Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:17][O:18][C:19](=[O:25])[CH2:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClC(Cl)C>[CH3:17][O:18][C:19](=[O:25])[CH2:20][S:21](=[O:23])(=[O:22])[NH:4][C:3]1[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=1[F:10]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: Nc1c(F)cc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)CS(=O)(=O)Nc1c(F)cc(F)cc1F
Temperature: 0 °C
Reaction time: 12 h

Procedure:
0.76 g (5 mmol) of 2,4,6-trifluoroaniline is dissolved in 40 ml of dichloroethane with exclusion of moisture, 0.4 ml (5 mmol) of pyridine is added, 0.86 g (5 mmol) of chlorosulfonyl acetic acid methyl ester, dissolved in 10 ml of dichloroethane, is instilled at 0° C. and then it is stirred for 1 hour at 0° C. and 12 hours at room temperature. The reaction solution is then shaken out twice with 10 ml of 2N hydrochloric acid each, the phases are separated, the organic phase is dried on magnesium sulfate, filtered and evaporated to dryness. The residue is crystallized from diethyl ether/pentane 1:1. 790 mg (2.79 mmol)=55.79% of the theoretical yield is obtained as a crystallizate. Melting point 99-100° C.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[H][H]>O1CCCC1.C(O)(=O)C.[Pt]=O>[C:1]1([C:7]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCC1=CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1CCC(c2ccccc2)(c2ccccc2)CC1
Yield: 94.9 %

Procedure:
4,4-diphenyl-1-butylcyclohexene (containing 4,4-diphenyl-1-butylidenecyclohexane) 32.0 g was dissolved in tetrahydrofuran 200 ml and acetic acid 300 ml, platinum oxide 1.0 g was added, and the mixture was cooled with water at atmospheric pressure and contacted to hydrogen gas with stirring. After the absorption of hydrogen was stopped, the catalyst was filtered off, water two liters was added to the solution, and the solution was extracted with toluene one liter. The extracted solution was washed with water, toluene was removed with a rotary evaporator and 1,1-diphenyl-4-butylcyclohexane 30.58 g was obtained.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[N:11][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:13][CH:14]=1>C1C=CC=CC=1.CO>[CH3:1][O:20][C:19]([C:10]1[C:9]([Br:8])=[CH:14][N:13]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[N:11]=1)=[O:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1nc(C(C)(C)C)ncc1Br
Reaction time: 48 h
Yield: 80.6 %

