Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[NH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:46].O>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10][C@H:9]2[C:28]([NH:35][C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][C:37]=2[CH3:46])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round bottom flask containing (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (133 mg) was combined with methylene chloride (10 ml), methyl 4-amino-3-methylbenzoate and DiPea. The mixture was stirred at rt for 2 hrs and another 100 mg of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid was added and the mixture was stirred for another 2 hrs. The mixture was pardoned between water (10 ml) and methylene chloride (10 ml) and the organic layer was dried and concentrated to give a solid, which was treated with 3 ml of acetonitrile. The mixture was stirred and filtered. the solid was dried to give a white solid, 102 mg as the desired product. The filtrate was chromatographed on a reverse phase column (40 g, 30-100% acetonitrile) to give another 34 mg of desired product after removal of solvent. combined product: 102+34=136 mg. MS (ES+) m/z Calcd: [(M+H)+]: 614. found: 614.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reaction time: 15 h
Yield: 98 %

Procedure:
To a mixture of 5-fluoro-2-nitrophenol (50.0 g), potassium carbonate (44.0 g) and N,N-dimethylformamide (150 mL) was added benzyl bromide (59.9 g) under ice-cooling, and the mixture was stirred for 15 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (77.1 g, yield 98%) as pale-yellow crystals.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.CC1(C)O[C@H](CN2C=CC(NC(=O)[C@@H](N3[CH2:56][C:55]([O:57][C:58]4[C:63]([F:64])=[CH:62][CH:61]=[C:60]([O:65][CH2:66][CH3:67])[C:59]=4[F:68])=[CH:54][C:53]3=[O:69])CC(C)C)=N2)CO1>C(#N)C>[CH2:66]([O:65][C:60]1[C:59]([F:68])=[C:58]([C:63]([F:64])=[CH:62][CH:61]=1)[O:57][C:55]1[CH2:56][N:2]([CH:3]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:53](=[O:69])[CH:54]=1)[CH3:67]
Reactant: CC(C)(O)Cn1ccc(NC(=O)C(N)CC2CCOCC2)n1
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(F)c(OC2=CC(=O)N(C(CC3CCOCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
A suspension of 2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide hydrochloride salt (766 mg, 2.0 mmol) in acetonitrile (15 mL) was treated with N,N-diisopropylethylamine (1.0 mL) and the resulting mixture stirred at 60° C. for 15 min. After this time N,N-diisopropylethylamine (0.5 mL) and a solution of (E)-4-bromo-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared in Example 116, 705 mg, 1.93 mmol) in acetonitrile (10 mL) were added and the resulting solution refluxed for 20 h. The resulting mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The layers were separated and the organic layer was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue dissolved in tetrahydrofuran (4 mL) and transferred to an Emrys Optimizer microwave tube and microwaved at 160° C. for 6 h. The mixture was concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica 40 g, 5% to 80% (10% methanol/dichloromethane)/hexanes) which afforded 2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (148 mg, 14%): HR-ES-MS (m/z) calculated for C27H34F2N4O6 [M+H]+ 549.2519, observed 549.2520; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.07 (br. s., 3H), 1.13-1.31 (m, 3H), 1.35 (t, J=6.9 Hz, 3H), 1.55-1.74 (m, 3H), 1.75-1.88 (m, 1H), 3.09-3.31 (m, 2H), 3.82 (br. s., 2H), 3.90 (s, 2H), 4.14 (q, J=6.9 Hz, 2H), 4.32 (d, J=18.6 Hz, 1H), 4.66 (br. s., 1H), 4.64 (d, J=18.6 Hz, 1H), 4.91 (dd, J=10.8, 4.4 Hz, 1H), 5.06 (s, 1H), 6.45 (d, J=1.8 Hz, 1H), 7.17 (td, J=9.4, 4.9 Hz, 1H), 7.27 (td, J=9.4, 1.3 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:30][CH2:31][N:32]4[CH2:35][CH2:34][CH2:33]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23](OC)[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.N1(CCN2C=C(C3C=CC(F)=C(C)C=3)N=C2C2CCNCC2)CC[CH2:37]1.Cl.N1(CCN2C=C(C3C=CC(F)=C(OC)C=3)N=C2C2CCNCC2)CCC1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:30][CH2:31][N:32]4[CH2:35][CH2:34][CH2:33]4)[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH3:37])[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: COc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: Cl
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidine-5-carbonitrile of using 4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl)piperidine instead 4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methoxy-phenyl)-1H-imidazol-2-yl]-piperidine hydrochloride.
