Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>C(O)(C)(C)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28])[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
Dimethyl malonate (59.7 g, 0.44 mol) was added dropwise to a stirred solution of potassium tert-butoxide (51 g, 0.44 mol) in dry t-butanol (500 mL). To the resultant suspension, a warm solution of 2-chloro-5-trifluoromethylnitrobenzene (50 g, 0.22 mol) in t-butanol (100 mL) was added and the mixture was refluxed for 6 h (reaction monitored by TLC). After completion of the reaction, most of the t-butanol was distilled off under vacuum, and chilled water was then added to the reaction mixture. The pH was adjusted to neutral with dilute hydrochloric acid, which resulted in the precipitation of the product. The mixture was stirred for 30 minutes and the product was filtered off (68 g, 95%). This material was used without further purification in the next step. A small amount was crystallized (EtOAc/hexane, 4:6) for analysis, to yield a yellow crystalline material, mp 65-67° C. 1H NMR (CDCl3) 8.30 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 5.37 (s, 1H), 3.80 (s, 6H). MS (FAB) m/z: 322.1 (M++1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([N:2]2[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CCNCC1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 37 %

Procedure:
Piperidin-4-one hydrochloride was added to a methanolic solution of sodium methoxide (prepared from anhydrous methanol (50 mL) and sodium metal (0.85 g, 37 mmol)) and heated at reflux for 2 h then concentrated to dryness in vacuo. The residue was dissolved in acetonitrile (100 mL), then potassium carbonate (10.22 g, 74 mmol) and 1-fluoro-4-nitro-benzene (3.92 mL, 37 mmol) were added and the mixture was heated at reflux overnight. The solvent was evaporated in vacuo, the residue being washed with water then 50% diethyl ether/petroleum ether and dried in vacuo to afford 1-(4-nitro-phenyl)-piperidin-4-one (3.01 g, 37%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:29])([F:28])[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1C(F)(F)F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccccc4C(F)(F)F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-])=O.CO>[C].[Pd].C(O)(=O)C>[NH2:15][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[CH2:4][CH:3]([O:18][CH3:19])[O:2][CH3:1])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(CC(OC)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CC(OC)OC)c(N)c1
Yield: 106.7 %

Procedure:
To a mixture of 4.40 g (16.3 mmol) of methyl 4-(2,2-dimethoxyethyl)-3-nitrobenzoate in a solvent mixture of 200 ml of methanol and 2 ml of acetic acid was added 0.50 g of 5% palladium-carbon to perform catalytic hydrogenation at ambient temperature under normal.pressure and then treat the reaction mixture in a conventional manner. Thus, 4.16 g of methyl 3-amino-4-(2,2-dimethoxyethyl)benzoate was obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27](O)=[O:28])=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:31][C:32]1[CH:45]=[CH:44][C:35]([CH2:36][P:37]2(=[O:43])[O:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:25])(=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:31][C:32]4[CH:45]=[CH:44][C:35]([CH2:36][P:37]5(=[O:43])[O:38][CH2:39][CH2:40][CH2:41][O:42]5)=[CH:34][CH:33]=4)=[O:28])=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reactant: Nc1ccc(CP2(=O)OCCCO2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CP4(=O)OCCCO4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
In DMF (8 ml) were dissolved 7-(4-(2-butoxyethoxy)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.4 g), 2-(4-aminobenzyl)-1,3,2-dioxaphosphorinane-2-oxide (0.22 g) and 1-hydroxybenzotriazole (0.13 g), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g) and triethylamine (0.4 ml). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give crude crystals, which were recrystallized from ethanol to give 2-(4-(7-(4-(2-butoxyethoxy)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carbonylamino) benzyl)-1,3,2-dioxaphosphorinane-2-oxide (Compound 156) (0.40 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=NC2C=C(F)C=C3C=2C=CC(=O)N3)[C:9](O)([CH2:14][O:15]C)[C:10]([F:13])([F:12])[F:11])=[C:4]([O:31][CH3:32])[C:3]=1[F:33].B.[Na].C[OH:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2([C:10]([F:11])([F:12])[F:13])[CH2:14][O:15]2)=[O:37])=[C:4]([O:31][CH3:32])[C:3]=1[F:33]
Reactant: CO
Reactant: COCC(O)(C(=Nc1cc(F)cc2[nH]c(=O)ccc12)c1ccc(Cl)c(F)c1OC)C(F)(F)F
Agent: B
Agent: [Na]
Product: COc1c(C(=O)C2(C(F)(F)F)CO2)ccc(Cl)c1F

