Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38](Cl)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].C1(P(C2CCCCC2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[C:57]2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCCC1.CN1CCCC1=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:57][CH:52]4[CH2:53][CH2:54][CH2:55][CH2:56][CH2:51]4)[C:37]=3[CH3:43])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: Cc1c(Cl)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C
Reactant: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1c(CC2CCCCC2)cccc1-c1ccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)nc1C(=O)OC(C)(C)C

Procedure:
A mixture of EXAMPLE 107A (60 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 4.58 mg) and tris(dibenzylideneacetone)dipalladium(0) (2.25 mg) in tetrahydrofuran (0.5 mL) and 1-methyl-2-pyrrolidinone (0.5 mL) was stirred at room temperature for 5 minutes while bubbling N2 through the reaction mixture. To this solution was added 0.5 M (cyclohexylmethyl)zinc(II) bromide (0.393 mL) at room temperature. The reaction mixture in a sealed tube was heated in a preheated oil bath at 100(C overnight and cooled. The reaction mixture was quenched with water and diluted with dichloromethane. The dichloromethane layer was washed with water and concentrated. The residue was purified by flash chromatography, and eluted with 5% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13](=[O:30])[N:12]2[CH2:31][C:32]([O:34]C)=[O:33])[CH:7]=[C:8]([F:10])[CH:9]=1.Cl>C1COCC1.O>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:11]([C:6]2[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=2)[N:12]([CH2:31][C:32]([OH:34])=[O:33])[C:13](=[O:30])[CH:14]1[CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CN1C(=O)C(C2CCOCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 mg (0.48 mmol) lithium hydroxide were added to 0.20 g (0.43 mmol) tert-butyl 5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (isomer mixture 2.1) in 5 ml THF and 1 ml of water. The mixture was stirred for 2 h at RT, adjusted to pH=7 with 0.1 M hydrochloric acid solution and then evaporated to dryness.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)=[C:6]([CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(C)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(Cl)n1
Temperature: 25 °C

Procedure:
4-Chloro-2,6-dimethyl-5-iodopyrimidine and 4-ethynyl-α,α,α-trifluorotoluene were reacted in toluene in the presence of dichlorobis(triphenylphosphine)palladium, cuprous iodide and triethylamine while stirring under room temperature to heating to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: [CH:1]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.[F:38][C:39]([F:49])([F:48])[C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44].C(N(CC)C(C)C)(C)C>ClCCCl>[CH:4]12[N:7]([CH2:8][CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:35]([NH:44][CH2:43][C:42]4[CH:45]=[CH:46][CH:47]=[C:40]([C:39]([F:48])([F:49])[F:38])[CH:41]=4)=[O:36])=[CH:13][C:12]=3[C:18]3[N:19]([CH3:24])[N:20]=[CH:21][C:22]=3[Br:23])[CH:1]([CH2:2][CH2:3]1)[CH2:6][CH2:5]2
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1C2CCC1CC2
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cn1ncc(Br)c1-c1cc(NC(=O)NCc2cccc(C(F)(F)F)c2)ccc1OCCN1C2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (50.0 mg, 0.13 mmol) was added to a solution of 4-nitrophenylchloroformate (26.0 mg, 0.13 mmol) in 1,2-dichloroethane (4.0 mL) and the mixture stirred at room temperature for 1 hour. To the resulting precipitate mixture was added 3-trifluoromethylbenzylamine (0.022 mL, 0.15 mmol) and N,N-diisopropylethylamine (0.030 mL, 0.17 mmol), and the mixture stirred an additional 1 hour. The mixture was concentrated and purified by RP-HPLC. The collected fractions were concentrated and 12% sodium hydroxide (aq) (0.2 mL) was added to give pH 9. The solution was extracted into ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to give a white solid (49 mg, 65%). LCMS m/z (%)=592 (M+H79Br, 100), 594 (M+H81Br, 67). 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (bs, 1H), 7.67 (bs, 1H), 7.65-7.59 (m, 4H), 7.53-7.50 (m, 1H), 7.33 (d, J=2.69 Hz, 1H), 7.12 (d, J=9.04 Hz, 1H), 6.77-6.74 (m, 1H), 4.40 (d, J=4.0 Hz, 2H), 4.08-3.98 (m, 2H), 3.67 (s, 3H), 3.12 (m, 2H), 2.59-2.55 (m, 2H), 1.56-1.54 (m, 4H), 1.17-1.15 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17](Cl)=[O:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.[CH3:20][NH:21][CH3:22]>C(Cl)Cl>[CH3:20][N:21]([CH3:22])[C:17]([C:5]1([CH2:4][CH2:3][CH2:2][Cl:1])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:18]
Reactant: O=C(Cl)C1(CCCCl)CC=CCC1c1ccccc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)C(=O)C1(CCCCl)CC=CCC1c1ccccc1
Yield: 90.4 %

