Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]3=[N:19][N:20]=[CH:21][N:11]3[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[P:22](=[O:26])([OH:25])([OH:24])[OH:23]>C(O)C>[OH:26][P:22]([O:25][P:22]([OH:25])([OH:24])=[O:23])(=[O:24])[OH:23].[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]3=[N:19][N:20]=[CH:21][N:11]3[N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=P(O)(O)O
Agent: c1nnc2c3c(c(NCCN4CCCC4)nn12)CCCC3
Solvent: CCO
Product: O=P(O)(O)OP(=O)(O)O

Procedure:
To a refluxing solution of 15.0 g of 6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine in 45 ml of ethanol was slowly added a solution of 13.2 g of phosphoric acid in an equal volume of ethanol. An exothermic reaction with vigorous foaming took place. The resulting slurry was refluxed for 1 hour and then cooled. The solid was separated by filtration, washed with ethanol and with absolute ethanol, and then dried at 50° C. under reduced pressure to give 6-[2-(1-pyrrolidinyl)ethylamino]-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine diphosphate.
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].N[C@@H:49]([C:54]([OH:56])=[O:55])[C@H](CC)C.N[C@H:58]([C:63]([OH:65])=[O:64])[C@H](CC)C.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:49][C:54]([OH:56])=[O:55].[CH3:58][C:63]([OH:65])=[O:64]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](N)CCCNC(=N)N)[C@@H](C)CC)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(=O)O

Procedure:
On purification of H-D-Arg-Ile-D-Leu-Arg-Ile-OH by column chromatography there was isolated a fraction which, according to amino acid analysis, was H-D-Arg-D-allo-Ile-D-Leu-Arg-Ile-OH. Amorphous substance, amino acid analysis: D-allo-Ile (0.9), Ile (1.06), Leu (1.03), Arg (1.87).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
4-Aminopyridine (1.94 g, 20.6 mmol) was added to a solution of p-anisoyl chloride (3.5 g, 20.6 mmol) and triethylamine (8.6 mL, 62 mmol) in dichloromethane (100 mL) at 0° C. The mixture was stirred 3 h at RT, and then extracted successively with 1N NaOH, water and brine, dried over sodium sulfate, and concentrated. Chromatography on silica (gradient of 30% to 100% ethyl acetate-hexanes) gave 3.8 g (81%) of a colorless solid. 1H NMR (CDCl3, 400 mHz) δ 8.49 (m, 2H), 8.19 (br, 1H), 7.85 (m, 2H), 7.59 (m, 2H), 6.95 (m, 2H), 3.85 (s, 3H), MS (AP+) 229 (MH+).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]1[O:23][C:7]2([C:12]3[CH:13]=[CH:14][C:15]4[C:20]([C:11]=3[S:10](=[O:22])(=[O:21])[NH:9][CH2:8]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:6][CH2:5]1.[OH-].[Na+].O>C(O)(C)C>[CH2:4]1[O:23][C:7]2([C:12]3[CH:13]=[CH:14][C:15]4[C:20]([C:11]=3[S:10](=[O:22])(=[O:21])[N:9]([CH2:1][CH3:2])[CH2:8]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:6][CH2:5]1
Reactant: CCI
Reactant: O=S1(=O)NCC2(OCCO2)c2ccc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCN1CC2(OCCO2)c2ccc3ccccc3c2S1(=O)=O
Reaction time: 84 h
Yield: 100.4 %

Procedure:
15.6 gm (0.1 mol) of ethyl iodide were added dropwise in several portions to a solution of 10.0 gm (0.034 mol) of 2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal in a mixture of 150 ml of isopropanol, 36 ml of 1 N sodium hydroxide and 36 ml of water, while stirring. Stirring was continued for 84 hours, whereupon the mixture was evaporated in vacuo, the residue was taken up in methylenechloride, and the solution was washed with water, dried and evaporated. 10.9 gm (99% of theory) of 2-ethyl-2H-naphtho[2,1-e]-1,2-thiazine-4(3H)-one-1,1-dioxide-ethylene ketal were obtained, which were used as such in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 173.8 %

