Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH:10](N)[CH2:11]C1C=CC=C(O)C=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1cccc(O)c1)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 8.72 g (0.032 mol) of rac.-2-amino-3-(3-hydroxyphenyl)propanoic acid benzyl ester in 400 mL of ice cold dichloromethane was treated dropwise with 1.9 mL (0.020 mol) of acetic anhydride. Upon completion of the addition, a solution of 3.70 g of sodium carbonate in 30 mL of water was added simultaneously with an additional 1.9 mL of acetic anhydride. After 1 hour, the layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with dichloromethane and the combined extracts were washed with brine and dried over magnesium sulfate. Filtration and concentration afforded a residue which was chromatographed on a Waters Prep 500 liquid chromatograph fitted with two silica gel cartridges, eluting with 20% ethyl acetate-hexane to give 8.49 g (84%) of rac.-2-acetamido-3-hydroxyphenyl)propanoic acid benzyl ester as a thick oil.
Reaction SMILES: [CH2:1]([Br:4])[CH2:2][OH:3].N1C=CN=C1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C1C=CC=CC=1>CN(C)C=O>[Si:10]([O:3][CH2:2][CH2:1][Br:4])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: OCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCBr
Yield: 94 %

Procedure:
2 g of ethylene bromohydrin and 2.4 g of imidazole were dissolved in 40 ml of N,N-dimethylformamide, to which 2.65 g of t-butyldimethylsilyl chloride were added at room temperature. After completion of the reaction, benzene was added, followed by washing with water and a sodium hydrogencarbonate aqueous solution and drying with anhydrous magnesium sulfate. This was filtered and the solvent was distilled off, thereby obtaining 3.60 g of the captioned compound (yield 94%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Br:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:20][C@H:21]([C:23]([OH:25])=[O:24])[CH3:22].C[O-].[Na+]>CO>[Br:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:20][C@@H:21]([CH3:22])[C:23]([OH:25])=[O:24])=[O:7])[N:9]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(Br)c2ccccc2c1O)C(=O)O
Temperature: 160 °C

Procedure:
400 mg of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 890 mg of (L)-Alanine was suspended in a 20 ml solution of 0.5 M of sodium methoxide in methanol. The mixture was heated to 160° C. for 12 min using a CEM Discover microwave reactor. The resultant solution was concentrated to ca. 10 ml, and 0.5 N HCl was added until a pH 3 was reached. The solution was extracted three times with ethyl acetate, and the organic fractions dried over sodium sulfate and concentrated to a tan solid; MS (−): m/z 337.14 (M−1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.CN(C)C=O.[H-].[Na+].[Cl-].[NH4+].[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH:2]3[CH2:3][CH2:4][CH:5]([CH2:36][C:35]([O:38][CH2:39][CH3:40])=[O:37])[CH2:6][CH2:10]3)[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCc1nc(SC2CCC(CC(=O)OCC)CC2)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.25 h

