Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[C:4]1([CH2:10][CH2:11][CH:12]=[CH2:13])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>C(#N)C>[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][P:1]([OH:3])[OH:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[PH2]O
Reactant: C=CCCc1ccccc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OP(O)CCCCc1ccccc1
Temperature: 77 °C
Yield: 87.6 %

Procedure:
To a 30 wt % aqueous solution of hypophosphorous acid (41.8 ml, 0.19 moles) in acetonitrile (100 ml) was added 4-phenyl-1-butene (5 gm, 0.038 moles) and sodium persulfate (1.8 gm, 0.00756 moles). To the stirred mixture triethylamine was added and the pH of the reaction mixture was adjusted to 6.5±0.5. The reaction mixture was heated at 77° C. for 15 minutes for the reaction to be complete. Acetonitrile was distilled off at 40° C. under vacuum and the reaction mixture was diluted with water (20 ml). The pH of the mixture was adjusted to 8.5 with 50% aqueous sodium hydroxide followed by acidification to a pH of 5.0±0.2. The aqueous medium was extracted with dichloromethane (20 ml) and kept aside. The pH of the aqueous layer was adjusted to 1-1.5 using conc. H2SO4 and reextracted with dichloromethane (2×20 ml). The total organic layers were combined, dried over anhydrous sodium sulfate and the solvent distilled off to yield 6.6 gm (88.0%) of the title compound as an oil, having a purity 97.6%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:8]2[S:9][C:10]([C:12]([O:14]C)=[O:13])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.O.[OH-].[Li+].O>CO>[F:16][C:2]([F:1])([F:17])[C:3]1[C:8]2[S:9][C:10]([C:12]([OH:14])=[O:13])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2cccc(C(F)(F)F)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: 75 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 800 mg of methyl 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 154 mg of lithium hydroxide monohydrate, 4 ml of water and 12 ml of methanol was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue was added water, and then washed with tert-butyl methyl ether 3 times. To the aqueous layer was added concentrated hydrochloric acid, and then extracted with tert-butyl methyl ether 3 times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain 632 mg of 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid (the present compound 4).
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([NH:41][C:42](=[O:56])[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=2[C:52]([F:55])([F:54])[F:53])[CH:38]=[CH:37][C:3]=1[C:4]([N:6]([CH2:32][C:33]([O:35]C)=[O:34])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)=[O:5].CO.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:40]=[C:39]([NH:41][C:42](=[O:56])[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][C:45]=2[C:52]([F:55])([F:53])[F:54])[CH:38]=[CH:37][C:3]=1[C:4]([N:6]([CH2:32][C:33]([OH:35])=[O:34])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: COC(=O)CN(Cc1ccc(-c2noc(-c3ccc(-c4ccc(C)cc4)cc3)n2)cc1)C(=O)c1ccc(NC(=O)Cc2ccc(OC)cc2C(F)(F)F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)c(F)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
Prepared using General Procedure 9. To a stirring solution of methyl 2-(2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetate INT-79 (91 mg, 0.119 mmol) in THF (2 mL) and MeOH (0.25 mL) was added 1 M LiOH (146 μL, 0.146 mmol). The reaction mixture was stirred at room temperature for 18 h. The solvent was removed and the residue suspended in water (5 mL). The mixture was acidified to pH 1 using 1 M HCl, filtered under vacuum and the captured solid washed with MeOH (1 mL). The captured solid was triturated with diethyl ether (3 mL) to afford 25 mg (28%) of 2-(2-fluoro-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 496. LCMS-ESI (m/z) calculated for C41H32F4N4O6: 752; found 753 [M+H]+, tR=9.64 min (Method 9). 1H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.35-8.18 (m, 2H), 8.07 (d, J=7.8 Hz, 2H), 7.98-7.86 (m, 2H), 7.73-7.65 (m, 2H), 7.64-7.39 (m, 5H), 7.39-7.33 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.25-7.17 (m, 2H), 4.82 (br, 2H), 3.96-3.78 (m, 5H), 3.42 (br, 2H), 2.40 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:43]=[CH:42][C:6]2[N:7]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=[CH:31][C:30]=3[CH:39]3[CH2:41][CH2:40]3)[C:8](=[O:27])[C@@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[C:50](Cl)(=[O:52])[CH3:51]>C(Cl)Cl.O>[C:50]([N:11]1[C@@H:10]([CH3:12])[C@H:9]([NH:13][C:14](=[O:26])[C@@H:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[CH3:16])[C:8](=[O:27])[N:7]([CH2:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]=[CH:31][C:30]=2[CH:39]2[CH2:40][CH2:41]2)[C:6]2[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][C:5]1=2)(=[O:52])[CH3:51]
Reactant: CC(=O)Cl
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 35.7 %