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([O:23]C)=[C:18]([O:21]C)[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH2:2][CH3:3].B(Br)(Br)Br.CO>ClCCl>[CH2:1]([N:4]1[CH2:13][CH:12]2[C:14]3[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([OH:21])[C:19]=3[O:20][C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1Cc2cccc3c2C(C1)c1ccc(OC)c(OC)c1O3
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCCN1Cc2cccc3c2C(C1)c1ccc(O)c(O)c1O3
Temperature: -78 °C
Reaction time: 8 h

Procedure:
The N-propyl amine 12a (0.90 g; 2.8 mmol) was dissolved in 200 ml of dichloromethane and cooled to −78° C. In a separate 250 ml round bottom flask, 125 ml of dry dichloromethane was cooled to −78° C., and 1.4 ml (14.8 mmol) of BBr3 was added via syringe. The BBr3 solution was transferred using a cannula to the flask containing the starting material. The solution was stirred overnight, while the reaction slowly warmed to room temperature. After recooling the solution to −78° C., 50 ml of methanol was slowly added to quench the reaction. The reaction was then concentrated to dryness. Methanol was added and the solution was concentrated. This process was repeated three times. The resulting tan solid was suspended in hot isopropyl alcohol. Slowly cooling to room temperature resulted in a fine yellow precipitate. The solid was collected by filtration (0.660 g; 63%): mp 259-264° C. dec; 1H NMR: (300 MHz, CDCl3): 7.16 (t, 1H, J=9 Hz); 6.97 (d, 1H, J=12 Hz); 6.83 (d, 1H, J=9 Hz); 6.55 (d, 1H, J=9 Hz); 6.46 (d, 1H, J=9 Hz); 4.45 (d, 1H, J=15 Hz); 4.10 (m, 3H); 3.17 (q, 2H, J=6 Hz); 3.04 (t, 1H, J=9 Hz); 1.73 (q, 2H, J=9 Hz); 0.90 (t, 3H, J=6 Hz). Anal. Calc'd. for C18H20BrNO3: C, 57.16; H, 5.33; N, 3.70. Found: C, 56.78; H, 5.26; N, 3.65.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:4]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:6])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloronicotinic acid (5.005 g, 26.18 mmol) in DCM (60 ML) was added a few drops of DMF followed by the addition dropwise of oxalyl chloride (2.27 mL, 26.18 mmol). The reaction was stirred at room temperature for two hours until gas bubbling had stopped. The solvent was evaporated under reduced pressure to give an oil. DCM (60 mL) was added and the reaction mixture was cooled in an ice bath. Cyclohexylamine (5.98 mL, 52.36 mmol) was added slowly keeping the temperature below 15° C. The reaction was stirred at room temperature overnight.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9]1)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[F:18][C:15]([F:16])([F:17])[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCCN(CC(F)(F)F)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCCN(CC(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[1-(2,2,2-Trifluoro-ethyl)-piperidin-3-yl]-carbamic acid tert-butyl ester (0.380 g, 1.3 mmol) was dissolved in 3 mL of dioxane. A 4 M solution of HCl in dioxane (3.3 mL, 13.3 mmol) was added and the resulting mixture was stirred overnight at RT before being evaporated to give racemic 1-(2,2,2-trifluoro-ethyl)-piperidin-3-ylamine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[F:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
4-Nitrobenzoyl chloride (3.08 g) was added slowly to a stirred mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (4.0 g) and triethylamine (4.98 g) in methylene chloride (110 ml) at room temperature. The resulting mixture was stirred at this temperature for 1 hour, washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine, dried over magnesiun sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of acetone and methanol to give 4-(4-fluorobenzoyl)-1-(4-nitrobenzoyl)piperidine (5.0 g) as colourless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.CCOC(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A brown solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.01 g, 9.61 mmol) and 3-hydroxypyridine (0.923 g, 9.71 mmol) in dry DMF (15 ml) under Ar was treated with cesium carbonate (3.28 g, 10.07 mmol) at once and the brown mixture was stirred at RT for 2 h. H2O (50 mL) and EtOAc (50 mL) were added and the organic layer was isolated. The water layer was extracted with EtOAc (2×30 mL). The combined organic layer was washed with H2O (3×40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated to dryness to give a light yellow solid. Yield: 2.62 g (96%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][C:22]=2[F:29])=[CH:18][C:17]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C>[Cl:15][C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:2]3[CH:3]=[C:4]4[N:11]([CH3:12])[CH2:10][CH2:9][N:5]4[C:6](=[O:8])[N:7]=3)=[CH:23][C:22]=2[F:29])=[CH:18][C:17]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (80 mg, 0.431 mmol), sodium hydride (35 mg, 0.875 mmol) and (4-(4-chloro-3-(trifluoromethyl)phenoxy)-3-fluorophenyl)methanol (138 mg, 0.431 mmol) in DMF (2 mL).
