Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([OH:10])=[N:6][O:7][C:8]=1[CH3:9].[H-].[Na+].[C:13](Cl)(=[O:15])[CH3:14]>O1CCCC1>[C:13]([O:10][C:5]1[C:4]([CH2:3][CH2:2][OH:1])=[C:8]([CH3:9])[O:7][N:6]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: Cc1onc(O)c1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1noc(C)c1CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
7.8 g of 4-(2-hydroxyethyl)-5-methylisoxazol-3-ol was dissolved in 1 l of tetrahydrofuran. 1.70 g of sodium hydride was added to the solution under cooling with ice. The mixture was stirred at room temperature for 30 min and then cooled again with ice. 4.7 g of acetyl chloride was added thereto and the mixture was stirred at room temperature. The solvent was distilled off and water was added to the residue. After extraction with chloroform, the extract was washed with a saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off and the residue was purified according to silica gel column chromatography (chloroform) to obtain 2.96 g of the intended compound in the form of colorless prismatic crystals.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[N:20]2[CH2:23][CH:22]([S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21]2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:20]2[CH2:21][CH:22]([S:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:9])[CH2:23]2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CC(Sc3ccccc3)C2)cc1
Solvent: ClCCl
Product: O=S(c1ccccc1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
0.25 g of meta-chloroperbenzoic acid is added at room temperature to a solution of 0.40 g of 1-[bis(4-chlorophenyl)methyl]-3-(phenylsulfanyl)azetidine in 20 cm3 of dichloromethane. After stirring for 3 hours at room temperature, the reaction mixture is washed with 30 cm3 of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane {fraction (20/80)} by volume mixture and collecting 60-cm3 fractions, fractions 9 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa), taken up in heptane in order to isolate 100 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(RS)-phenylsulfinyl]azetidine in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 3.01 (broad t, J=7.5 Hz: 1H); 3.32 (broad t, J=7.5 Hz: 1H); 3.45 (broad t, J=7.5 Hz: 2H); 3.59 (mt: 1H); 4.45 (broad s,: 1H); from 7.15 to 7,65 (mts: 13H)].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:2]([CH3:4])[CH3:3].NC(N)=[O:18].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[N+:8]([O-:18])[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cncc(OCC(C)C)c1
Reactant: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1cc(OCC(C)C)c[n+]([O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 127.5 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 5-isobutoxynicotinate (5.13 g), urea-hydrogen peroxide adduct (4.84 g) and acetonitrile (82 mL) was added trifluoroacetic anhydride (8.25 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was filtered, and washed with acetonitrile. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (7.04 g) as a white amorphous solid. This compound was used for the next step without further purification.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH2:15][CH2:16][CH2:17][OH:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(O)(=O)C>[OH:18][CH2:17][CH2:16][NH:15][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NCCO)CC1
Yield: 89 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (15 g), 2-aminoethanol (14 ml), acetic acid (6.6 ml) in 1,2-dichloroethane (300 ml) was mixed at room temperature for 1 hour, and then sodium triacetoxyborohydride (49 g) was added thereto, followed by mixing at room temperature for 15 hours. pH of the aqueous layer was adjusted to about 12 by adding a 1 N aqueous sodium hydroxide solution to the reaction mixture, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound as a colorless oil (18 g, 89%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:28].[Li+].[OH-]>>[Cl:27][C:23]1[CH:22]=[C:21]([C:17]2[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([CH2:5][C@H:4]([O:29][CH2:30][CH3:31])[C:3]([OH:32])=[O:2])=[C:7]([CH3:28])[CH:8]=3)[N:16]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3cccc(Cl)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{4-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)[CH:13]=2)=[CH:8][CH:7]=1.[H-].[Na+].[CH2:32](Cl)[O:33][CH2:34][CH2:35][O:36][CH3:37].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:14]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1ccc(-c2ccc(/C=C/C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (120 mg, 0.309 mmol) in 1 ml of anhydrous DMF, was dropped into a 1 ml suspension of NaH (14.8 mg, 0.371 mmol, 60% in mineral oil) in anhydrous DMF (0.3 ml) at 0° C. The resulting red solution was stirred at RT for 30 min, then MEM-Cl (46 mg, 0.371 mmol) was added. After stirring overnight at RT, iced water was added and the mixture was extracted several times with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuo. The resulting crude product was purified on silica gel (acetone:hexane 15:85) to obtain (E)-3-[3′-adamantan-1-yl-4′-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acrylic acid methyl ester (123 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[O:14]>C(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([O:12][CH3:11])=[O:14])(=[O:23])=[O:22])=[O:26])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC)n1
