Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([CH:11]=[O:12])[CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[C:4]([CH:3]=1)[CH:11]=[O:12]
Reactant: c1cn[nH]c1
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1-n1cccn1
Reaction time: 48 h
Yield: 22.2 %

Procedure:
To a solution of 4-chloro-2-formylphenylboronic acid (200 mg, 1.09 mmol) in DMF (10 mL) are added pyrazole (88 mg, 1.3 mmol), Cu(OAc)2 (295 mg, 1.6 mmol), pyridine (171 mg, 2.2 mmol) and molecular sieve (200 mg) at room temperature. The mixture is stirred for 48 hours with open cap. The mixture is filtered through a short pad of diatomaceous earth (2 g) rinsing with MeOH (10 mL). The combined filtrate is extracted with H2O (15 mL) and EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography eluting with 10% EtOAc in heptane to afford 5-chloro-2-pyrazol-1-yl-benzaldehyde (50 mg, 22%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][C:17]3=[N:18][S:19][N:20]=[C:16]3[CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2ccc3nsnc3c2)c1
Agent: [Ni]
Solvent: CO
Product: Nc1cccc(S(=O)(=O)Nc2ccc3nsnc3c2)c1

Procedure:
A solution of 1 g of 3-nitro-N-(2,1,3-benzothiadiazol-5-yl)-1-benzenesulfonamide in 25 ml of methanol is hydrogenated to completion on 1 g of Raney Nickel at normal pressure and 20°. The solution is filtered, evaporated and 3-amino-N-(2,1,3-benzothiadiazol-5-yl)-1-benzenesulfonamide is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[CH:6][N:5]=[C:4]2[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:3]=12.Cl.[NH2:24]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:21]([N:18]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:17][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:3]=2[CH:20]=[N:19]1)[CH3:22]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3OC)cnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c3noc(-c4ccccc4OC)c3cnc21

Procedure:
Five grams of 4-chloro-1-ethyl-5-(2-methoxybenzoyl)-1H-pyrazolo[3,4-b]pyridine was refluxed for 2 hours in 500 ml of acetic acid containing 15 g of hydroxylamine hydrochloride and 1 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed well with water, dried, evaporated and chromatographed over 230-400 mesh silica gel. The appropriate fractions were combined and evaporated to give 2.95 g of product, mp 126°-127° C. The melting point was unchanged after recrystallization from ethyl acetate/pentane.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:23]([N+:40]([O-])=O)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1>O1CCOCC1.O>[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]3[C:23]([NH:40][C:1](=[O:2])[N:26]3[CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
1,1′-Carbonyldiimidazole (689 mg, 4.25 mmol) was added to a solution of the above amine (244 mg, 0.425 mmol) in 1,4-dioxane (25 mL) and the mixture was refluxed under nitrogen for 4.5 hrs. Additional 1,1′-carbonyldiimidazole (689 mg, 4.25 mmol) was added, and the mixture refluxed for additional 17.5 hrs. The mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, washed with H2O, and dried. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate (176 mg, 69%): mp (CH2Cl2/i-Pr2O) 269-272° C.; 1H NMR (CDCl3) δ 10.94 (br s, 1H), 7.73 (dd, J=8.3, 0.3 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.36 (t, JHF=53.6 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.49 (tt, J=12.1, 4.1 Hz, 1H), 4.38 (br s, 2H), 4.06 (s, 3H), 3.89 (dd, J=5.6, 3.6 Hz, 4H), 3.82 (dd, J=5.6, 3.7 Hz, 4H), 2.85 (m, 2H), 2.56 (m, 2H), 1.83 (d, J=11.0 Hz, 2H), 1.48 (s, 9H); Anal. Calcd. for C28H34F2N8O5.0.1 i-Pr2O: C, 56.2; H, 5.8; N, 18.3. Found: C, 56.2; H, 5.90; N, 18.0%.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]COC(C)=O.CCCCCCC>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:20])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)c1ccc(Br)c2ccccc12
Yield: 91 %

