Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:21])[C:4]([CH3:20])([NH:6][C:7]([N:9]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:8])[CH3:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:32]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:42][C:41]([NH2:51])=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:42][C:41]([NH:51][C:3]([C:4]([NH:6][C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)=[O:8])([CH3:5])[CH3:20])=[O:21])=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Reactant: COC(=O)C(C)(C)NC(=O)N1CC[C@H](c2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(NC(=O)N1CC[C@H](c2ccccc2)C1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF (3 mL) was added to a flask containing 2-methyl-2-[((R)-3-phenyl-pyrrolidine-1-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.344 mmol) at 0° C. under N2. In a dropwise fashion 1 M LiHMDS in THF (344 uL, 0.344 mmol) was added to the flask. Upon complete addition the reaction was allowed to warm to room temp. After 2.5 hr 1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (92 mg, 0.344 mmol) in THF (1 mL) was added to the reaction. The reaction was allowed to stir overnight. The next day more 1 M LiHMDS in THF (172 uL, 0.172 mmol) was added. The reaction was stirred an additional 5.5 hr before being quenched with sat. NH4Cl (10 mL). The reaction was diluted with EtOAc (60 mL) and extracted with water (5 mL). The organic phase was dried over Na2SO4 and the solvent evaporated. The residue was purified by silica gel chromatography (60-100 EtOAc/HEP) followed by HPLC (C18, 50-100% MeOH/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, DICHLOROMETHANE-d2) 1.58 (d, J=3.92 Hz, 6H) 2.01-2.15 (m, 1H) 2.25-2.36 (m, 1H) 3.36 (t, J=9.22 Hz, 1H) 3.40-3.53 (m, 2H) 3.62-3.70 (m, 1H) 3.87 (t, J=8.21 Hz, 1H) 4.74 (br. s., 1H) 5.44 (s, 2H) 7.19-7.36 (m, 9H) 7.36-7.44 (m, 3H) 7.62-7.70 (m, 2H) 10.76 (br. s., 1H); Rt (method A)=1.61 min (M+H)+=527.2.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]([C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])[CH:24]=3)=[CH:19][CH:18]=2)=[N:14][N:13]=1.C(N(CC)CC)C>C1COCC1>[C:1]([NH:10][CH2:11][C:12]1[O:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]([C:30]([NH:32][CH:33]4[CH2:35][CH2:34]4)=[O:31])[CH:24]=3)=[CH:21][CH:22]=2)=[N:14][N:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of benzoyl chloride (6.3 μl) in THF (1 ml) was added dropwise to 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (18.8 mg) and triethylamine (7.5 μl) in THF (4 ml). The reaction was stirred at room temperature for 16 hours, the solvent evaporated, the residue dissolved in water (10 ml) and extracted with DCM (2×10 ml). The combined organics were reduced to dryness under vacuum, the residue dissolved in methanol and the solution applied to a bond-elut (aminopropyl, 1 g), eluting with further methanol. The eluent was reduced to ca 10 ml in vacuo and passed through a bond-elut (SCX, 2 g), eluting with methanol. The solvent was evaporated from the eluent under vacuum. The residue was applied to a bond-elut (silica, 2 g) and eluted with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent 4′-{5-[(benzoylamino)methyl]-1,3,4-oxadiazol-2-yl}-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:6]1[CH2:7][CH2:8][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccn2)CC1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.28 g (0.71 mmol) of sodium hydride (60% mineral oil dispersion) in 5 mL anhydrous N,N-dimethylformamide at 0° C. was added 0.12 g (0.65 mmol) tert-butyl 1-piperazine-carboxylate. The resulting mixture was stirred under an atmosphere of nitrogen for 15 min and then allowed to warm to ambient temperature at which point 0.14 g (0.59 mmol) of 2-(bromomethyl)pyridine was added. After 4 h, quench the reaction with 25 mL cold water and extract the resulting solution with 25 mL ethyl acetate. The organic layer was washed with water (2×25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound which was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 278.1 (MH)+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH2:11]([O:13][C:14]1[CH:29]=[CH:28][C:17]([CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[CH3:12].CON(C)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:34]1([C:33](=[O:40])[C:27]#[C:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:18][C:17]3[CH:28]=[CH:29][C:14]([O:13][CH2:11][CH3:12])=[CH:15][CH:16]=3)[CH:21]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#Cc1cccc(OCc2ccc(OCC)cc2)c1
