Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:10]=1[NH+:18]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])[CH2:19]1)([CH3:8])[CH3:7].[O-:35][CH2:36]C.[Na+].FC(F)(F)C1C=CC=C(C(F)(F)F)C=1>CO>[CH3:36][O:35][CH:19]1[N:18]([C:10]2[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=[CH:14][C:9]=2[CH:6]([CH3:8])[CH3:7])[CH2:22][CH2:21][N:20]1[C:23]1[C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][CH:26]=[CH:27][C:28]=1[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Reactant: CC[O-]
Agent: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Product: COC1N(c2c(C(C)C)cccc2C(C)C)CCN1c1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A 50 mL flask replaced with nitrogen was charged with 500 mg of 1,3-bis[(2,6-diisopropyl)phenyl]imidazolinium tetrafluoroborate and 3 g of methanol. To the resulting mixture, 1.4 mL of a methanol solution of 1 M sodium ethoxide was added dropwise at room temperature over 30 minutes. The resulting mixture was stirred at room temperature for 2 hours and then concentrated. To the residue thus obtained, 5 g of 1,3-bis(trifluoromethyl)benzene was added and then the precipitated solid was removed by filtration. The filtrate was concentrated to obtain 430 mg of 2-methoxy-1,3-bis[(2,6-diisopropyl)phenyl]imidazolidine as a pale yellow crystal, yield: 97%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4].[NH4+].[NH4+].[O-:24]S(OOS([O-])(=O)=O)(=O)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:24])[CH2:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1c2ccccc2CCC1(C)C
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)CC1(C)C
Reaction time: 1.5 h
Yield: 28.2 %

Procedure:
142 g of 1-(2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester are suspended in 1 liter of distilled water. The suspension is heated to +87° C. and, while stirring, a total of 335 g of ammonium peroxodisulfate is added in portions thereto within a period of 1.5 hours in such a manner that the temperature does not exceed +90° C. After the reaction mixture has been cooled to +15° C., the pH value is adjusted to pH 4 by the addition of approximately 335 g of 30% sodium hydroxide solution and the whole is extracted with 500 ml of methylene chloride. The organic phase is separated off, dried over sodium sulfate, treated with activated carbon and concentrated by evaporation. Crystallisation of the residue from ether yields 42 g of 1-(2,2-dimethyl-4-oxotetralin-1-yl)-5-imidazolecarboxylic acid methyl ester having a melting point of 93°-95° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11][CH2:10]1>ClCCl>[CH3:8][C:9]1([CH3:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]([C:5](=[O:7])[CH3:6])[CH2:10]1
Reactant: CC1(C)CNCc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1Cc2ccccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A solution of acetic anhydride (1.17 ml, 12.4 mmol) was added dropwise to a stirred, ice-cooled solution of 4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (1.0 g, 6.2 mmol) (for preparation see J. Org. Chem., 1983, 48, 5348) in dry dichloromethane (5 ml). The cooling bath was removed and the solution was stirred for 2 h at room temperature. The reaction mixture was then concentrated in vacuo to give the title compound (D2) as an oil (1.1 g, 87%), δH (CDCl3, rotamers observed)/ppm 1.28, 1.32 (6H, 2×s), 2.20, 2.22 (3H, 2×s), 3.43, 3.61 (2H, 2×s), 4.66, 4.77 (2H, 2×s), 7.07-7.37 (4H, m).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[CH2:15][CH2:16][N+:17]([O-])=O)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@:11]3([OH:29])[CH2:12][CH2:13][C@@H:14]2[CH2:15][C:16]#[N:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](CC[N+](=O)[O-])CC[C@]32O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](CC#N)CC[C@]32O)C1
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of 13.34 g of 3β-acetoxy-21-nitro-5β-pregnane-14β-ol and 39.1 g of triphenylphosphine in 370 ml of dry methylene chloride was kept at 0° C. under nitrogen; 19.3 ml of diethyl azodicarboxylate were added dropwise during 1 hr. After 2 hrs. the solvent was removed in vacuo and the crude product was purified by flash-chromatography (SiO2) using methylene chloride/diethyl ether 95/5 as the eluant to give 11.20 g of 3β-acetoxy-14β-hydroxy-5β-pregnane-21-nitrile.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([C@@:8]1([OH:9])[C@:10]([S:20]([CH3:19])(=[O:22])=[O:21])([OH:11])[C@@H:12]([CH:13]([S:20]([CH3:19])(=[O:22])=[O:21])[OH:14])[O:15][C@H:7]1[N:6]1[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]1=[O:17])(=[O:22])=[O:21]
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cn([C@@H]2O[C@H](C(O)S(C)(=O)=O)[C@](O)(S(C)(=O)=O)[C@]2(O)S(C)(=O)=O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of 5-methyluridine (12.8 g, 50 mmol) in pyridine (75 mL) at 0° C. was added methanesulfonyl chloride (17.4 mL, 225 mmol). The reaction mixture was stirred at 0° C. for five hours then poured into ice-water (500 mL) with stirring. Trimethanesulfonyl-5-methyluridine (2) precipitated and the mixture was stirred for 5 min. The solid product was collected by filtration and washed with water (3×200 mL) and dried. Yield, 21.6 g, 89%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:14][C@H:15]([C:17]([NH:19][C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH3:16].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:14][C@H:15]([C:17]([NH:19][C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:18])[CH3:16])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)(NC(=O)[C@H](C)N)c1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C(C)(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccccc1

