromophenol (10.0 g, 57.8 mmole) in 50 mL of ethyl acrylate was treated with 0.9 mL of Triton B. The reaction mixture was heated at reflux for 18 hours. Excess ethyl acrylate was removed by distillation at atmospheric pressure. The resulting residue was diluted with 50 mL toluene and co-evaporated. The remaining product was diluted in 100 mL ether and washed with two 50 mL portions of sodium carbonate solution, 50 mL water and 50 mL saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow liquid. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to afford 6.435 g of 3-(3-bromo-phenoxy)-propionic acid ethyl ester as a colorless liquid.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([OH:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:14][CH:13]=2)=[O:11])=[CH:3][CH:2]=1.C[O-].[Na+:41].CO>CO.C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:26]=[C:25]4[C:20]([CH:21]([C:27]([O-:29])=[O:28])[CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[Cl:30])=[CH:31][CH:32]=2)=[O:11])=[CH:5][CH:6]=1.[Na+:41]
Reactant: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Yield: 102 %

Procedure:
7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (42 mg, 0.07955 mmol) was dissolved in MeOH-THF (1 ml-1 ml). A 0.5 M solution of NaOMe in MeOH (159.1 μl, 0.0795 mmol) was added and the mixture was stirred for few minutes. The crude mixture was concentrated and chased with EtOAc and dichloromethane to provide 44.6 mg of the title compound as a white solid (102%). MS (apci) m/z=528.1 (M+2H-Na).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C:9]([O:15][CH3:16])(=[O:14])[CH2:10][C:11]([CH3:13])=O>C(OCC)C>[S:6]1[CH:7]=[CH:8][C:4]([CH2:3][CH2:2][NH:1]/[C:11](/[CH3:13])=[CH:10]\[C:9]([O:15][CH3:16])=[O:14])=[CH:5]1
Reactant: NCCc1ccsc1
Reactant: COC(=O)CC(C)=O
Solvent: CCOCC
Product: COC(=O)/C=C(/C)NCCc1ccsc1
Yield: 97.5 %

Procedure:
3.82 grams (30 millimoles) of 3-(2-aminoethyl)thiophene was added dropwise with stirring at room temperature to 3.6 grams (31 millimoles) of methyl acetoacetate and the stirring was continued over the weekend at ambient temperature. Thereafter, the mixture was diluted with 250 milliliters of diethyl ether and the resulting ether solution washed with 50 milliliters of brine and then dried over sodium sulfate. The ether solvent was then vaporized from the dried and filtered solution to obtain 6.59 grams of a methyl 3-(3-thienylethyl)aminocrotonate intermediate as a slightly yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH:4]=1.N1C=CN=C1.[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH2:8][CH:7]=[C:6]([CH2:9][CH:10]([OH:11])[Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:5][CH:4]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC1=CCC(CCO)=CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC1=CCC(CC(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)=CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The crude compound (1) was dissolved in N,N-dimethylformamide (150 mL) and treated at room temperature with imidazole (44.8 g, 658 mmol) and t-butyldiphenylsilyl chloride (85.6 mL, 329 mmol). The resulting solution was stirred at room temperature for 2 d (reaction was essentially complete after a few hours) after which time it was diluted with 10% ethyl acetate in hexane, washed 3× with water, dried over anhydrous MgSO4, filtered and evaporated to give crude 1-methoxy-4-[2-(t-butyldiphenylsilyl)hydroxyethyl]-cyclohexa-1,4-diene (3). The mixture, which was contaminated with the over-reduced product 4-[2-(t-butyldiphenylsilyl)hydroxyethyl]-cyclohex-1-ene (4), was used in the next step without further purification. Compound (3): 1H NMR (CDCl3) δ 1.07 (9H, s), 2.25 (2H, t, J=6.0 Hz), 2.70 (4H, s), 3.55 (3H, s), 3.77 (2H, t, J=6.0 Hz), 4.62 (1H, br s), 5.43 (1H, br s), 7.22-7.93 (10H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[C:23]1([S:29][CH2:30][C:31]([NH2:33])=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:30]([S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:31]([NH2:33])=[O:32]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NC(=O)CSc1ccccc1
Agent: CC(C)(C)OCl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C(Sc1ccccc1)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cold (-70° C.) solution of 80.72 g (0.349 mole) of 2-amino-5-chlorobenzophenone in 1.5 liter of methylenechloride, under nitrogen atmosphere, was added 39.1 g (0.360 mole) of t-butyl hypochlorite in 100 ml of methylene chloride. After stirring for 10 min, a solution of 59.1 g (0.354 mole) of α-(phenylthio)acetamide in 1.5 liter of tetrahydrofuran was added. The mixture was stirred for 1.25 hr at -65° C., 37.5 g (0.371 mole) of triethylamine was added and the solution was allowed to warm to room temperature. The reaction mixture was extracted with several portions of water and the organic layer was dried over anhydrous sodium sulfate. The volume of solution was reduced in vacuo and yellow solid precipitated which when recrystallized from acetonitrile was a yellow crystalline solid, m.p. 190°-191° C.(d). Analysis: Calculated for C21H17N2O2SCl: C,63.55; H,4.32; N,7.06. Found: C,63.62 ; H,4.29; N,7.08.
