Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:10]([O:9][CH2:8][CH2:7][C:6]1[N:5]([CH3:17])[N:4]=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:2]=1[C:31]1[C:27]([CH3:26])=[N:28][O:29][C:30]=1[CH3:35])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2-c2c(C)noc2C)cc1
Yield: 23.6 %

Procedure:
A mixture of 4-bromo-5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1-H-pyrazole (140 mg, 0.33 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (92.8 mg, 0.66 mmol), K2CO3 (328 mg, 2.37 mmol) and Pd(PPh3)4 (19.0 mg, 0.02 mmol) in DME (1 mL) and water (1 mL) was flushed with argon and irradiated in the microwave at 140° C. for 20 min. Full conversion was not achieved. The mixture was filtered to remove palladium black. Irradiation in the microwave was continued until full conversion was achieved. Altogether 3,5-dimethylisoxazol-4-ylboronic acid (233 mg, 1.66 mmol) and Pd(PPh3)4 (57.0 mg, 0.06 mmol) were used and three irradiations were run. Water was added and the crude mixture was extracted with EtOAc. Purification on silica gel gave 4-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylisoxazole (34.4 mg, 0.078 mmol, 24%).
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][C:15]([Br:27])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C1COCC1.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:27][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCCCCCCC(=O)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 670 %

Procedure:
1,2-Dichloroethane (30 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-nitrophenyl)isonicotinate (6.5 g, 17 2 mmol), rhodium octanoate dimer (0.669 g, 0.859 mmol) and crushed 4A° molecular sieves (6.5 g). The reaction heated at 80° C. for 14 hr. The crude mixture was diluted with THF and filtered. The collected solid were then extracted with additional hot THF. The solvents were removed from the combined filtrates and the residue was suspended in methanol, filtered and air dried to leave methyl 2-bromo-7-nitro-5H-pyrido[3,2-b]indole-4-carboxylate (5.0 g, 13.4 mmol, 78% yield). MS (ESI) m/z 351.91 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.31 (1H, br. s.), 8.63 (1H, d, J=2.14 Hz), 8.45 (1H, d, J=8.55 Hz), 8.17 (1H, dd, J=8.55, 2.14 Hz), 8.08 (1H, s), 4.07 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[C:47](=[O:48])[C:39]4=[CH:40][N:41]5[C:46]([CH2:45][CH2:44][CH2:43][CH2:42]5)=[C:38]4[CH:37]=[N:36]3)[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[C:47](=[O:48])[C:39]3=[CH:40][N:41]4[C:46]([CH2:45][CH2:44][CH2:43][CH2:42]4)=[C:38]3[CH:37]=[N:36]2)=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6n(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c6n(cc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of 192d (160 mg, 0.25 mmol) in MeOH (20 mL) was added NaBH4 (28 mg, 0.75 mmol). The mixture was stirred at 20° C. for 2 h and evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 192 (97 mg, 60%) as a yellow solid. MS-ESI: [M+H]+ 650.4. 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J=2.5 Hz, 1H), 8.54 (d, J=4.5 Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J=2.5 Hz, 1H), 7.47 (d, J=5.0 Hz, 1H), 7.38-7.36 (m, 1H), 7.25 (d, J=9.5 Hz, 1H), 4.66 (s, 1H), 4.57-4.54 (m, 2H), 4.48-4.46 (m, 1H), 4.43-4.41 (m, 1H), 4.33 (s, 2H), 4.25-4.21 (m, 2H), 3.69-3.66 (m, 1H), 3.60 (s, 3H), 3.42-3.37 (m, 1H), 3.11-3.07 (m, 1H), 3.06-3.04 (m, 2H), 2.97-2.92 (m, 1H), 2.55-2.53 (m, 1H), 2.35-2.29 (m, 2H), 2.19-2.17 (m, 1H), 2.04-1.96 (m, 2H), 1.93-1.85 (m, 2H), 0.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]=[C:2]([CH:19]([CH3:21])[CH3:20])[C:3]([C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[CH:16]=1)=[O:4].S(=O)(=O)(O)O>>[CH3:17][C:7]1[C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[C:16]2[CH2:1][CH:2]([CH:19]([CH3:21])[CH3:20])[C:3](=[O:4])[C:5]=2[C:6]=1[CH3:18]
Reactant: C=C(C(=O)c1cc2cc(C(=O)O)oc2c(C)c1C)C(C)C
Agent: O=S(=O)(O)O
Product: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(C(C)C)C2=O
Temperature: 57 °C

