Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][C:11]=1[CH2:10][CH2:9]3.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C:2](=[CH2:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10][C:11]=2[CH:12]=1)(=[O:29])[CH3:28]
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(OC(C)=O)ccc4[C@H]3CC[C@]12C

Procedure:
A solution of 17-methylenestra-1,3,5(10)-trien-3-ol (10, 5.84 g, 21.8 mmol) in anh. pyridine (32 ml, 0.40 mol) and acetic anhydride (9.7 ml, 0.10 mol) was stirred 24, after which ethyl acetate (250 ml) was added. See FIG. 160. The mixture was washed with three 100 ml portions of 1 N hydrochloric acid+100 ml of saturated sodium bicarbonate+100 ml of saturated copper sulfate+100 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. The residue was washed with 25 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from aqueous ethanol gave lustrous white platelets (5.84 g, 18.8 mmol), m.p. 77-79° C.
Reaction SMILES: B.C1COCC1.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:19](=[O:27])[N:20]=[N:21][C:22]=2[C:23]([F:26])([F:25])[F:24])=[CH:13][CH:12]=1)(=O)[CH3:8].C(NC1C=CC(CCl)=CC=1)(=O)C.C1(C)C(C)=CC=CC=1>O1CCCC1>[CH2:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:19](=[O:27])[NH:20][NH:21][C:22]=2[C:23]([F:25])([F:24])[F:26])=[CH:13][CH:12]=1)[CH3:8]
Reactant: CC(=O)Nc1ccc(CC2=C(C(F)(F)F)N=NC2=O)cc1
Agent: B
Agent: CC(=O)Nc1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: CCNc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Temperature: -30 °C
Reaction time: 15 h

Procedure:
A solution of borane-THF complex (188 mL, 1M solution in tetrahydrofuran), diluted with 200 mL tetrahydrofuran, was cooled to -30° C. under N2 atmosphere. A solution of 4-[(4-acetamidophenyl)methyl]-5-(trifluoromethyl)-3H-pyrazol-3-one (6 g, prepared as in Example 1 (except that 4-acetamidobenzylchloride was reacted with the β-keto ester anion in refluxing xylene) in tetrahydrofuran (300 mL) was added over 0.75 hours and the mixture allowed to warm gradually to ambient temperature with stirring for 15 hours. The reaction mixture was refluxed for 3 hours, then cooled in ice and quenched with aqueous sodium hydroxide solution (24 mL, 2.5N). The mixture was stirred for 2 hours at ice temperature and 15 hours at room temperature. Volatile materials were removed in vacuo on the rotary evaporator. The residue was solubilized in distilled water, brought to pH 7 with dilute, aqueous HCl solution and extracted with ethyl acetate. The extracts were washed with saturated brine solution, dried over MgSO4, filtered and concentrated. The residue was dissolved in isopropyl alcohol saturated with anhydrous HCl and cooled in ice. The precipitate was collected on a suction funnel and dried under vacuum (abderhalden apparatus) to afford the title compound as a pale yellow glass; sinters at 104° C., liquefies 169°-171° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@@H:13]([NH2:16])C2)=[O:10])[CH2:4][CH2:3]1.[C:17](OC(N1CC[C@@H](N)C1)=O)(C)(C)C>>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([NH:11][C@@H:15]2[CH2:14][CH2:13][NH:16][CH2:17]2)=[O:10])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: NC1CCC(NC(=O)N2CC[C@@H](N)C2)CC1
Product: NC1CCC(NC(=O)N[C@@H]2CCNC2)CC1

Procedure:
1-(4-Amino-cyclohexyl)-3-(R)-pyrrolidin-3-yl-urea is prepared analogously to (R)-3-amino-pyrrolidine-1-carboxylic acid (4-amino-cyclohexyl)-amide (Intermediate IF) by replacing (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:18]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]4=[C:22]([C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=4)[C:32]([O:34]C)=[O:33])[N:21]=3)=[O:19])[CH:10]=2)[N:5]=1>C1COCC1>[CH3:3][C:4]1[N:13]([CH2:14][CH2:15][CH3:16])[C:12](=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:18]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]4=[C:22]([C:29]4[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=4)[C:32]([OH:34])=[O:33])[N:21]=3)=[O:19])[CH:10]=2)[N:5]=1
Reactant: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(=O)OC)c4)c4ccccn34)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Yield: 72.9 %

