Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=C.[O:23]=[O+][O-].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:23]
Reactant: O=[O+][O-]
Reactant: C=CCC(C(=O)OC)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(CC=O)c1ccc(OCc2ccccc2)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 2-(4-benzyloxy-phenyl)-pent-4-enoic acid methyl ester (750 g; 2.53 mol) is dissolved in ethyl acetate (7.5 L), and the resulting mixture cooled to −70° C. Ozone is introduced subsurface into the reaction for 3 h causing the reaction mixture to turn blue. The reaction mass is purged subsurface with nitrogen for 0.5 h to displace any residual ozone. At this point HPLC analysis indicates complete consumption of the starting material. The reaction mixture is warmed to −30° C. and held. In a separate vessel, zinc (450 g; 6.88 mol) and aqueous acetic acid (500 mL in 500 mL water) are combined and cooled to 0° C. The contents of the ozonolysis reactor are added to the aqueous acidic zinc mixture at such a rate as to maintain a reaction temperature of ≦0° C. After the addition is complete and the mixture has been held for 2 h, HPLC indicates conversion of intermediates to the desired aldehyde. The reaction mixture is filtered through Celite®, washed with water (2×4.5 L), and water (4.5 L) is added to the organic phase. Sodium bicarbonate (150 g; 1.79 mol) is added to the mixture, and stirring for 0.25 h gives a pH of >7. The aqueous layer is removed, and the volume is reduced to 2.25 L by reduced pressure distillation. The mixture is held at 50° C., and heptane (3L) is added to slowly provide a precipitate. The resulting slurry is cooled to 20° C. over 2 h, the solids are filtered, washed with heptane (3 L), and dried to constant weight at 45° C. and ˜25″ Hg. The title aldehyde, compound A (513 g; 68% isolated yield) is afforded as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:9][N+:10]([O-:12])=[O:11])[C@H:14]([CH:15]([CH3:17])[CH3:16])[CH:13]=[O:18])=[CH:6][CH:7]=1
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
The title compound was prepared from (E)-1-bromo-4-(2-nitrovinyl)benzene and isovaleraldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 254 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=7.6 min, tminor=7.2 min, the diastereomeric ratio was determined by 1H NMR. [α]D20=−30.2 (c=0.27, CHCl3);
Reaction SMILES: [CH3:1][N:2]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14]CC)=[O:13])=[CH:8]2.[OH-].[Na+].O1CCCC1>CO>[CH3:1][N:2]([S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A mixture of ethyl 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.40 g), 8N aqueous sodium hydroxide solution (0.40 ml), tetrahydrofuran (5 ml) and methanol (5 ml) was stirred at 60° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were collected by filtration; washed with water, and dried to give the title compound (0.35 g, yield 91%) as colorless crystals. melting point >240° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([CH3:23])[N:9]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=[C:10]32)=[CH:5][CH:4]=1.C(Cl)(Cl)Cl>C1C2C(CCCC2)CCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([CH3:23])[N:9]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:22])[N:13]=[C:10]32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)-c1nc(-c3ccccc3C)cn1C(C)C2
Agent: [Pd]
Solvent: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(C)n3cc(-c4ccccc4C)nc3c2c1
Yield: 61.6 %

Procedure:
To a solution of 4.9 g of 9-methoxy-5-methyl-2-(2-methylphenyl)-5,6-dihydroimidazo[2,1-a]isoquinoline in 30 ml of decalin was added 0.97 g of palladium on activated carbon (Pd 10%) and the mixture was refluxed for 6 hours. After being cooled and an addition of 200 ml of chloroform, the mixture was filtered and the filtrate was evaporated in vacuo. The resultant residue was crystallized from a mixture of hexane and ethyl acetate(6:1) to give 3.0 g of the tide compound.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]3[N:5]([C:13]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)=[N:14][CH:15]=2)[CH2:6][CH2:7][C:8]=3[NH:9][C:10](=[O:12])[CH:11]=1.S(Cl)([Cl:26])=O.ClCC1C=CC(C2N3CCC4NC(=O)C=CC(C=43)=CN=2)=CC=1>>[Cl:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:5]3[CH2:6][CH2:7][C:8]4[NH:9][C:10](=[O:12])[CH:11]=[C:2]([F:1])[C:3]([C:4]=43)=[CH:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=C(F)C2=CN=C(c3ccc(CO)cc3)N3CCC(=C23)N1
Agent: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3CCC(=C23)N1
Product: O=C1C=C(F)C2=CN=C(c3ccc(CCl)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared from intermediate 97 and thionyl chloride using the procedure described in Example 171 for 171a. HPLC Rt=3.260 min.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=O)=C(F)C(F)=C(F)C=1F.[CH3:37][NH:38][CH3:39].N1C=CC=CC=1>C(#N)C.C(O)C>[CH3:37][N:38]([CH3:39])[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=1)=[O:8]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: CNC
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCO
Product: CN(C)C(=O)c1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Reaction time: 8 h
Yield: 53 %

