Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:49]([CH2:51][NH2:52])[OH:50]>ClCCl>[OH:50][CH2:49][CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncc(C)cc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
See FIG. 20(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (75 mg, 0.24 mmol) was taken in dichloromethane (10 mL) to get a suspension. Added triethyl amine (0.0669 mL, 0.48 mmol) followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.286 mL, 0.48 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (0.029 mL, 0.48 mmol) was added and stirred at RT for overnight. After the completion of the reaction, diluted the reaction mass with DCM, washed with water and brine solution. The DCM layer was dried over sodium sulphate, evaporated to get the crude compound which was purified by column chromatography. Yield-52.7%. ES+MS m/z: 356.4 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.23 (s, 3 H ) 2.39 (s, 3 H) 3.39-3.65 (m, 4 H ) 3.93 (s, 3 H ) 4.84 (t, J=5.09 Hz, 1 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H) 8.33 (s, 1 H ) 8.41 (s, 1 H ) 8.80 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:28]1([N:33]=[C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH2:35]2)[CH2:32][CH2:31][CH2:30][CH2:29]1.C(Cl)CCl>CN(C=O)C.O>[N:28]1([N:33]=[C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:21]([C@@H:20]3[CH2:19][C:18]4[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=4)[CH2:12][N:11]3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[O:10])=[O:23])=[CH:38][CH2:39]2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: NC1=CCC(=NN2CCCC2)C=C1
Reactant: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)O)C2
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)NC1=CCC(=NN3CCCC3)C=C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a solution of (3S)-2N-(4-chlorophenylaminocarbonyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (100 mg, 0.26 mmol) and 4-(pyrrolidinylimino)phenylamine (97 mg, 0.51 mmol) in DMF (4 mL) and H2O (1 mL) at room temperature, EDC (196 mg, 1.02 mmol) was added. The mixture was stirred at room temperature for 2 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (118 mg). MS 562.2 and 564.2 (M+H, Cl pattern).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]#[N:17])[C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[Br:18]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(=O)(O)O.O>C(#N)C>[Br:18][C:12]1[C:13]([F:14])=[C:8]([C:5]2[C:4]([C:16]#[N:17])=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([F:15])=[CH:10][CH:11]=1
Reactant: N#Cc1cc(F)ccc1-c1c(F)cccc1F
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: N#Cc1cc(F)ccc1-c1c(F)ccc(Br)c1F
Temperature: 70 °C
Reaction time: 7 h
Yield: 171.1 %

Procedure:
To a slurry of 4,2′,6′-trifluorobiphenyl-2-carbonitrile (5.0 g, 21.4 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (3.37 g, 11.8 mmol) in acetonitrile (45 ml) was added concentrated sulfuric acid (3.15 g, 32.2 mmol). The slurry was warmed to 70° C. and the resulting solution stirred for 7 h then aged at ambient temperature for 18 h. Water (45 ml) was added dropwise to the solution over 15 min. The layers were allowed to settle and the product rapidly crystallised. The slurry was left to stir for 0.5 h then the solid was collected by filtration, washed with 1:1 acetonitrile:water (10 ml) and left to air dry, which gave 3′-bromo-4,2′,6′-trifluorobiphenyl-2-carbonitrile (6.3 g, 94%) as a white solid: δH (360 MHz, CDCl3) 6.97–7.08 (1H, m), 7.38–7.54 (2H, m), 7.62–7.68 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:5]=1[F:11].[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]=1[F:11]
Reactant: O=C1CCCN1
Reactant: COC(=O)c1cccc(Br)c1F
Product: COC(=O)c1cccc(N2CCCC2=O)c1F
Yield: 26.9 %

Procedure:
3-Bromo-2-fluorobenzoic acid methyl ester (500 mg, 2.15 mmol) was treated with pyrrolidin-2-one (273 mg, 3.22 mmol) as described in D24 to afford the title ester (137 mg).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>ClCCl>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc2c(cnn2CC(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(O)ccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a cooled (-78° C.) solution of 1-isobutyl-5-methoxy-1H-indazole (2.57 g, 12.6 mmol) in dichloromethane (100 mL) was added BBr3 (25 mL of 1M solution in dichloromethane). The mixture was stirred at −78° C. for 2 hours and then warmed to room temperature and stirred for 18 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic extract was filtered and concentrated under reduced pressure to afford 2.3 g of solid (96% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:15][CH:14]3[CH:10]([CH2:11][NH:12][CH2:13]3)[CH2:9]2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21]>>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:12]1[CH2:13][CH:14]2[CH:10]([CH2:9][N:8]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=3)[CH2:15]2)[CH2:11]1)=[O:21]
Reactant: COc1ccccc1C(=O)O
Reactant: Cc1ccnc(N2CC3CNCC3C2)n1
Product: COc1ccccc1C(=O)N1CC2CN(c3nccc(C)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 27 and 2-methoxybenzoic acid. MS (ESI): mass calculated for C19H22N4O2, 338.41; m/z found 339.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][S:12][CH2:13][CH:14]=1.N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:5]=[CH:4][C:3]=1[C:9]1[CH2:14][CH2:13][S:12][CH2:11][CH:10]=1
Reactant: Nc1ccc(C2=CCSCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C2=CCSCC2)c(F)c1)OCc1ccccc1
Temperature: 25 °C