Reaction time: 16 h
Yield: 21.1 %

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 30 ml of anhydrous methylene chloride was added at ambient temperature 2.4 g of 2-methoxycarbonylbenzenesulfonyl isocyanate. After stirring for 16 hours, the foregoing mixture was filtered to remove unreacted amine, and the filtrate evaporated at temperatures up to 40° and reduced pressure. The resultant residue was stirred in 25 ml of water, the pH adjusted to 10 by the addition of 50% sodium hydroxide and the solution filtered. Acidification of the filtrate to pH 3 with hydrochloric acid caused precipitation of the desired product which was removed by filtration and dried to yield 0.8 g of product melting at 173°-179°. It showed infrared absorption peaks at 1720, 1680, 1630 and 1550 cm-1, consistent for N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[S:5][CH:6]=1.[N:10]1([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)=[O:22])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([N:17]3[CH2:18][CH2:19][CH2:20][C@H:16]3[CH2:15][N:10]3[CH2:11][CH2:12][CH2:13][CH2:14]3)=[O:22])=[CH:24][CH:25]=2)[S:5][CH:6]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Reactant: Cc1csc(B(O)O)c1
Product: Cc1csc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 4-Methyl-2-thiophene boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 70 mg (67%). MS (ES+) 355.2
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(Cl)c(Cl)c2)CC1
Yield: 6.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.51 g) as starting compound, potassium carbonate (0.77 g) and 6-bromo-1-(3,4-dichlorophenyl)-1-hexanone (0.45 g) were reacted and treated in the same manner as in Example 172 to give 50 mg of 4-amino-5-chloro-N-((1-(6-(3,4-dichlorophenyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]O)[C:6]=2[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:33]I.N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][I:33])[C:6]=2[CH:13]=1
Reactant: OCCc1coc2ccc(Cl)cc12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc2occ(CCI)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(5-chloro-1-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.2 g (80%); 306 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C1COCC1.[O:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[OH:25][C:22]1([CH:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[C:10]#[N:11])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#CC(c1ccc(C(F)(F)F)nc1)C1(O)CCOCC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 47.1 %

Procedure:
2-(6-(Trifluoromethyl)pyridin-3-yl)acetonitrile (260 mg, 1.4 mmol) was dissolved in THF (3 mL, 30 mmol) under Ar and cooled at −78° C. A solution of 0.6 Ni sodium bis(trimethylsilyl)amide in toluene (3.49 mL) was added dropwise. After stirring at −78° C. for 4 hours the reaction was allowed to reach −50° C. for 30 minutes. Then tetrahydro-4H-pyran-4-one (0.189 mL, 2.10 mmol) was added dropwise at −60° C. and the reaction was kept at this temperature for 45 minutes. To the reaction was added sat. aq. NH4Cl (10 mL) and it was extracted AcOEt (3×20 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography to yield 2-(4-Hydroxytetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (189 mg, 0.660 mmol, 47%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[Cl:29].[Br:30]C(Br)(Br)Br>O1CCCC1>[Br:30][CH2:21][C:22]1[S:26][CH:25]=[C:24]([C:27]#[N:28])[C:23]=1[Cl:29]
Reactant: N#Cc1csc(CO)c1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1csc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36.1 g (137 mmol) of triphenylphosphine were added at 5° C. to a solution of 21.7 g (125 mmol) of 5-hydroxymethyl-4-chlorothiophene-3-carbonitrile in 250 ml of tetrahydrofuran. Then, a solution of 45.6 g (137 mmol) of tetrabromomethane in 100 ml of tetrahydrofuran was added. The mixture was stirred overnight at room temperature. The precipitate was filtered off, the filtrate was concentrated on a rotary evaporator under a water pump vacuum, and the residue was purified by column chromatography (eluant petroleum ether:dichloromethane 1:1). This gave 26.0 g (88%) of the title compound as an oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19]>N1C=CC=CC=1>[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:26])=[CH:23][CH:22]=1)=[O:19]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 0.181 g (1.0 mmol) of 5,6-dihydrophenanthridine in 2 ml of warm pyridine is added 0.273 g (1.0 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred overnight at room temperature, 1.2 ml of 2NHCl added. The solid which separates is filtered and washed with water. The solid is dissolved in dichloromethane and the solution washed with 2M sodium carbonate. The organic layer is concentrated and the residue chromatographed twice on silica gel with ethyl acetate-hexane as solvent to give 79 mg of crystals, m.p. 190°-194° C. Mass Spec-FAB 419 (M+H).
