Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:7][S:6][CH2:5][C:4]1=[O:8])#[N:2].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1>CN(C)C=O>[C:1]([C:3]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=2)[C:4](=[O:8])[CH2:5][S:6][CH2:7]1)#[N:2]
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Reactant: N#CC1CSCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc(CC2(C#N)CSCC2=O)cc1
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
4-Cyano-3-tetrahydrothiophenone (5.0 g) was dissolved in N,N-dimethylformamide (30 ml), then, sodium hydride (oil, about 60%, 950 mg) was added under ice cooling, and stirred at the same temperature for 30 minutes. Then, to the mixture was added a solution of methyl 2-(4-bromomethylphenyl)propionate (10.1 g) in N,N-dimethylformamide (10.0 ml) under ice cooling, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (5.5 g, 46%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>O1CCOCC1.CCOC(C)=O.[Cu]I>[O:14]=[C:10]1[N:11]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Brc1ccsc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccsc2)C(=O)C1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 1-Boc-3-oxopiperazine (1.0 eq.), 3-bromothiophene (1.5 eq.), K3PO4(2.0 eq.), CuI (0.4 eq.) and N,N′-dimethylethylendiamine (0.8 eq.) in 1,4-dioxane (0.5M) was put in a sealed vial and stirred at 110° C. for 18 hr. Reaction mixture was diluted with EtOAc and filtered through a pad of SolcaFloc® 200 FCC. After removal of the solvent, the crude product was purified by flash column chromatography on silica gel using 10-40% EtOAc/Petroleum ether as eluent to afford the desired product H1 as pink solid (80% yield). 1H NMR (400 MHz, CDCl3, 300K) δ 7.32-7.28 (3H, m), 4.25 (2H, s), 3.82-3.75 (4H, m), 1.49 (9H, s). MS (ES) C13H18N2O3S requires: 282, found: 283 (M+H)+.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:5][O:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[CH2:4][O:3]1.[ClH:18]>>[Cl:18][CH2:4][C@@:2]([OH:3])([CH3:1])[CH2:5][O:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17]
Reactant: C[C@@]1(CON2C(=O)c3ccccc3C2=O)CO1
Reactant: Cl
Product: C[C@](O)(CCl)CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[[(2S)-2-Methyloxiranyl]methoxy]-1H-isoindole-1,3(2H)-dione (3.0 g, 12.9 mmol) was treated with concentrated hydrochloric acid (12 ml) and stirred at ambient temperature for 2 h. The mixture was partitioned between water and dichloromethane, the organics were dried and purified by chromatography (EtOAc) to give the sub-title compound as a colourless solid (3.3 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:4]1=[O:18].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C([O-])(O)=O.[Na+]>ClCCl>[O:18]=[C:4]1[CH:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:7][CH2:6][N:5]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1
Reactant: O=C1C(CO)CCN1c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 113.6 %

Procedure:
A mixture of 3-hydroxymethyl-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one obtained in step 3 (0.17 g, 0.6 mmol), dichloromethane (8 ml) and triethyl amine (0.085 g, 0.84 mol) was cooled to 0° C. and stirred for 15 min at that temperature. Methane sulfonyl chloride (0.090 g, 0.78 mmol) was added to the mixture over a period of 5 min and the reaction mixture was stirred for 1.5 hrs at 10-15° C. To this reaction mixture saturated NaHCO3 solution (10 ml) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain methanesulfonic acid 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester as a brown oil (0.23 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(OCC)(=O)C>[C:11]([NH:10][NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: NNc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: CC(=O)NNc1ccc(Cl)cc1Cl