Procedure:
7.65 ml of a 1N aqueous solution of sodium hydroxide are added to 0.735 g (1.53 mmol) of methyl 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoate in 30 ml of THF. The reaction medium is refluxed for 2.5 hours. After acidification with 10 ml of a 1N aqueous solution of hydrochloric acid, the reaction medium is concentrated under reduced pressure. The residue is taken up in 20 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 50° C. overnight. 0.52 g of a yellow solid is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>ClCCl>[CH:4]1[CH:3]=[CH:2][N:1]=[C:6]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:5]=1
Reactant: c1ccncc1
Solvent: ClCCl
Product: c1ccc(-c2ccccn2)nc1
Reaction time: 8 h

Procedure:
A suspension of CeBr3(THF)4 (complex 2) (0.050 grams, 0.075 millimoles) in dichloromethane (10 milliliters) was prepared. A solution of bipyridine (0.023 grams, 0.150 millimoles) in dichloromethane was prepared and added to the suspension. After allowing the resulting yellow suspension to continue stirring overnight, the reaction mixture was allowed to settle. The solvent was decanted. The yellow solid was washed twice with cold dichloromethane to remove unreacted bipyridine. The solid was dried in vacuo, affording a bright yellow solid. A saturated solution of the yellow solid in pyridine was prepared. Slow diffusion of hexanes into the saturated solution produced yellow block-shaped crystals of CeBr3(bipyridine)(pyridine)3 (complex 6) that proved to be suitable for X-ray diffraction. The crystals were washed with cold toluene and dried under argon. Yield: 0.035 grams, 62%). The FT-IR spectrum included peaks at 1600 and 1441 cm−1 assigned to pyridine C═C and C═N stretches (compared to 1541 and 1439 cm−1, respectively, for neat pyridine), and peaks at 1595 and 1436 cm−1 assigned to C═C and C═N stretches for bipyridine. Analysis calculated for C25H23N3CeBr3: C (38.83%), H (3.00%), N (9.06%). Found: C (37.71%), H (2.81%), N (8.58%). An ORTEP representation of 6 is shown in FIG. 4. Hydrogen atoms were omitted for clarity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)[OH:5].[H-].[Na+].[H][H].F[C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[C:30]([F:33])([F:32])[F:31]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)[O:5][C:25]1[CH:26]=[C:27]([Cl:29])[CH:28]=[CH:23][C:24]=1[C:30]([F:31])([F:32])[F:33]
Reactant: [H][H]
Reactant: COC(=O)C(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Fc1cc(Cl)ccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1cc(Cl)ccc1C(F)(F)F)c1cc(F)cc(C(F)(F)F)c1

Procedure:
(3-Fluoro-5-trifluoromethyl-phenyl)-hydroxy-acetic acid methyl ester 91 (0.1 mol) was dissolved in dimethylformamide (100 mL) and sodium hydride (0.1 mol) was added. When hydrogen evolution stopped, a solution of 2-fluoro-4-chloro-1-trifluoromethyl-benzene 92 (0.1 mol) in dimethylformamide (25 mL) was added. The progress of the reaction was monitored by TLC. When the reaction was complete, water and ethyl acetate were added. The organic phase was dried and concentrated, and the residue was chromatographed to afford (3-fluoro-5-trifluoromethyl-phenyl)-(5-chloro-2-trifluoromethyl-phenoxy)-acetic acid methyl ester 93. Basic hydrolysis of this compound, as described in Example 1, then afforded the title compound 94.
Reaction SMILES: [CH3:1][C:2]([C:22]1[N:27]=[CH:26][C:25]([C:28]2[N:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH2:19]SC)[CH:17]=2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Xe](F)[F:39]>ClCCCl>[F:39][CH2:19][O:18][C:16]1[CH:17]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[N:29]=[N:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)([CH3:1])[CH:3]([CH3:4])[CH3:5])=[CH:11][CH:10]=2)[CH:13]=[N:14][CH:15]=1
Reactant: CSCOc1cncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(F)(F)F)nn4)cn3)C(C)C)cc2)c1
Reactant: F[Xe]F
Solvent: ClCCCl
Product: CC(C)C(C)(c1ccc(-c2cncc(OCF)c2)cc1)c1ccc(-c2ccc(C(F)(F)F)nn2)cn1
Reaction time: 2 h