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@@H:16]([CH3:20])[C:17](Cl)=[O:18])[CH:13]=[CH:14][CH:15]=1.C([C@H:24]1[CH2:29][CH2:28][C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)CC>O>[CH:30]1([C:27]2[CH:26]=[CH:25][C:24]([C:17](=[O:18])[C@@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH3:20])=[CH:29][CH:28]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCC[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: COc1cccc([C@@H](C)C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc([C@@H](C)C(=O)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 0.25 h

Procedure:
To a methylene chloride suspension of aluminum chloride, a methylene chloride solution of (R)-2-(3-methoxyphenyl)propionic acid chloride was added dropwise under ice cooling. After stirring at the same temperature for 15 minutes, a methylene chloride solution of trans-4-propylcyclohexylbenzene was added dropwise. After the completion of the reaction, the reaction system was added to iced water and the organic layer was separated by adding methylene chloride. The organic layer was washed twice with water and then washed with saturated brine. The aqueous layer was washed with methylene chloride and, after combining the organic layer, the solvent was concentrated to obtain a crude product of (R)-1-(4-cyclohexylphenyl)-2-(3-methoxyphenyl)-propan-1-one. To an ethylene glycol solution of the resulting crude product, hydrazine monohydrate was added and the solution was stirred at 110° C. while removing water as a by-product. After efflux of water has nearly terminated, excess hydrazine was distilled off by stirring at 120° C. The temperature of the reaction system was reduced and potassium hydroxide was added, followed by heating to 160° C. After the completion of the reaction, the temperature of the reaction system was reduced and water and toluene were added, followed by stirring. After separating the organic layer, the aqueous layer was washed with toluene and the organic layer was combined and then washed three times with water. The residue was washed with saturated brine and concentrated to obtain a crude product of a compound represented by the formula (XI-a). The resulting crude product was purified by column chromatography and recrystallized from ethanol to obtain (S)-1-{2-(3-methoxyphenyl)propyl}-4-(trans-4-propylcyclohexyl) benzene (S-isomer of the compound represented by the formula (XI-a)).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (1.0 equiv.) and triethylamine (1.5 equiv.) in dichloromethane (0.1 M) was added acetic anhydride (1.1 equiv.). The resulting mixture was stirred at RT for 45 min. After concentration, the residue was partitioned between EtOAc and water. The organic phase was washed with water and then with brine. After drying over sodium sulfate the solution was concentrated in vaccuo to give crude (R)-tert-butyl 2-(acetamidomethyl)morpholine-4-carboxylate which was used in the next step without further purification. LCMS (m/z) (M+H)=159.1 (-Boc), Rt=0.53 min.
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[CH2:9][N:8]([C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=C)[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)[CH:2]=C.SC1N=CC=CC=1C(O)=O>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:35]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:36]=[CH:37][C:32]([C@@:5]23[CH2:9][N:8]([C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]2)[C:10](=[O:27])[C@@H:11]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH:2][CH2:1][S:4]3)=[CH:33][CH:34]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCC=C)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCC/C=C/CS2
Agent: O=C(O)c1cccnc1S
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCC=CCS2

Procedure:
A solution of (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)pyrrolidine-2-carboxylate (123 mg, 0.203 mmol) in Dichloromethane (50 mL) was purged with nitrogen for 30 min. And then Hoveyda-Grubbs Catalyst 2nd Generation (153 mg, 0.243 mmol) was added. The resulting green solution was heated to reflux for 5 h. The reaction was quenched with 2-Mercaptonicotinic acid (62.9 mg, 0.405 mmol) and washed with sat. Na2CO3, and brine. Dried over MgSO4, filtered, concentrated in vacuo. The brown residue was purified by Biotage column, eluted with gradient 5%˜40% EtOAc-Hexane to afford the desired product (3S,13R,15S,E)-methyl 13-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-12-thia-1-azabicyclo[11.2.1]hexadec-9-ene-15-carboxylate (93 mg, 0.145 mmol, 71.3% yield) as an off-white solid. NMR analysis showed the configuration of the double bond is exclusively trans. 1H NMR (500 MHz, MeOD) δ ppm 1.39-1.55 (m, 13 H), 1.55-1.75 (m, 4 H), 1.81-1.92 (m, 1 H), 1.97-2.08 (m, 1 H), 2.20-2.31 (m, 1 H), 2.57 (dd, J=12.82, 7.93 Hz, 1 H), 2.76-2.85 (m, 1 H), 2.92 (dd, J=15.87, 7.93 Hz, 1 H, 3.68-3.80 (m, 3 H), 4.20 (t, J=7.78 Hz, 1 H), 4.31-4.40 (m, 1 H), 4.52-4.65 (m, 2 H), 5.65 (dd, J=14.19, 6.87 Hz, 1 H), 5.85 (dd, J=14.95, 7.32 Hz, 1 H), 7.36 (t, J=7.32 Hz, 1 H), 7.41-7.50 (m, 2 H), 7.58-7.74 (m, 6 H). LC-MS (retention time: 3.42 min, method C), MS m/z 579 (M+H).