Reactant: CON(C)C(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOc1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4-ethoxybenzyloxy)phenylacetylene (0.51 g, 2 mmol) in tetrahydrofuran and stir the solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath and stir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:9](=O)([O-])[O-:10].[Ca+2]>CO>[CH3:9][O:10][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCC1Cl
Agent: [Ca+2]
Solvent: CO
Product: COC1CCCCC1=O
Yield: 80 %

Procedure:
2-methoxycyclohexanone was prepared by dissolving 132 gm. 2-chlorocyclohexanone in 600 ml. of methanol in the presence of 50 gm. calcium carbonate and heating the suspension at 160° C. for 15-20 minutes. After removal of the methanol, the calcium chloride was precipitated by the addition of methylene chloride to the residual material. The calcium chloride was removed by filtration and the filtrate was distilled to yield an 80-85% yield of 2-methoxycyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30](=O)[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:4]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[C:3]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:14][CH2:13][C:12]3[N:8]([C:9]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:10][C:11]=3[CH3:25])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CN(C)C)n(-c2cccc(Cl)c2C(=O)c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccc(F)cc1)c1c(Cl)cccc1-2

Procedure:
In the manner given in Example 4, N-[[1[3-chloro-2-(p-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 7-chloro-6-(p-fluorophenyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: I[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2.[O:21]=[S:22]1(=[O:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1COCC1.O>[O:21]=[S:22]1(=[O:28])[CH2:27][CH2:26][N:25]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6]3)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(CI)cc2cc(-c3ccccc3)[nH]c12
Reactant: O=S1(=O)CCNCC1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(CN2CCS(=O)(=O)CC2)cc2cc(-c3ccccc3)[nH]c12
Reaction time: 2 h
Yield: 72.1 %

Procedure:
5-Iodomethyl-2-phenyl-7-nitro-1H-indole (850 mg, 2.5 mmol) prepared in Step A was dissolved in THF (10 mL). 1,1-Dioxo-thiomorpholine (405 mg, 2.25 mmol) was added thereto, and the mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The residue was recrystallized from DCM and hexane to give the title compound (625 mg, Yield 65%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:33]=[N+:34]=[N-:35].[Na+].[NH4+].[Cl-]>CN(C=O)C>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]5[NH:35][N:34]=[N:33][N:32]=5)[CH:26]=4)[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(c2nc(-c3ccccc3)c(-c3ccccc3)o2)C(Cc2cccc(-c3nnn[nH]3)c2)CCC1
Temperature: 120 °C
Reaction time: 12 h
Yield: 81.6 %

Procedure:
To a solution of 2-(4,5-diphenyloxazol-2-yl)-1-(3-cyanobenzyl)-2-cyclohexene (400 mg) in DMF (8 ml) were added NaN3 (100 mg) and NH4Cl (80 mg). After stirred for 12 hours at 120° C., the mixture was partitioned between ethyl acetate and water and the organic layer was washed with 1N-HCl and brine. The dried solvent was evaporated in vacuo and the obtained solid was washed with a mixture of ether and n-hexane to afford 2-(4,5-diphenyloxazol-2-yl)-1-{3-(1H-tetrazol-5-yl)benzyl}-2-cyclohexene (0.36 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][CH:6]1[CH2:15][CH2:14][C:13](=[O:16])[N:7]12.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:34]([CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:35])(=O)=O>C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:34]([CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:35])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[CH2:5][CH:6]1[CH2:15][CH2:14][C:13](=[O:16])[N:7]12