Procedure:
A solution of 6b (18.0 mg, 0.0340 mmol) in 1,2-dichloroethane (2.00 mL) was added to a stirred solution of xenon difluoride (58.0 mg, 0.340 mmol) in 1,2-dichloroethane (1.00 mL) at 0° C. After approximately 2 h, the reaction mixture was quenched with triethylamine (0.250 mL) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-30% EtOAc/hexanes as eluent) afforded the title compound 6c. m/z (ES) 497 (MH)+
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]1[CH2:27][CH2:28]1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1cnc2ccccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (48 mg, 0.128 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.3 (M+H); UV 202.9, 223.0, 246.8, 296.0, 351.7 nm; t 0.437 min.
Reaction SMILES: [CH2:1]([C:7]1[O:8][C:9](I)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>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>[CH2:1]([C:7]1[O:8][C:9]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(I)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCc1ccc(-c2ccco2)o1
Yield: 174.1 %

Procedure:
Pd(PPh3)4 (1.15 g, 1 mmol, 5% mol) was added to 2-tributyltinfuran (7.05 g, 20 mmol) and 2-hexyl-5-iodofuran (5.5 g, 20 mmol) in dry toluene (150 mL) and the reaction mixture was refluxed under N2 for 5 h. The mixture was then cooled, separated with hexane, the organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane) to afford 3.8 g of 5-hexyl-2,2′-bifuran (88%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.35 (d, J=1.1 Hz, 1H), 6.39-6.45 (m, 3H), 6.00 (d, J=3.2 Hz, 1H), 2.62 (t, J=7.6, 2H), 1.64 (td, J=2H), 1.28-1.34 (m, 6H) 0.87 (t, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 156.3, 147.0, 144.8, 141.3, 111.3, 106.5, 105.9, 104.1, 31.6, 28.9, 28.1, 28.0, 22.6, 14.1 ppm. HRMS (FD): m/z calcd for C14H18O2: 218.1307. Found 218.1315.
Reaction SMILES: [O-:1]Cl=O.[Na+].[Cl:5][C:6]1[N:7]=[C:8]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10]=1[CH:11]=[O:12].CC(=CC)C>O.C1COCC1.CC(O)(C)C>[Cl:5][C:6]1[N:7]=[C:8]([S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C:10]=1[C:11]([OH:1])=[O:12]
Reactant: [O-][Cl+][O-]
Reactant: CN(C)S(=O)(=O)c1nc(Cl)c(C=O)n1COCC[Si](C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CN(C)S(=O)(=O)c1nc(Cl)c(C(=O)O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaClO2 (0.21 g, 2.31 mmol) and NaH2PO4.H2O (0.19 g, 1.39 mmol) in H2O (0.5 mL) was added to a solution of 4-chloro-5-formyl-N,N-dimethyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-2-sulfonamide (0.085 g, 0.23 mmol) and 2-methyl-2-butene (1.39 mL of a 2M solution in THF, 2.77 mmol) in THF (0.70 mL) and t-BuOH (0.16 mL). The reaction mixture was stirred at RT for 1 h and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and dried to provide 4-chloro-2-[(dimethylamino)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid as a clear oil that was assumed to be quantitative and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C@@H:39]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([S:55]([NH2:58])(=[O:57])=[O:56])=[CH:51][C:50]=2[S:59]([C:62]([F:65])([F:64])[F:63])(=[O:61])=[O:60])[CH2:40][S:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:33][CH2:32]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:30])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH:58][S:55]([C:52]4[CH:53]=[CH:54][C:49]([NH:48][C@H:39]([CH2:38][CH2:37][N:34]5[CH2:35][CH2:36][O:31][CH2:32][CH2:33]5)[CH2:40][S:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[C:50]([S:59]([C:62]([F:65])([F:63])[F:64])(=[O:61])=[O:60])[CH:51]=4)(=[O:56])=[O:57])=[O:26])=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C(O)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
(S)-4-(4-((4′-Chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 70, 137.4 mg, 0.33 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 190.3 mg, 0.34 mmol), DMAP (81.0 mg, 0.66 mmol), and EDC (134.5 mg, 0.70 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (6.5 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N aq. sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH in DCM). Clean fractions were combined, evaporated under vacuum, and dried overnight in a 40° C. vacuum oven to provide the title product as a substantially separated isomer (129.3 mg, yield: 41.5%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[C:5]([F:13])=[C:4]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1.[CH3:21][C:22]([S@@:25]([NH2:27])=[O:26])([CH3:24])[CH3:23]>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[N:27][S@:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])[CH:9]([F:11])[F:10])[C:5]([F:13])=[C:4]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)C(F)F)c1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=N[S@@](=O)C(C)(C)C)C(F)F)c1F