Procedure:
To a solution of 3-fluorobenzoic acid (25.5 g, 182 mmol) in tetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (32.4 g, 200 mmol) and the mixture was stirred at room temperature for 30 min. Monoethyl malonate magnesium salt (27.1 g, 94.7 mmol) was added to the reaction solution and the mixture was heated under reflux for 30 min. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(3-fluorophenyl)-3-oxopropionate (34.6 g, 91%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](F)[C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[H-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([F:19])=[C:11]([CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:20]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1F
Temperature: 0 °C
Reaction time: 9 h
Yield: 94.8 %

Procedure:
In THF (100 ml) were dissolved 1-benzyloxy-2,3-difluoro-6-nitrobenzene (4.17 g, 15.7 mmol) and di-tert-butyl malonate (3.52 ml, 15.7 mmol). To the resulting solution was added sodium hydride (60% in oil, 1.26 g, 31.4 mmol) in portions under stirring at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and then at 80° C. for 9 hours. Di-tert-butyl malonate (7.04 ml, 31.4 mmol) and sodium hydride (60%; 2.52 g, 52.8 mmol) were added and the mixture was stirred at 80° C. for 2 days. After cooling to room temperature, the reaction mixture was poured in ice water (100 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 200 g), whereby from hexane/ethyl acetate (8/1) eluate fractions, the title compound (6.87 g, 95%) was obtained as an orange solid.
Reaction SMILES: [C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:37](=[CH:38][CH:39]=3)[CH2:36][CH2:35]4)[C:25]3[CH:24]=[C:23](Br)[CH:22]=[CH:21][C:20]=3[C:19]3[C:14]1=[CH:15][C:16](Br)=[CH:17][CH:18]=3)=[CH:2]2.[CH3:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:42]=1>C1(C)C=CC=CC=1>[C:1]12[CH2:8][CH2:7][C:6]=1[CH:5]=[CH:4][C:3]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[C:34]4[C:37](=[CH:38][CH:39]=3)[CH2:36][CH2:35]4)[C:25]3[CH:24]=[C:23]([N:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:43]4[CH:42]=[C:41]([CH3:40])[CH:46]=[CH:45][CH:44]=4)[CH:22]=[CH:21][C:20]=3[C:19]3[C:14]1=[CH:15][C:16]([N:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:43]1[CH:42]=[C:41]([CH3:40])[CH:46]=[CH:45][CH:44]=1)=[CH:17][CH:18]=3)=[CH:2]2
Reactant: Brc1ccc2c(c1)C(CCCCc1ccc3c(c1)CC3)(CCCCc1ccc3c(c1)CC3)c1cc(Br)ccc1-2
Reactant: Cc1cccc(Nc2ccccc2)c1
Solvent: Cc1ccccc1
Product: Cc1cccc(N(c2ccccc2)c2ccc3c(c2)C(CCCCc2ccc4c(c2)CC4)(CCCCc2ccc4c(c2)CC4)c2cc(N(c4ccccc4)c4cccc(C)c4)ccc2-3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an oven-dried three-neck round-bottom flask under nitrogen, were added 600 mL anhydrous toluene, 14.3 g 9-(4-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)butyl)-9-(4-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)butyl)-2,7-dibromo-9H-fluorene, and 9.2 mL 3-methyldiphenylamine. After the reaction mixture was degassed with strong nitrogen flow for 30 minutes, 6.44 g sodium tert-butoxide, 0.82 g tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), and 0.54 g tri-tert-butyl phosphine in 15 mL toluene were added. The reaction mixture was heated to reflux. After three hours, the heating was turn off, and the reaction was allowed to cool down to room temperature. The reaction mixture was filter through a Celite/silica gel plug. The product (13.1 g) was purified by flash chromatography using hexane, 1% then 5% ethyl acetate in hexane solution. The structure was confirmed by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C@H:8]([CH3:13])[NH:7]2.[OH-].[Na+].OO.Cl>O.CO>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH3:13])=[N:7]2
Reactant: C[C@@H]1Nc2cccc(Br)c2NC1=O
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2cccc(Br)c2[nH]c1=O
Temperature: 85 °C
Yield: 78.2 %

