Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[C@H:13]([CH2:20]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:17])([F:18])[F:19])[C@H:13]([CH2:20][N:26]2[C:25](=[O:27])[C:24]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]3[C:22]2=[O:32])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(OCc1ccccc1)N1C[C@@H](CO)[C@H](C(F)(F)F)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@@H](CN2C(=O)c3ccccc3C2=O)[C@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
In 250 ml of absolute tetrahydrofuran, is dissolved 8.0 g (26.4 mmol) of trans-1-benzyloxycarbonyl-3-hydroxymethyl-4-trifluoromethylpyrrolidine. To the above solution, are added 4.27 g (29.0 mmol) of phthalimide and 8.30 g (31.7 mmol) of triphenylphosphine. Further, 5.0 ml (31.7 mmol) of azo dicarboxylic acid diethyl ester is added dropwise to the above solution on cooling with ice. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the concentrated mixture to give a precipitate. The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (elusion solvent; chloroform/n-hexane (4/1→8/1)) to give 9.72 g of the objective substance as a colorless powder (yield 85.2%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:19])[C:3]=1[CH:4]=[O:5].O.[BH4-].[Na+].Cl>C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:19])[C:3]=1[CH2:4][OH:5]
Reactant: CCCc1ccc(-c2cc(F)c(C=O)c(F)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1ccc(-c2cc(F)c(CO)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Then, 50.01 g of 2,6-difluoro-4-(4-propylphenyl)benzaldehyde and 7 mL g of water were dissolved in 35 mL of ethanol, the resultant solution was cooled with ice, and 2.18 g of sodium tetrahydroborate was slowly added to the solution. After stirring at room temperature for 2 hours, 10% hydrochloric acid was added until the reaction system became acidic, followed by stirring for 1 hour. Then, toluene was added to separate an organic layer, an aqueous layer was subjected to extraction with toluene, and the toluene extract was combined with the organic layer. The resultant mixture was washed with saturated brine and dried by adding sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to yield 48.02 g of 2,6-difluoro-4-(4-propylphenyl)benzyl alcohol.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@:18]3([OH:36])[CH2:19][CH2:20][C@@H:21]2/[CH:22]=[C:23](\[CH3:26])/[CH:24]=O)[CH2:13]1>O.O1CCOCC1>[NH:6](/[N:5]=[CH:24]/[C:23](/[CH3:26])=[CH:22]/[C@H:21]1[CH2:20][CH2:19][C@:18]2([OH:36])[C@H:17]3[C@H:30]([CH2:29][CH2:28][C@:27]12[CH3:35])[C@:31]1([CH3:34])[C@@H:14]([CH2:13][C@@H:12]([OH:11])[CH2:33][CH2:32]1)[CH2:15][CH2:16]3)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)NN
Reactant: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(/C=N/NC(=N)N)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.50 g of aminoguanidine hydrogencarbonate in 10 ml of water and 30 ml of dioxane was made acid to pH 3 with 3N HCl. A solution of 0.95 g of (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxaldehyde (Prepn. 1) in 10 ml of dioxane was added at room temperature. After 3 days the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 80/20/3 as the eluant: the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diethyl ether and ethanol to give 0.75 g of the title compound (I-aa) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[OH-].[Na+:9].[Br:10][CH:11]([CH3:15])[C:12](Br)=[O:13]>O.ClCCl>[Br:10][CH:11]([CH3:15])[C:12]([NH:1][CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5])=[O:13].[Na+:9]
Reactant: NCCS(=O)(=O)O
Reactant: CC(Br)C(=O)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)NCCS(=O)(=O)[O-]
Reaction time: 1 h

Procedure:
25.6 g of taurine (204 mmol) and 16.38 g of NaOH (409 mmol) were dissolved in 20 ml of deionized water. 2-Bromopropionyl bromide (44 g, 21.36 ml, 204 mmol) dissolved in 50 ml of dichloromethane was then added to the solution drop wise at 0° C. over 30 minutes. During the addition, a large amount of solid was produced. The reaction flask was manually agitated to thoroughly mix the compounds until no more exotherm was observed with additional agitation. The reaction mixture was then allowed to sit for 1 hour. The solid was filtered and washed with a small amount of absolute ethanol and then ethyl ether and then dried in vacuo. The compound can be used in this state or recrystallized from methanol.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:22]