Temperature: 80 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-ethanone (9.8 g, 26.6 mmol), (S)-2-methylpropane-2-sulfinamide (3.23 g, 26.6 mmol) and tetraethoxytitanium (13.81 ml, 53.2 mmol) in THF (66.5 ml) was stirred at 80° C. in 3 capped microwave vials (3×25 ml) for 3 hours. The cold reaction mixture was poured into ice cold water and the precipitate was filtered through a pad of hyflo and washed thoroughly with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product (12.5 g) was chromatographed over silica gel (cyclohexane:ethyl acetate 5:1) to afford the title compound. 7.96 g (63% yield).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:38][CH3:39])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.ClC(O[C:59]1[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=1)=O.[C:68]([O:71]CC)(=[O:70])C>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:4][CH:5]1[C:6]([OH:45])([CH3:44])[CH2:7][CH2:8][CH:9]([O:36][Si:37]([CH2:42][CH3:43])([CH2:38][CH3:39])[CH2:40][CH3:41])[CH:10]([C:68]([OH:71])=[O:70])[C:11]([O:13][CH:14](/[C:19](/[CH3:35])=[CH:20]/[CH:21]=[CH:22]/[CH:23]([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][C:59]2[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=2)[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(Oc1ccc([N+](=O)[O-])cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)C(C(=O)O)C(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)C(C(=O)O)C(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
(8E,12E,14E)-7-acetoxy-6,21-dihydroxy-6,10,12,16,20-pentamethyl-3-triethylsiloxy-18,19-epoxytricosa-8,12,14-trien-11-olide (201 mg, 309 μmol) was dissolved in methylene chloride (2 mL). Triethylamine (220 μL, 1.58 μmol) and dimethylaminopyridine (17.0 mg, 139 μmol) were added to the reaction solution, and the reaction solution was cooled to 0° C. A solution of 4-nitrophenyl chloroformate (125 mg, 620 μmol) in methylene chloride (2 mL) was added to the solution. The reaction solution was warmed to room temperature, and then stirred for five hours. 4-nitrophenyl chloroformate (50.0 mg, 248 μmol) was further added to the reaction solution, and the solution was stirred at room temperature for two hours. The reaction solution was diluted with ethyl acetate (30 mL), and the dilution was washed with saturated aqueous solution of sodium hydrogencarbonate (6 mL) twice, purified water (6 mL) twice, and brine (6 mL). The resulting organic layer was dried over sodium sulfate, and then filtered. The filtrate was concentrated. The concentrate was purified by silica gel column chromatography (MERCK Silica gel 60, 63 to 200 μm; hexane:ethyl acetate=5:1→3:1) to obtain the title compound (246 mg, 302 μmol, 97.6%) as a colorless oil.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1>C1COCC1>[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:6]([NH2:5])=[O:7])=[CH:11][CH:10]=1
Reactant: NCc1ccc(N)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: NC(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trimethylsilylisocyanate (3.2 ml; 85%) was added to a solution of 4-amino-benzylamine (1.55 ml) in dry THF (40 ml). A white solid precipitated. The reaction mixture was stirred at r.t. overnight then the precipitate was filtered and washed with ethyl acetate giving the title compound (1.2 g) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:10][C@H:9]1[CH2:17][N:18](C(OCC1C=CC=CC=1)=O)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27])=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+]>Br.C(O)(=O)C.CCOCC>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14](=[O:16])[CH3:15])[CH2:10][C@H:9]1[CH2:17][NH:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[F:27])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CN(Cc1cc(F)ccc1F)C(=O)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCOC(=O)N1C[C@H](SC(C)=O)C[C@H]1CNCc1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
50 mg (0.09 mmol) (2S,4R)-4-acetylsulfanyl-2-{[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid butyl ester were dissolved in 130 μl 33%HBr in acetic acid and stirred at 0° C. for 30 min, and at RT for 1 h. The solution was diluted with ether and poured on saturated NaHCO3 solution, carefully. The inorganic layer was extracted with EtOAc, the combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated. Column chromatography yielded 13 mg (35%) (2S,4R)-4-acetylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-pyrrolidine-1-carboxylic acid butyl ester as colorless oil, MS: 401 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH3:20][CH:21]([CH3:49])[CH2:22][C:23]([C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=1)=[O:24]>>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:23]([C:25]1[N:26]=[CH:27][N:28]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=1)([OH:24])[CH2:22][CH:21]([CH3:49])[CH3:20])[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Product: CC(C)CC(O)(c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 77.9 %

Procedure:
6-Bromo-2-tert-butyldimethylsilyloxynaphthalene (33.7 g) and 3-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-butanone (31.5 g) were used as the starting materials. By the same procedure described in Reference example 1, the titled compound (40.6 g) was obtained as a colorless powder.