Procedure:
A solution of (S)-8-bromo-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (17 g, 70.5 mmol), MeOH (141 mL), and 1.0 N aq. NaOH (141 mL, 141 mmol) was stirred at 85° C. in a three-necked round-bottom flask fitted with a septum, reflux condenser, and addition funnel. A mixture of H2O2 (30% in water; 25.2 mL, 247 mmol) and deionized water (10 mL) was then added, dropwise via the addition funnel, over 45 min, and the resulting mixture was heated at 85° C. for 17 h. The mixture was cooled to RT, 5 N aq. HCl (36 mL) was added, and the resulting slurry was extracted with 10% MeOH/DCM (3×150 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-3-methylquinoxalin-2(1H)-one (126d; 13.16 g, 55.1 mmol, 78% yield) as a tan solid, which was used without further purification in the subsequent step: 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (1H, s), 7.77 (1H, d, J=8.2 Hz), 7.67 (1H, d, J=7.6 Hz), 7.22 (1H, t, J=7.8 Hz), 2.61 (3H, s). m/z (ESI, +ve) 239.0 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=4)[CH:27]=[CH:28][CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C#N)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M181) (265 mg, 0.492 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (122 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[Br:13]Br.O>C(Cl)Cl>[Br:13][CH:10]([CH3:11])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: CCC(=O)c1ccc(F)cc1F
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
In methylene chloride (300 ml) was dissolved 2',4'-difluoropropiophenone (55 g), to which was added bromine (50 g) dropwise, while stirring, during 30 minutes. The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added water (200 ml), and the methylene chloride layer was washed three times, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to leave 2-bromo-2',4'-difluoropropiophenone (77 g) as a pale yellow oily product.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([NH:12][C:13](=[O:16])[O:14][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)on1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)on1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 160.1 %

Procedure:
5-Phenylisoxazol-3-amine (428 mg, 2.67 mmol) in tetrahydrofuran (4.8 mL) was treated with potassium carbonate (481 mg, 3.47 mmol) and phenyl choloroformate (0.67 mL, 5.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a celite pad, washed with ethyl acetate and concentrated to dryness. The residue was taken into chloroform, washed with brine, and the organics dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 8:2) to give phenyl 5-phenylisoxazol-3-ylcarbamate (599 mg, 80%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.92 (bs, 1H), 7.78 (d, 2H), 7.45 (m, 6H), 7.26 (m, 2H), 7.12 (s, 1H); LC-MS (ESI) m/z 281 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[NH2:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>P([O-])([O-])([O-])=O.[NH4+].[NH4+].[NH4+]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][CH3:45])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[NH2:24])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(N)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Agent: O=P([O-])([O-])[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(N)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.33 h
Yield: 52 %

Procedure:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-(2-amino-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (400 mg) was added to a stirred, cooled (ice/H2O bath) solution of trifluoroacetic acid (6 mL) and anisole (0.5 mL). The cooling bath was removed and the solution stirred for 0.33 hr at ambient temperatures. The solution was concentrated and the residue macerated with methylene chloride to afford a yellow solid. The solid was dissolved in 0.05M (pH 6.5) ammonium phosphate. The solution was applied to a Michel-Miller HPLPLC column (22×300 mm) containing Partisil Prep 40 ODS-3. The column was eluted with 0.05M (pH 6.5) ammonium phosphate/acetonitrile (90:10). The appropriate fractions were combined and the pH lowered to 3.7 with the addition of dilute hydrochloric acid. The solution was concentrated to a volume of 50 mL when the title compound crystallized (155 mg, 52% yield).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12]N1C(=O)CCC1=O.O.CCOCC>CN(C=O)C>[Br:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2ccccc2N1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)ccc2N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dihydro-1H-quinolin-2-one (10.0 g, 67.9 mmol) in 100 ml dry DMF was added dropwise a solution of N-bromosuccinimide (12.7 g, 71.3 mmol) in 150 ml dry DMF at 0° C. The mixture was stirred at 0° C. for 2 h, then 400 ml water was added and the solution was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water (2×200 ml), then dried over MgSO4 and evaporated, affording a yellow solid which was purified by washing with cold ether providing pure 6-bromo-3,4-dihydro-1H-quinolin-2-one (13.6 g, 60.3 mmol, 89%) as colorless needles.
Reaction SMILES: [OH:1][C@H:2]([CH2:18][OH:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[N:8][C:7]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]1=2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl.O>[CH3:46][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:19][CH2:18][C@@H:2]([OH:1])[CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[N:8][C:7]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]2=3)(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2ncc(=O)n(CC[C@H](O)CO)c2n1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(=O)n(CC[C@H](O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.8 %