Procedure:
Generally in a process of condensing a hydrazonoyl derivative of formula (A) to form a compound of formula (I), the free hydrazine (1) as described above, for example, 2,4-dichlorophenylhydrazine (1) is reacted with acetic anhydride at a temperature of about 10° C. in an appropriate solvent such as ethyl acetate, yielding the corresponding 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2). The hydrazine (2) is then chlorinated with phosphorous oxychloride at a temperature of about 110° C. in an appropriate solvent such as toluene, yielding the hydrazonoyl derivative of formula (A), N-(2,4-dichlorophenyl)ethanehydrozonoyl chloride. The hydrozonoyl chloride (A) is condensed with a ring forming agent, for example, potassium cyanate at a temperature of about 40° C. to about 65° C. in an appropriate solvent such as DMAC, yielding the corresponding compound of formula (I), 45-dihydro-1-(2,4-dichlorophenyl)-3-methyl-1,2,4-triazol-5(1H)-one. The condensing of hydrozonoyl chloride (A) to the compound of formula (I) in solvents such as DMAC is routinely aided by the presence of a catalyst, such as potassium fluoride. A detailed procedure for the preparation, and the potassium fluoride-catalized condensing of the hydrozonoyl chloride (A) with the ring forming agent potassium cyanate in DMAC to yield a compound of formula (I) is set forth in Example 1 hereinbelow.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The mixture of ethyl (5-nitropyridin-2-yl)acetate (3.27 g, 15.6 mmol, step 2 of Example 1) and 5 wt. % palladium on carbon (320 mg) in methanol (25 mL) was stirred under hydrogen (1 atom) at room temperature for 4 h. The mixture was filtered through a pad of Celite washing with methanol and the filtrate was concentrated to give 2.98 g (quant.) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1>[Pd].O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]#[N:11])=[CH:4][N:3]=1
Reactant: N#Cc1cc(C#N)c(Cl)nc1N
Agent: [Pd]
Solvent: C1COCCO1
Product: N#Cc1cnc(N)c(C#N)c1
Reaction time: 16 h

Procedure:
A mixture of 2-amino-6-chloro-3,5-dicyanopyridine (Synth. Comm. 1993, 2605, 15.0 g, 84 mmol) and 10% palladium on carbon (10.0 g) in dioxane (150 mL) was shaken on a Parr apparatus under hydrogen (55 psi) for 16 h. More catalyst (7.5 g) was added and after a further 4 h the reaction mixture was filtered through celite washing through with ethanol and evaporated in vacuo. The residue was partitioned between methylene chloride and 1 M HCl. The insoluble material was collected by filtration and dried to give the title compound. The methylene chloride layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to give additional product:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]([C:6]1[C:18]2[CH:17]=[N:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:20]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH3:21])[CH2:11]2)=O.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C:6]1[C:18]2[CH:17]=[N:16][C:15]([Cl:19])=[CH:14][C:13]=2[N:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:20]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH3:21])[CH2:11]2
Reactant: COC(=O)C(=O)c1c2n(c3cc(Cl)ncc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1c2n(c3cc(Cl)ncc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (±)-{3-chloro-6-[(4-fluoro-benzenesulfonyl)-methyl-amino]-5,6,7,8-tetrahydro-2,4b-diaza-fluoren-9-yl}-oxo-acetic acid methyl ester (0.006 g) in 0.2 mL of CH2Cl2 were added 0.2 mL of TFA and 0.2 mL of Et3SiH. The reaction mixture was stirred overnight at r.t. and concentrated under vacuum. The residue was purified by silica gel chromatography eluted with 50% EtOAc/hexane to give 0.005 g desired product as a white solid. MS (ESI): 466.1. (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([C:28]([O:30]C)=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[N:4]1)[CH3:2].[OH-].[Li+].Cl>CO>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:32][CH3:33])=[C:25]([C:28]([OH:30])=[O:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(C(=O)OC)cc34)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(C(=O)O)cc34)cc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.8 %