Procedure:
To 100 mg (0.190 mmol) 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester in 5 mL acetonitrile was added 50 μL (5.6 M in ethanol, 0.28 mmol) of a solution of dimethylamine and 20 μL (0.25 mmol) of pyridine, and the reaction was stirred overnight. The solution was concentrated, and the resulting solid was triturated with EtOAc to give the title compound as a yellow solid (39 mg, 53%): mp>230° C.; 1H NMR (DMSO-d6): δ 12.71 (s, 1H), 11.22 (s, 1H), 7.75 (d, J=8.8 Hz, 2H), 7.60 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.31 (dd, J=1.7, 8.1 Hz, 1H), 7.23 (s, 2H), 6.93 (d, J=8.0 Hz, 1H), 2.95 (s, 6H); APCI−MS: m/z 386 (m−H). Anal. Calcd for C17H17N5O5S.1/2H2O: C, 51.51; H, 4.58; N, 17.67. Found: C, 51.69; H, 4.25; N, 17.63.
Reaction SMILES: O=[C:2]1[CH:10]([C:11]([O:13]CC)=O)[CH2:9][CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>ClCCCl.O>[Br:16][C:17]1[CH:22]=[CH:21][N:20]2[C:11](=[O:13])[C:10]3[CH2:9][CH:8]4[N:4]([CH2:5][CH2:6][CH2:7]4)[CH2:3][C:2]=3[N:23]=[C:19]2[CH:18]=1
Reactant: CCOC(=O)C1CC2CCCN2CC1=O
Reactant: Nc1cc(Br)ccn1
Solvent: O
Solvent: ClCCCl
Product: O=c1c2c(nc3cc(Br)ccn13)CN1CCCC1C2
Yield: 19.9 %

Procedure:
A solution of ethyl 6-oxooctahydroindolizine-7-carboxylate (230 mg, 1.1 mmol), 4-bromopyridin-2-amine (188 mg, 1.1 mmol) and excess PPA (2 g) in 1,2-dichloroethane was stirred at 80° C. overnight. After the suspension was diluted with water (20 mL) and adjusted to pH 8. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers were concentrated to give the crude product. 70 mg of the desired product was obtained after column chromatography. MS (ESI): 320, 322 (MH+).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([OH:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)(=[O:24])=[O:23].[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)C.ClCCl>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[O:33][CH2:34][CH2:35][CH2:36][OH:37])(=[O:23])=[O:24]
Reactant: OCCCO
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
Tri-n-butylphosphine (8.4 mL, 34 mmol) was added dropwise over 5 min to 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (4.97 g, 16.9 mmol, prepared in the preceding step), 1,3-propanediol (12 mL, 170 mmol) and 1,1′-(azodicarbonyl)dipiperidine (8.54 g, 33.8 mmol) in anhydrous tetrahydrofuran (75 mL) at 0° C. under a nitrogen atmosphere. Dichloromethane (75 mL) was added mid-way through the tri-n-butylphosphine addition to aid stirring. The slurry was stirred at ambient temperature for 1 h, then the mixture was cooled to 0° C. and additional 1,1′-(azodicarbonyl)dipiperidine (4.27 g, 16.9 mmol) and tri-n-butylphosphine (4.2 mL, 16.9 mmol) were added. The reaction was stirred overnight at ambient temperature. Diethyl ether (200 mL) was added and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by flash column chromatography (25% ethyl acetate in hexane to 60% ethyl acetate in hexane, then 2% acetone in dichloromethane to 7% acetone in dichloromethane in two separate chromatographic separations) to give the title compound (3.79 g, 64%) as a gold oil. 1H-NMR (300 MHz, CDCl3) δ7.82 (dd, 1H, J=7.9, 1.7 Hz), 7.61 (ddd, 1H, J=8.4, 7.5, 1.8 Hz), 7.08 (d, 1H, J=8.4 Hz), 7.01 (ddd, 1H, J=7.9, 7.5, 1 Hz), 6.58 (br s, 1H), 6,51 (br s, 1H), 6.46 (t, 1H, J=2.1 Hz), 4.02 (s, 3H), 4.00 (t, 2H, J=6.0 Hz), 3.81 (dt, 2H, J=5.7, 5.3 Hz), 2.24 (s, 3H), 1.98 (pentet, 2H, J=6.0 Hz), 1.72 (t, 1H, J=5.0 Hz). Mass spectrum (MALDI-TOF, (α-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20O6S: 375.1 (M+Na). Found: 375.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([I:10])[CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:10])[CH:3]=1
Reactant: COc1ccc(Cl)cc1I
Agent: BrB(Br)Br
Product: Oc1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 88.7 %

