Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]1([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:7]1([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=C(C)C(=O)Cl
Reactant: O=S(=O)(Nc1ccccc1)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reaction time: 2 h

Procedure:
A solution of 3.31 g (0.03169 mol) of methacryloyl chloride in 60 ml of methylene chloride was added to a solution of 7.9 (0.03169 mol) of N-phenyl-4-hydroxybenzenesulfonamide, 7.06 g (0.0697 mol) of triethylamine and 60 ml of methylene chloride at -5° C. over a period of 15 minutes. The reaction mixture was stirred at reduced temperature for another 2 hours, after which the solution was washed once with 2 percent hydrochloric acid and twice with water. The solution was dried over sodium sulfate, and concentrated in vacuo with warm bath-heating. The resultant oil crystallized on cooling. This solid was recrystallized from ethanol:water (3:2), collected and dried in vacuo. The yield of N-phenyl-4-methacryloyloxybenzenesulfonamide was 7.05 g; m.p.=101° to 102° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: C1=CNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.2 g (35 mmol) of 4-formylbenzoic acid was dissolved in 100 ml of dichloromethane. 2.0 g (29 mmol) of pyrroline, 5.9 g (35 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 6.1 ml (43 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 5 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19](Cl)(=[O:21])=[O:20]>C1(C)C=CC=CC=1>[C:11]1([CH3:23])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:20])=[O:21]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(S(=O)(=O)Oc2ccccc2)c(C)c1
Reaction time: 1 h

Procedure:
9.4 g of phenol is added to a mixture containing 9.17 g of 48% NaOH, 50 ml of water and 50 ml of toluene. To the resulting mixture is added 22.9 g of mesitylenesulfonyl chloride, and reaction is carried out at 60° to 65° C. for 1 hour. After separating the aqueous layer, toluene is removed from the toluene layer by distillation. The resulting desired compound is purified with methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CCCCCC.CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Br:25])=[CH:27][CH:28]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1ccc(Br)cc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 86.4 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.6 g (2.4 mmol) of p-bromobenzyl bromide provided 0.896 g (86%) of the desired product as a white solid after trituration with hexane/ether. Electrospray Mass Spec 518.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=O)[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=O)([O-:3])=[O:2].[CH:16]([C:19]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:20]=1[NH2:21])([CH3:18])[CH3:17]>C(OCC)(=O)C>[CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:19]([CH:16]([CH3:18])[CH3:17])[C:20]=1[N:21]1[C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[C:13]1=[O:15])([CH3:28])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 50 %

Procedure:
0.386 g of anhydride obtained by dehydrating 4-nitrophthalic acid (including 20% of 3-nitrophthalic acid) at a temperature of about 190° C., and 0.354 g of 2,6-diisopropylaniline were mixed, and reacted at a temperature of 180° C. for 4 hours. After the reaction was finished, the reaction mixture was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and subjected to filtration. The filtrate was concentrated and dried and solidified. Then, it was recrystallized by using a mixture of hexane and ethanol, to obtain 0.352 g (yield 50%) of the specified compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([CH3:38])=[N:35]2)=[CH:30][CH:29]=1.Cl[Si](C)(C)C.[Br:44]Br>O1CCCC1.C(OCC)(=O)C>[Br:44][CH2:38][C:34]1[CH:33]=[CH:32][C:31]2[C:36](=[CH:37][C:28]([Cl:27])=[CH:29][CH:30]=2)[N:35]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: BrBr
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Clc1ccc2ccc(CBr)nc2c1
Temperature: -10 °C
Yield: 62.4 %