Procedure:
1 g of the product obtained in Stage 6 above is introduced into dimethylformamide, 146 mg of a suspension of sodium hydride at 60% in oil is added and the reaction medium is left under agitation for 15 minutes at ambient temperature. Then 1.08 mg of the product obtained in Stage 2 of Preparation 1 is added, and the reaction medium is left under agitation for 24 hours at ambient temperature, followed by hydrolysis with a saturated solution of ammonium chloride and extraction with ethyl acetate. In this way, after chromatography, 1.1 g of expected product (amorphous solid) is obtained.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:50][CH:51]=[C:45]([CH:46]=[CH:47]2)[O:44][CH2:43][CH:42]=[CH:41][CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:54])[CH3:53])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-:56].[Na+].OO>C1COCC1>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:30][C:31]([NH:33][C@@H:34]1[CH2:49][C:48]2=[CH:47][CH:46]=[C:45]([CH:51]=[CH:50]2)[O:44][CH2:43][CH2:42][CH:41]([OH:56])[CH2:40][O:39][CH2:38][C@H:37]([CH:52]([CH3:53])[CH3:54])[NH:36][C:35]1=[O:55])=[O:32])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)[C@H]1COCC=CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COCC(O)CCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 ml (773 μmol) (0.5M in THF) of 9-borabicyclo[3.3.1]nonane were added to a solution of 50 mg (77 μmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)ureido]hexanoate (8-1B) in 1.5 ml of THF, and the mixture was stirred at RT overnight. Addition of 250 μl (1.49 mmol) of 6N sodium hydroxide solution and 207 μl (1.83 mmol) of hydrogen peroxide was followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: CCCC(=O)Nc1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: CCCC(=O)Nc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2ccc(OC)c(OC)c2)c2ccccc21
Yield: 36 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (800 mg, 2.44 mmol) prepared in Reference Example 1 and N-(1,2,3,4-tetrahydro-6-quinolinyl)butanamide (1.33 g, 6.1 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (463 mg, yield: 36%) as a colorless oil. (cis:trans=1:1.3)
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[C:22](O)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[CH2:28]([N:30](CC)CC)C.C(Cl)(=O)C(C)(C)C.CN>ClC.O>[CH3:28][NH:30][C:22](=[O:23])[CH:21]([O:25][CH2:26][CH3:27])[CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2][CH2:3]2)=[CH:15][CH:16]=1
Reactant: CCN(CC)CC
Reactant: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CCl
Agent: CN
Solvent: O
Product: CCOC(Cc1ccc(OCCN2CCSc3ccccc32)cc1)C(=O)NC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid (0.3 g, 0.78 mmol) obtained in example 29 and triethylamine (0.162 g, 1.6 mmol) in dry chloromethane (10 mL) was added pivaloyl chloride (0.10 g, 0.86 mmol) and stirring was continued for 30 min at 0° C. To the above reaction mixture, methyl amine (40% solution) (0.124 mL) was added at 25° C. and stirring was continued for 1 h at 25° C. Water (20 mL) was added and extracted with ethyl acetate (2×20 mL). The combined organic extract was washed with water (10 mL), brine (10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using a mixture of ethyl acetate and pet. ether (1:1) to afford the title compound as a colorless solid. mp : 80-82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:28][CH3:29])=[O:27])[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][C:3]=1[N+:30]([O-])=O>C(O)(=O)C.[Fe]>[NH2:30][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]([NH:28][CH3:29])=[O:27])[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c([N+](=O)[O-])c2)n3C)ccn1
Agent: [Fe]
Solvent: CC(=O)O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(Nc2ccc(Cl)c(N)c2)n3C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (4-{2-[(4-chloro-3-nitrophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide in acetic acid was added Fe dust (3 eq) and stirred at ambient temperature for 16 h. The mixture was then filtered and basified with saturated sodium bicarbonate and partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated and passed through a plug of silica to yield (4-{2-[(3-amino-4-chlorophenyl)amino]-1-methylbenzimidazol-5-yloxy}-(2-pyridyl))-N-methylcarboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C.O>C(OCC)(=O)C.CCCCCC.[Fe]>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Nc3ccccc3)ncn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: Nc1ccc(Oc2cc(Nc3ccccc3)ncn2)cc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 84.2 %

Procedure:
After suspending N-(6-(4-nitrophenoxy)pyrimidin-4-yl)phenylamine (508 mg, 1.65 mmol), iron powder (461 mg, 8.25 mmol) and ammonium chloride (882 mg, 16.5 mmol) in an ethanol (16 ml)-water (4 ml) mixed solvent, the suspension was heated and stirred at 80° C. for 20 minutes. Upon completion of the reaction, the reaction mixture was filtered with celite and washed in ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (387 mg, 1.39 mmol, 84%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9](NC(=O)C)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.C1C[O:21]CC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:21])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(=O)NC(=Cc1ccc(Cl)cc1)C(=O)O
Agent: Cl
Product: O=C(O)C(=O)Cc1ccc(Cl)cc1
Yield: 77.3 %

Procedure:
4.55 g β-(4-chlorophenyl)-α-acetamidoacrylic acid, 91 mL of 1 mol·L−1 hydrochloric acid solution and 45 mL THF were added to a flask, and the mixture was heated for reflux for 10 h. After decolorization using active carbon and filtration, the filtrate was placed for crystallization, and an off-white crystalline powder was obtained in a yield of 77.3% by sucking filtration, washing and drying.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][OH:15].C[O-].[Na+].Cl>O>[CH3:14][O:15][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.83 h

