Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].C([Li])CCC.C=O.N1C=CC=CC=1.[C:24]([O:27][C:28](=O)C)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:27][CH2:28][C:3]#[C:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCOc1ccccc1
Agent: C=O
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCC#CCOc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A 0.5-L reactor (#1) was equipped with a thermometer, an addition funnel, an overhead stirrer, and a nitrogen inlet. 150 mL of THF was charged followed by 27.5 g (0.21 mole) of phenyl propargyl ether. The solution was cooled to −20° C. 100 mL (0.25 mole) of n-butyllithium in hexanes was charged into an addition funnel. This solution was added to the reactor at a temperature between −25 and −35° C. The temperature was controlled by the rate of addition and the mixture was stirred for 1 h at −25 to −35° C. A second 1-L reactor (#2) was equipped with a thermometer, an overhead stirrer and a cannulation device. 120 mL of THF was charged followed by 9.4 g (0.42 mol) of paraformaldehyde as a solid in one portion. The resulting suspension was stirred for 5 min. and cooled to 5–10° C. The contents of reactor #1 were cannulated into reactor #2 maintaining temperature in reactor #2 between 5 and 15° C. The temperature in reactor #1 was maintained below −15° C. The cooling bath from reactor #2 was removed and the reaction mixture was allowed to warm up slowly to 20–25° C. Stirring was continued for 16 h at ambient temperature. 200 mL of water was added to the reaction mixture and the mixture was stirred for 15–30 min at ambient temperature. The reaction mixture was extracted twice with 200 mL and then 100 mL of ethyl acetate. The combined organic solution was washed with 200 mL of water. The organic solution was dried with 50 g of anhydrous sodium sulfate. The drying agent was filtered off and rinsed with 50 mL of ethyl acetate. The filtrate was transferred into a 1-L reactor fitted with an overhead stirrer. Pyridine (67 mL, 0.83 mol) was charged followed by acetic anhydride (39 mL, 0.42 mol). The solution was stirred overnight at ambient temperature. The solution was washed sequentially with water (200 mL), sodium bicarbonate solution (2×150 mL) until pH=7–8, hydrochloric acid solution (2×150 mL) until pH=1–3, and brine (1×150 mL). The solution was dried with anhydrous sodium sulfate (50 g). The drying agent was filtered off, and the filtrate was concentrated in vacuo at a temperature that did not exceed 60° C. to yield 37 g (87% yield, HPLC strength 65%) of product as a dark-red slightly viscous fluid.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].C(O)(C)(C)C.[H][H]>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH2:5][C@@H:6]2[CH2:20][C:19](=[O:21])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Agent: [Pd]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Yield: 37.3 %

Procedure:
An ambient temperature mixture of benzyl 2-azido-carbapen-2-em-3-carboxylate (7.7 mg, 27 micromol) and palladium on calcium carbonate poisoned with lead (12.8 mg) in dry dioxane (0.80 ml) containing t-butanol (50 microliter) was stirred while hydrogen was bubbled through for 20 min. The mixture was filtered and the solid washed with diethyl ether (3×0.5 ml). The combined filtrate and washes were concentrated to 0.5 ml under vacuum, and the residue was chromatographed on one 20 cm×20 cm 250 micron silica gel preparative thin layer chromatography plate developed with 1:1 (v/v) toluene-ethyl acetate. The band centered at Rf 0.2 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 2.6 mg (37%) benzyl 2-amino-carbapen-2-em-3-carboxylate as a light yellow glass; I.R. (neat film): 3450, 3330, 1780, 1690 cm-1 ; NMR (CDCl3): δ2.81 dd (J1 =4 Hz, J2 =16 Hz, 1H), 2.93 m (2H), 3.21 dd (J1 =5 Hz, J2 =16 Hz, 1H), 5.25 d (J=13 Hz, 1H), 5.32 d (J=13 Hz, 1H), 7.37 m (5H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:17]1[S:21](=O)[CH2:20][CH2:19][CH2:18]1.C(OC(C)C)(C)C.[F:30][C:31]([F:70])([S:66]([O-:69])(=[O:68])=[O:67])[CH:32]([O:37][C:38](=[O:65])[CH2:39][CH2:40][C@H:41]([C@@H:43]1[C@:60]2([CH3:61])[C@H:46]([C@H:47]3[C@H:57]([CH2:58][C:59]2=[O:62])[C@:55]2([CH3:56])[CH:50]([CH2:51][C:52](=[O:63])[CH2:53][CH2:54]2)[CH2:49][C:48]3=[O:64])[CH2:45][CH2:44]1)[CH3:42])[C:33]([F:36])([F:35])[F:34].C([N+](C)(C)C)C1C=CC=CC=1>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>[F:70][C:31]([F:30])([S:66]([O-:69])(=[O:67])=[O:68])[CH:32]([O:37][C:38](=[O:65])[CH2:39][CH2:40][C@H:41]([C@@H:43]1[C@:60]2([CH3:61])[C@H:46]([C@H:47]3[C@H:57]([CH2:58][C:59]2=[O:62])[C@:55]2([CH3:56])[CH:50]([CH2:51][C:52](=[O:63])[CH2:53][CH2:54]2)[CH2:49][C:48]3=[O:64])[CH2:45][CH2:44]1)[CH3:42])[C:33]([F:34])([F:36])[F:35].[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S+:21]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)COc1cccc2ccccc12
Reactant: O=S1CCCC1
Agent: CS(=O)(=O)O
Agent: C[C@H](CCC(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])[C@H]1CC[C@H]2[C@@H]3C(=O)CC4CC(=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O
Product: FC(F)(F)COc1ccc([S+]2CCCC2)c2ccccc12
Reaction time: 8 h