Procedure:
Following General Procedure C and using 3,5-difluorophenylacetic acid (Oakwood) and ethyl N-(L-alaninyl)-2-amino-2-phenylpropionate hydrochloride (prepared from N-BOC-L-alanine (Sigma) and D,L-α-methylphenylglycine ethyl ester (from Example D9 above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=128-130° C.). The reaction was monitored by tlc (Rf=0.2 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>CO.[Pd]>[OH:1][C:2]([CH3:28])([CH3:27])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[C:6](=[O:20])[N:5]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: Cc1c(C(=O)OCc2ccccc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Yield: 96 %

Procedure:
To a stirring solution of benzyl 1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (300 mg, 789 μmol) in MeOH (10 mL) was purged with argon for 10 min. To this solution was added Pd/C (40 mg), and the mixture was stirred for 3 h under balloon of hydrogen. Reaction was monitored by LCMS. The reaction mixture was filtered through a bed of celite and concentrated under reduced pressure to give the title compound (220 mg, 96.1% yield) as an off-white solid. MS (ESI pos. ion) m/z: 291 (MH+). Calc'd exact mass for C15H18N2O4 290.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:6]([OH:23])=[CH:7][C:8]([OH:22])=[C:9]([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:10]=1>C(O)C>[Cl:4][C:5]1[C:6]([OH:23])=[CH:7][C:8]([OH:22])=[C:9]([C:11](=[N:2][NH2:3])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: COc1ccc(CC(=O)c2cc(Cl)c(O)cc2O)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=NN)c2cc(Cl)c(O)cc2O)cc1

Procedure:
Hydrazine hydrate (0.166 ml, 3.42 mmol) is added to a solution of 1-(5-chloro-2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone (1a) (0.5 g, 1.71 mmol) in 95% ethanol (5 ml). The mixture is heated under reflux for 7 hours. Solvent is concentrated in vacuo, the residue treated with water, filtered of and recrystallyzed from 2-propanol.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:7][C:6]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[Cl:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(OCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.8 %