Procedure:
In dichloromethane (4 ml) was dissolved 4-[(3S)-3,4-dihydroxybutyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (200 mg, 0.754 mmol), and triethylamine (0.126 ml, 0.905 mmol), dimethylamino pyridine (18.4 mg, 0.151 mmol) and p-toluene sulfonyl chloride (158 mg, 0.829 mmol) were added thereto under cooling on ice and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction solution which was extracted with dichloromethane. After drying the extract with anhydrous sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 227 mg (72%) of the title compound in the form of a yellow oily product.
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=S)C.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>CN(C)C=O>[C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
To a solution of (E)-3-({1-[3-ethoxycarbonyl]propyl]-1H-tetrazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (715.6 mg) in N,N-dimethylformamide (10 ml) were added thioacetic acid (950 μl) and N,N-dimethylformamide dineopentyl acetal (3.7 ml). The resulting mixture was stirred at room temperature for one hour. Then, thioacetic acid (950 μl) and N,N-dimethylformamide dineopentyl acetal (3.7 ml) were added further, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer partitioned was washed with water and saturated aqueous sodium chloride successively, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and hexane (1:9 to 3:7) as the eluent to afford crude (E)-4-(acetylsulfanyl)-3-({1-[3-ethoxycarbonyl]propyl]-1H-tetrazol-5-yl}methylidene)-1-(triphenylmethyl)piperidine (419 mg) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:47])[CH2:31][CH:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]3=[N:38][O:39][CH2:40][C:41](C(C)(C)C)=[O:42])[C:27](=[O:48])[N:9]2[C:10]=1[C:11]([O:13]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])=[N+:2]=[N-:3].C1([O:55]C)C=CC=CC=1.FC(F)(F)C(O)=O>>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:47])[CH2:31][CH:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]3=[N:38][O:39][CH2:40][C:41]([OH:42])=[O:55])[C:27](=[O:48])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: CC(C)(C)C(=O)CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CN=[N+]=[N-])CS[C@H]12
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CC3C=CC=CC3=NOCC(=O)O)[C@H]2SC1
Reaction time: 0.67 h

Procedure:
Diphenylmethyl (6R,7R)-3-azidomethyl-7-(2-tertbutylcarbonylmethoxyiminophenylacetamido)-ceph-3-em-4-carboxylate (287 mg) was added to a mixture of anisole (0.3 ml) and trifluoroacetic acid (4 ml). The solution was stirred for 40 min. then evaporated. Benzene (50 ml) was added to the residue and removed by evaporation. The residue was partitioned between ethyl acetate and sodium bicarbonate solution; and the latter was acidified (10 N-HCl) under ethyl acetate, and extracted twice more with ethyl acetate. The organic extracts were washed with water and dried (Na2SO4), then evaporated, leaving an orange foam (183 mg). The foam was dissolved in ethyl acetate (2 ml) and added dropwise to vigorously stirred light petroleum (b.p. 40°-60°, 200 ml). Filtration gave the title-compound (100 mg, 51%), λmax (EtOH) 257.5 nm (ε 15,600), νmax (Nujol) 2100(N3), 1778(β-lactam), 1724(CO2H), 1670 and 1534 cm-1 (CONH), τ(Me2SO d6) values include 0.17(d, J=8 Hz; CONH), 2.2-2.7(Ph), 4.10 (C- 7H), 4.73(C-6H), 5.30(OCH2), 5.58 and 6.04(AB quartet, J=13 Hz, CH2N3), 6.29 and 6.52(AB quartet, J=18 Hz, SCH2).