Procedure:
In 6 g of Eaton's reagent (Aldrich, diphosphorus pentoxide/methanesulfonic acid solution) was dispersed 3.4 g (0.0150 mol) of 1-(2,2,2-trifluoroethoxy)naphthalene in Synthesis Example 1-3. With stirring, 3.2 g (0.0300 mol) of tetramethylene sulfoxide was added dropwise to the dispersion. The solution was matured overnight at room temperature and combined with 30 g of water and 30 g of diisopropyl ether, from which a water layer was separated. The water layer was again washed with 30 g of diisopropyl ether. This aqueous solution was combined with 3.4 g (0.0100 mol) of benzyltrimethylammonium 1,1,3,3,3-pentafluoro-2-(3,7,12-trioxocholanoyloxy)-1-propanesulfonate in Synthesis Example 1-7, after which extraction was effected twice with 50 g of dichloromethane. The organic layer was washed with water, distilled in vacuum to remove the solvent, and purified by silica gel column chromatography (elute, dichloromethane/methanol). The product was dissolved in methyl isobutyl ketone, washed with water, distilled in vacuum to remove the solvent, and dried in vacuum. The product was poured into isopropyl ether for crystallization, filtered and dried, obtaining the target compound. White crystals, 6.2 g, yield 67%.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CN(C)CCCN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN(C)C)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N1,N1-dimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-2.01 (m, 2H) 2.44 (s, 3H) 2.80 (d, J=4.04 Hz, 6H) 3.13 (dt, J=10.36, 4.93 Hz, 2H) 3.37 (q, J=6.40 Hz, 2H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.79 (br. s., 1H) 8.22 (d, J=16.93 Hz, 1H) 8.43 (br. s., 1H) 8.86 (br. s., 1H) 8.93 (dd, J=2.15, 0.88 Hz, 1H) 9.38 (br. s., 1H) 13.25 (br. s., 1H). MS m/z [M+H]+ 405.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.BrC1C=CC=C(Br)N=1.C([Li])CCC.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C.C(N(CC)CC)C.CCOCC>[CH2:38]([O:37][C:33](=[O:36])/[CH:34]=[CH:35]/[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1)[CH3:39]
Reactant: C=CC(=O)OCC
Reactant: O=C(c1ccc(C(F)(F)F)cc1)c1cccc(Br)n1
Agent: [Pd+2]
Agent: Brc1cccc(Br)n1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cccc(C(=O)c2ccc(C(F)(F)F)cc2)n1
Reaction time: 6 h