Reactant: CC(C)(C)Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(C(=O)CBr)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a stirred solution of 7.91 g (53.0 mmol) tert-Butyl-phenyl-amine (Biehl, Smith, Reeves, J. Org. Chem., 1971, 13, 1842) and 5.36 g (58.3 mmol, 1.1 equiv) Et3N in 60 mL DCM is added 11.77 g (58.3 mmol, 1.1 equiv) Bromoacetyl bromide in 40 mL DCM dropwise over 45 minutes at 0° C. The reaction mixture is stirred 3 h at 0° C., diluted with 200 mL DCM, washed with 1N HCl (2×150 mL), dried (MgSO4), and concentrated in vacuo. The crude product is filtered through a pad of 15 g silica gel eluted with 300 mL DCM. The filtrate is concentrated in vacuo to give 12.40 g (45.9 mmol) of 2-Bromo-N-tert-butyl-N-phenyl-acetamide as an amber oil: 1H NMR (CDCl3, 300 MHz) δ7.45-7.21 (m, 12H), 7.08 (t, 1H), 6.90 (m, 1H), 4.30 (d, 1H, J=16.4), 3.85 (d, 1H, J=16.6), 3.59 (d, 1H, J=12.0), 3.49 (d, 1H, J=11.9), 1.43 (s, 9H); TLC Rf =0.24 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].N12CCN(CC1)CC2.CO/[CH:24]=[CH:25]/[C:26](=O)[CH2:27][CH3:28]>COCCO.Cl.C(OCC)(=O)C>[CH2:27]([C:26]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:24][CH:25]=1)[CH3:28]
Reactant: CCC(=O)/C=C/OC
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Product: CCc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (1.7 g, 10.6 mmol) in dimethyleneglycol monomethylether (20 mL) were added 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.6 mmol) and (1E)-1-methoxypent-1-en-3-one (1.82 g, 15.9 mmol), and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=50/50→100/0) to give a white solid. The white solid was washed with ethyl acetate to give the title compound (410 mg, 16%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
4'-hydroxy 4-biphenylcarboxylic acid (5.0 g) was added to a stirred suspension of sodium hydride (60% w/w dispersion in mineral oil, 2.34 g) in dry dimethylformamide (45 ml) whilst maintaining the temperature of the reaction mixture below 10° C. The reaction mixture was stirred at 10° C. for 20 minutes. A solution of benzyl bromide (8.4 g) in dry dimethylformamide (10 ml) was added over a period of 10 minutes. The reaction mixture was stirred at 70° C. for 2 hours and the mixture was then poured into cold water (900 ml) to precipitate a solid. The solid was collected by filtration, washed with water (3×200 ml) and added to a mixture of 2M aqueous sodium hydroxide solution (100 ml) and ethanol (100 ml). The mixture was stirred at 100° C. for 12 hours. The ethanol was removed by evaporation and the aqueous residue taken to pH 1.0 by the addition of 12M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, washed with water (3×100 ml), ethyl acetate (3×100 ml) and dried to give 4'-benzyloxy-4-biphenylcarboxylic acid (100% yield) as a colourless solid, m.p. >300° C.; m/z 304 (M).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[C:25](F)=[N:26][CH:27]=[CH:28][CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Na].[CH2:32]([SH:34])[CH3:33].[H-].[Na+]>O1CCCC1>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:24]5[C:25]([S:34][CH2:32][CH3:33])=[N:26][CH:27]=[CH:28][CH:29]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2cccnc2F)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCSc1ncccc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 90.4 %

Procedure:
To a solution of the 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)piperidin-4-ol (described in example 58) (2.00 g, 5.00 mmol, 1 eq) in tetrahydrofuran (50 mL) under nitrogen was added the sodium salt of ethanethiol (0.90 g, 10.7 mmol, 2.2 eq). The thiolate salt was prepared from ethanethiol and sodium hydride under standard conditions. The reaction was heated to reflux for 18 h and quenched by pouring into water (100 mL). The aqueous phase was extracted with diethyl ether (2×100 mL). Combined organic extracts were washed with water (2×100 mL), dried over anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (200 mL, eluent: 50% ether in hexane) to yield 2.00 g (90%) of the title compound. TLC analysis (Rf 0.29, 50% ether in hexane). 1H NMR (CDCl3, 250 HHz) 8.35 (dd, J=1.6, 4.7 Hz, 1H), 7.58 (dd, J=1.7, 7.7 Hz, 1H), 7.22 (m, 4H), 6.95 (m 5H), 4.27 (s, 1H), 3.58 (s, 1H), 3.48 (s, 2H), 3.28 (q, J=7.3 Hz, 2H), 2.89 (m, 2H), 2.80 (ddd, J=9.3, 14.9, 10.7 Hz, 2H), 2.62 (d, J=1.5 Hz, 2H), 2.12 (m, 4H), 1.35 (t, J=7.2 Hz, 3H) MS (CI, CH4) m/z 443 (M+1,100), 471 (M+29,16), 425 (25) The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 176°-179° C. (dec).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21](O)=[O:22])[CH2:18][N:19]=1)=[CH:11]2.Cl.C([N:39]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:27][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:16][CH:17]([CH2:20][C:21]([NH2:39])=[O:22])[CH2:18][N:19]=1)=[CH:11]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(N)=O)S3)[nH]c12
Temperature: 25 °C

Procedure:
To a solution of (2-{7-(2-methoxy-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (48 mg) in N,N-dimethylformamide (2 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg) and 1-hydroxybenzotriazole ammonium salt (28 mg) at room temperature. The mixture was stirred at room temperature over night. The mixture was concentrated in vacuo. Ethyl acetate was added to the residue and the resultant was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 90:10, volume ratio) to give the title compound. The compound was triturated and washed with diethyl ether-ethyl acetate-hexane to give the title compound (11 mg, 23%) as a white powder. mp 107-112° C.
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.[S:20]1[C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=[C:21]1[C:28]([OH:30])=[O:29].[CH2:31](N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:31][O:30][C:28]([C:21]1[S:20][C:24]([C:25]([N:5]2[CH2:6][C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:2][CH2:3][CH2:4]2)=[O:27])=[CH:23][CH:22]=1)=[O:29]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Reactant: O=C(O)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (WuXi PharmaTech) (0.6 g) and thiophene-2,5-dicarboxylic acid (1.7 g) in DMF (10 mL) was treated with triethylamine (2.75 mL) and cooled to 0° C. HATU (1.013 g) was added and the mixture stirred at 20° C. for 2 hours. The mixture was partitioned between ethyl acetate and brine containing acetic acid (2 mL), the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash silica chromatography using 1% acetic acid in ethyl acetate as solvent. This material was dissolved in THF (30 mL), treated with carbonyldiimidazole (0.332 g) and the mixture was allowed to stand at 45° C. for 1 hour. Methanol (20 mL) was added and the reaction heated at 50° C. for 30 minutes. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 40% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.45 g.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[S:17][C:16]=1[C:24]1[N:36]([CH3:37])[C:27]2=[N:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:26]2[N:25]=1)C.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:38]([C:15]1[CH:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[S:17][C:16]=1[C:24]1[N:36]([CH3:37])[C:27]2=[N:28][CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=[C:26]2[N:25]=1)(=[O:42])=[O:40])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cc(C(F)(F)F)sc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)sc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.08 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a solution of 0.06 g of 2-(3-ethylthio-5-trifluoromethylthiophen-2-yl)-3-methyl-6-t rifluoromethyl-3H-imidazo[4,5,b]pyridine in 3 ml of chloroform under ice cooling, and the mixture was stirred for 2 hours and at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.06 g of 2-(3-ethylsulfonyl-5-trifluoromethylthiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (6)).