Procedure:
To a methylene chliride (3 ml) solution of tert-butyl (4-tert-butyl-3-chlorophenoxy)acetate (820 mg, 2.4 mmol) was added trifluoroacetic acid (TFA) (3 ml). The mixture was stirred for 5 hours at ambient temperature. The solvent was removed under reduced pressure to give a residue, which was applied to a recrystallization from hexane-methylene dichloride to furnish 657 mg (100% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11](=O)[CH3:12].[CH3:14][NH:15][NH2:16].ClC(Cl)C(Cl)Cl>C(O)C.[O-2].[Mn+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:15]([CH3:14])[N:16]=[C:11]([CH3:12])[CH:10]=1
Reactant: CNN
Reactant: CC(=O)C=Cc1c(F)cccc1F
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CCO
Product: Cc1cc(-c2c(F)cccc2F)n(C)n1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a mixture of 4-(2,6-difluorophenyl)-3-buten-2-one (i.e. the product of Step A) (8.1 g, 44.5 mmol) in ethanol (50 mL) was added methylhydrazine (2.1 g, 49 mmol). After 24 h, the reaction mixture was concentrated under reduced pressure. To the resulting oil (10.1 g) was added 1,1,2,2-tetrachloroethane (65 mL) and manganese oxide (41.7 g, 480 mmol). The reaction mixture was heated at 140° C. for 20 minutes, and then cooled to room temperature and filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel rinsing with dichloromethane (2×20 mL). The filtrate was concentrated under reduced pressure and the resulting material was purified by MPLC (10 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a light yellow solid (4.02 g).
Reaction SMILES: I[CH2:2][Si:3]([CH3:11])([CH3:10])[O:4][Si:5]([CH2:8]I)([CH3:7])[CH3:6].[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C1(C)C=CC=CC=1>O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[CH2:8][Si:5]([CH3:6])([CH3:7])[O:4][Si:3]([CH3:11])([CH3:10])[CH2:2]1
Reactant: C[Si](C)(CI)O[Si](C)(C)CI
Reactant: NCc1ccccn1
Solvent: O
Solvent: Cc1ccccc1
Product: C[Si]1(C)CN(Cc2ccccn2)C[Si](C)(C)O1
Reaction time: 24 h

Procedure:
To 41.4 g. (0.1 mole) of 1,3-bis-iodomethyl-1,1,3,3-tetramethyl-disiloxane there is added dropwise with stirring 32.4 g. (0.3 mole) of 2-aminomethyl-pyridine while maintaining the temperature at 20° C. Stirring is continued at room temperature for 24 hours. The now heterogeneous mixture is combined with approximately 0.5 l. of toluene followed by approximately 0.5 l. of water. The equilibrated aqueous phase is then extracted with two 100 ml. portions of toluene. The combined organic phase is then washed twice with approximately 100 ml. of water to give 4-(2-pyridylmethyl)-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane as the crude free base.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[CH:9][C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)nc1C
Yield: 41.5 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (135 mg) described in Preparation Example 25 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (103 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 109, the title compound (89 mg) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][Cl:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:33]([C:37]1[O:41][C:40]([CH2:42][S:43][C:44]2[S:48][C:47]([NH2:49])=[N:46][CH:45]=2)=[N:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:17][CH2:16][CH2:15][N:4]([CH2:3][CH2:2][Cl:1])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:49][C:47]2[S:48][C:44]([S:43][CH2:42][C:40]3[O:41][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][N:39]=3)=[CH:45][N:46]=2)=[O:14])=[CH:9][CH:10]=1
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Reactant: O=C(O)Cc1ccc(N(CCCl)CCCl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1cnc(CSc2cnc(NC(=O)Cc3ccc(N(CCCl)CCCl)cc3)s2)o1
Reaction time: 24 h
Yield: 76 %