Procedure:
To a solution of 4-bromo naphthoic acid (4.0 g, 15.9 mmol) in MeOH (75 mL) was added sulfuric acid (0.5 mL) and the reaction was heated to reflux for 18 hours. TLC 50:50 EtOAc:heptane showed consumption of starting material. The reaction was cooled and concentrated under vacuum to remove MeOH. The residue was diluted with EtOAc (150 mL), washed with water (100 mL), diluted with saturated NaHCO3 (100 mL), dried over Na2SO4 and concentrated under vacuum to afford a solid (3.85 g, 91%). 1H NMR (CDCl3) δ ppm: 8.96 (1H), 8.36 (1H), 8.02 (1H), 7.85 (1H), 7.70-7.66 (2H), 4.03 (3H).
Reaction SMILES: [C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].CCN(CC)CC.[C:22](OC(=O)C)(=[O:24])[CH3:23]>[Pd].CCOC(C)=O>[C:1]([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:22](=[O:24])[CH3:23])=[C:7]2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)n1ccc2c(C#N)ccnc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccnc2c1CCN2C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.691 g, example 15, step D), 10% Pd/C (0.702 g), 5 mL of Et3N, and 20 mL of EtOAc was added acetic anhydride (1.0 mL). The mixture was stirred at RT under balloon pressure of H2 for overnight. Solid was removed by filtration through a pad of Celite® and the filtrate was concentrated to yield a white residue, which was purified by chromatography through silica gel (150 g, 1 to 5% MeOH/CHCl3 with 1% NH4OH, stepwise gradient) to afford N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide (0.50 g) as white solid.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:44])([CH3:43])[CH2:6][NH:7][C:8](=[O:42])[C@H:9]([N:17]([C:19](=[O:41])[C@H:20]([N:32](C(OC(C)(C)C)=O)[CH3:33])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:44])([CH3:43])[CH2:6][NH:7][C:8](=[O:42])[C@H:9]([N:17]([CH3:18])[C:19](=[O:41])[C@H:20]([NH:32][CH3:33])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
2-((2R)-2-(N-((2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate (511 mg, 0.85 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Trifluoroacetic acid (2 ml) was added, and the solution was stirred for 15 min at 0° C. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (50 ml), and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatogrpahy on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 160 mg of 1,1dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenyl-propionylamino)ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=[C:4]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)CNc1nc(Cl)cc(Cl)n1
Product: CC(C)(C)CNc1nc(Cl)cc(N2CCCC2)n1
Yield: 96.7 %

Procedure:
4,6-Dichloro-2-(2,2-dimethylpropylamino)pyrimidine is reacted with pyrrolidine as described in Example 7 to give the title compound in a yield of 96.7%, m.p.:147°-150° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([CH:17]=[O:18])=[C:15]([OH:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35].O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([CH:17]=[O:18])=[C:15]([O:22][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(O)c1C=O
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(OS(=O)(=O)C(F)(F)F)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 4-(3-benzyloxy-phenoxy)-2-hydroxy-6-methyl-benzaldehyde (2.5 g, 6.5 mmol) and Et3N (2.72 mL, 19.5 mmol) in DCM (60 mL) at −78° C. was added Tf2O (1.64 mL, 9.76 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Water was added and the solution extracted with DCM (2×25 mL). The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hexane:EtOAc 80:20) to give trifluoro-methanesulfonic acid 5-(3-benzyloxy-phenoxy)-2-formyl-3-methyl-phenyl ester (2.8 g, 93%). 1H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 7.43-7.32 (m, 6H), 6.90 (dd, J=2.0, 8.4 Hz, 1H), 6.79-6.67 (m, 4H), 5.06 (s, 2H), 2.61 (s, 3H). MS (ESI) m/z=467 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19].C(=O)([O-])[O-].[K+].[K+]>CO.Cl[Pd]Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(F)c(F)c2)c1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A mixture of methyl 2-chloroisonicotinate (5 g, 29.14 mmol), 3,4-difluorophenylboronic acid (5.06 g, 32.05 mmol), potassium carbonate (2.416 g, 17.48 mmol) and PdCl2 (dppf) (1.066 g, 1.46 mmol) was stirred in methanol (30 mL) and heated in a single-node microwave reactor at 100° C. for 30 min. The solvent was evaporated in vacuo. DCM (400 mL) and 8% NaHCO3 (aq) (400 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (400 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on three Biotage® KP-SIL 100 g columns. A gradient from 5% EtOAc in heptane over 2 CV followed by 5% to 20% of EtOAc in heptane over 9 CV was used as mobile phase. Methyl 2-(3,4-difluorophenyl)isonicotinate (5.82 g, 80%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 7.23-7.33 (m, 1H), 7.76-7.84 (m, 2H), 7.90-8.00 (m, 1H), 8.21-8.27 (m, 1H), 8.82 (dd, 1H).
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C@H:12]3[NH:15][CH2:16][CH2:17][C@:6]4([C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)[C:5]=2[CH:4]=[C:3]([C:18](=[O:20])[CH3:19])[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27]1([CH2:31]Cl)[CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[C:18]([C:3]1[CH:2]=[CH:1][C:14]2[CH2:13][C@H:12]3[N:15]([CH2:31][CH:27]4[CH2:30][CH2:29][CH2:28]4)[CH2:16][CH2:17][C@@:6]4([C:5]=2[CH:4]=1)[C@H:11]3[CH2:10][CH2:9][CH2:8][CH2:7]4)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: ClCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(CC1CCC1)CC3
Temperature: 25 °C
Yield: 76 %