Procedure:
1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carbonyl chloride (5.22 g, 17.5 mmol) was treated with excess dimethylamine (10 g) in methylene chloride (100 ml) to afford 4.84 g (90% yield) of N,N-dimethyl-1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxamide as a viscous oil. The infrared spectrum had a carbonyl stretching frequency at 1660 cm-1 indicative of an amide which replaced the carbonyl stretch at 1790 cm-1 for the acid chloride. The tertiary amide isolated above (4.80 g, 15.1 mmol) was dissolved in DMF (25 ml) to which 10 ml of piperidine (excess) was added and the contents stirred at 50° C. under N2 for two days. The solution was concentrated in vacuo at 3 mm pressure. The resulting oil was dissolved in ethyl ether and washed with 2.5N aqueous HCl. The organic fraction was discarded. The aqueous phase was washed with 2.5N aqueous NaOH and extracted with ethyl ether. The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo to afford 5.38 g of a dark yellow viscous oil. Flash chromatography, employing 10% MeOH/CHCl3, as eluent, afforded 1.95 g of N,N-dimethyl-1-[3-(1-piperidinyl)propyl]-6-phenyl-3-cyclohexene-1-carboxamide as a tan solid, mp 105°-106° C.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([S:15][CH2:16][CH3:17])[CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[C:1]([Si:5]([CH3:19])([CH3:18])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([S:15][CH2:16][CH3:17])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCSc1cnc2c(c1)CCN2[Si](C)(C)C(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCSc1cnc2c(ccn2[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.5 %

Procedure:
To a solution of 1-(tert-butyl-dimethyl-silanyl)-5-ethylsulfanyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (2.2 g, 7.6 mmol) in dichloromethane (50 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (2.07 g, 9.1 mmol) at room temperature. After stirring for 12 h at room temperature, the mixture was concentrated. The residue. was purified by flash column chromatography (Qingdao silica gel, 300 mesh, 11% dichloromethane/hexanes) to afford 1-(tert-butyl-dimethyl-silanyl)-5-ethylsulfanyl-1H-pyrrolo[2,3-b]pyridine (0.5 g, 23%) as a yellow oil: LC/MS m/e calcd for C15H24N2SSi [M+H]+ 292.52.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.4 %

Procedure:
A suspension of 18 (2.91 g, 8.68 mmol), Cs2CO3 (4.25 g, 13.02 mmol) and DMF (anhydrous, 40 mL) was stirred at room temperature for 1.5 h. To the mixture was then added methyl iodide (0.83 mL, 13.02 mmol), and stifling was continued for an additional 3 h at the ambient temperature. The mixture was then partitioned between water (150 mL) and dichloromethane (150 mL), aqueous layer was separated and washed with dichloromethane (3×300 mL). Organics were combined, dried over anhydrous Na2SO4, concentrated and further dried under high vacuum overnight to afford the desired methyl ester 19 (3.41 g, quant yield): 1H NMR (500 MHz, CDCl3) δ 1.26 (m, 12H), 1.47 (m, 2H), 1.52 (m, 2H), 2.28 (m, 2H), 3.16 (m, 2H), 3.66 (s, 3H), 5.10 (s, 2H), 7.32 (m, 5H); m/z (ESI) 350 [M+H]+.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][S:8][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(S)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a stirred solution of N-(2-mercapto-2-methylpropionyl)-L-cysteine (11.2 g) in dimethylformamide(50 ml), trityl chloride(16.7 g) was added slowly. The reaction mixture was stirred for 2 hours at room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 14.2 g(60%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4](I)[CH:3]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([CH:11]=[CH2:12])[CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cc(Cl)c(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(Cl)c(Cl)cc1N
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A mixture of 4,5-dichloro-2-iodobenzenamine (6 g, 20.8 mmol), tributyl(vinyl)stannane (6.6 g, 20.8 mmol), Pd(PPh3)4 (2.4 g, 2.1 mmol) in toluene (60 mL) was stirred at reflux under argon for 6 h. The mixture was allowed to cool to room temperature, quenched with aqueous KF solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desired product (3.0 g, 76.7% yield) as a colorless oil.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:27](Br)[CH2:28][CH3:29]>>[ClH:1].[CH2:27]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[CH2:11]1)[CH2:28][CH3:29]
Reactant: CCCBr
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CNCC[C@H]2c2ccc(F)cc2)cc1
Agent: Cl
Product: CCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc(C(C)(C)C)cc2)C1