Procedure:
A 2.0 M hexanes solution of trimethylsilyldiazomethane (11.8 mL, 23.62 mMol) was added dropwise to a stirring solution of 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (6.12 g, 23.62 mMol) in 9:1 benzene/methanol (100 mL), and the reaction was stirred for 2 days. TLC analysis showed that the reaction was complete, so the mixture was concentrated in-vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (3×20 mL), dried over sodium sulfate, then concentrated in-vacuo. Purified over silica gel, eluting with 10% ethyl acetate/hexanes, to yield 5.2 g of a colorless oil as product. MS (ES+)=273,275 (M+H)+. Yield=81%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C)C=O>[Cl:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 2-bromo-3′-chloroacetophenone (0.9271 g, 3.971 mmol, 1.0 equiv) and potassium phthalimide (0.8129 g, 4.389 mmol, 1.1 equiv) in N,N-dimethylformamide (15 mL) was heated at 50° C. After 1 hour, the solvent was removed by rotary evaporation. The resultant solids were triturated with ethyl acetate and filtered. The collected solids were dried under vacuum to yield 1.19 g (117%) of 2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione, which was carried forward without purification. 1H NMR (400 MHz, DMSO-d6) δ: 8.13 (s, 1H), 8.05 (d, 1H), 7.96 (m, 2H), 7.93 (m, 2H), 7.83 (d, 1H), 7.65 (t, 1H), 5.29 (s, 2H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[NH:13][C:12]1=[O:21])[CH2:8]2.Br[CH2:23][CH:24]1[CH2:26][CH2:25]1>>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[CH:15]=[C:14]([CH2:16][C:17]([F:20])([F:18])[F:19])[N:13]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:12]1=[O:21])[CH2:10]2
Reactant: BrCC1CC1
Reactant: O=c1[nH]c(CC(F)(F)F)cn1C1C2CC3CC(C2)CC1C3
Product: O=c1n(C2C3CC4CC(C3)CC2C4)cc(CC(F)(F)F)n1CC1CC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 1-adamantan-2-yl-4-(2,2,2-trifluoro-ethyl)-1,3-dihydro-imidazol-2-one (obtained in example 16, 100 mg) by alkylation with bromomethylcyclopropane (67 mg). 1-Adamantan-2-yl-3-cyclopropylmethyl-4-(2,2,2-trifluoro-ethyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow solid (72 mg). MS (EI): 354.2 (M+).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][OH:21])[CH:16]=[CH:15][C:14]=2[CH3:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:26]>C1COCC1>[CH:1]1([N:4]([CH2:12][C:13]2[CH:18]=[C:17]([CH2:19][CH2:20][O:21][CH3:26])[CH:16]=[CH:15][C:14]=2[CH3:22])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: CI
Reactant: Cc1ccc(CCO)cc1CN(C(=O)OC(C)(C)C)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1ccc(C)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl cyclopropyl[5-(2-hydroxyethyl)-2-methylbenzyl]carbamate from the previous step (1 eq.) in THF (0.2 M) was added sodium hydride (2 eq.). The resulting suspension was stirred at RT for 30 min and then added iodomethane (8 eq.). After 12 h of heating at reflux, the reaction mixture was cooled to RT and quenched with sat. aq. NH4Cl. The aqueous layer was separated and extracted with ether. The combined organic extracts were washed with brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the crude product as a colorless oil. Further purification by way of column chromatography (SiO2, Hex→7:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH3:38]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH3:38]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A mixture of 6-methoxy-4-(3-methylindol-5-yloxy)-7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)quinazoline (1.290 g, 2.49 mmol), (prepared as described in Example 274), in 25% trifluoroacetic acid/75% dichloromethane solution (75 ml) was stirred at ambient temperature for 2 hours. The solvents were then removed in vacuo and the dark yellow gum triturated with concentrated ammonia. The resulting solid was filtered off and dried to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (648 mg, 62%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[CH3:24].C(OCC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:29][CH2:28][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:30])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)CCNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the 4-bromomethylphenylsulfonylchloride (10 g, 37 mmol) in CH2Cl2 (200 mL) at 0° C. was added diisopropylethylamine (16 mL, 93 mmol) followed by ethyl-3-aminopropionate hydrochloride (5.1 g, 37 mmol)). The reaction was stirred for 10 minutes at 0° C. and the solvent was evaporated at room temperature under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N HCl (3×), H2O, aqueous NaHCO3 (3×), brine (3×) and dried over MgSO4. The solvent was concentrated to give a syrup. Addition of ethyl ether induced crystallization of the product as a white solid (10 g, 30 mmol, 81%).
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].C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.O.CCOC(C)=O>C1(C)C=CC=C(C)C=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][N:11]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1cccc(C)c1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(-c2ccccn2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available methyl 2-chloroisonicotinate (300 mg; 1.74 mmol), 2-(trimethylstannyl)pyridine (422 mg; 1.74 mmol), and PdCl2(PPh3)2 (122 mg; 0.17 mmol) in anh. meta-xylene (7 ml) was heated to 75° C., under nitrogen, for 18 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=15/1) afforded methyl[2,2′-bipyridine]-4-carboxylate as a yellow solid. LC-MS (conditions A): tR=0.46 min.; [M+H]+: 215.15 g/mol.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31].CCOC(C)=O>CCOC(C)=O>[ClH:31].[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)(=[O:16])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(OCC3CCCCC3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(OCC2CCCCC2)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The resulting tert-butyl 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine-1-carboxylate (635 mg) was dissolved in EtOAc (7 ml), and a 4 M hydrogen chloride/EtOAc solution (3.6 ml) was added thereto, followed by stirring at room temperature for 6 hours. The solid was collected by filtration and washed with EtOAc to obtain 4-{[4-(cyclohexylmethoxy)phenyl]sulfonyl}piperidine hydrochloride (485 mg) as colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:32][C:13]3=[N:14][C:15]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:16][C:17](=[O:18])[N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[S:32][C:13]3=[N:14][C:15]([N:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]4)=[CH:16][C:17](=[O:18])[N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc([N+](=O)[O-])c4)sc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(=O)n3nc(-c4cccc(N)c4)sc3n2)CC1
Reaction time: 3 h