Procedure:
To a mixture of 1.7 g, (-)-1-(morphinan-3-yl)ethanone, 1.5 g of potassium carbonate and 40 ml dimethylformamide, was added 1.2 g of cyclobutylmethyl chloride. After the mixture had been heated at 100°-110° for 16 hours it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 120 ml of ether. The ether solution was washed with water (2×20 ml), dried over magnesium sulfate and removal of the solvent gave 1.6 g (76%) of crude (-)-3-acetyl-N-cyclobutylmethylmorphinan. For analysis, a sample of this compound was distilled, bp 200°-210° (0.05 mm), [α]25D-80.64° (c 1.03, MeOH).
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:52]/[O:53][CH3:54])/[C:27]([NH:29][C@@H:30]2[C:50](=[O:51])[N:32]3[C:33]([C:47]([OH:49])=[O:48])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH:44][CH:45]=[O:46])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCCC1.CCOCC>C(O)=O>[CH:47]([OH:49])=[O:48].[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:52]/[O:53][CH3:54])/[C:27]([NH:29][C@@H:30]2[C:50](=[O:51])[N:32]3[C:33]([C:47]([OH:49])=[O:48])=[C:34]([CH2:37][S:38][C:39]4[N:43]([NH:44][CH:45]=[O:46])[N:42]=[N:41][N:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=CO
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3NC=O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
2.60 g of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid were dissolved in 10 ml of 80% formic acid, and the solution was stirred at room temperature for one hour. 40 ml of water were added to the reaction solution, and insoluble materials were removed by filtration. The filtrate was condensed at a temperature below 40° C. under reduced pressure. One ml of tetrahydrofuran and 2 ml of ether were added to the residue, and the resultant precipitates were collected by filtration. 0.72 g of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid formate thus obtained as pale yellow powder were suspended in 8 ml of ethanol, and the suspension was stirred at 50° C. for 30 minutes. After cooling, the precipitates were collected by filtration. 0.53 g of 7β -[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-formamido-1H-tetrazol-5-yl)thiomethyl]-3cephem-4-carboxylic acid was thereby obtained as pale yellow powder.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@H:11]1[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:14](=[O:25])[CH2:13][N:12]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:29]([O:28][C:26]([N:12]1[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:16][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH3:24])[C:14](=[O:25])[CH2:13]1)=[O:27])([CH3:31])([CH3:30])[CH3:32]
Reactant: Cc1cccc(N2C[C@H](CCOCc3ccccc3)N(C(=O)OC(C)(C)C)CC2=O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(N2C[C@H](CCO)N(C(=O)OC(C)(C)C)CC2=O)c1C

Procedure:
The product from Step D was dissolved in methanol (40 mL) and 10% Pd/C was added (0.160 g). The reaction was shaken under 60 psi hydrogen overnight. The catalyst was removed by filtration, and the solvent evaporated to give the title compound.
Reaction SMILES: [C:1]([O:20][C@:21]1([C@:42]2([CH3:43])[C@H:28]([C@H:29]3[C:39](=[CH:40][CH2:41]2)[C@:37]2([CH3:38])[C:32](=[CH:33][C:34](=[O:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[C:22](=[O:25])[CH2:23][OH:24])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(OC(=O)CCC)(=O)CCC.[Cl-].C([N+](CCCC)(CCCC)C)CCC>[C:1]([O:20][C@:21]1([C@:42]2([CH3:43])[C@H:28]([C@H:29]3[C:39](=[CH:40][CH2:41]2)[C@:37]2([CH3:38])[C:32](=[CH:33][C:34](=[O:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[C:22](=[O:25])[CH2:23][O:24][C:1](=[O:19])[CH2:2][CH2:3][CH3:4])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Agent: CCCC(=O)OC(=O)CCC
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Product: CCCCCCCCCCCCCCCCCC(=O)O[C@]1(C(=O)COC(=O)CCC)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 159.2 %