Procedure:
4-(2-Fluoro-4-aminophenyl)-3,6-dihydro-2H-thiopyran (9.8 g, 46.8 mM) was dissolved in dry dichloromethane (196 ml), pyridine (6.23 g, 79.1 mM) added, and the mixture stirred under nitrogen at −20°. A solution of benzyl chloroformate (9.54 g, 53.9 mM) dissolved in dry dichloromethane (25 ml) was added dropwise, and the mixture left to warm to ambient temperature over 18 hours. The mixture was washed with 1M hydrochloric acid (200 ml), then brine (100 ml), dried (magnesium sulfate), filtered and evaporated to a small volume. The addition of isohexane (300 ml) precipitated the desired product (15.5 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:18])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C@@H:8]([OH:19])[CH2:7][C:5]=2[CH:6]=1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl.C(OCC)(=O)C>[CH3:36][C:35]([O:19][C@@H:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]([C:16]([NH2:18])=[O:17])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:37]
Reactant: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Temperature: 37.5 °C
Reaction time: 5.5 h

Procedure:
A solution of eslicarbazepine (15.0 gm), pyridine (8 mL), dimethylaminopyridine (0.17 gm) in dichloromethane (150 mL) was cooled to 5-10° C. Added acetyl chloride (7.6 mL) at about 5-10° C. followed by stirring at 35-40° C. for about 5-6 h. Washed the reaction mass with 0.5N HCl solution (45 mL) and followed by washing the organic layer with water (100 mL). Distilled out the solvent completely under vacuum to obtain crude eslicarbazepine acetate. The residue was dissolved in a mixture (60 mL) of dichloromethane and ethyl acetate (1:1) at 35-40° C. then cooled to 25-30° C. Reaction mass was filtered, washed with ethyl acetate and dried to obtain the title compound (m. p. 186.0-187.2° C.).
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[Cl:5][C:6]1[C:11](C)=[CH:10][CH:9]=[CH:8][C:7]=1[C:13](=O)[C:14](C)([O:19][SiH3])C(C)(C)C.O.O1CCOCC1>CO>[CH3:2][O:3][N:4]=[C:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[Cl:5])[CH2:14][OH:19]
Reactant: CON
Reactant: Cc1cccc(C(=O)C(C)(O[SiH3])C(C)(C)C)c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CON=C(CO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1.78 g of O-methylhydroxylamine hydrochloride were added to a solution of the 3.05 g of 2'-chloro-2-t-butyldimethyl silyloxyacetophenone prepared above in a mixture of methanol, water and 1,4-dioxane. The resulting mixture was stirred at room temperature for 14 hours, and the reaction mixture was then poured into water and extracted three times with 50 ml portions of ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography through silica gel, eluted with a stepwise gradient of ethyl acetate (10-40%) in hexane, to give 691 mg (32.4% yield) of the less polar isomer of 2'-chloro-2-hydroxyacetophenone O-methyloxime compound and 370 mg (17.3% yield) of the more polar isomer of the title compound.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:15]1([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:15]1([C:21](=[N:22][CH:23]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
Tert-butyl 4-bromobenzoate (10.3 g, 40.1 mmol), ethyl N-(diphenylmethylene)glycinate (14.99 g, 56.1 mmol), potassium phosphate (25.5 g, 120 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.409 g, 0.801 mmol) were stirred in toluene (120 mL) at 100° C. under nitrogen for 3 days. Room temperature was attained and the mixture filtered through Celite and concentrated in vacuo. The residue was purified by MPLC to give the desired product as a yellow oil. 1H NMR (DMSO-d6, 600 MHz) δ 7.86 (d, J=7.8 Hz, 2H), 7.58 (m, 2H), 7.51 (m, 3H), 7.48 (d, J=7.8 Hz, 2H), 7.45 (m, 1H), 7.41 (t, J=7.5 Hz, 2H), 7.08 (m, 1H), 5.08 (s, 1H), 4.00 (m, 2H), 1.51 (s, 9H), 1.05 (t, J=6.9 Hz, 3H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH2:6]([O:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:12]([OH:13])[C:11]=1[OH:17])[CH:7]=[CH2:8].[C:18]([O-])(O)=[O:19].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:6]([O:9][C:10]1[CH:16]=[CH:15][C:14]([CH:18]=[O:19])=[C:12]([OH:13])[C:11]=1[OH:17])[CH:7]=[CH2:8]
Reactant: O=C([O-])O
Reactant: C=CCOc1cccc(O)c1O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOc1ccc(C=O)c(O)c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Tin tetrachloride (0.31 g, 0.14 mL, 1.32 mmol) was added to a solution of 39 (0.20 g, 1.20 mmol) and αα′-dichloromethyl methyl ether (0.15 g, 0.12 mL, 1.32 mmol) in CH2Cl2 at −78° C. The pale brown reaction mixture was stirred at this temperature for 1.5 h, then poured into an excess of saturated NaHCO3 aq. cooled at 0° C. The mixture was stirred for 15 min, acidified to pH 5 by the addition of 5% w/v citric acid then extracted with CH2Cl2 (3×). The organic phase was dried (Na2SO4) and evaporated to dryness to give 40 compound (0.18 g, 76%) which was used as such in the next step.
Reaction SMILES: [CH3:1][N:2]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:1][N:2]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
A mixture of ethyl 7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylate (2.50 g), 1N aqueous sodium hydroxide solution (10 mL), ethanol (10 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 1.5 hr. 1N Hydrochloric acid (10 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (2.30 g, yield 98%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 207-208° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Na+:32]>>[Na+:32].[S:27]1[CH:28]=[CH:29][C:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][C:3]([O-:30])=[O:2])[CH2:11][CH2:10]4)=[CH:17][CH:16]=3)=[CH:24][CH:23]=2)=[CH:26]1
Reactant: COC(=O)CCN1CCN(c2ccc(Oc3ccc(-c4ccsc4)cc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CCN1CCN(c2ccc(Oc3ccc(-c4ccsc4)cc3)cc2)CC1
Yield: 86.3 %