Procedure:
To a rt solution of tert-butyl(S)-1-((3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (70 mg, 120 μmol) in CH2Cl2 (801 μl) was added pyridine (29.4 μl, 360 μmol), followed by acetyl chloride (12.8 μl, 180 μmol), dropwise. The reaction was stirred at rt for 22 h, then diluted with H2O and extracted with CH2Cl2. The combined organic layers were washed with sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse phase preparative HPLC then flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (26.8 mg, 36%) as a white solid. MS m/z 625 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH2:17][C:18]#[N:19])[CH:5]=[CH:4][N:3]=1.CO>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[CH2:17][C:18]#[N:19])[CH:5]=[CH:4][N:3]=1
Reactant: N#CCc1cc(F)ccc1C#Cc1ccnc(Cl)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCc1cc(F)ccc1CCc1ccnc(Cl)n1
Reaction time: 24 h
Yield: 54.7 %

Procedure:
2-(2-((2-Chloropyrimidin-4-yl)ethynyl)-5-fluorophenyl)acetonitrile (0.695 g, 2.56 mmol) is dissolved in ethyl acetate (90 ml), and 10% Pd/C (0.142 g, 0.133 mmol) are added. The suspension is hydrogenated at RT for 24 h under an H2 pressure of 40 psi in a Parr apparatus (hydrogenation apparatus). Since the reaction proceeds very sluggishly, 9 ml of methanol and further catalyst are added (10% Pd/C (0.142 g, 0.133 mmol). Over a further 28 h, 142 mg of catalyst are added three further times until complete conversion is observed. The dark suspension is filtered, washed with ethyl acetate and methanol, and the filtrate is evaporated to dryness in vacuo. Chromatography of the 700 mg of crude product on silica gel with petroleum ether/ethyl acetate=7:3 gives 386 mg of 2-(2-(2-(2-chloropyrimidin-4-yl)ethyl)-5-fluorophenyl)acetonitrile (1.400 mmol, 54.7% yield) as yellowish oil;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]([Cl:22])[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(C(Cl)=Nc2ccccc2Cl)nc1