Procedure:
A mixture of N-(1-ethylpyrazol-4-yl)-2-[4-(7-methoxy-6-methoxycarbonylquinolin-4-yloxy)phenyl]acetamide (0.05 g), lithium hydroxide (0.01 g) and methanol (1 ml) was stirred at ambient temperature for 14 hours. The resultant mixture was acidified to pH2 by the addition of 2N aqueous hydrochloric acid. The precipitate was isolated, washed with water and with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.028 g); 1H NMR: (DMSOd6) 1.32 (t, 3H), 3.63 (s, 2H), 3.97 (s, 3H), 4.03-4.11 (m, 2H), 6.48 (d, 1H), 7.27 (d, 2H), 7.42 (s, 1H), 7.46 (d, 2H), 7.5 (s, 1H), 7.9 (s, 1H), 8.54 (s, 1H), 6.67 (d, 1H), 10.21 (s, 1H); Mass Spectrum: M+H+ 447.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[NH2:30][C:31]1[C:36]([C:37]([OH:39])=O)=[CH:35][C:34]([Br:40])=[CH:33][N:32]=1.[C:41]([NH:49][NH2:50])(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C.O.CCOC(C)=O>[NH2:30][C:31]1[C:36]([C:37]([NH:50][NH:49][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:48])=[O:39])=[CH:35][C:34]([Br:40])=[CH:33][N:32]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
TBTU (2.219 g, 6.912 mmol) and triethylamine (466.3 mg, 642.3 μL, 4.608 mmol) were added to a solution of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g, 4.608 mmol) and benzohydrazide (752.9 mg, 5.530 mmol) in DMF (40.00 mL) and the resulting solution stirred at ambient temperature over the weekend. The reaction was treated with water/EtOAc and the organics separated. The organic layer was washed with water (3×), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil which was triturated with ether and dried under high vacuum to give the product as an off-white solid that was used directly in the next step without further purification (1.177 g, 62% Yield). MS (ES+) 336.86.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].Cl[C:14]([F:19])([F:18])C([O-])=O.[Na+].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:18][CH:14]([F:19])[O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(C(F)(F)F)cc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100-L round bottom flask equipped with overhead stirrer, thermocouple, nitrogen inlet, condenser and steam bath was charged with 2-fluoro-5-(trifluoromethyl)phenol (5.50 kg), sodium chlorodifluoroacetate (9.31 kg), and DMF (4 L). There was an exotherm to 46.7° C. when the 4 L of DMF was charged to the flask. The temperature of the reaction was immediately reduced to 19° C. by rapid cooling with an ice/water bath. An additional 37.3 L of DMF (total DMF, 41.3 L) was then slowly charged, maintaining the internal temperature below 30° C. After cooling to ambient temperature, water (5.5 L) was charged, resulting in a 10° C. exotherm. Potassium carbonate (5.28 kg) was then added. The ice water bath was removed and the batch was heated to 97° C. using a steam bath. The reaction was complete after aging for 2 h at 97° C., as evidenced by HPLC assay, with <1% starting material remaining. The reaction was cooled to ambient temperature, and water (42 L) was slowly added. The batch was transferred to a 170-L extractor and extracted with MTBE (2×18 L). The organic layers were combined and washed with water (1×11 L) and brine (1×11 L). The MTBE solution was pumped into a 22-L flask equipped with a thermocouple, distillation apparatus, and a heating mantle. The MTBE was distilled off at 55-118° C. and atmospheric pressure. The desired product was purified by distillation at 120-157° C. and atmospheric pressure, and was isolated as a clear oil.
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(C(C)C)C(C)C)C.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](=[O:29])[CH2:27][NH:26][C:25]2=[O:30])=[CH:20][C:19]=1[CH3:31].N#N>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH3:31][C:19]1[CH:20]=[C:21]([N:24]2[C:28](=[O:29])[CH2:27][NH:26][C:25]2=[O:30])[CH:22]=[CH:23][C:18]=1[CH:1]=[CH2:2]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1cc(N2C(=O)CNC2=O)ccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Solvent: ClCCl
Product: C=Cc1ccc(N2C(=O)CNC2=O)cc1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Potassium vinyltrifluoroborate (356 mg, 242 μmol), ethyldiisopropylamine (48 μL, 279 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane adduct (15.1 mg, 18.6 μmol) were added to a solution of 3-(4-bromo-3-methyl-phenyl)-imidazolidine-2,4-dione (50 mg, 186 μmol) in n-PrOH (372 μL) at room temperature in an N2 atmosphere. The mixture was stirred at 100° C. for 1.5 hours, and the reaction solution was then cooled. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 3-(3-methyl-4-vinyl-phenyl)-imidazolidine-2,4-dione as a yellow brown form (33 mg, 82%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([Mg]Br)[CH:17]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(F)cc1[Mg]Br
Reactant: O=Cc1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(F)cc1C(O)c1cccc(Br)c1F
Temperature: -78 °C
Yield: 100 %