Procedure:
tert-butyl 4-(2-(3-nitrophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (220, 0.480 mmol, 1.0 equiv) is dissolved in 5 mL methanol. To the solution is added palladium on carbon (51.1 mg). The reaction is stirred under an atmosphere of hydrogen for 3 h. Upon completion, the mixture is filtered through celite and concentrated in vacuo to give crude tert-butyl 4-(2-(3-aminophenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 (s, 1H), 7.20-7.29 (m, 1H), 7.13 (d, J=7.83 Hz, 1H), 6.83 (dd, J=7.63, 1.76 Hz, 1H), 5.46 (s, 1H), 3.87 (s, 2H), 3.45-3.65 (m, 8H), 1.48 (m, 9H);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[CH:27]1([NH:30][C:31]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31](=[O:32])[C:33]2[CH:40]=[CH:39][C:36]([C:37]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:35][CH:34]=2)[CH2:28][CH2:29]1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Reactant: O=Cc1ccc(C(=O)NC2CC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(C(=O)NC4CC4)cc3)nc2c1)c1ccc(N2CCCC2)cc1

Procedure:
Compound 228 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-cyclopropylaminocarbonylbenzaldehyde. [M+H]+ calcd for C28H27N5O2: 466.23; found: 466.55.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:28][CH:29]1[C:49](=[O:50])[N:31]2[C:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]12.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.CC(C)=O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]([NH:28][CH:29]2[C:49](=[O:50])[N:31]3[C:32]([C:36]([O:38][CH2:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)=[O:37])=[CH:33][CH2:34][S:35][C@H:30]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Yield: 103.9 %

Procedure:
2-(2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 5 g.), N,N-dimethylformamide (1.68 g.), phosphoryl chloride (3.52 g.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example 1(1) to give an activated acid solution. The solution was added to a stined suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (5.23 g.), in tetrahydrofuran (26 ml.), acetone (13 ml.) and water (13 ml.) at -5° to 0° C., and stirred at the same temperature for 30 minutes while keeping at pH 7 to 7.5 with 20% aqueous solution of sodium carbonate. After removing the insoluble substance from the resultant mixture, the filtrate was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solution was concentrated in vacuo, and the residue was triturated with diethyl ether. The precipitates were collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 10.2 g.)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([N:6]1[CH2:7][C@H:2]([CH3:1])[N:3]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:4][C@H:5]1[CH3:8])(=[O:20])[CH3:19]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1
Reactant: CC(=O)Cl
Product: CC(=O)N1C[C@H](C)N(c2ccc([N+](=O)[O-])cc2)C[C@H]1C
Reaction time: 8 h

Procedure:
The title compound was prepared from (2S,5R)-2,5-dimethyl-1-(4-nitrophenyl)piperazine (Method 28, 8.22 g, 34.95 mmol) and acetyl chloride (4.5 ml, 62.91) by the procedure of Method 26. It was obtained as an oil which solidified on standing overnight (11.39 g, >100%, contaminated with solvent) NMR (400 MHz) 1.13 (m, 6H), 3.07 (m, 1H), 3.33 (m, 1H), 3.68 (m, 1H), 4.25 (m, 2H), 4.69 (m, 1H), 7.00 (d, 2H), 8.05 (d, 2H); m/z 278.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[C@@:13]3([CH2:22][C@@:21]3([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:23]([CH3:25])[CH3:24])[C:12]2=[O:33])[CH:10]=1)[C:5]([O-:7])=[O:6].O[Li].[OH2:36]>CO.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C@:21]2([CH:23]([CH3:24])[CH3:25])[C@:13]3([C:14]4[C:19](=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=4)[N:11]([C:9]4[CH:8]=[C:4]([CH:3]=[C:2]([N:11]5[CH2:9][CH2:8][O:36][C:12]5=[O:33])[CH:10]=4)[C:5]([OH:7])=[O:6])[C:12]3=[O:33])[CH2:22]2)=[CH:27][CH:28]=1
Reactant: CC(C)[C@]1(c2ccc(Cl)cc2)C[C@]12C(=O)N(c1cc(Br)cc(C(=O)[O-])c1)c1ccc(F)cc12
Reactant: O
Agent: [Li]O
Solvent: CO
Product: CC(C)[C@]1(c2ccc(Cl)cc2)C[C@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 108 %