Procedure:
trans-1-propyl-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride M.p. 221.1° C. was prepared exactly as described in example 1 from trans-4-(4-fluorophenyl)-3-(4-t-butylphenoxymethyl)-piperidine hydrochloride and propyl bromide by refluxing for 96 hours.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([C:15]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[O:16])[CH:3]=2)[CH:32]=[C:33]([F:35])[CH:34]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Reactant: OB(O)c1cc(F)cc(F)c1
Product: O=C(O)COc1ccc(-c2cc(F)cc(F)c2)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and 3,5-difluorophenylboronic acid according to GP4: LC/MS (an10n8): Rt 3.03 min, m/z 434.5 [M+H]+; 1H NMR (CDCl3): δ 4.85 (s, 2H), 6.81 (td, J=8.9, 2.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.9 Hz, 1H), 7.41 (d, J=6.6 Hz, 1H), 7.48 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.66-7.78 (m, 4H), 8.23 (s, 1H), 8.57 (s, 1H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=C)[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14].[O:31]=[O+][O-]>C(Cl)Cl.CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=[O:31])[C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])=[O:14]
Reactant: C=Cc1ccccc1CC(C(=O)OCC[Si](C)(C)C)N1C(=O)c2ccccc2C1=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Product: C[Si](C)(C)CCOC(=O)C(Cc1ccccc1C=O)N1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Yield: 100 %

Procedure:
Dissolve 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionic acid, 2-trimethylsilanyl-ethyl ester (2.61 g, 6.19 mmol) in methylene chloride (70 mL) and methanol (75 mL). Cool to -78° C. and treat with ozone until a blue color persists. Purge with nitrogen and add dimethylsulfide (7 mL) and pyridine (0.35 mL). Allow to warm to room temperature gradually overnight. Partition between methylene chloride (100 mL) and water (40 mL). Extract the aqueous with methylene chloride (50 mL), dry (Na2SO4) and purify by silica gel chromatography (2.5:1 hexane/ethyl acetate) to give the title compound as a colorless viscous oil (2.65 g, 100%).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:12][C:11]=2[N+:21]([O-])=O)[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[NH2:21][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:14]=[CH:15][C:10]=1[NH:9][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:24])([F:1])[CH2:3][CH2:4]1
Reactant: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1