Procedure:
A solution of diisopropylamine (3.6 ml, 24.86 mmol) in dry tetrahydrofuran (25.0 ml) at -20° C. under nitrogen was treated with a 2.5M solution of n-butyllithium in hexane (10.0 ml, 24.86 mmol). This lithium diisopropylamide solution was stirred below -10° C. for 30 min and 7-chloroquinaldine (4.0 g, 22.6 mmol) was added in portions. The resulting dark red solution was stirred at -10° C., increasing to 0° C. for 1 h, cooled to -30° C. and treated with chlorotrimethylsilane (4.4 ml, 33.92 mol) dropwise to return a golden yellow solution. After stirring below -20° C. for 2 h a solution of bromine (1.2 ml, 22.6 mmol) in tetrahydrofuran (25.0 ml) was added dropwise over a 30 min period maintaining an addition temperature of below -20° C. at all times. The mixture was stirred below -20° C. for 1 h, quenched with water (300 ml), extracted into ethyl acetate (3×100 ml), the combined organic extracts were washed with saturated ammonium chloride solution (2×200 ml), dried (Na2SO4) and evaporation of the solvent afforded a brown oily solid. Column chromatography (ethyl acetate--light petroleum (b.p. 40°-60° C.), 1:4) gave the title compound (3.62 g, 76%) as a yellow solid. Crystallised from light petroleum (b.p. 40°-60° C.) as white crystals, m.p. 108°-112° C. (lit. m.p. 112° C. (dec.)). νmax (nujol)/cm-1 1593.5, 1559.5. δH (270 MHz) 4.68 (2H, s, CH2Br); 7.50 (1H, dd, 6-H, Jo =8.6, Jm =2.0 Hz); 7.56 (1H, d, 3-H, Jo =8.3 Hz); 7.74 (1H, d, 5-H, Jo =8.9 Hz); 8.06 (1H, d, 8-H, Jm =2.0 Hz); 8.14 (1H, d, 4-H, Jo =8.6 Hz). δC (67.8 MHz) 34.0 (CH2Br), 121.4 (3-C), 125.6 (4a-C), 135.9 (8a-C), 137.1 (4-C), 158.0 (2-C). Remaining signals fall in the narrow range 128.0-128.3 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([O:29][CH3:30])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C>C(O)C.[Fe]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([O:29][CH3:30])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
A mixture of 1′-(3-Methoxy-4-nitro-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (2.0 g, 4.77 mmol), iron powder (1.33 g, 23.85 mmol), 1N hydrogen chloride (9.54 mL, 9.54 mmol) in ethanol (50 mL) is stirred at 80° C. for 3 h. After cooling to room temperature, 2N hydrogen chloride (5 mL) and ethyl acetate are added and then the mixture is filtrated. After concentration in vacuo, the mixture is extracted with AcOEt, washed with brine, dried over sodium sulfate and evaporated to give 1′-(4-Amino-3-methoxy-phenyl)-[4,4′]bipiperidinyl-1-carboxylic acid tert-butyl ester (1.77 g, 95% yield) as pale purple solids.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH:19]=O)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][NH:32][CH:29]2[CH2:31][CH2:30]2)[CH:13]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CCc1ccc(Cl)c(CNC2CC2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-ethyl-carbamic acid tert-butyl ester (80.1 mg, 0.257 mmol), Et3N (0.054 mL, 0.386 mmol) and cyclopropylamine (0.027 mL, 0.386 mmol) in MeOH (0.86 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (24.2 mg, 0.642 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (40 mg, 44%). LC-MS: tR=0.81 min; ES+: 353.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([OH:23])=O)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[N:12]=[C:11]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2ccc(F)c(Br)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Br)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 84A in analogy to the synthesis of the compound of Example 1. 26 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: O[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@H:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[ClH:29].O=S(Cl)[Cl:32]>C(Cl)Cl>[ClH:32].[Cl:29][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@H:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(C(O)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(Cl)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1