Procedure:
To a solution of (1R,2R) and (1S,2S)-3-bromo-5-(2-(4-chlorophenyl)-5′-fluoro-2-isopropyl-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)benzoate (27.4 mg) in methanol (2 mL) and water (1 mL) was added LiOH.H2O (18 mg, 0.4 mmol) in one portion. The mixture was stirred at room temperature for 3 hours until the starting material was consumed. The mixture was concentrated under reduced pressure and acidified to pH˜3. The precipitates was collected by filtration and dissolved in 2 mL of DMF. Purification by preparative HPLC gave the title compound as white solid (15 mg). LC/MS m/e calcd. for C29H24ClFN2O5 534, observed (M+H)+: 545.7. 1H NMR (400 MHz, MeOD-d4) δppm 0.89 (dd, J=20.34, 6.69 Hz, 6 H) 2.21-2.28 (m, 2 H) 2.89-3.01 (m, 1H) 4.22 (t, J=8.08 Hz, 2 H) 4.55 (t, J=8.08 Hz, 2 H) 5.28 (dd, J=8.84, 2.27 Hz, 1 H) 6.65 (dd, J=8.34, 1.77 Hz, 1 H) 6.80-6.89 (m, 2 H) 7.19 (dd, J=8.34, 2.02 Hz, 1 H) 7.45-7.54 (m, 2 H) 7.86 (s, 1 H) 8.09 (s, 1 H) 8.22 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12](C(OCC)=O)([C:16]([O:18]CC)=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.Cl>C(O)(C)(C)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][CH:12]([C:16]([OH:18])=[O:17])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(C(=O)OCC)CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CC(C(=O)O)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To the diethyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7,7-dicarboxylate (10.5 g, 29.5 mmol) was added water (25 mL) and concentrated (12 N) hydrochloric acid (75 mL). The mixture was heated at reflux for 8 h. The volatiles were evaporated, and the residue was dissolved in water (10 mL) and the pH of the solution was adjusted to pH 8 with 10% aqueous sodium bicarbonate. Di-tert-butyl dicarbonate (8.5 g, 39 mmol) in tert-butanol (60 mL) was added and the reaction was stirred overnight at ambient temperature. Ethyl acetate (100 mL) was added to the reaction and the pH of the solution was adjusted to pH 3 with 2 M aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×200 mL) and brine (100 mL), dried (anhydrous sodium sulfate), concentrated (rotary evaporation), and purified by silica gel column chromatography to give 5.1 g of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid, as a white solid (1H NMR (CDCl3, 300 MHz): δ 3.59-3.40 (m, 2H), 3.36-3.05 (m, 2H), 3.02-2.76 (m, 2H), 2.65-2.60 (m, 1H), 2.24-2.04 (m, 2H), 1.85-1.66 (m, 2H), 1.46 (s, 9H); MS (m/z): 256 (M+1), 200 (M+1-56)).
Reaction SMILES: NC[C:3]([C:5]1[N:6]=[CH:7][N:8]([C@@H:15]2[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@H:16]2[F:23])[C:9]=1[N:10]=[CH:11][N:12](C)[CH3:13])=[O:4].C[O-].[Na+].C(=O)=O>CO>[F:23][C@@H:16]1[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:15]1[N:8]1[C:9]2[N:10]=[CH:11][NH:12][CH2:13][C:3](=[O:4])[C:5]=2[N:6]=[CH:7]1
Reactant: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: O=C1CNC=Nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reaction time: 8 h
Yield: 35.9 %

Procedure:
The compound (24) (20 mg) obtained in item (13) above was dissolved in methanol (0.4 ml), to which was added a 0.2M sodium methylate solution (0.4 ml) in methanol and the resulting mixture was allowed to stand at room temperature overnight. The reaction solution obtained was neutralized with addition of dry ice, then concentrated to leave a residue and the residue was purified by silica gel column chromatography (developer; chloroform-methanol, 4:1), affording the titled compound (25) (6.2 mg) as a colorless solid. Yield: 36%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH:22]=[O:23].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][OH:23]
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-formyl-4-oxoazetidin-3-yl)carbamate (218 g, 0.546 mol) in a mixture of DCM:MeOH (4:1, 2.25 L) at 0° C. was added sodium borohydride (41.3 g, 1.09 mol), portion-wise. The resulting mixture was stirred at 0° C. for 2 h, whereupon it was quenched with cold water (1 L) for 30 min and the layers were separated. The aqueous layer was extracted with DCM (3×200 mL) and the combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound (208 g, 95%) as an off white solid. LCMS: m/z=401.2 (M+1); 1H NMR (300 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.21-7.18 (m, 1H), 6.46-6.49 (m, 2H), 5.82 (bd, J=9.6 Hz, 1H), 5.18-5.08 (m, 3H), 4.45 (d, J=14.4 Hz, 1H), 4.28 (d, J=14.4 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.76-3.72 (m, 1H), 3.63-3.52 (m, 2H), 1.87 (dd, J=9.6, 4.0 Hz, 1H).