Procedure:
To 4-Chloro-2-iodo-1-methoxy-benzene (5.00 g, 18.6 mmol) in an ice bath under argon was added dropwise neat BBr3 (2.20 mL, 23.2 mmol). This mixture was stirred at 0° C. for 3.5 hours and then quenched with MeOH (20 mL). This mixture was concentrated in vacuo to give 4.2 g of 4-Chloro-2-iodo-phenol in 88% yield. HPLC Rt=3.17 min (YMC S5 ODS column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 45 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of 2-(4-fluorophenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (48 ml of 2.29 M solution, 0.111 mole) was added and the reaction mixture was stirred at 45° C. under nitrogen overnight. The solvents were removed under reduced pressure and the residue was triturated in water (100 ml), the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature and isopropyl ether was added to the cloud point. The resulting solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at 42° C. overnight to give 2.15 g (39%) of title compound, mp. 180°-183° C.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])C.[OH-].[Na+]>C(O)C>[NH2:21][C:18]1[N:17]=[C:16]([NH2:22])[C:15]([CH2:14][C:9]2[CH:8]=[C:7]([O:23][CH3:24])[C:6]([NH2:5])=[C:11]([O:12][CH3:13])[CH:10]=2)=[CH:20][N:19]=1
Reactant: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Reaction time: 1 h

Procedure:
A suspension of 1.04 g. of 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester in a mixture of 50 ml. of 4N sodium hydroxide and 50 ml. of ethanol was boiled under reflux for 18 hours, whereby a solution gradually resulted. The alcohol was removed under vacuum. After standing at room temperature for 1 hour, the crystallized 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine was removed by filtration with suction, washed with water, recrystallized from methanol and had a melting point of 215°-216° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26].[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([O:21][CH2:22][C:23]([NH:36][CH2:35][CH2:34][CH2:33][N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[O:24])[CH:18]=[CH:19][CH:20]=3)[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:26]
Reactant: NCCCN1CCOCC1
Reactant: Cc1cc(-c2cc(-c3cccc(OCC(=O)O)c3)[nH]c(=O)n2)ccc1O
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(-c3cccc(OCC(=O)NCCCN4CCOCC4)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.9 %