Procedure:
To a solution of 3-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) in THF (21.42 mL) cooled to −78° C. was added (5-fluoro-2-methoxyphenyl)magnesium bromide in THF (11.82 mL, 5.91 mmol). The reaction mixture was maintained at −78° C. for at least 1 hr, then allowed to warm to room temperature. The reaction mixture was then re-cooled to 0° C. and additional (5-fluoro-2-methoxyphenyl) magnesium bromide in THF (11.82 mL, 5.91 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with a saturated aqueous solution of NH4Cl and diluted with CH2Cl2. The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (80 g column, 60 mL/min, 0-30% EtOAc in hexanes over 20 min, tr=17.5 min) gave the title compound (1.62 g, 4.92 mmol, 100% yield) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]CC2C=CC(OC)=CC=2)[CH2:10][C@H:9]1[CH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=O)=[O:7])[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:23][CH2:24][CH2:25][C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1C[C@H](SCc2ccc(OC)cc2)C[C@H]1CCC(=O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1C[C@H](S)C[C@H]1CCCc1ccc(F)cc1
Yield: 15.5 %

Procedure:
A solution of 72 mg (0.152 mmol) (2R,4R)-2-[3-(4-fluoro-phenyl)-3-oxo-propyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester and 0.12 (1.4 mmol) triethylsilane in 2.7 ml TFA was heated for 18 h at 80° C. Evaporation followed by flash chromatography on silica gel (EtOAc/hexane 7:3) gave 8 mg (15%) (2R,4R)-2-[3-(4-fluoro-phenyl)-propyl]-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester, MS: 340 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[C:18](Br)=[CH:19][CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:13]=3[C:12](=[O:27])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:1]([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[C:13]=3[C:12](=[O:27])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(Cc1ccccc1)C3
Yield: 62.4 %

Procedure:
To a solution of methyl 2-benzyl-9-bromo-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (0.1 g, 0.23 mmol) in MeOH (3 mL) was added Pd/C (0.04 g, 5%, 50% water), and the mixture was stirred at atmosphere of hydrogen for about 2.5 h. Debromination occurred without substantially removing benzyl group under this condition. Then the mixture was filtered, washed with MeOH (50 mL), concentrated and was chromatographed on silica gel to afford the product (0.05 g). MS (ESI) m/e [M+1]+ 349.0.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32].C[O-].[Na+:37]>CO>[CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH2:19][CH2:20][C:21]([O-:23])=[O:22])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=1[F:32].[Na+:37]
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(C)cc(CCC(=O)O)c3)nc2CC(C)(C)C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C)cc(CCC(=O)[O-])c3)nc2CC(C)(C)C)c1
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of 3-(3-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-5-methylphenyl)propanoic acid (259 mg) in methanol (5.0 mL) was added sodium methoxide (29 mg) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was washed with hexane, and dried to give the title compound (147 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][Si](OC(C)C)(C)C)[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].C(=O)([O-])[OH:42].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:40])([CH2:32][OH:42])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: O=C([O-])O
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccc(F)cc1F)[C@@H](C)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Yield: 90.5 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2-hydroxy-3-(isopropoxydimethylsilyl)-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (11 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 90 ml), to which 19.2 ml of 30% aqueous hydrogen peroxide and 1.57 g of sodium hydrogencarbonate were added. Then, the mixture was heated at 70° to 80° C. for 90 minutes. The reaction solution was cooled and extracted with a mixture of 500 ml of ethyl acetate and 100 ml of diisopropyl ether. The extract was washed with 100 ml of water, an aqueous solution of Na2S2O3 (50 ml×2) and 50 ml of an aqueous solution of sodium chloride successively, and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was recrystallized from 50 ml of diisopropyl ether to give 8.27 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless prisms. The mother liquor of recrystallization was submitted to silica gel chromatography (silica gel: 40 g, eluent; hexane:ethyl acetate=1:1). The resultant was recrystallized from diisopropyl ether to give 0.33 g of the above compound (total yield: 93.7%).