Procedure:
N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 (1.26 g, 0.0040 mol) in anhydrous benzene (20 mL) was added to PCl5 (1.26 g, 6.0 mmol) and the mixture was heated to reflux overnight. The solvent was removed and the residue was further dried under high vacuum. Crude N-(2-chlorophenyl)-5-(methylsulfonyl)picolinimidoyl chloride 6 was obtained as a yellow solid (1.60 g). The N-(2-chlorophenyl)-5-(methylsulfonyl)picolinimidoyl chloride 6 was dissolved into anhydrous THF (30 mL) and the reaction was cooled down to 0° C. and hydrazine monohydrate (9.0 mL) was added. The reaction was kept at 0° C. for 10 min and warmed to ambient temperature in 0.5 h. The solvent was removed and the residue was purified by column chromatography (eluting with hexane and ethyl acetate 1:1) to give N′-(2-chlorophenyl)-5-(methylsulfonyl) picolinimidohydrazide 7 as a yellow solid. Yield: 1.22 g, 92.0%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)=[O:4].[H-].[Na+].Cl[C:13]1[CH2:17][C:16]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=1.N1C=CC=N1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:19])([F:20])[F:21])[O:15][N:14]=2)[N:6]=1)=[O:4]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(Cl)=NO1
Reactant: COC(=O)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: CC#N
Product: COC(=O)c1ccn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of pyrazole-3-carboxylic acid methyl ester (504 mg) in acetonitrile (25 ml) under argon was added sodium hydride (160 mg). The reaction mixture was stirred at room temperature for 1 h. 15 mf of this solution was added dropwise to a solution of chloroisoxazoline of example 17.2 (630 mg) in acetonitrile (10 ml). It was then stirred at room temperature for 1 h; 10 ml of pyrazole solution was added again and the mixture was stirred for 1.5 hour. The reaction was quenched by adding water and dichloromethane. The two layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (from c-Hex (100%) to c-Hex:EtOAc (80:20)) to afford the title intermediate (680 mg). 1H-NMR (CDCl3, 400 MHz): 8.15 (s, 1H), 7.5 (m, 2H), 7.45 (m, 1H), 4.45 (d, 1H), 4.10 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[C:23](O)=[O:24])[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.C(COC)OC>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][OH:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(C(=O)O)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
4-Butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (2.97 g, 8.5 mmol) was dissolved in tetrahydrofuran (30 ml) and oxalyl chloride (0.9 ml, 10.2 mmol) and N,N-dimethylformamide (2 drops) were added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 ml). The obtained solution was added dropwise to sodium tetrahydroborate (1.13 g, 30 mmol) in dimethoxyethane (20 ml) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 4-butoxy-7-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (2.52 g, 88.4%) as crystals.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].I.C(=O)(O)[O-].[Na+].[CH3:17][C:18]([CH3:20])=O>>[CH3:17][C:18]1([CH3:20])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-ribose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of aqueous sodium bicarbonate was added. The acetone was then distilled off under reduced pressure, and the residue was dissolved in benzene, washed with aqueous sodium bicarbonate and water and dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure and the residue was further distilled under reduced pressure, whereby 3.84 g (30%) of 2,3-O-isopropylidene-D-ribofuranose was obtained as a fraction boiling at 108°-111° C./0.04 mmHg.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([Si](C)(C)C)([F:11])[F:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.[SiH3]O[SiH3]>O1CCCC1>[F:8][C:9]([F:11])([F:10])[C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCCC1
Reaction time: 1 h
Yield: 77 %

Procedure:
K. Prakash, et a., J. Am. Chem. Soc., Vol. 111, 393-395 (1989) describe the reaction of the fluoride ion catalyzed reaction of trifluoromethyltrimethylsilane with ketones and aldehydes to give the corresponding α-trifluoromethyl substituted alcohol and trimethylfluorosilane. In a typical reaction, cyclohexanone was reacted with trifluoromethyltrimethylsilane in tetrahydrofuran in the presence of tetrabutylammonium fluoride at 0° C. After 1 hour, the solution was mixed with 0.5N HCl to hydrolyze the intermediate silyl ether, and then the product was isolated by distillation. In this case, a 77% yield of 1-trifluoromethylcyclohexanol is reported.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[N:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)=[CH:3][N:4]=1
Reactant: Brc1ccnnc1
Reactant: OCc1ccc(B(O)O)cc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: OCc1ccc(-c2ccnnc2)cc1
Yield: 63.7 %

Procedure:
To a solution of 4-bromopyridazine (131 mg, 0.824 mmol) in 1,2-dimethoxyethane (16.4 ml) were added 4-hydroxymethylphenylboronic acid (189 mg, 1.24 mmol), potassium carbonate (517 mg, 3.74 mmol) and water (8.2 ml), which was deaerated under reduced pressure, followed by argon substitution. Tetrakis(triphenylphosphine)palladium (73.5 mg, 0.0636 mmol) was then added, followed by heating to reflux for 5 hours under argon atmosphere. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was subjected to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=0:1→1:4 (V/V), then methanol), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (97.7 mg) as a slightly brown solid. (Yield: 64%)
Reaction SMILES: Br[CH2:2]/[C:3](=[C:8](\[CH3:13])/[C:9]([O:11][CH3:12])=[O:10])/[C:4]([O:6][CH3:7])=[O:5].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH3:13]/[C:8](/[C:9]([O:11][CH3:12])=[O:10])=[C:3](\[CH2:2][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)/[C:4]([O:6][CH3:7])=[O:5]
Reactant: C1CCNCC1
Reactant: COC(=O)/C(C)=C(/CBr)C(=O)OC
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)/C(C)=C(/CN1CCCCC1)C(=O)OC
Reaction time: 4 h
Yield: 9 %