Reaction SMILES: FC(F)(F)C(O)=O.O.[C:9]([C:13]1[CH:63]=[CH:62][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH:22]3[CH2:25][CH:24]([N:26]([CH2:30][C@@H:31]4[C@H:35]5[O:36]C(C)(C)[O:38][C@H:34]5[C@H:33]([N:41]5[CH:49]=[N:48][C:47]6[C:42]5=[N:43][CH:44]=[N:45][C:46]=6[NH:50]CC5C=CC(OC)=CC=5OC)[CH2:32]4)[CH:27]([CH3:29])[CH3:28])[CH2:23]3)=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:50][C:46]1[N:45]=[CH:44][N:43]=[C:42]2[C:47]=1[N:48]=[CH:49][N:41]2[C@@H:33]1[CH2:32][C@H:31]([CH2:30][N:26]([CH:24]2[CH2:25][CH:22]([CH2:21][CH2:20][C:18]3[NH:17][C:16]4[CH:62]=[CH:63][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][C:15]=4[N:19]=3)[CH2:23]2)[CH:27]([CH3:28])[CH3:29])[C@@H:35]([OH:36])[C@H:34]1[OH:38]
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN(C(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N(C[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
Trifluoroacetic Acid (10 ml, 100 mmol) added to a mixture of Water (1 ml, 60 mmol) and 9-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-9H-purin-6-amine (0.91 g, 1.2 mmol) at RT. The reaction was stirred overnight at RT. The reaction was then heated to 35° C. and triethylsilane (0.39 ml, 2.4 mmol) was added. The reaction was stirred at 35° C. for a further 2 days. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 mls). 500 mgs of K2CO3 and 8 drops H2O were added and reaction stirred at RT for 1 hour. The mixture was filtered and filter cake washed with 10 mls MeOH. The filtrate was concentrated and the resulting residue was purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.142 g) as a colorless solid after several days of lyophilization.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:8]=[C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[O:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2cc(Cn3ccnc3)on2)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2ccc(-c3cc(Cn4ccnc4)on3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(5-imidazol-1-ylmethyl-isoxazol-3-yl)-phenol (150 mg, 0.62 mmol) and potassium carbonate (172 mg, 1.25 mmol) were placed in 10 ml of DMF, to which solution was added dropwise 3-fluorobenzyl bromide (89 μl, 0.75 mmol), and the mixture was stirred at room temperature for 4 hours. The completion of the reaction was confirmed by LC, and then DMF was distilled off under reduced pressure. A crude solid compound was extracted with ethyl acetate and water, and the organic solvent was distilled off under reduced pressure to obtain a white solid compound. The compound was purified by silica chromatography (methylene chloride:MeOH=20:1) to obtain 3-[4-(3-fluoro-benzyloxy)-phenyl]-5-imidazol-1-ylmethyl-isoxazole as a desired white solid compound.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[NH:17][C:18]3=[O:21])=[CH:13][CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>O1CCCC1>[NH2:1][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:29])([F:31])[F:30])[NH:17][C:18]3=[O:21])=[CH:13][CH:12]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 40 °C
Reaction time: 14 h
Yield: 97.9 %

Procedure:
The 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (50.0 mg, 0.116 mmol) obtained in Example 1-30 was dissolved in tetrahydrofuran (387 μl). Thereafter, triphenylphosphine (33.6 mg, 0.128 mmol) and water (20.9 μl) were added to the obtained solution, and the obtained mixture was then stirred at 40° C. for 14 hours. Thereafter, 1 N hydrochloric acid (0.5 ml) was added to the reaction solution, followed by washing with ethyl acetate. A 1 N sodium hydroxide aqueous solution (1.0 ml) was added to the residual water layer, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by column chromatography using Bond Elut (registered trademark) NH2 (Varian; 1g), so as to obtain 7-(5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (45.8 mg; yield: 98%) in the form of a colorless foaming substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:7][N:6]=[CH:5]2.CS(O)(=O)=O.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)[N:6]=[CH:5]2
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1cc2[nH]ncc2cc1O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(cnn2C2CCCCO2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of ethyl 5-hydroxy-1H-indazole-6-carboxylate (15.5 g, 75 mmol) in DCM (100 mL) and THF (100 mL) containing methanesulfonic acid (721 mg, 7.5 mmol) is added a solution of 3,4-dihydro-2H-pyran (6.6 g, 79 mmol) in DCM (20 mL) dropwise at RT. The resulting solution is stirred at RT overnight. After the solvent is removed, EtOAc (500 mL), saturated aqueous sodium chloride (500 mL) and NaHCO3 (5 g) are added. The organic layer is separated, dried and concentrated. The residue is purified by silica gel column chromatography to afford the product (16.8 g, 77% yield). MS (m/z): 291.1 (M+H).