Procedure:
2-Bromo-6-(4-trifluoromethylbenzoyl)pyridine, m.p. 66°-68° C. (prepared by reacting 2,6-dibromopyridine and 4-trifluoromethylenzonitrile in dry ether in the presence of butyllithium) ethyl acrylate, triethylamine, palladium(II) acetate, triphenylphosphine and acetonitrile were heated at 150° C. in an autoclave with stirring for six hours to yield (E)-ethyl-3-[6-(4-trifluoromethylbenzoyl)-2-pyridyl]acrylate, m.p. 129°-132° C. Butyllithium was added under nitrogen to a stirred suspension of triphenyl-2-pyrrolidinoethylphosphonium bromide in dry toluene to form a Wittig reagent. After 0.5 hours, the acrylate compound prepared above, in toluene was added and the resulting suspension was heated at 75° C. with stirring for 2 hours. The cooled solution was diluted with ether and treated with hydrochloric acid (2M). The aqueous phase was separated, washed with ether, and basified with potassium carbonate (ice) and extracted with ether. The mixture of isomeric esters obtained by evaporation was dissolved in ethanol containing sodium hydroxide solution (1M) and partially evaporated on the steam bath under reduced pressure for 5 minutes. The residual aqueous solution was neutralized with sulfuric acid and evaporated to dryness. The solid residue was extracted with hot isopropanol and the extracts were concentrated until crystallization commenced. The (E)-3-{6-[3-pyrrolidino-1-(4-Trifluoromethylphenyl)prop-1E-enyl]-2-pyridyl}acrylic acid after recrystallization from isopropanol, melted at m.p. 223°-225° C. (decomp).
Reaction SMILES: [CH2:1]([O:19][C:20](=[O:66])[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[ClH:67]>C(Cl)Cl.CCOC(C)=O>[ClH:67].[ClH:67].[CH2:1]([O:19][C:20](=[O:66])[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCC=CCCCCCCCOC(=O)CCN(CCCCN(CCC(=O)OCCCCCCCC=CCCCCCCCCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOC(=O)CCNCCCCNCCC(=O)OCCCCCCCCC=CCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
The ester 5 (n=4, R=oleyl; 13.0 g, 13.9 mmol) was dissolved in CH2Cl2 (70 mL) and treated with 4M HCl in EtOAc (140 mL). The resulting mixture was stirred at rt. for 2 h, then the solvent was removed in vacuo and the residue was triturated with anhydrous diethyl ether (150 mL) to afford a solid which was dried in vacuo to afford bis hydrochloride 6 as a white powder (10.23 g, 91%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:8]2.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:20]3[CH2:21][O:22]3)=[CH:15][CH:16]=1)[CH2:10]2
Reactant: ClCC1CO1
Reactant: Oc1ccc(C2C3CC4CC(C3)CC2C4)cc1
Product: c1cc(C2C3CC4CC(C3)CC2C4)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-tricyclo[3.3.1.13,7]decan-2-yl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[N:7]1.Cl.[OH-].[Na+]>CCOCC>[CH3:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2([NH2:12])[CH2:2][CH2:1]2)=[N:7]1
Reactant: Cn1ccc(C#N)n1
Reactant: CC[Mg]Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cn1ccc(C2(N)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl magnesium bromide (2.5 mol, 1 M in ether) was added at −78° C. to a solution of a 1-methyl-1H-pyrazole-3-carbonitrile (0.5 g, 1 mmol) and Ti(Oi-Pr)4 (1.1 mmol) in Et2O (5 mL). The yellow solution was stirred for 10 min. After the solution was warmed to ambient temperature (1 h), BF3OEt2 (2 mmol) was added. After the mixture was stirred for 1 h, 1 N HCl and ether were added. NaOH (10%) was added to the resulting two clear phases and the mixture was extracted with ether. The combined ether layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (Et2O). 1H NMR (400 MHz, CDCl3): δ 0.94-1.05 (m, 4H), 2.32 (s, 2H), 3.83 (s, 3H), 5.92 (d, 1H), 7.23-7.24 (d, 1H). LCMS: (ES+) m/z observed 137.7.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[CH:21][C:10]=1[O:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])C1C=CC=CC=1>C(O)C.[Pd]>[OH:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:9]=1[OH:8]
Reactant: OC(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(O)c(OCC(O)c2ccccc2)c1

Procedure:
A solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanol (3.9 g) in ethanol (175 ml) was hydrogenated in the presence of 10% palladium on charcoal (100 mg) at 30 psi. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was recrystallized from the mixture of toluene-ethyl acetate 8:1 (15 ml). The yield of 2-(2-Hydroxy-2-phenylethoxy)benzene-1,4-diol is 1.2 g. 1H NMR (DMSO-d6) δ: 3.79 (dd, J 9.6, 8.3 Hz, 1H), 4.00 (dd, J 9.6, 3.6 Hz, 1H), 4.94 (ddd, J 3.6, 8.3, 3.9 Hz, 1H), 5.66 (d, J 3.9 Hz, 1H), 6.18 (dd, J 8.5, 2.3 Hz, 1H), 6.34 (d, J 2.3, 1H), 6.57 (d, J 8.5, 1H), 7.26-7.47 (m, 5H), 7.97 (s, 1H), 8.66 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O([CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])S(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(OCC(F)(F)C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and 2,2,3,3,3,-pentafluoropropyl triflate with potassium carbonate in acetone at ambient temperature for 18 hours. Kugelrohr distillation provided a colorless oil, b.p. 105-110° C./12 mbar.
Reaction SMILES: [C:1]([O:18]CCCCCC)(=[O:17])[C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][CH2:9]CCCCC)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+:26].C(O)CCCCC>C1(C)C=CC=CC=1>[C:6]([O:8][CH3:9])(=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([C:1]([O-:18])=[O:17])=[CH:3][CH:4]=1.[K+:26]
Reactant: CCCCCCOC(=O)c1ccc(C(=O)OCCCCCC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCCCCCO
Product: COC(=O)c1ccc(C(=O)[O-])cc1