Reactant: O=C1CC2CCC(=O)N2c2cc(O)cc(O)c21
Reactant: CC(CCCc1ccccc1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1C(=O)CCC1CC2=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under anhydrous conditions and in a nitrogen atmosphere, 70 g. (0.30 mole) 6,8-dihydroxy-3a,4-dihydro-(2H,3H)-pyrrolo[1,2-a]quinolin-1,5-dione was dissolved in 750 ml. dimethylformamide by warming to 60° C. To the resulting deep red solution was added 51.6 g. (0.675 mole) potassium carbonate. The mixture was heated to 70° C., a solution of 2-methylsulfonyloxy-5-phenylpentane in 250 ml. dimethylformamide was added in a fast stream, and heated at 75°-80° C. for 12 hours. Additional portions of 2-methylsulfonyloxy-5-phenylpentane (5.3 g.) and potassium carbonate (3.8 g.) and heating continued at 75°-80° C. for two hours. The mixture was poured over a mixture (one liter each) ethyl acetate and ice and, after shaking in a separtory funnel, the layers were separated. The aqueous phase was extracted with 5×1000 ml. ethyl acetate. The combined organic layers were washed with 3×4 liters water, 3×2 liters of 0.5N hydrochloric acid, dried (MgSO4) and concentrated to a volume of about 2.5 liters. Upon cooling, the precipitated product which formed was collected: 9.0 g., M.P. 151°-153° C. The mother liquor was concentrated to half volume, cooled, and a second crop, 34.2 g., M.P. 148°-151° C., was collected. Total yield by crystallization: 52.2 g. This material was shown to be primarily a single diastereomer, designated as "Diastereomer B." Upon recrystallization from ethyl acetate, colorless crystals were obtained, M.P. 159°-161° C. This was found to be about 90% diastereomer B. 1H--NMR (CDCl3) ppm (delta): 1.33 (d, 3H, J=6 Hz).
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>CN(C)C=O.C(OCC)(=O)C>[I:20][C:21]1[CH:22]=[C:23]([CH2:24][N:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:26]=[CH:27][CH:28]=1
Reactant: CCS(=O)(=O)NCc1cccnc1
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)Cc1cccc(I)c1

Procedure:
A solution of N-(ethylsulfonyl)pyrid-3-ylmethylamine (1.1 g, 5.5 mmol), cesium carbonate (1.79 g, 5.5 mmol), and 3-iodobenzyl bromide (1.64 g, 5.5 mmol) was stirred in N,N-dimethylformamide (25 ml) for 5 h at room temperature. The mixture was diluted with ethyl acetate (100 ml) and washed four times with water (50 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated in vacuo to a crude residue. The residue was purified by radial chromatography on a 4 micron silica plate eluting with 3% methanol/dichloromethane to afford the title compound. 1H NMR: 8.6 (d,1H,J=4 Hz), 8.41 (s,1H), 7.75 (m,1H), 7.65 (m,1H), 7.60 (s,1H), 7.25-7.40 (m,2H), 7.08 (m,1H), 4.43 (s,2H), 4.33 (s,2H), 3.08 (q,2H,J=8 Hz), 1.43 (t,3H,J=8 Hz). MS calcd. 416.3; MS (M+1) 417.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCC1CCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:7][S:8]C(=O)C.[OH-].[K+].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH3:21][C:15]([S:8][CH2:7][C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)SC[C@@H]1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC[C@@H]1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
A solution of 2.79 g (13.45 mmol) of 1-{[(2S)-oxan-2-ylmethyl]sulfanyl}ethan-1-one in ethanol (60 mL) is degassed with nitrogen over 0.5 h and 1.51 g (26.91 mmol) of KOH are added. Then 3.99 mL (26.91 mmol) of ethyl α-bromoisobutyrate are added slowly. The reaction is stirred for 18 h at room temperature under a nitrogen atmosphere. The reaction mixture is filtered, the solid is rinsed with ethanol and the filtrate is concentrated under reduced pressure. The crude material is purified by column chromatography (silica, eluent: n-heptanes, 0-20% ethyl acetate) to afford 2.68 g of ethyl 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoate (purity 90%). Yield: 72%; ES-MS: m/z 247 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.23-1.36 (5 H, m), 1.45-1.59 (8 H, m), 1.68 (1 H, d, J=13.12 Hz), 1.83 (1 H, d, J=10.99 Hz), 2.62-2.71 (1 H, m), 2.72-2.80 (1 H, m), 3.25-3.47 (2 H, m), 3.95-4.03 (1 H, m), 4.17 (2 H, q, J=7.12 Hz).