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([N:34]([CH2:37][C@H:38]1[CH2:43][O:42][CH2:41][CH2:40][N:39]1C(OC(C)(C)C)=O)[CH2:35][CH3:36])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:32]([N:34]([CH2:37][C@@H:38]1[N:39]([C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:22])(=[O:23])=[O:24])=[CH:17][C:16]=2[S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:40][CH2:41][O:42][CH2:43]1)[CH2:35][CH3:36])[CH3:33]
Reactant: CCN(CC)C[C@H]1COCCN1C(=O)OC(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCN(CC)C[C@H]1COCCN1C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino) butanoic acid (INTERMEDIATE 8, 500 mg, 1.00 mmol), (S)—N-ethyl-N-(morpholin-3-ylmethyl)ethanamine hydrochloride salt (INTERMEDIATE 86, 50 mg, 1.2 mmol), DIPEA (0.526 ml, 3.01 mmol), in DMA (5 ml) was added HATU (458 mg, 1.20 mmol). The mixture was stirred for 1 hour at room temperature and diluted with ethyl acetate (200 ml). The mixture was washed successively with 1 M aq. sodium bisulfate, saturated sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified column chromatography (ISCO, eluting with 0→100% DCM/10% 2 M ammonia in MeOH in DCM over 24 minutes) to give the title product (380 mg, yield: 58%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.[Cl-].[NH4+]>CN(C=O)C>[CH3:3][O:4][C:5]([C:6]1([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: BrCCOCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Br)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, sodium hydride (60 wt %) (240 mg) was added to a solution of 2-(4-bromophenyl)acetic acid methyl ester (916 mg) in anhydrous DMF (20 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. To the reaction solution, bis(2-bromoethyl)ether (0.70 mL) was added, and the resulting mixture was stirred at 0° C. for 1 hour. Sodium hydride (60 wt %) (240 mg) was added thereto and the resulting mixture was further stirred at 0° C. for 1 hour. Saturated aqueous ammonium chloride solution was added thereto, and the resulting mixture was extracted with ethyl acetate. Organic layer was washed once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=4/1) to obtain 4-(4-bromophenyl)-tetrahydro-2H-pyran-4-carboxylic acid methyl ester (472 mg). (2) Under an argon atmosphere, a solution of 4-(4-bromophenyl)-tetrahydro-2H-pyran-4-carboxylic acid methyl ester (472 mg) obtained in (1) in anhydrous THF (8.7 mL) was added to a 1.0 M solution of diisobutylaluminum hydride in hexane (8.7 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. After adding methanol (2.1 ml) to the reaction solution, 1N hydrochloric acid (8.7 mL) was added thereto and the resulting mixture was extracted 4 times with diethyl ether. Organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain (4-(4-bromophenyl)-tetrahydro-2H-pyran-4-yl)methanol (405 mg). (3) Under an argon atmosphere, sodium hydride (60 wt %) (88 mg) was added to a solution of (4-(4-bromophenyl)-tetrahydro-2H-pyran-4-yl)methanol (397 mg) obtained in (2) in anhydrous DMF (1.5 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. Methyl iodide (0.13 ml) was added dropwise to the reaction solution, and the resulting mixture was stirred at room temperature for 2 hours. Saturated brine was added thereto and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: hexane/ethyl acetate=5/1) to obtain 4-(4-bromophenyl)-tetrahydro-4-(methoxymethyl)-2H-pyran (399 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:53][N:54]=[CH:55]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:53][N:54]([CH3:55])[C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:9][CH:8]=1
Reactant: COC(C(=O)O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: N
Product: COC(C(=O)N(C)O)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