Procedure:
To a solution of dimethyl 2-bromomethyl-3-methylmaleate (32 mg, 0.13 mmol) in anhydrous dimethylformamide (450 μL) was added piperidine (21 mg, 0.25 mmol) at room temperature, and the mixture was left standing at 50° C. for 4 h. The reaction mixture was directly concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 3:2) to give 3 mg of the title compound as oil (yield: 39%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:27]3[O:31][N:30]=[CH:29][CH:28]=3)[CH2:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O.Cl>C(O)(=O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([C:27]3[O:31][N:30]=[CH:29][CH:28]=3)[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccno1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1ccno1

Procedure:
Compound 62.4 was dissolved in glacial acetic acid (1 mL) and water (0.3 mL) and heated to 95° C. for 16 h. 1N HCl (0.1 mL) was added and the reaction mixture was heated for another 16 h. The reaction mixture was poured into deionized water (50 mL) and extracted twice with diethyl ether. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in dichloromethane eluant). Compound 62 was obtained as a thick oil (26 mg). LC-MS ESI (pos.) m/e: 468.1 (M+H). 1H NMR (500 MHz) (CDCl3) δ 8.14 (s, 1H); 7.70 (s, 4H); 7.66 (s, 1H); 7.56 (d, J=7.5 Hz, 1H); 7.50-7.45 (m, 2H); 7.22 (d, J=8.5 Hz, 2H); 6.96 (d, J=8.5, 2H); 5.99 (s, 1H); 5.12 (s, 2H); 4.67 (t, J=7.7 Hz, 1H); 4.08 (n, 2H); 3.16 (dd, J=16, 7.5 Hz, 1H); 2.95 (dd, J=16, 8.0 Hz, 1H); 1.17 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH:17]3[CH2:32][CH2:33][N:34]=[N+]=[N-])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:34][CH2:33][CH2:32][CH:17]1[CH:16]([NH:15][C:10]2[N:9]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[C:12]([Cl:14])[N:11]=2)[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23]
Reactant: [N-]=[N+]=NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCC1C(Nc2nc(Cl)cc(N3CCCCCC3)n2)CCCN1C(=O)OCc1ccccc1
Yield: 77.4 %

Procedure:
The compound 17 (75.5 mg), tetrahydrofuran (2 mL) and triphenylphosphine (46.3 mg) were stirred at room temperature for 1 day and then added water (0.01 mL). The reaction solution was heated at reflux for 1 day and then concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol:triethylamine=90:10:1) to obtain the title compound (55.5 mg) having the following physical properties.
Reaction SMILES: [OH-].[K+].C([O:6][C:7]1[C:16]([S:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:18])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)(=O)C.Cl>C(O)C>[CH2:19]([S:17]([C:16]1[C:7]([OH:6])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCS(=O)c1cc2ccccc2cc1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCS(=O)c1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of 25 g potassium hydroxide in 500 ml ethanol was added 25 g (0.051 mole) 3-octadecanesulfinyl-2-naphthyl acetate. The mixture was stirred at room temperature in a nitrogen atmosphere for 1.5 hr. then acidified with 5% hydrochloric acid. The solid was collected, dried, and recrystallized from hexane-ethyl acetate to give 17 g of light pink solid, m.p. 107°-108° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3([C:23]([OH:25])=O)[CH2:22][CH2:21]3)=[O:19])=[C:13]([F:26])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O1CCCC1>[F:26][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[NH:17][C:18]([C:20]1([C:23](=[O:25])[NH:32][C:31]2[CH:33]=[CH:34][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:22][CH2:21]1)=[O:19])[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: Nc1ccc(F)cc1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)O)CC3)c(F)c2)ccn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 87.1 %

Procedure:
To a suspension of 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid (743 mg) and 4-fluoroaniline (459 mg) in tetrahydrofuran (30 ml) was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (1.22 g), followed by stirring at room temperature for 7.5 hr. The reaction mixture was partitioned between ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was suspended by addition of tert-butyl methyl ether—ethyl acetate (1:1, 20 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as a white solid (815 mg, 87%).