Procedure:
856 g of 2-nitrobenzenesulfonyl chloride and 7 L of methanol are placed in a reaction container having a stirrer, a thermometer, and a nitrogen introducing pipe attached thereto, and a mixed solution of 745 g of 28% sodium methylate and 600 mL of methanol is dropped at a temperature of not more than 10° C. over 45 minutes. Subsequently, the solution is stirred for 50 minutes while the temperature is kept at 10° C. 1.6 kg of 0.1 mol/L hydrochloric acid is added to the reaction mixture to make the reaction solution acidic, and 3 L of water is further added to precipitate crystals. The crystals are filtered out, and washed with 2 L of water. Then, the crystals are dried under reduced pressure at 30° C. for 10 hours to obtain 702 g of 2-nitrobenzenesulfonic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][Br:18])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(Br)c(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(C)c(Br)c(CBr)n1
Temperature: 25 °C
Yield: 16.1 %

Procedure:
A mixture of 3-bromo-2,4,6-trimethylpyridine (15.6 g), NBS (13.9 g) and benzoyl peroxide (567 mg) was heated under reflux in a carbon tetrachloride solvent (300 mL) for two hours. The reaction mixture was cooled to room temperature and then filtered, and the filtration residue was washed with carbon tetrachloride. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 10%) to give the title compound (3.51 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=1)=[O:7].[NH2:22][CH:23]1[C:43](=[O:44])[N:25]2[C:26]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])=[CH:27][CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C>C(Cl)Cl.CN(C)C=O>[CH:6]([NH:8][C:9]1[N:14]=[C:13]([C:15](=[N:19][O:20][CH3:21])[C:16]([NH:22][CH:23]2[C:43](=[O:44])[N:25]3[C:26]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=4)=[O:31])=[CH:27][CH2:28][S:29][C@H:24]23)=[O:18])[CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: CON=C(C(=O)O)c1cccc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1cccc(NC=O)n1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A mixture of N,N-dimethylformamide (3 ml.) and phosphoryl chloride (460 mg.) was stirred at 37° to 40° C. for 30 minutes. To the solution were added methylene chloride (3 ml.) and 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (669 mg.) at -20° to -25° C. and stirred at -10° to -15° C. for one hour. A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (670 mg.) and trimethylsilylacetamide (2 g.) in methylene chloride (200 ml.) was added to the above solution at -10° to -15° C., and then stirred at the same temperature for 30 minutes. After the solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue. The ethyl acetate layer was separated, washed with an aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give 4-nitrobenzyl 7-[2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (730 mg.), mp. 195° to 200° C. (dec.).
Reaction SMILES: [C:1]([N:4]([CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][S:49](=[O:53])(=[O:52])[CH2:48][CH2:47]1)[C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([N:4]([CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][S:49](=[O:52])(=[O:53])[CH2:48][CH2:47]1)[C@:5]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:37])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:25])([CH3:26])[C:14]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(N(CCN3CCS(=O)(=O)CC3)C(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(N(CCN3CCS(=O)(=O)CC3)C(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 33.3 %

Procedure:
To a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.054 mmol) in 1,4-dioxane (1 mL) was added NaOH (1N) (0.27 mL, 0.27 mmol). The mixture was stirred at rt for 16.5 h then was purified directly by prep HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to give 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(acetyl(2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (14 mg, 0.018 mmol, 33%) as a white solid. LCMS: m/e 733.5 (M+H)+, 1.96 min (method 2). 1H NMR (400 MHz, Chloroform-d) δ=7.99 (d, J=7.8 Hz, 2H), 7.22 (d, J=7.8 Hz, 2H), 5.23 (d, J=4.0 Hz, 1H), 4.85 (br. s., 1H), 4.68 (br. s., 1H), 3.65 (br. s., 2H), 3.40-3.04 (m, 8H), 2.97-2.46 (m, 4H), 1.74 (s, 3H), 1.27 (s, 3H), 1.03-0.98 (m, 9H), 0.95 (br. s., 3H), 0.89 (br. s., 3H), 2.20-0.71 (m, 21H).
Reaction SMILES: [C:1]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[C:1]([C:6](=[CH:12][NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][OH:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1CO
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccccc1CO)C(=O)OCC