Procedure:
The title compound (13 mg, 86%) was prepared from the compound from step 2 (15 mg, 0.035 mmol) and 1N NaOH (0.036 mL, 0.036 mmol) by the procedure described in Example 2: MS (ESI) m/z 409 (M+H). 1H NMR (400 MHz, CD3OD) δ 2.44 (m, 2H), 2.70 (t, J=4.8 Hz, 4H), 2.76 (m, 2H), 3.17 (t, J=4.8 Hz, 4H), 6.91-6.96 (m, 4H), 7.02 (m, 2H), 7.39 (dd, J=1.6, 4.8 Hz, 1H), 7.44 (m, 1H), 7.51 (dd, J=1.2, 2.8 Hz, 1H), 7.58 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C:14]3([C:17](=[O:18])[C:11]=2[CH:10]=1)[CH2:16][CH2:15]3)C1C=CC=CC=1>CO>[OH:8][C:9]1[CH:20]=[CH:19][C:12]2[O:13][C:14]3([C:17](=[O:18])[C:11]=2[CH:10]=1)[CH2:16][CH2:15]3
Reactant: O=C1c2cc(OCc3ccccc3)ccc2OC12CC2
Solvent: CO
Product: O=C1c2cc(O)ccc2OC12CC2

Procedure:
5-Benzyloxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (3.3 g.) was debenzylated by catalytic reduction in methanol. By this procedure there was obtained 5-hydroxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as pale yellow needles, m.p. 180°-185° C. Yield 1.8 g.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[F:5][C:6]1([F:17])[C:15]2C(=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)CC[CH2:7]1.[Mn]([O-])(=O)(=O)=O.[K+]>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Mg+2]>[F:5][C:6]1([F:17])[C:15]2[C:4](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:2](=[O:3])[CH2:1][CH2:7]1
Reactant: Fc1ccc2c(c1)C(F)(F)CCC2
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCC(F)(F)c2cc(F)ccc21
Temperature: 0 °C
Yield: 63 %