Procedure:
285 mg (0.95 mmol) (4-Chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone are stirred with 622 mg (1.9 mmol) caesium carbonate in 6.7 ml methanol. The reaction is quenched by addition of water after one day. The aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine, dried over sodium sulphate and then evaporated to yield 262 mg 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one. To 27 mg (0.15 mmol) 5-Amino-7-fluoro-1H-quinolin-2-one and 50 mg (0.15 mmol) 1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethypropan-1-one in 0.45 ml toluene and 0.13 ml 1,4-dioxane are added 33 μl acetic acid and 0.12 ml tetra butyl orthotitanate. The mixture is heated over 20 hours to 110° C., cooled to room temperature and poured into aqueous ammonium fluoride solution. Ethyl acetate is added and the mixture is stirred vigorously for 30 minutes. Phases are separated and two times extracted with ethyl acetate. The combined organic phases are concentrated to yield quantitatively 5-{[1-(4-chloro-3-fluoro-2-methoxyphenyl)-3,3,3-trifluoro-2-hydroxy-2-methoxymethylpropylidene]amino}-7-fluoro-1H-quinolin-2-one. The raw imine in 4.2 ml methanol is cooled to 5° C. and 120 mg sodium boron hydride are added in multiple portions over the period of 72 hours. The reaction is quenched by addition of saturated ammonium chloride solution and diluted with water and ethyl acetate. The phases are separated, the aqueous layer is extracted with ethyl acetate, the combined organic phases are washed with brine and dried over sodium sulphate. After removal of the solvent preparative thin layer chromatography on silica gel (acetone in methylene chloride, 30%) yields 9.5 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[C:8]=2[OH:24])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:7]2[C:8]([OH:24])=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)=[O:35])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cc2ccc(F)cc2)c(O)c1-c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(O)c1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
Synthesis of 3-(4-Fluoro-benzyl)-6-methoxy-3′-nitro-biphenyl-2-ol (P-099) In an 8 mL vial equipped with a stir bar was placed I-246 (60 mg, 0.163 mmol) and triethylsilane (350 μL). The mixture was cooled in an ice-water bath and then TFA (350 μL) was added. The reaction mixture was warmed to room temperature and reacted for 17 hours. After this time period, additional triethylsilane (1.1 mL) and TFA (1.1 mL) was introduced and the reaction mixture was heated to 60° C. in an oil bath for 24 hours. The reaction mixture was concentrated by a stream of N2, quenched with water (20 mL) and extracted with dichloromethane (2×30 mL). The organic portions were combined, washed with brine (30 mL), dried (MgSO4) and concentrated. The residue was purified by SiO2 column chromatography utilizing 15% EtOAc/hexanes as the eluent to produce 18.9 mg of P-099 as a viscous, tan oil in 33% yield. 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.94 (s, 2H), 4.73 (s, 1H), 6.55 (d, J=8 Hz, 1H), 6.96-7.00 (m, 2H), 7.01 (d, J=8 Hz, 1H), 7.19-7.22 (m, 2H), 7.63 (t, J=7 Hz, 1H), 7.69 (dt, J=8, 2 Hz, 1H), 8.22-8.26 (m, 2H) ppm. MS (APCI−): 352.1 (M−1); LC-MS: 98%.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH:21]([NH2:24])([CH3:23])[CH3:22].ClCCl>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]([NH:24][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(C)C)c1
Temperature: 160 °C
Reaction time: 1.17 h

Procedure:
Potassium phosphate (1.38 g, 6.5 mmol), palladium(II) acetate (56 mg, 0.25 mmol), and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (139 mg, 0.25 mmol) were combined in a microwave tube under nitrogen. Ethyl 3-bromobenzoate (1.145 g, 5 mmol) in dimethoxyethane (2 mL) and isopropylamine (385 mg, 6.5 mmol) in dimethoxyethane (2 mL) were added. The tube was filled with nitrogen again. The tube was then capped, and the reaction mixture was heated in a microwave oven (Biotage Initiator™ 2.0, 0 to 100 watts) with stirring at 160° C. for 70 minutes. Then dichloromethane was added, and the crude mixture was filtered. The filtrate was concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=7:1) to give ethyl 3-(isopropylamino)benzoate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].Cl>ClCCl>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 63.9 %