Procedure:
Following the same procedure as in Step D of Example 1 using methyl (4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)carbamate (200 mg, 0.583 mmol) and a catalytic amount of 10% Pd/C in 20 mL of EtOAc. Yield: 185 mg (99%). MS (ESI) (M+H)+314.29.
Reaction SMILES: C(O[C@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C[Si]([N:32]=[N+:33]=[N-:34])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[N:32]=[N+:33]=[N-:34])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
1,2,3,4,6-Penta-O-acetyl-α-D-glucopyranose (5.00 g, 12.8 mmol) was dissolved in 10-15 mL dry CH2Cl2 under an inert atmosphere. Trimethylsilyl azide (4.24 mL, 32.1 mmol) and tin (IV) chloride (0.75 mL, 6.41 mmol) were added, and the reaction was stirred for 18 hours at room temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed twice with saturated NaHCO3 (20 mL) and with brine (20 mL). The organic phase was dried, filtered and concentrated to leave 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl azide as a white solid (3.92 g, 82%). 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl azide (0.30 g, 80 mmol) was then dissolved in dry THF (115 mL), and Pd/C was added (˜5%) to this solution. The mixture was stirred under H2 overnight. TLC revealed the reduction was completed (Rfazide=0.80, Rfamine=0.10). In a separate flask, compound 23 (0.17 g, 0.30 mmol) and 0.5 M HBTU in DMF (1.20 mL, 0.60 mmol) were combined, followed by the addition of DMF (˜2 mL) and DIEA (104 μL, 0.60 mmol). This solution was then added to the reaction flask, and the reaction mixture was stirred under N2 overnight. The resulting suspension was filtered through celite which was washed well with ethyl acetate (˜100 mL), and the filtrate was washed with 5 M HCl (50 mL), saturated NaHCO3 (2×50 mL), and brine (1×50 mL). The organic solution was dried over magnesium sulfate, filtered, and concentrated. The residue was purified using a silica gel column chromatography with 10% MeOH/DCM to yield V (0.16 g, 59.33). 1H NMR δ (CDCl3) 0.78 (3H, t, J=7 Hz), 1.16-1.23 (32H, brm), 1.35 (2H, m) 1.52 (2H, m) 1.57 (6H, brs), 1.86 (6H, brs), 1.91-2.00 (15H, m), 2.14 (2H, m), 2.99 (2H, t, J=7 Hz), 3.75 (2H, m), 3.95-4.07 (3H, m), 4.15-4.29 (4H, m), 4.43-4.38 (1H, m) 4.80 (1H, dd, J=5, 11 Hz), 4.84-4.89 (2H, m), 4.95-5.02 (3H, m), 5.12-5.24 (3H, m), 5.35 (1H, d, J=3 Hz), 5.47 (11H, t, J=9.8 Hz), 6.28 (1H, dd, J=7.6, 19 Hz), 6.60 (11H, d, J=9.3 Hz), 7.18 (1H, d, J=9.1 Hz), 7.34 (1H, d, J=9.1 Hz). LC-MS (ESI) m/z calcd for C47H78N4O12 [M+H]+ 891.56, found [M+H]+ 891.69.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH2:18])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=[C:34]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([BH3-])#N.[Na+]>C(O)C>[C:35]([C@@H:34]([NH:18][C@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:11])[CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
10 g (0.0268 mol) of tert-butyl Nε -benzyloxycarbonyllysinate hydrochloride are dissolved in 150 cm3 of anhydrous ethanol; 2.71 g (0.0268 mol) of triethylamine, 20.6 g (0.1 mol) of ethyl 2-oxo-4-phenylbutyrate and 20 g of 4Å molecular sieve are added. The mixture is stirred for one hour at 20° C. A solution of 1.68 g (0.0268 mol) of sodium cyanoborohydride in 20 cm3 of ethanol is then added in the course of 4 hours, after which stirring is continued for 18 hours at 20° C. The mixture is filtered and taken to dryness, the residue is redissolved in 200 cm3 of ethyl acetate and the solution is then washed twice with 100 cm3 of a 10% strength aqueous citric acid solution and then with water until the washing liquors are neutral. The mixture is dried over magnesium sulfate and evaporated. 28.7 g of an oil are collected, and this is purified by chromatography on silica gel (eluent: methylene chloride/acetone 95:5). After the removal of impurities and then the (S, R) isomer, 4.1 g of tert-butyl (S)-Nα -[(S)-1-carbethoxy-3-phenylpropyl]-Nε -benzyloxycarbonyllysinate are collected, and used without further treatment in the following stage.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:34])[NH:28]2>ClCCl>[CH3:33][C:30]1[CH:31]=[CH:32][C:23]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:24]2[C:29]=1[NH:28][C:27](=[O:34])[CH2:26][CH2:25]2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(O)c2c1NC(=O)CC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(OS(=O)(=O)C(F)(F)F)c2c1NC(=O)CC2
Reaction time: 1 h
Yield: 97 %

Procedure:
Pyridine (6.2 ml) and trifluoromethanesulfonic anhydride (10.3 ml) were added with stirring at 0° C. to an anhydrous dichloromethane solution (30 ml) of 5-hydroxy-8-methyl-3,4-dihydro-1H-quinolin-2-one (9.0 g), followed by stirring for 1 hour. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diisopropyl ether mixed solvent to thereby obtain 28 g (yield: 97%) of 8-methyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a light brown powder.