Procedure:
An acetone solution (278 mL) of trifluoride 52 (3.11 g, 16.7 mmol) was diluted with an aqueous solution (209 mL) of magnesium sulfate heptahydrate (12.4 g). The solution was then cooled to 0° C. and potassium permanganate (7.92 g) was added portion wise over 1 hour. The reaction was allowed to warm to ambient temperature over 16 h. The reaction was quenched by addition of an aqueous 50% citric acid solution (100 mL) followed by sodium thiosulfate (5.21 g). The dark purple reaction became colorless and biphasic. The volatiles were removed and the aqueous was then extracted with dichloromethane (300 mL). The organic phase was separated, dried over sodium sulfate and concentrated. The product was purified by silica gel with a gradient heptanes/ethyl acetate eluent system on an ISCO companion to give the desired product as a yellow oil (2.09 g, 10.4 mmol, 63% yield). 1H NMR (400 MHz, CDCl3) δ: 8.10 (t, J=8 Hz, 1H), 7.44 (d, J=4 Hz, 1H), 7.26 (m, 1H), 2.91 (t, J=4 Hz, 2H), 2.66 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2([C@H:10]3[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][O:8]2)=[N:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:38].F.[F-]>O>[Br:1][C:2]1[S:6][C:5]([C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)([OH:8])[CH2:9][F:38])=[N:4][CH:3]=1
Reactant: F
Reactant: CCOC(=O)[C@H]1CC[C@H](C2(c3ncc(Br)s3)CO2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](C(O)(CF)c2ncc(Br)s2)CC1
Temperature: 120 °C

Procedure:
To a vial were added ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]-cyclohexanecarboxylate (101 mg, 0.28 mmol) and tetra-N-butylammonium dihydrogentrifluoride (422 mg, 1.34 mmol). The mixture was heated at 120° C. for 3 h 45 min. The mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated to afford racemic ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-2-fluoro-1-hydroxyethyl]cyclohexane-carboxylate which was used without further purification. MS ESI calc'd. for C14H19BrFNO3S [M+H]+ 380, 382. found 380, 382.
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19]Br)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>O>[CH2:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:3]=[CH:1][O:2][CH:19]=2)=[CH:16][CH:17]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: NC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: c1ccc(COc2ccc(-c3cocn3)cc2)cc1
Yield: 16.6 %

Procedure:
Formamide (1.0ml) was added to 4'-benzyloxy-2-bromoacetophenone (3.0g) and heated at 130° to 135° C. for 1 hour. Water was added to the reaction product, and the mixture was alkalified with aqueous solution of sodium bicarbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, treated with activated charcoal, dried with anhydrous sodium sulfate and then concentrated. The residue was purified by column chromatography on silica gel [eluting solvent: ethyl acetate-hexane (1:9)] to give 4-(4-benzyloxyphenyl) oxazole (410 mg, 16.6%). The product was further purified by recrystallization from diethyl etherhexane. m.p. 101°-102° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9](I)[O:8][C:7]=12.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.O>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([C:9]2[O:8][C:7]3=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=2)[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: Clc1nccc2cc(I)oc12
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1cc(-c2cc3ccnc(Cl)c3o2)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 73.7 %

Procedure:
In a three-neck flask was placed a mixture of 7-chloro-2-iodofuro[2,3-c]pyridine (1.00 g, 3.58 mmol), 3,5-bis(trifluoromethyl)phenyl boronic acid (0.92 g, 3.6 mmol), 1,4-dioxane/water (50 mL/10 mL) and K2CO3 (0.74 g, 5.38 mmol). After the suspension was degassed with nitrogen for 15 min, (PPh3)2PdCl2 (0.12 g, 0.17 mmol) was added and the mixture was degassed with nitrogen for 5 min. The resultant mixture was stirred at 50° C. for 48 h under nitrogen. The mixture was then cooled to RT and the solvent was evaporated to give a black residue, which was purified by flash chromatography (2% MeOH:DCM) to afford 965 mg (74%) of the title compound as a white crystalline. 1H NMR (300 MHz, CDCl3): δ 7.06 (s, 1H), 7.50 (m, 4H), 7.94 (dd, J=1.5 Hz, 2.4 Hz, 1H), 8.19 (d, J=5.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[C:13]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:21]([SH:24])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:21]([S:24][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:15][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:22][CH3:23]
Reactant: CCCS
Reactant: COC(=O)c1ccc(-c2c[nH]nc2C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cc(-c2c[nH]nc2C(F)(F)F)ccc1C(=O)OC
Yield: 18 %

Procedure:
1.52 g (5.0 mmol) of methyl 2-chloro-4-(3-trifluoromethylpyrazolyl)benzoate, 0.66 g (8.6 mmol) of 1-propanethiol and 0.83 g (6.0 mmol) of potassium carbonate were stirred in 5 ml of N,N-dimethylformamide at 60° C. for 24 hours. The resulting reaction mixture was poured into 50 ml of water, and the organic matters were extracted with 20 ml of ethyl acetate twice. The ethyl acetate layers were combined, washed with 30 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by thin layer chromatography afforded 0.31 g of methyl 2-propylthio-4-(3-trifluoromethylpyrazolyl)benzoate as a white powder (m.p. 114-116° C.).