Procedure:
A solution of 4-hydroxybenzoic acid (6.91 g) and pyridine (12.1 ml) in dichloromethane (100 ml) was cooled to an ice-water temperature, and hereto was added dropwise pivaloyl chloride (13.26 g). The mixture was stirred at same temperature for 1.5 hours, and thereto was added a 10% aqueous hydrochloric acid solution (50 ml). The organic layer was washed with H2O (100 ml) and brine, and dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml)-H2O (15 ml), and the mixture was stirred at 50° C. for 17.5 hours. After being cooled to an ice-water temperature, the mixture was basified with a saturated aqueous sodium hydrogen carbonate solution (about 100 ml). After being stirred at room temperature for 4 hours, the mixture was acidified with a 36% aqueous hydrochloric acid solution at an ice-water temperature. The resultant mixture was extracted with ethyl acetate (100 ml), and the organic layer was dried over magnesium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1-9:1) and triturated with diisopropyl ether to give 4-pivaloyloxybenzoic acid (7.10 g) as a colorless solid. ESI-Mass m/Z 221 (M−H). 1H-NMR (DMSO-d6) δ 1.31 (s, 9H), 7.23 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H), 10.03 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:24][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CNC1CCCCC1NC>C1(C)C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([F:23])=[CH:20][CH:21]=3)[N:16]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:15]=2[CH2:24][CH3:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1ccccc1
Reactant: CCc1[nH]c2cc(F)ccc2c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: I[Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1c(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 27.3 %

Procedure:
To a solution of 4-(2-ethyl-6-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (0.36 g) in degassed toluene (10 ml) at r.t., is added potassium phosphate (0.1 g), copper iodide (20 mg), iodobenzene (254 mg) and N,N′-dimethylcyclohexane-1,2-diamine (30 mg). The mixture is heated at reflux for 3 days. Thereafter the mixture is allowed to cool to r.t., and water (20 ml) added. Ethyl acetate (3×10 ml) is used to extract the organic components and the organic layer is washed with water, dried over MgSO4 and concentrated in vacuo. Flash chromatography (9:1 cyclohexane:ethyl acetate) gives 120 mg pure product (27%) as a brown solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C(=O)=O.[CH:14]1[C:24]2[CH:23]([CH:25]([CH2:28][CH:29]=[CH2:30])[CH2:26][OH:27])[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[CH2:20][O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl.O>[CH:14]1[C:24]2[CH:23]([CH:25]([CH2:28][CH:29]=[CH2:30])[CH:26]=[O:27])[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[CH2:20][O:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: C=CCC(CO)C1c2ccccc2COc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCC(C=O)C1c2ccccc2COc2ccccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Dissolved oxalyl chloride (3.83 g, 0.0302 mol) in 60 mL of dry dichloromethane, and cooled to -78° C. under a nitrogen atmosphere. Added DMSO (4.3 mL, 4.72 g, 0.0604 mol) dissolved in 15 mL of dry dichloromethane dropwise via addition funnel. CO and CO2 evolution observed. Stirred at -78° C. for 10 mins. Added 2-[6,11-dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-en-1-ol (6.77 g, 0.0241 mol) dissolved in 50 mL of dry dichloromethane via addition funnel. Stirred at -78° C. for 15 mins. Added triethylamine (10.1 mL, 7.33 g, 0.0724 mol) via addition funnel, and warmed reaction mixture slowly to room temperature. Added 200 mL of water, and separated layers. Extracted aqueous solution with dichloromethane. Washed combined organic extracts with 0.5N HCl, saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 10% ethyl acetate-hexane then 15% ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 6.44 g (96% yield) of 2-[6,11-dihydro-dibenzo[b,e]oxepin-11-yl]-pent-4-en-l-al.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][CH:11]([CH3:40])[CH:12]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[C:13]12[O:20][CH2:19][C:16]([CH3:21])([CH2:17][O:18]1)[CH2:15][O:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:49][C:50]([O:52][CH3:53])=[O:51]>CN(C)C=O.C(OCC)(=O)C>[CH3:53][O:52][C:50](=[O:51])[CH2:49][N:22]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH:12]([C:13]12[O:20][CH2:19][C:16]([CH3:21])([CH2:17][O:18]1)[CH2:15][O:14]2)[CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:41])[CH3:40]
Reactant: COC(=O)CBr
Reactant: CC(NC(=O)OCc1ccccc1)C(NS(=O)(=O)c1ccc(OCc2ccccc2)cc1)C12OCC(C)(CO1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN(C(C(C)NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of [2-(4-benzyloxy-benzenesulfonylamino)-1-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-ethyl]-carbamic acid benzyl ester (compound of formula LII, 1.2 g, 2.0 mmol) in 2 ml of dimethylformamide was treated with cesium carbonate (1.12 g, 3.4 mmol) and methyl bromoacetate (0.2 ml, 0.32 g, 2.1 mmol). After stirring for about 2 hours, the mixture was diluted with ethyl acetate, washed 5 times with water, and the organic phase was dried over sodium sulfate, filtered and concentrated, affording 1.3 g of {(4-benzyloxy-benzenesulfonyl)-[2-benzyloxycarbonylamino-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-propyl]-amino}-acetic acid methyl ester (compound of formula LIII) as a colorless syrup.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:28]=[CH:27][C:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[C:19]([CH:23]=2)[C:20]([OH:22])=O)=[CH:11][CH:10]=1)#[N:8].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.O1CCCC1.O.CN(C)C=O>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:20](=[O:22])[C:19]1[CH:23]=[C:15]([O:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:28][CH:27]=2)[CH:16]=[CH:17][C:18]=1[N+:24]([O-:26])=[O:25])[CH3:31]
Reactant: N#Cc1ccc(COc2ccc([N+](=O)[O-])c(C(=O)O)c2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 91.1 %