The desired material was prepared according to the procedures described in Example 5 substituting 2-methoxy-2-[4-(quinolin-2-yl-methoxy)phenyl]acetic acid for {[1-(3-[2-naphthylmethoxy]phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 3.06 (s, 3H), 3.21 (s, 3H), 5.24 (s, 1H), 5.37 (s, 2H), 7.03 (d, J=7Hz, 2H), 7.3 (d, J=7Hz, 2H), 7.63 (m, 1H), 7.68 (d, J=8Hz, 1H), 7.8 (dt, J=8Hz, 2Hz, 1H), 8.0 (m, 2H), 8.42 (d, J=8Hz, 1H), 9.9 (s, 1H). IR (CDCl3): 3640, 3500, 3220, 1640, 1610 cm-1. MS (DCI/NH3) m/e 353 (M+H)+. Analysis calcd for C20H20N2O4 : C, 68.17; H, 5.72; N, 7.95. Found: C, 67.32; H, 5.61; N, 7.94.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH:11]=[CH:12][CH:13]1[CH2:22][CH2:21][C:16]2(OCC[O:17]2)[CH2:15][CH2:14]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([CH:11]=[CH:12][CH:13]3[CH2:22][CH2:21][C:16](=[O:17])[CH2:15][CH2:14]3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1NC(=O)C=CC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCC(C=Cc2nc3cc(Br)ccc3[nH]2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of N-(2-amino-4-bromo-phenyl)-3-(1,4-dioxa-spiro[4.5]dec-8-yl)-acrylamide (6.0 g, 28 mmol, prepared as in STEP D above) in 1,4-dioxane (100 mL) was treated with 1N HCl (30 mL, 30 mmol). The resulting solution was stirred at 100° C. for 1 h and then allowed to cool to room temperature. The resulting mixture was made basic with saturated aqueous sodium bicarbonate and extracted thrice with ethyl acetate. The ethyl acetate layers were combined and washed successively with water and brine, separated, dried over sodium sulfate, filtered and concentrated. The residue was taken up in ethyl acetate and applied to a silica gel plug (100 g) equilibrated with ethyl acetate and eluted with ethyl acetate. The desired fractions were pooled, concentrated and dried in vacuo to yield 4-[2-(5-bromo-1H-benzimidazol-2-yl)-vinyl]-cyclohexanone.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([C:25]([C:27]3[C:28]([C:37]4[CH:42]=[CH:41][C:40]([O:43]CC5C=CC=CC=5)=[C:39]([O:51][CH3:52])[CH:38]=4)=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:26])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][C:10]=1[O:53][CH3:54])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:24]([C:25]([C:27]3[C:28]([C:37]4[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([O:51][CH3:52])[CH:38]=4)=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:26])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:11][C:10]=1[O:53][CH3:54]
Reactant: COc1cc(-c2nc3ccccc3cc2C(=O)c2cc3ccccc3nc2-c2ccc(OCc3ccccc3)c(OC)c2)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nc3ccccc3cc2C(=O)c2cc3ccccc3nc2-c2ccc(O)c(OC)c2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.0 g of 4-(benzyloxy)-3-methoxyphenyl(3-quinolinyl)ketone are treated with 50 ml of trifluoroacetic acid, whereupon the mixture is stirred at room temperature for 2 hours. After distillation of the trifluoroacetic acid, the residue is treated twice with SO ml of ethanol each time and the solvent is distilled each time. The oil obtained crystallizes upon treatment with ethanol. After recrystallization from ethanol, there is obtained 4-hydroxy-3-methoxyphenyl(3-quinolinyl)ketone in the form of yellowish crystals of m.p. 196°-197°.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (1) (50.50 g, 195.6 mmol) in t-butyl methyl ether (750 ml), lithium hydroxide monohydrate (7.94 g, 189 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (52.00 g, 130.5 mmol) in t-butyl methyl ether (150 ml) and water (27 ml) were added thereto, and the mixture was heat refluxed for approximately 49 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (300 ml) was added and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (200 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (300 ml), and dried with anhydrous magnesium sulfate (50 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethyl acetate:hexane =1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 580 g; ethyl acetate:hexane =1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (62.38 g; 117.6 mmol; yield: 90.1%) as a pale yellow oil.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:27][C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:23][C:13]1[C:12]([CH3:24])=[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:26][CH:25]=2)[CH:20]=[C:15]2[C:14]=1[CH2:21][N:27]([C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1)[C:16]2=[O:17]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1F)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
A mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate (0.21 g), (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.07 g), anhydrous magnesium sulfate (0.14 g) and THF (4.00 mL) was stirred at room temperature for 6 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixed solvent of methanol (4.00 mL)-THF (4.00 mL), sodium triacetoxyborohydride (0.25 g) was added thereto, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).