Procedure:
the residue (6.2 g) of 17α-octadecanoyloxy-21-hydroxy-pregna-4,9(11)-diene-3,20-dione was dissolved in 4 ml butyric anhydride in the presence of 0.5 g of tributylmethylammonium chloride. The mixture was stirred at room temperature for 2 hours, then poured in ice and the resulting product was separated from water by extraction. The extract was washed to neutrality with water and concentrated under vacuum, the residue was crystallized from methanol to obtain 5.5 g (8.05 mM) of 17α-octadecanoyloxy-21-butanoyloxy-pregna-4,9(11)-diene-3,20-dione. This compound was used for the preparation of a pharmaceutical formulation in the form of a cream suitable for cutaneous administration.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[N:14]1([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:22]3[CH2:23][CH2:24][CH:19]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:20][CH2:21]3)=[CH:7][CH:6]=2)[CH:9]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Clc1ccc(-c2cccnc2)nn1
Product: c1cncc(-c2ccc(N3CCC(N4CCCC4)CC3)nn2)c1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(pyridin-3-yl)-pyridazine and 4-(1-pyrrolidinyl)piperidine. 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.61 (dd, 1H), 8.39 (dt, 1H), 8.01 (d, 1H), 7.51 (m, 1H), 7.40 (d, 1H), 4.34 (dt, 2H), 3.09 (m, 2H), 2.56 (s, 4H), 2.33 (m, 1H), 1.95 (m, 2H), 1.69 (m, 4H), 1.44 (m, 2H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH2:17])[CH:2]=1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:23]=1)=[O:21].CN(C)C=O.[ClH:38].C(O)C>CO.C(Cl)(Cl)Cl>[ClH:38].[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:19][CH:20]([C:22]2[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)[OH:21])[CH:2]=1
Reactant: NCCOc1ccc2c(c1)oc1ccccc12
Reactant: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cccc(C(O)CNCCOc2ccc3c(c2)oc2ccccc23)c1

Procedure:
Following the procedures of Example 7, the above-identified compound was synthesized from 224.6 mg of Intermediate 5 and 170 mg of Intermediate 14, with the proviso that the following modification was incorporated. Thus, addition of dimethylformamide was omitted and the purification of the crude product was effected twice by a chromatography (methanol/chloroform of 1/20-1/10). The free amine compound (98.4 mg) was converted into its hydrochloride salt (the above-identified compound) with 1.1 eq. of 0.1 N hydrogenchloride/ethanol, whereupon the solvent was evaporated off under a reduced pressure. To the resulting residue was added diethyl ether and the deposited precipitate was washed diethyl ether and dried under a reduced pressure at 46° C., whereby the above-identified compound was obtained as a powdery product. Rf=0.27 (methanol/chloroform of 1/10).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:60]([C@H:9]1[CH2:10][CH2:11][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH2:8]1)=[N+:61]=[N-:62]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (±)-cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (1.5 g, 6.93 mmol) (from Example 9a supra) and triphenylphosphine (1.99 g, 7.63 mmol) (Aldrich) in anhydrous tetrahydrofuran (60 mL) was added dropwise diethyl azodicarboxylate (1.2 mL, 1.32 g, 7.63 mmol) (Aldrich) at 0° C. Then after 2 minutes this was followed by the addition of diphenylphosphoryl azide (1.6 mL, 2.09 g, 7.63 mmol) (Aldrich) and the resulting solution was allowed to slowly warm up to room temperature. After stirring overnight the reaction mixture was partitioned between diethyl ether and water. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated and the residue was purified by chromatography on a silica gel column using a 0–20% diethyl ether in hexanes gradient to give (±)-trans-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane as a colorless liquid. (Yield 1.2 g, 72%).