Procedure:
Oxalyl chloride (5.70 mL, 65.4 mmol) was added slowly to a rapidly stirred suspension of 14.6 g (48.9 mmol) of 5-(4-cyanobenzyloxy)-2-nitrobenzoic acid and 2 mL of dimethylformamide in 100 mL of benzene. When gas evolution ceased, the solution was heated briefly to 60° C., concentrated in vacuo, and redissolved in 75 mL of tetrahydrofuran. This solution was added dropwise to a rapidly stirred suspension of 8.50 g (55.3 mmol) of b-alanine ethyl ester hydrochloride and 21.1 g (251 mmol) of sodium bicarbonate in 325 mL of 2:1 tetrahydrofuran/water at 0° C. The mixture was warmed to ambient temperature for 12 h and the tetrahydrofuran was removed in vacuo. The residue was partitioned between ethyl acetate and 1N sodium bicarbonate and the aqueous phase was separated and extracted with ethyl acetate. The combined organics were washed with 1N sodium hydrogen sulfate, water, brine, dried over anhydrous magnesium sulfate, and concentrated to give 17.7 g (91%) of N-(5-(4-cyanobenzyloxy)-2-nitrobenzoyl)-b-alanine ethyl ester as a tan powder. 1H NMR (300 MHz, CDCl3) d 8.11 (1H, d, J=8.3 Hz, O--Ar--H), 7.71 (2H, d, J=8.3 Hz, NC--Ar--H2) d, J=8.3 Hz, NC--Ar--H2), 7.01 (2H, m, O--Ar--H2), 6.50 (1H, bt, J=5.9 Hz, N--H), 5.21 (2H, s, ArCH2O), 4.14 (2H, q, J=7.3 Hz, OCH2CH3), 3.69 (2H, bq, J=5.8 Hz, NCH2CH2), 2.70 (2H, t, J=5.8 Hz, NCH2CH2), 1.26 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C20H20N3O6 : 398.1352; Found: 398.1343.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C:13]([O:23][CH3:24])([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:25])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].ClC(Cl)(Cl)C[O:29][C:30]([N:32]=C=O)=O>>[C:30]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C:13]([O:23][CH3:24])([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:25])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])(=[O:29])[NH2:32]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(CO)CS[C@@H]21
Reactant: O=C=NC(=O)OCC(Cl)(Cl)Cl
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@@H]21

Procedure:
When 3-hydroxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid is reacted with 2,2,2-trichloroethoxycarbonyl isocyanate and the resulting imidodicarboxylate is deblocked following the procedures described in Example 5, 3-carbamoyloxymethyl-7-methoxy-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.[CH3:29][CH:30]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[CH3:31].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:29][CH:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:35][CH:34]=1)[CH3:31]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)C)cc2)c2ncnn12
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a suspension (15 mL) of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), [4-(1-methylethoxy)phenyl]boronic acid (0.49 g), triethylamine (0.5 mL), pyridine (1 mL) and molecular sieves 4A (1 g) in dichloromethane was added copper(II) acetate (0.49 g), and the mixture was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 82%).