Procedure:
A mixture of 5-(2-methyleneisovaleryl)-6,7-dimethylbenzofuran-2-carboxylic acid (5 g.) and concentrated sulfuric acid (25 ml.) is heated at 57°C. for 6 hours and poured into ice water (300 ml.). The 4,5-dimethyl -6-oxo-7-isopropyl-7,8-dihydro-6H-indeno-[5,4-b]furan-2-carboxylic acid which separates is filtered and dried.
Reaction SMILES: Br[C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH3:14][O:15][C:16](=[O:49])[NH:17][C@H:18]([C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[N:33]=1)=[O:23])[CH:19]([CH3:21])[CH3:20].C1(C)C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][O:15][C:16](=[O:49])[NH:17][C@H:18]([C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]1[NH:30][CH:31]=[C:32]([C:34]2[CH:35]=[CH:36][C:37]([C:2]3[CH:3]=[C:4]([F:13])[C:5]([NH2:6])=[CH:7][C:8]=3[C:9]([F:12])([F:11])[F:10])=[CH:38][CH:39]=2)[N:33]=1)=[O:23])[CH:19]([CH3:21])[CH3:20]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C
Yield: 77.4 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-(trifluoromethyl)aniline (78 mg, 0.302 mmol) and [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (150 mg, 0.302 mmol) in toluene (0.6 mL, 6 mmol) and water (0.4 mL, 20 mmol) was purged with nitrogen. Potassium carbonate (208.8 g, 1.511 mmol) and tetrakis(triphenylphosphine)-palladium(0) (35 mg, 0.030 mmol) were added under an atmosphere of nitrogen. The reaction mixture was capped and heated at 100° C. overnight, cooled to RT, and partitioned between ethyl acetate (5.0 mL) and water (1.5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a yellowish oil, which was purified by silica gel chromatography (12 g silica gel, 0-100% EtOAc/hexanes). Desired fractions were combined and concentrated to give the title intermediate as a yellowish solid (128 mg, 77% yield). (m/z): [M+H]+ calcd for C27H24F4N5O3 548.22 found 548.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][N:10]1[CH2:15][CH:14]([CH3:16])[NH:13][NH:12][C:11]1=[O:17]>S(=O)(=O)(O)O.C(O)C>[CH3:16][CH:14]1[NH:13][NH:12][C:11](=[O:17])[N:10]([N:9]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:15]1
Reactant: O=Cc1cccnc1
Reactant: CC1CN(N)C(=O)NN1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1CN(N=Cc2cccnc2)C(=O)NN1

Procedure:
2.2 g of pyridine-3-carbaldehyde and 2 drops of sulfuric acid are added to a solution of 3 g of 4-amino-6-methyl-3-oxo-1,4,5,6-tetrahydro-1,2,4-triazine in 30 ml of ethanol. The reaction mixture is then maintained under reflux for 90 minutes and then the resulting suspension is cooled to 20°, filtered and dried. 4.1 g of the title compound having a melting point of 235-237° are obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10][CH2:9]2.Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+]>CCO>[F:1][C:2]([F:27])([F:26])[CH:3]([C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:29][OH:30])[CH2:11][CH2:10][CH2:9]2
Reactant: O=C1CCCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21

Procedure:
To a stirred solution of ((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (NaOAc, 0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158° C.; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Reaction time: 0.25 h