Reaction SMILES: CN(C)C=O.P(Cl)(Cl)(Cl)=O.[CH3:11][O:12][N:13]=[C:14]([C:18]1[N:19]([CH3:28])[C:20](=[N:23][S:24]([CH3:27])(=[O:26])=[O:25])[S:21][CH:22]=1)[C:15]([OH:17])=O.[NH2:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12>C(Cl)Cl.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>[CH3:11][O:12][N:13]=[C:14]([C:18]1[N:19]([CH3:28])[C:20](=[N:23][S:24]([CH3:27])(=[O:26])=[O:25])[S:21][CH:22]=1)[C:15]([NH:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:17]
Reactant: CON=C(C(=O)O)c1csc(=NS(C)(=O)=O)n1C
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(=NS(C)(=O)=O)n1C
Temperature: 40 °C
Yield: 66.6 %

Procedure:
A mixture of dimethylformamide (0.22 g.) and phosphorus oxychloride (0.46 g.) was warmed for 1 hour at 40° C. The mixture was dissolved in dry methylene chloride (20 ml.) and 2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetic acid (anti isomer) (0.73 g.) was added thereto with stirring and ice-cooling, after which the resulting mixture was stirred for 1.5 hours under ice-cooling. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (0.82 g.) was dissolved in a solution of bis-(trimethylsilyl)acetamide (1.5 g.) in dry methylene chloride (20 ml.). To this solution was added at -30° C. the above obtained methylene chloride solution, after which the mixture was stirred for 2 hours at -5° to -20° C. After distilling off methylene chloride at low temperature, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and water (50 ml.) was added thereto. The resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate and the aqueous layer was separated. The aqueous layer was adjusted to pH 1.5, saturated with sodium chloride and extracted with ethyl acetate. The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized by a mixture of diisopropyl ether and ether. The powder was collected by filtration and dried to give 7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (anti isomer) (1.0 g.). This powder (1.0 g.) was suspended in water (30 ml.) and dissolved by adjusting to pH 6 by an aqueous solution of sodium bicarbonate. After removing the solvent by bubbling of nitrogen gas, the aqueous solution was lyophilized to give sodium 7-[2-methoxyimino-2-(2-mesylimino-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (anti isomer) (0.98 g.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12]CCl)=[CH:8][S:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH2:12][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)CCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of 4-(3-chloro-propionylamino)-thiophene-3-carboxylic acid methyl ester ([51486-30-7], 0.1 g, 0.43 mmol) in dimethylformamide (1.5 mL) was added potassium carbonate (0.88 g, 0.64 mmol) and 4-hydroxybiphenyl (0.087 g, 0.514 mmol) and the reaction mixture was then stirred overnight at 90° C. After such time the reaction mixture was allowed to cool to room temperature, water was added (in excess of 5 mL) leading to precipitation. The precipitate was then filtered, washed with water and dried in vacuo to yield the title compound as a white solid (0.16 g, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[CH:11]=[C:12]([CH3:15])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([NH2:26])[C:20]=2[N:19]=[CH:18]1>CC(O)=O.O>[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([N:26]3[CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:10](=[O:16])[CH:11]=[C:12]3[CH3:15])[C:20]=2[N:19]=[CH:18]1
Reactant: Cc1cc(=O)c(OCc2ccccc2)co1
Reactant: Nc1cccc2[nH]cnc12
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(=O)c(OCc2ccccc2)cn1-c1cccc2[nH]cnc12
Temperature: 140 °C

Procedure:
5-(Benzyloxy)-2-methyl-4H-pyran-4-one (450 mg, 2.081 mmol) and 1H-benzimidazol-4-amine (279 mg, 2.095 mmol) were taken up in 40% HOAc/H2O (10 ml) in a microwave vial. The vial was sealed and the mixture heated to 140° C. for 30 min by microwave irradiation. The reaction was incomplete by LC/MS. The mixture was heated to 200° C. for 30 min by microwave irradiation. The reaction was incomplete by LC/MS. The mixture was heated to 170° C. for 1 h by microwave irradiation. The mixture was concentrated. The crude material was purified by preparative reversed-phase HPLC (30×150 mm Waters Sunfire (0.1% TFA), 5-35% ACN/water over 20 min at 50 mL/min, 2 injections). Fractions containing each compound were pooled separately then applied to separate Phenomenex Strata-X—C ion exchange columns (5 g). Each column was washed with H2O and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fractions for each were concentrated separately to give the title compounds below: 1-(1H-benzimidazol-4-yl)-5-(benzyloxy)-2-methylpyridin-4(1H)-one: tan solid LC/MS rt=1.24 min, 1H NMR (500 MHz, d6-DMSO) δ 12.90 (bs, 1 H), 8.33 (s, 1 H), 7.72 (bs, 1 H), 7.49 (bs, 1 H), 7.41-7.25 (m, 7 H), 6.26 (s, 1 H), 4.94 (s, 2 H), 1.92 (s, 3 H). 1-(1H-benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one: tan solid, LC/MS rt=0.47 min, 1H NMR (500 MHz, d6-DMSO) δ 12.88 (bs, 1 H), 8.32 (s, 1 H), 7.70 (d, J=8.06 Hz, 1 H), 7.38-7.25 (m, 3 H), 6.25 (s, 1 H), 1.92 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18][CH2:19][CH3:20])=[CH2:17])CCC.[F-].[K+].CC(OC)(C)C>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[CH2:17])[N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Cl)nc(Cl)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(Cl)nc(Cl)c1C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
2,4,6-Trichloro-5-methylpyrimidine (2.0 g, 10.13 mmol) and bis(triphenylphosphine)palladium chloride (0.142 g, 0.20 mmol) in DMF (40 mL) was degased. Tributyl(1-ethoxyvinyl)stannane (3.59 mL, 10.64 mmol) was added. The mixture was heated at 100° C. for 1.5 h under nitrogen atmosphere. The mixture was poured into a solution of KF (6 g) in water (100 mL). MTBE (100 mL) was added mixture was for stirred 10 min. The solid was removed by filtration and was washed with MTBE (60 mL). The organic phase was washed with water, dried over sodium sulfate and evaporated. The mixture was purified by column chromatography eluting with DCM to give the title compound as a solid, 1.15 g (49%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH3:20][N:21]([CH2:23][CH2:24][CH2:25]Cl)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH2:25][CH2:24][CH2:23][N:21]([CH3:22])[CH3:20])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)CCCCl
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(C(=O)c2ccccc2)c(=O)c2cn(C)nc21

Procedure:
5.1 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.02 mol.), 4.8 g. of dimethylaminopropyl chloride (0.04 mol.) and 5.6 g. of potassium carbonate (0.04 mol.) are heated in 50 ml. of dimethylformamide at 80° for 12 hours with stirring. The mixture is filtered hot, evaporated to dryness and the residue is recrystallized from ethyl acetate to obtain 5-benzoyl-7-[3-(dimethylamino)Propyl]-2,7-dihydro-2-methyl-4H-pyrazolo[3,4-b]pyridin-4-one, yield 4.6 g. (68%); m.p. 186°-188°.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH3:26])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:27].CO>>[ClH:27].[CH3:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15][C@H:12]2[CH2:13][CH2:14][C@@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH:21]=[N:20][CH:19]=1
Reactant: Cc1cncc2cccc(N[C@H]3CC[C@@H](NC(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: Cc1cncc2cccc(N[C@H]3CC[C@@H](N)CC3)c12

Procedure:
According to the method of Example 1, Step C, deprotection was performed (room temperature, 2 hours) by using Intermediate 94 (35.8 mg) and 10% hydrogen chloride/methanol solution (2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (1.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (30.3 mg) as light yellow powdery solid.