Procedure:
Typical reagent levels were as follows: dihexyl terephthalate (33.5 g, 0.10 mole), potassium hydroxide (5.6 g, 0.10 mole), 100 ml of toluene and 20 ml of 1-hexanol. After workup 20.2g (70%) of product was recovered.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:16][OH:17].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:14])[NH:16][OH:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
(R)-3-Cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (2.04 g, 10.4 mmol), hydroxylamine hydrochloride (0.79 g, 11.4 mmol) and NaHCO3 (0.97 g, 11.6 mmol) were added to MeOH (24 mL) and the solution was heated to reflux. After 4 h, the reaction was cooled to room temperature and filtered through a fritted funnel. The solution was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford (R)-3-(N-hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.28 g, 5.58 mmol, 54%) as a yellow foam.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:31][CH:32]1[C:59](=[O:60])[N:34]2[C:35]([C:56]([OH:58])=[O:57])=[C:36]([CH2:39][S:40][C:41]3[N:45]([CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[N:44]=[N:43][N:42]=3)[CH2:37][S:38][C@H:33]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([NH:31][CH:32]2[C:59](=[O:60])[N:34]3[C:35]([C:56]([OH:58])=[O:57])=[C:36]([CH2:39][S:40][C:41]4[N:45]([CH2:46][CH2:47][NH:48][C:49]([O:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])[N:44]=[N:43][N:42]=4)[CH2:37][S:38][C@H:33]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC(C)(C)OC(=O)NCCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCNC(=O)OC(C)(C)C)CS[C@H]12)c1csc(NC=O)n1
Yield: 22.9 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(3-tert-butoxycarbonylaminopropoxyimino)acetic acid (syn isomer, 2.6 g.), N,N-dimethylformamide (0.6 g.), phosphoryl chloride (1.2 g.), 7-amino-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (3.2 g.), trimethylsilylacetamide (5.5 g.) and ethyl acetate (65 ml.) were treated in a similar manner to that of Example 6-(1) to give 7-[2-(2-formamidothiazol-4-yl) -2-(3-tert-butoxycarbonylaminopropoxyimino)acetamido]-3-[1-(2-tert-butoxycarbonylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[CH:54][C:53]([NH2:56])=[N:52][CH:51]=1>CN(C)C=O>[N:50]1[CH:55]=[CH:54][C:53]([NH:56][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])=[N:52][CH:51]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1ccncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3ccncn3)c(=O)oc12
Temperature: 25 °C
Yield: 11.2 %

Procedure:
DIEA (0.044 mL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.030 g, 0.14 mmol) and HATU (0.095 g, 0.25 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, pyrimidin-4-ylamine (0.009 g, 0.09 mmol) was added and allowed to react overnight, when a solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.003 g of 1541E in an 11% yield: LCMS (ESI) m/z 298 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].C[O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19](Cl)[N:18]=1.O>O1CCOCC1.[Cu](I)I>[Cl:23][C:21]1[CH:20]=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:18]=[C:17]([C:16]([OH:25])=[O:15])[CH:22]=1
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cc(Oc2cccc(C(F)(F)F)c2)n1
Temperature: 125 °C
Reaction time: 10 h

Procedure:
3-(trifluoromethyl) phenol (3.15 g, 0.0019 mol) was dissolved in 50 ml of dried dioxane. Sodium hydride (0.8 g (ca. 60% in mineral oil), 0.0019×1.05 mol) was added to the obtained solution at room temperature. After completion of the foaming, a solution obtained by dissolving 4,6-dichloro picolinic acid methyl ester (4.0 g, 0.0019 mol) in 5 ml of dried dioxane, was dropped into the above solution. Successively, copper iodide (3.7 g, 0.0019×1.0 mol) was added to the obtained solution. The resultant mixture was heated and stirred at a temperature of 120 to 130° C. for 10 hours. Thereafter, the obtained reaction solution was cooled, mixed with 10 ml of water, and then filtered through a glass filter provided with High-flow Super Cell. The obtained filtrate was extracted with 100 ml of ethyl acetate two times, thereby separating an organic phase therefrom. The obtained organic phase was dried with sodium anhydride. After the dried organic phase was subjected to distillation to remove the solvent therefrom, the obtained distillation residues were purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si](C(C)(C)C)(C)C)[C:22]=4[Cl:35])[CH3:20])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1>>[Cl:35][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C@H:19]([O:18][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:36]=[CH:37][C:2]([C:40]4[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[S:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:20]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Product: COC(=O)c1sc(-n2cnc3cc(-c4cccnc4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 52.6 %

Procedure:
Methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (Intermediate 8, 500 mg, 0.80 mmol) and pyridine-3-boronic acid (120 mg, 0.96 mmol) were coupled using a procedure analogous to Intermediate 9 to give 213 mg of the title compound (53%). MS m/z=506 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: ClCc1ccccn1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccccn2)c(=O)[nH]c1=O
Yield: 39.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (145 mg, yield: 39.9%).