Procedure:
A mixture of ethyl 2-butyryl-3-ethoxyacrylate (23.5 g, 0.11 mol) and 2-aminobenzyl alcohol (12.3 g, 0.1 mol) was heated to 100° for 10 minutes, then diluted with petroleum ether. On cooling, ethyl 2-butyryl-3-(2-(hydroxymethyl)phenylamino)acrylate (24.9 g, 85%) crystallized as a mixture of E/Z isomers, and was filtered off and washed with petroleum ether.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:17]=[CH:16][C:15](=O)[C:14]([O:19]C)=[CH:13][CH:12]=1)([OH:3])=[O:2].[NH3:21]>CO>[NH2:21][C:15]1[C:14](=[O:19])[CH:13]=[CH:12][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:1]([OH:3])=[O:2])=[CH:17][CH:16]=1
Reactant: N
Reactant: COc1ccc(Sc2ccccc2C(=O)O)ccc1=O
Solvent: CO
Product: Nc1ccc(Sc2ccccc2C(=O)O)ccc1=O
Temperature: 80 °C

Procedure:
A solution of 5-[(2-carboxyphenyl)thio]-2-methoxy-2,4,6-cycloheptatrien-1-one (1.0 g, prepared from 5-chloro-2-methoxy-2,4,6-cycloheptatrien-1-one and 2-mercaptobenzoic acid) in methanol (30 ml) at -25° C. is saturated with ammonia gas. The solution is heated in a pressure bottle at 80° C. for 8 hours and cooled to -70° C. The bottle is opened and the solvent is evaporated to give 2-amino-5-[(2-carboxyphenyl)thio]-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]([C:9]1[C:10]([Cl:20])=[N:11][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=1)[CH2:7][CH3:8])=[O:5].[I-:21].[Na+]>CC(C)=O>[Cl:20][C:10]1[C:9]([N:6]([CH2:7][CH3:8])[C:4](=[O:5])[CH2:3][CH2:2][I:21])=[CH:13][N:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]=1
Reactant: [I-]
Reactant: CCN(C(=O)CCCl)c1cn(-c2cccnc2)nc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: CCN(C(=O)CCI)c1cn(-c2cccnc2)nc1Cl
Yield: 56.1 %

Procedure:
To 3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropan amide (0.500 g, 1.60 mmol) in acetone (8 mL) was added sodium iodide (0.359 g, 2.40 mmol). The reaction was heated to reflux for 24 hours. The reaction product was filtered and concentrated to provide N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-iodopropanamide (0.363 g, 0.898 mmol), which was used immediately without further purification. To 3-(but-3-en-1-yl)pyrrolidin-2-one (0.125 g, 0.898 mmol) dissolved in DMF (4.49 ml) was added sodium hydride (60% in mineral oil, 0.0360 g, 0.898 mmol). The reaction stirred for 45 minutes. Then, N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-iodopropanamide (0.363 g, 0.898 mmol) was added as a solution in DMF (2 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction product was poured into water, extracted with diethyl ether, and washed with brine. The organics were dried and concentrated to give an oil that was purified by flash column chromatography using 0-60% acetone/hexanes as eluent providing the title compound as a clear, colorless oil. (0.257 g, 69%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].[CH2:13](Br)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([CH2:14][CH2:13][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reaction time: 20 h
Yield: 91.3 %

Procedure:
Ethyl acetoacetate (53.8 g., 0.29 mole) was dissolved in 110 ml. of anhydrous ethanol. Sodium methoxide (17.3 g., 0.36 mole) was added portionwise to the stirred solution, allowing the temperature to rise to 40°-50°. The mixture was then heated to reflux (80°-82°) and phenethyl bromide (53.8 g., 0.32 mole) added dropwise over 1 hour. Reflux was continued for 20 hours. The reaction mixture was cooled to 30°-35° and filtered over diatomaceous earth with ethanol wash. The combined filtrate and wash were concentrated in vacuo to a pot temperature of 50°, cooled to 25° , diluted with 150 ml. of hexane and 40 ml. of water, acidified to pH 6.5-7.0 with 6N HCl. The hexane layer was separated and washed with 25 ml. of fresh water. The aqueous layers were combined and back-washed with 40 ml. of fresh hexane. The hexane layers were combined, washed with 60 ml. of water, dried over 15 g. MgSO4, filtered and evaporated to yield title product as an oil (62 g., 91%).