Procedure:
({3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]phenyl}-oxy)acetic acid (Compound 222, 17 mg, 48 umol) and 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 4 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 8.31 (s, 1H), 8.17 (t, 1H), 7.96 (s, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.47 (t, 1H), 7.38 (s, 1H), 7.17 (dd, 1H), 6.92 (d, 1H), 4.61 (s, 2H), 3.61 (t, 4H), 3.21-3.16 (m, 2H), 2.30-2.22 (m, 6H), 2.20 (s, 3H), 1.63-1.57 (m, 2H). MS (EI): 480 (MH+).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].CC(C)=O.C(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C@:32]1([CH2:2][C:1]([O:4][CH3:5])=[O:3])[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(C)=O
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl acetate (0.25 mL, 3.2 mmol) was dissolved in THF (3 mL) under an atmosphere of Ar and cooled to −78° C. (acetone/dry ice). A solution of LHMDS (3.13 mL, 1M/THF) was added dropwise. After 15 minutes, a solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (5, 1.35 g, 2.5 mmol) in THF (7 mL) was added dropwise. After 3 hr, the reaction mixture was quenched with NH4Cl (aq), warmed to room temperature and extracted with EtOAc (1×). The organic layer was washed with brine (1×), dried (Na2SO4), and concentrated to a syrup (1.4 g, 92%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.15-7.31 (m, 20H), 2.26 (d, J=1.5 Hz, 1H), 4.81-4.97 (m, 4H), 4.45-4.66 (m, 4H), 3.98 (m, 1H), 3.58-3.75 (m, 7H), 3.31 (dd, J=9.6, 1.5 Hz, 1H), 2.73 (d, J=15.6 Hz, 1H), 2.30 (d, J=15.6 Hz, 1H). LC/MS tR=3.16 min, calcd for C37H40O8: 612.27, found 635.6 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([C:15]1[N:16]=[CH:17][N:18](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:19]=1)=[O:14])[CH:7]=[CH:6]2.[F:39][C:40]([Si](C)(C)C)([F:42])[F:41].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(O)(C)C>[NH:18]1[CH:19]=[C:15]([C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)([OH:14])[C:40]([F:42])([F:41])[F:39])[N:16]=[CH:17]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(F)(F)F)ccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
(6-Methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) was dissolved in THF (10 ml) and to the solution was added trifluoromethyltrimethylsilane (1.40 g). The reaction mixture was cooled to 0° C., and tetrabutylammonium fluoride (0.4 ml) was added. The mixture was stirred at room temperature for 2 h. To the mixture were added 1 N-hydrochloric acid (10 ml) and isopropanol (5 ml), and the mixture was stirred at room temperature for 24 h. The reaction mixture was neutralized, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform methanol=20:1→10:1). Recrystallization from ethyl acetate gave the titled compound (0.40 g) as a colorless powder.
Reaction SMILES: [Si](O[C@@H]([C@@H]1[C@@H](CC(S[C@H]2CCN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)C2)=O)N(CCOCC2C=CC([N+]([O-])=O)=CC=2)C1=O)C)(C(C)(C)C)(C)C.P(OCC)(OCC)OCC.C1(C=CC(O)=CC=1)O.[Si:69]([O:76][C@@H:77]([C@@H:79]1[C@@H:82]([CH2:83][C:84]([S:86][C@H:87]2[CH2:91][CH2:90][N:89]([C:92]([O:94][CH2:95][C:96]3[CH:101]=[CH:100][C:99]([N+:102]([O-:104])=[O:103])=[CH:98][CH:97]=3)=[O:93])[CH2:88]2)=O)[N:81]([C:105]([C:116]([O:118][CH2:119][C:120]2[CH:125]=[CH:124][C:123]([N+:126]([O-:128])=[O:127])=[CH:122][CH:121]=2)=[O:117])=P(OCC)(OCC)OCC)[C:80]1=[O:129])[CH3:78])([C:72]([CH3:75])([CH3:74])[CH3:73])([CH3:71])[CH3:70]>C1(C)C=CC=CC=1>[Si:69]([O:76][C@@H:77]([C@H:79]1[C:80](=[O:129])[N:81]2[C:105]([C:116]([O:118][CH2:119][C:120]3[CH:121]=[CH:122][C:123]([N+:126]([O-:128])=[O:127])=[CH:124][CH:125]=3)=[O:117])=[C:84]([S:86][C@H:87]3[CH2:91][CH2:90][N:89]([C:92]([O:94][CH2:95][C:96]4[CH:101]=[CH:100][C:99]([N+:102]([O-:104])=[O:103])=[CH:98][CH:97]=4)=[O:93])[CH2:88]3)[CH2:83][C@H:82]12)[CH3:78])([C:72]([CH3:74])([CH3:75])[CH3:73])([CH3:71])[CH3:70]
Reactant: CCOP(OCC)(OCC)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CCOP(OCC)OCC
Agent: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CCOCc2ccc([N+](=O)[O-])cc2)[C@@H]1CC(=O)S[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Temperature: 95 °C
Reaction time: 57 h
Yield: 83 %

Procedure:
A solution of 190 mg (0.25 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-(p-nitrobenzyloxyethyl)-4-([(S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl)-2-azetidinone, 250 mg (1.5 mmole) of triethyl phosphite and 10 mg (0.90 mmole) of hydroquinone in 20 ml of toluene was heated at 95° C. for 15 hours. On thin layer chromatography, disappearance of the starting materials and appearance of 1-(N-methylformimidoyl)pyrrolidin-3-yl, (3S,4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-1-[1-(p-nitrobenzyloxycarbonyl)-1-triethoxyphosphoranylidenemethyl]-4-([(S)-1-(p-nitrobenzyloxy-carbonyl)pyrrolidin-3-ylthio]carbonylmethyl)-2-azetidinone and the desired carbapenem compound were observed. The solvent and excess triethyl phosphite were evaporated off under reduced pressure. To the oily residue were added 20 ml of toluene and the mixture was heated at 95° C. For 57 hours to complete the cyclization reaction of the phosphoranylidene compound. After evaporation of the solvent, the residue was purified with a Lobar column. The fraction eluted with a 2:1 by volume mixture of benzene and ethyl acetate was collected and 151.5 mg (yield 83%) of the title compound was obtained as an oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.[K+].[Br-]>>[F:33][C:31]([F:32])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 79C. mp 145-146° C.; IR (KBr) cm−1: 3076, 3028, 1705, 1318, 1232, 1109; 400 MHz 1H NMR (DMSO-d6): δ 12.94 (br(s), 1H), 7.71 (d, 2H, J=8.2 Hz), 7.59 (d, 2H, J=8.0 Hz), 7.10-7.19 (m, 1H), 7.05 (d, 1H, J=8.5 Hz), 6.75-6.86 (m, 4H), 6.58 (d, 1H, J=8.5 Hz), 5.08 (s, 2H), 4.61 (s, 2H), 3.95 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.64 (t, 2H, J=7.5 Hz), 1.88 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75. found: C, 63.78; H, 4.53.