Procedure:
To a solution of 2,4,5-tribromo-1H-imidazole (10.3 g, 32 8 mmol) in anhydrous N,N-dimethylformamide (100 ml) is slowly added NaH (1.4 g, 36.1 mmol, 60% in mineral oil) at room temperature. The suspension is stirred for 15 minutes and 2-(Trimethylsilyl)ethoxymethyl chloride (5.8 ml, 32.8 mmol) is added. The mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water (250 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layer is washed with water (50 ml), brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 2,4,5-tribromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole as a yellow waxy solid 13.8 g, 97%.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]4[CH:37]5[CH:33]([NH:34][C:35](=[O:38])[NH:36]5)[CH2:32][S:31]4)=[C:20]([OH:40])[CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C1COCC1.CN(C=O)C.CCOC(C)=O.O.[Cl-].[Na+].O>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH:37]3[CH:33]([NH:34][C:35](=[O:38])[NH:36]3)[CH2:32][S:31]2)=[C:20]([OH:40])[CH:19]=1
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(NC(=O)CCCCC2SCC3NC(=O)NC32)c(O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
{3-Hydroxy-4-[5-(2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-phenyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (390) (0.152 g, 0.266 mmol) was dissolved in a mixture of THF (10 mL) and DMF (4 mL). Piperidine (0.53 mL, 5.3 mmol) was added. The mixture was shaken at room temperature for 3 h. LC-MS indicated complete de-protection at this point. The mixture was diluted with EtOAc (100 mL), water (2×50 mL) and brine (2×50 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure to give an oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluting with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (391) as a beige oil (0.076 g, 0.217 mmol, 81.6% yield). LC-MS (ESI): (exact mass: 350.14) m/e=351.3 [M+1]+ (100%), 701.3 [2M+1]+ (15%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
Methyl 4-fluoro-3-nitrobenzoate Compound 3a (1.0 g, 5.02 mmol) (prepared as described in Nicolaou, et al., Bioorg. Med. Chem., 1998, 1185), 1-[bis(4-fluorophenyl)methyl]piperazine Compound 3b (1.59 g, 5.52 mmol) and potassium carbonate (0.76 g, 5.52 mmol) were dissolved in N,N-Dimethylformamide (15 mL) and heated to about 80° C. for about 5 h then cooled to rt. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (2×50 mL) and water (2×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester Compound 3c (2.4 g) as a yellow foam. MS m/z 468 (M+H). A mixture of the nitro substituted methyl ester Compound 3c (2.4 g, 5.13 mmol) and tin (II) chloride dihydrate (11.60 g, 51.34 mmol) was stirred in DMF (50 mL) for about 1 h. The reaction was diluted with ethyl acetate (100 mL), washed with brine (2×100 mL) and water (3×150 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 3-amino-4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-benzoic acid methyl ester Compound 3d (1.88 g) as a yellow foam. MS m/z 438 (M+H). A mixture of the amino substituted methyl ester Compound 3d (1.88 g, 4.30 mmol) and phenyl isocyanate Compound 3e (0.51 g, 4.30 mmol) was stirred in diethyl ether (50 mL) for about 18 h. The precipitate was collected by filtration, then washed with ether and hexane to provide Compound 11 (1.80 g) as an off-white solid. MS m/z 559 (M+H). A solution of Compound 11 (0.45 g, 0.81 mmol) and LiAlH4 in THF (1.0 M, 1 mL, 1.0 mmol) in THF (10 mL) was stirred for about 18 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give Compound 10 (0.31 g) as a white solid. MS m/z 529 (M+H).
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([O:17]CC)=[O:16])(=O)C1C=CC=CC=1.[OH-].[Na+].CO.Cl>O1CCCC1>[OH:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:20]1[N:21]=[C:22]([NH2:25])[S:23][CH:24]=1)[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(=NOCCOC(=O)c1ccccc1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCCO)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61 %

Procedure:
A mixture of ethyl 2-(2-benzoyloxyethoxyimino)-2-(2-aminothiazol-4-yl)acetate (syn isomer) (8.5 g.), 1N aqueous sodium hydroxide (35 ml.), methanol (40 ml.) and tetrahydrofuran (40 ml.) was stirred at 35° to 40° C. for 9 hours and at ambient temperature for 12 hours. After adjusting the resultant solution to pH 6.5 with conc. hydrochloric acid, the solution was concentrated to about 2/3 volume of the initial. The concentrate was adjusted to pH 3.5 with conc. hydrochloric acid under ice-cooling, and the precipitates were collected by filtration, washed with water and acetone in turn and then dried over phosphorus pentoxide under reduced pressure to give 2-(2-hydroxyethoxyimino)-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (3.3 g.).
Reaction SMILES: Br[C:2]1C=COC=1C(O)=O.C(O)C.[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([OH:26])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO>[C:13]([O:17][C:18]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:24]([O:26][CH3:2])=[O:25])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(C(=O)O)cc1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1occc1Br
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(NC(=O)OC(C)(C)C)c1