Procedure:
To a stirred methylene chloride solution (20 ml) was added DMAP (438 mg, 3.59 mmol) and 2-(4-(bis(2-chloroethyl)amino)phenyl)acetic acid (B-5) (906 mg, 3.27 mmol). Subsequently, DCC (690 mg, 3.35 mmol) was added to reaction mixture, followed by addition of 5-((5-tert-butyloxazol-2-yl)methylthio)thiazol-2-amine (Intermediate CY-200) (800 mg, 2.97 mmol). The mixture was stirred at r.t for 24 h. After removing dicyclohexylurea (DCU) by filtration, the filtrate was concentrated in vacuum and dried over Na2SO4. The residue was purified by silica gel chromatography eluting with CH2Cl2: EtOAc=20:1 to afford total product (1.2 g, 76%) as a gray solid. LC-MS: (M+H)+=528. 1H NMR (300 MHz, CDCl3) δ 10.17 (s, 1H), 7.28-7.30 (m, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.7 Hz, 2H), 6.58 (s, 1H), 3.95 (s, 2H), 363-3.79 (m, 10H), 1.26 (s, 9H).
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:27][C:26](=[O:28])[C:25]([CH3:29])=[C:24]([OH:30])[C:23]=1[CH3:31].OS([O-])(=O)=O.[K+]>C1COCC1>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:27][C:26](=[O:28])[C:25]([CH3:29])=[C:24]([O:30][S:9]([CH3:8])(=[O:11])=[O:10])[C:23]=1[CH3:31]
Reactant: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1O
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2cc3ccccc3o2)oc(=O)c(C)c1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Et3N (130 μl) and methanesulfonyl chloride (24 μl) were added to a suspension of 6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one (40 mg) in THF (5 ml), and the mixture was stirred at room temperature for one hour. The reaction solution was poured into aqueous KHSO4 and extracted with AcOEt, and the organic layer was rinsed with saturated saline and dried with MgSO4, and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to obtain 6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:3]=1.F[B-](F)(F)F.[CH3:24][O+](C)C.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:24])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCCC[C@H]1O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CO[C@@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R,R)-4-fluoro-2-(2-hydroxycyclohexyloxy)-nitrobenzene (0.200 g) dissolved in methylene chloride (10.0 ml) was added trimethyloxonium tetrafluoroborate (0.348 g). The mixture was stirred overnight at rt. Water was added; the organic phase was separated and evaporated to dryness to yield a brownish oil.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5]1)=[N+]=[N-].[H][H]>CO.[Pd]>[C:14]([O:13][C:11]([NH:10][C@H:9]1[CH2:8][CH2:7][C@@H:6]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:5][C@@H:4]1[NH2:1])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1N
Yield: 67.5 %

Procedure:
(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonyl-amino)-1-(tert-butyldiphenylsilyloxymethyl)cyclohexane (2.59 g) was dissolved in methanol (50 ml), and 10% palladium on carbon (200 mg) was added to stir the mixture for 20 hours in a hydrogen atmosphere. After the catalyst was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:20→1:10) to obtain (1S,2S,4R)-N1-tert-butoxycarbonyl-4-(tert-butyldiphenylsilyloxymethyl)-1,2-cyclohexanediamine (1.66 g) as a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCOC2C=CC(C(O)=O)=CC=2)C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>C(Cl)Cl.N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)CCCCCc1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccc(OCCCCc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CCCCCc1ccccc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of p-(4-phenylbutoxy)benzoyl chloride prepared from 1 g of p-(phenylbutoxy)benzoic acid and 2 ml of oxalyl chloride in methylene chloride was added to a solution of 0.6 g of ethyl 6-(o-aminophenyl)hexanate obtained in Reference Example 17 in 10 ml of pyridine at temperature less than -30° C. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Toluene was added to the residue. The mixture was washed with diluted hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The systems was concentrated under reduced pressure to obtain 1.0 g of oily ethyl 6-[o-[p-(4-phenylbutoxy)benzamido]phenyl]hexanate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.021 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H), 1.55 (m, 2 H), 2.29 (m, 1 H), 2.39 (s, 3H), 2.75 (m, 3 H), 3.15 (d, J=18.38 Hz, 1 H), 3.52 (s, 3 H), 3.61 (m, 1 H), 3.94 (m, 2 H), 4.19 (m, 3 H), 4.68 (d, J=10.30 Hz, 2 H), 4.89 (d, J=5.52 Hz, 1 H), 6.83 (d, J=9.93 Hz, 1 H), 7.00 (m, 6 H), 7.13 (d, J=7.72 Hz, 1 H), 7.31 (m, 3 H), 7.64 (m, 2 H), 7.88 (m, 4 H), 8.09 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.78 Hz, 1 H).