Procedure:
) (5S)-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.027 mol) was suspended in CH2Cl2 (250 ml). HCl, gas (excess) was allowed to bubble through the suspension for 2 minutes. SOCl2 (0.097 mol) was added dropwise and the reaction mixture was stirred and refluxed for 4 hours. The solvent was evaporated under reduced pressure. Toluene was added and azeotroped on the rotary evaporator (2×). The residue was stirred in toluene. The precipitate was filtered off, washed with toluene and dried, yielding 11.5 g (100% crude yield) of (5S)-N-[4-(chlorophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (compound 500).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl-].[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18][NH3+:19])=[CH:15][CH:14]=1>S(Cl)(Cl)=O>[C:1]([NH:19][CH2:18][C:17]([C:16]1[CH:21]=[CH:22][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)=[O:20])(=[O:9])[C:2]1[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1ccc(C(=O)C[NH3+])cc1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)CNC(=O)c2ccncc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Isonicotinic acid (24.93 g., 0.0938 mole) and thionyl chloride (50 ml) was refluxed for 1 hour. The crude acid chloride which remained after removal of excess thionyl chloride at diminished pressure was dissolved in dry pyridine (200 ml) and p-methoxy phenacylammonium chloride (19.00 g, 0.938 mole) was added portion wise to the stirred solution. During the addition, an exotherm occurred which raised the temperature of the stirred mixture to 40° C. After the addition was completed, the reaction mixture was heated and stirred on a boiling water bath for 2 hours and then poured into ice-water to precipitate the product. The solid was collected and dried under reduced pressure to give 12.07 g. (yield 48%) of α-isonicotinamido-p-methoxyacetophenone m.p. 227°-230° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[O:17])[O:15][C:13](=O)[C:12]2=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[O-]CC.[Na+].Cl.[CH2:28]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:29]([CH3:31])[CH3:30].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[O-]CC.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([C:13]([OH:15])=[C:33]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[N:32]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:16]2=[O:17])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNCC(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2cc(OCc3ccccc3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(C(=O)OC(C)(C)C)c(O)c2ccc(OCc3ccccc3)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
To a suspension of 4-benzyloxyphthalic anhydride (2.54 g, 10 mmol) in ethanol (30 mL) was added 20% sodium ethoxide ethanol solution (3.74 g, 11 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (150 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (200 mL) and tert-butyl 2-(isobutylamino)acetate (2.25 g, 12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.30 g, 12 mmol) and 1-hydroxybenzotriazole (1.84 g, 12 mmol) were added and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (30 mL) and a solution (6.80 g, 20 mmol) of 20% sodium ethoxide in ethanol was added thereto. The mixture was stirred at room temperature for 1 h. The reaction mixture was poured into 1N hydrochloric acid (20 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the component eluted earlier was concentrated to give tert-butyl 7-benzyloxy-4-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (0.40 g, 9.5%) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:70])[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:69])[C@H:13]([NH:35][C:36](=[O:68])[CH2:37][NH:38][C:39](=[O:67])[CH2:40][C@H:41]([OH:66])/[CH:42]=[CH:43]/[CH2:44][CH2:45][S:46][C:47]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[Li+].[OH-]>C1COCC1.O>[OH:66][C@H:41](/[CH:42]=[CH:43]/[CH2:44][CH2:45][S:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:40][C:39]([NH:38][CH2:37][C:36]([NH:35][C@H:13]([CH2:14][S:15][C:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]([NH:11][C:8]1([C:6]([NH:5][CH2:4][C:3]([OH:70])=[O:2])=[O:7])[CH2:10][CH2:9]1)=[O:69])=[O:68])=[O:67]
Reactant: COC(=O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)CNC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)C1(NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)CNC(=O)C[C@H](O)/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.92 h
Yield: 100 %