Reaction SMILES: CCCCCC.[Li]CCCC.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.[I:21]I>C1COCC1>[Cl:12][C:13]1[CH:20]=[C:19]([I:21])[C:16]([C:17]#[N:18])=[CH:15][N:14]=1
Reactant: II
Reactant: N#Cc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1cnc(Cl)cc1I
Temperature: -80 °C
Reaction time: 0.25 h

Procedure:
To a mixture of THF (100 mL) and hexane (40 mL) under nitrogen atmosphere was added DIPA (22.21 mL, 158.78 mmole, 1.1 eq). The mixture was cooled to −80° C. and to this was added n-BuLi (63.57 mL, 158.78 mmole, 1.1 eq) dropwise. After completion of addition the resulting mixture was allowed to warm and stirred at −10° C. for 15 min. The reaction mixture was again cooled to −80° C. and a solution of 6-chloro-nicotinonitrile (20 g, 144.35 mmol, 1 eq) in THF (100 mL) was added dropwise. The resulting mixture was stirred at −80° C. for 1 h. After 1 h a solution of iodine (43.96 g, 173.22 mmole, 1.2 eq) in THF (100 mL) was added in one portion. After completion of the reaction, the reaction was quenched with water (100 mL) and extracted with diethyl ether (6×100 mL). Combined organic layers were washed with saturated solution of sodium thiosulfate (2×100 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give crude product. Crude compound was purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate-hexane as the eluant to yield the title compound as a faintly yellow solid (15 g, 39%). 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 8.79 (s, 1H). LC-MS calculated for C6H2ClIN2 (M+H) 264.90. found 264.9.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].FC(F)(F)S(O)(=O)=O.[CH2:72](OC(=N)C(Cl)(Cl)Cl)[CH:73]=[CH2:74].C1CCCCC1>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:74][CH:73]=[CH2:72])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (820 mg in 9 ml 33% methylene chloride in cyclohexane allyl trichloroacetimidate (366 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (16 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 17 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ether: hexane (2:3)) gave the title compound (800 mg). (1H NMR was consistent with the desired structure).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:37])C=CC=CC=1.C(O)(=O)C>O1CCCC1>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:29])[C@H:25]([CH:26]1[CH2:27][CH2:28]1)[OH:37])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(CC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H](O)C1CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
A cooled (−78° C.) solution of sodium bis(trimethylsilyl)amide (0.6 M in toluene, 65 mL, 38.918 mmol) was diluted with anhydrous tetrahydrofuran (100 mL) and treated with a solution of (S)-4-benzyl-3-(2-cyclopropyl-acetyl)-oxazolidin-2-one (9.174 g, 35.380 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring at −78° C. for 45 min, the mixture was treated with a solution of 2-benzenesulfonyl-3-phenyl-oxaziridine (11.064 g, 42.456 mmol) in anhydrous tetrahydrofuran (50 mL). After stirring at −78° C. for 55 min, the reaction was quenched with acetic acid (10.1 mL, 176.9 mmol) and allowed to warm to room temperature. The mixture was quenched with sodium bicarbonate solution (300 mL) and poured over dichloromethane/iso-hexanes (3:1, 400 mL). The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated sodium thiosulfate, hydrochloric acid (1 M, 300 mL), water and filtered through a phase separator. The volatiles were removed in vacuo and the residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 7:3 followed by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (7.922 g, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.42-0.65 (m, 4H), 1.25-1.38 (m, 1H), 2.88 (dd, J=13.4, 9.6 Hz, 1H), 3.35 (dd, J=13.4, 3.4 Hz, 1H), 3.44 (d, J=8.2 Hz, 1H), 4.25-4.37 (m, 2H), 4.67-4.72 (m, 1H), 4.80 (dd, J=8.0, 6.0 Hz, 1H), 7.21-7.41 (m, 5H). LCMS (m/z) 298.1 [M+Na], Tr=2.27 min.