Procedure:
A reaction and treatment was conducted in the same manner as in Reference Example 1 except that the 3-bromo-2-furancarboxylic acid and ethanol used in Reference Example 1 were replaced with 3-(tert-butoxycarbonylamino)-4-methoxybenzoic acid (5.00 g) and methanol (0.76 ml), respectively, thereby giving 5.51 g of methyl 3-(tert-butoxycarbonylamino)-4-methoxybenzoate.
Reaction SMILES: [Cl-:1].[CH:2]1([C:8]2([CH2:28][N:29]3[C:33]([CH3:35])([CH3:34])[CH2:32][O:31][C:30]3=[O:36])[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]3[C@H:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:19][NH2+:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:37][C:38]([CH3:40])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl-:1].[CH:2]1([C:8]2([CH2:28][N:29]3[C:33]([CH3:34])([CH3:35])[CH2:32][O:31][C:30]3=[O:36])[CH2:9][CH2:10][N:11]([C:14]([C@H:16]3[C@H:20]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:19][NH+:18]([CH:38]([CH3:40])[CH3:37])[CH2:17]3)=[O:15])[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@H]2C[NH2+]C[C@H]2c2ccc(F)cc2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)[NH+]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(F)cc2)C1
Temperature: 0 °C
Yield: 120.3 %

Procedure:
A solution of the product of step E (100 mg; 0.1916 mmol) in methylene chloride (100 mL) was converted to the free-base by washing with saturated sodium bicarbonate. The organic phase was washed with brine, dried (Na2SO4), filtered and the volatiles were removed in vacuo. The residue was dissolved in methylene chloride (2 mL) and cooled to 0° C. Acetone (111 mg; 0.14 mmol) was added, followed by acetic acid (57 mg; 0.9579 mmol) and sodium triacetoxyborohydride (0.575 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 36 h at which time the reaction was quenched with saturated sodium bicarbonate. After extracting three times with methylene chloride, the organic solution was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the crude residue which was purified on silica gel (93:7 methylene chloride/methanol (contaiing 10% v/v ammonium hydroxide). The product was dissolved in ethyl acetate (2 mL) and converted to the hydrochloride salt by addition of a saturated solution of hydrogen chloride in ethyl acetate (2 mL). The reaction mixture was maintained at ambient temperature for 30 min at which time the volatiles were removed in vacuo. The solid was triturated to high purity with diethyl ether which furnished 95 mg of the title compound as the hydrochloride salt [MS: m/z 528 (MH+)].
Reaction SMILES: FC(F)(F)C(O)=O.C([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[CH:22]=[N:23][C:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:14]2[C:13]1=[O:32])(C)(C)C>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[CH:22][N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:12][C:13](=[O:32])[C:14]=23)=[CH:26][CH:27]=1
Reactant: CC(C)(C)n1c(=O)c2c(-c3ccc(F)cc3)ncn2c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2n2cnc(-c3ccc(F)cc3)c12
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (50.0 ml) is added to a solution of 5-tert-butyl-3-(4-fluorophenyl)-4,5-dihydroimidazo[1,5-a]quinoxalin-4-one (XXXIV, EXAMPLE 245, 4.01 g) and methylene chloride (50.0 ml) at 0°. The solution is stirred for 1 hr at 0° and is concentrated. The residue is triturated with water, filtered, washed with water (2×100 ml), ether (2×100 ml), and dried under reduced pressure to give the title compound, mp>300°; IR (mineral oil) 2955, 2922, 2868, 2855, 1667, 1499, 1377 and 1366 cm-1 ; NMR (d6 -DMSO) 11.45, 9.16, 8.3-8.45, 8.21 and 7.2-7.45 δ; MS (EI, m/z) 279, 251 and 223.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([O:10][N:11]=[C:12]([C:43]1[N:44]=[C:45]([NH:49]C=O)[S:46][C:47]=1[Cl:48])[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:20]([CH:23]=[CH2:24])[CH2:21][S:22][C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>>[C:1]([O:5][C:6]([CH:8]([O:10][N:11]=[C:12]([C:43]1[N:44]=[C:45]([NH2:49])[S:46][C:47]=1[Cl:48])[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])=[C:20]([CH:23]=[CH2:24])[CH2:21][S:22][C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)C(=O)OC(C)(C)C)c3nc(NC=O)sc3Cl)[C@H]2SC1
Agent: Cl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC(C)C(=O)OC(C)(C)C)c3nc(N)sc3Cl)[C@H]2SC1
Yield: 92.4 %

Procedure:
Benzhydryl 7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(2-amino-5-chlorothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.69 g) was prepared by reacting benzhydryl 7-[2-(1-tert-butoxycarbonylethoxyimino)-2-(2-formamido-5-chlorothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.9 g) with conc. hydrochloric acid (0.8 g) according to a similar manner to that of Example 310.