Procedure:
To 4 (157.3 mg, 0.154 mmol) in THF (2.45 mL) at 0° C. was added LiOH (9.19 mg, 0.384 mmol) in water (0.65 mL) dropwise and the reaction was stirred for 55 min. The reaction mixture was then quenched with 1M HCl (aq) (10 mL) and diluted with water (10 mL). EtOAc (30 mL) was added the layers separated and the aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were combined, washed with saturated brine (20 mL), separated, dried (MgSO4) and concentrated in vacuo to give 5 (153 mg, 0.154 mmol, 100%) as a white solid, which was used without further purification [MS (ES−) 959.2 (100%, [M−H]−)].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16](OC)[O:17]C)[CH:13]=2)=[CH:4][CH:3]=1>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][C:11](=[O:21])[N:12]([CH2:14][CH2:15][CH:16]=[O:17])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(CCn1cc(-c2ccc(Cl)nc2)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Product: O=CCCn1cc(-c2ccc(Cl)nc2)c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
5-(6-Chloro-pyridin-3-yl)-1-(3,3-dimethoxy-propyl)-1H-pyrimidine-2,4-dione (Prep92, 267 mg, 0.82 mmol) was dissolved in THF (10 ml) and then 1N HClaq (0.82 ml) was added. The solution was stirred at 40° C. for 1.5 hours. TEA (116 μl, 0.83 mmol) was added and the solvent was removed in vacuum at room temperature. Residue was freeze dried to give a white powder that was used in the next step without further purification (quantitative yield).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[CH:13]=[C:14]([C:24](=[O:26])[CH3:25])[CH:15]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]=1[O:18][CH3:19].C(OCC)(=O)C>CN(C)C=O>[C:24]([C:14]1[CH:15]=[C:16]([C:20]([CH3:21])([CH3:22])[CH3:23])[C:17]([O:18][CH3:19])=[C:12]([CH:13]=1)[NH:11][CH2:2][C:3]#[N:4])(=[O:26])[CH3:25]
Reactant: N#CCBr
Reactant: COc1c(N)cc(C(C)=O)cc1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(NCC#N)cc(C(C)=O)cc1C(C)(C)C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Bromoacetonitrile (6 ml) and potassium carbonate (1.4 g) were added to a solution of 1-[3-amino-5-(tert-butyl)-4-methoxyphenyl]-1-ethanone (2.0 g, 9.0 mmol) in dimethylformamide (50 ml) and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, washed was performed with water and brine in that order, the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (3.2 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:31]1[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=1)[C:5]([NH:7][CH:8]1[C:29](=[O:30])[N:10]2[C:11]([C:26]([OH:28])=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6].FC(F)(F)C([O-])=O.[ClH:46]>CO>[ClH:46].[ClH:46].[CH3:1][O:2][N:3]=[C:4]([C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)[C:5]([NH:7][CH:8]1[C:29](=[O:30])[N:10]2[C:11]([C:26]([OH:28])=[O:27])=[C:12]([CH2:15][O:16][C:17]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[O:18])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)N3CCN(C)CC3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (syn isomer) (1.0 g) in methanol (20 ml) was added conc.hydrochloric acid (0.62 ml) followed by stirring for 2 hours at ambient temperature. The reaction mixture was evaporated and the residue was pulverized in ethyl acetate, collected by filtration, washed with ethyl acetate and diethyl ether and then dried to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.dihydrochloride (syn isomer).
Reaction SMILES: [C:1]([C:5]1([Li])[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].O1C[CH2:14][CH2:13][CH2:12]1>>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:13]([CH3:14])[CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: [Li]C1(C(C)(C)C)C=CC=C1
Product: CC(C)=C1C=CC(C(C)(C)C)=C1
Reaction time: 8 h

Procedure:
Into a 200 ml, 3-neck flask, equipped with a reflux condenser, a gas inlet tube and a magnetic stirring bar, was charged, under nitrogen, 2 grams t-butylcyclopentadienyl lithium and 25 ml anhydrous tetrahydrofuran (THF). The solution was cooled in an ice-bath and 10 ml acetone, dried over 3A, was cautiously added. The reaction mixture was allowed stir overnight and quenched, cautiously, with 60 ml water. The resulting solution was extracted with ethyl ether using the standard lab extraction procedure. The resulting yellow oil was distilled under vacuum at 40-45° C. to obtain a clear yellow oil, 0.76 g.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][CH2:10][CH2:9]1)=O)(C)C.[ClH:17]>O1CCOCC1>[ClH:17].[NH:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C1CNCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(R,S)-Boc-2-carboxymorpholine (3 g, 13 mmol) was added to 4 N HCl in dioxane (15 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. Removal of solvent produced 2.2 g (100%) of the desired product as an HCl salt. 1H NMR (400 MHz, METHANOL-D4) δ 2.79-2.86 (m, 1 H), 2.87-2.94 (m, 2 H), 3.21 (dd, J=12.50, 3.52 Hz, 1 H), 3.51 (m, 1 H), 3.79 (m, 1 H), 4.07 (dd, J=9.77, 3.12 Hz, 1 H).