Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](C(O)=O)([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.N1C=CC=CC=1.O.Cl>[Fe].C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1(C(=O)O)CCOCC1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(O)C1CCOCC1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
In a flask made of glass equipped with a stirring device, a thermometer and a reflux condenser and having an inner volume of 50 ml were charged, under nitrogen atmosphere, 1.0 g (5.74 mmol) of tetrahydropyran-4,4-dicarboxylic acid, 32 mg (0.57 mmol) of iron and 3.0 ml of pyridine, and the mixture was reacted at 110 to 120° C. for 1 hour under stirring. After completion of the reaction, the reaction mixture was cooled to room temperature, and 5 ml of water, 5 ml (60 mmol) of conc. hydrochloric acid and 10 ml of ethyl acetate were successively added in this order to the reaction mixture. The aqueous layer and the organic layer (the ethyl acetate layer) were separated, and the aqueous layer was washed three times with each 10 ml of ethyl acetate. Then, the organic layer and the ethyl acetate extracts were combined and concentrated under reduced pressure to give 548 mg (Isolation yield: 73%) of tetrahydropyran-4-carboxylic acid with purity of 100% (analytical value by differential refractometry) as white crystals.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[C:14]1=[O:22]
Reactant: Fc1ccc(CCl)cc1
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccc(F)cc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.72 g. of NaH (80% suspension in mineral oil), 7 g. of 8-(2-oxo-benzimidazolin-1-yl)-caprylic acid methyl ester, 100 cc. of DMF, 3.5 g. of 4-fluorobenzylchloride and 0.72 g. of NaJ. Eluant for chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:19]=2[CH:18]=1)=[O:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].[Cl-].[NH4+]>C(OCC)(=O)C>[C:39]([O:38][C:36](=[O:37])[CH2:35][O:26][C:24]1[CH:23]=[CH:22][C:20]2[S:21][C:17]([C:15](=[O:16])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:18][C:19]=2[CH:25]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1cc2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc2sc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2c1
Yield: 45.6 %

Procedure:
To a solution of 96 mg (0.25 mmol) {2-[(5-Hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-phenyl}-carbamic acid tert-butyl ester (4) in 3 ml ethyl acetate was added 140 mg potassium carbonate and 60 mg (0.40 mmol) tert-butyl chloroacetate. The reaction mixture was heated at reflux for 16 h and poured into a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted with ethyl acetate and the organic phase was dried over sodium sulfate, the solvent was evaporated and the residue subjected to silica gel chromatography (petrolether/ethyl acetate 4:1). The product fraction was recrystallized from heptane/diethylether to yield 57 mg (0.114 mmol) [2-(2-tert-Butoxycarbonylamino-phenylcarbamoyl)-benzo[b]thiophen-5-yloxy]-acetic acid tert-butyl ester (46), mp. 166° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29](=[O:32])[NH:30][N:31]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.O1CCOCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([N:30]4[C:29](=[O:32])[CH:28]=[CH:27][C:26]([CH3:25])=[N:31]4)=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: Cc1ccc(=O)[nH]n1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(-n4nc(C)ccc4=O)cnc32)cc1
Temperature: 120 °C
Yield: 11.4 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (75 mg, 0.19 mmol), 6-methylpyridazin-3(2H)-one (43 mg, 0.39 mmol), copper(I) iodide (44 mg, 0.23 mmol), dioxane (3 ml), trans-1,2-diaminocyclohexane (0.030 ml, 0.25 mmol) and cesium carbonate (152 mg, 0.47 mmol) were combined and heated at 120° C. for 12 hours in the microwave. The mixture was filtered and the residue was purified by HPLC to afford 9 mg (11%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=2)[N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:4]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:3]1.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.CCCCCC>[O:1]=[C:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])[CH:10]=2)[NH:6][C@@H:5]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:4]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[O:3]1
Reactant: CCC(CC)c1cccc(C[C@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)c1cccc(C[C@@H]2N[C@@H](c3ccccc3)[C@@H](c3ccccc3)OC2=O)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a 250 mL round bottomed flask equipped with a magnetic stirrer and a nitrogen inlet were added 2.19 g of tert-butyl (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)-4-morpholinecarboxylate and 45 mL of anhydrous CH2Cl2. The solution was cooled to 0° C. and was treated with 3.5 mL of TFA. The solution was allowed to warm to RT and was stirred under nitrogen. After 5 h, tlc (SiO2, 9:1 hexane:EtOAc) indicated a trace of starting material and a major new component at Rf =0.42. The reaction mixture was poured into 150 mL of 6% aqueous NaHCO3 and stirred for several minutes. The phases were separated and the aqueous portion was extracted with 3 additional 40 mL portions of CH2Cl2. The extracts were combined with the original CH2Cl2 solution and washed with 5% aqueous NaHCO3 (3×60 mL. The solution was dried over anhydrous MgSO4 and concentrated to give a light tan solid. This material was purified by flash chromatography on silica gel (85:15 hexane:EtOAc) to afford 1.47 g (84%) of (2R, 3S, 5S)-6-oxo-2,3-diphenyl-5-(3-(3-pentyl)benzyl)morpholine as a white crystalline solid. An analytical sample was prepared by recrystallization from EtOH--H2O. Melting point, 96-97° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]([F:33])([F:32])[CH:29]1[O:31][CH2:30]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][CH:21]=2)[CH2:30][CH:29]([OH:31])[C:28]([F:33])([F:32])[F:27])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)c1ccc(CNc2cccc(Oc3ccccc3)c2)cc1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CCN(CC)c1ccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)cc1
Temperature: 40 °C
Yield: 17.4 %

Procedure:
The 3-[(3-phenoxyphenyl)[4-(N,N-diethylamino)phenyl]methylamine (0.69 g, 2.0 mmol) product from EX-631A and 1,1,1-trifluoro-2,3-epoxypropane (0.45 g, 4 mmol) were dissolved in 1 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (0.12 g, 0.1 mmol) was added, and the stirred solution was warmed to 40° C. for 4 h, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with water and brine, then dried over MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with 1:7:0.01 ethyl acetate: hexane:ammonium hydroxide followed by reverse phase preparative HPLC eluting with 10% to 90% acetonitrile in water to give 160 mg (17%) of the desired 3-[(3-phenoxyphenyl)-[[4-(N,N-diethylamino)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, >95% pure by HPLC analysis. 1H NMR (CD30D) δ 7.39 (d, 2H), 7.31 (d, 2H), 7.22 (m, 3H), 7.13 (d, 1H), 6.98 (t, 1H), 6.75 (dd, 2H), 6.47 (dd, 1H), 6.20 (d, 1H), 4.03 (m, 1H), 3.90 (s, 2H), 3.58 (m, 4H), 3.36 (dd, 1H), 3.12 (dd, 1H), 1.05 (t, 6H). 19F NMR (CD30D) δ −80.51 (d, 3F). HRMS calcd. 459.2259 M+H]+, found: 459.2250.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([N:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([N:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CN(C)c1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(N(C)C)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K28) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (309 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([Cl:9])[C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([Cl:9])[C:5]([CH3:8])=[N+:6]([O-:16])[CH:7]=1
Reactant: Cc1ncc(Br)c(C)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(Br)c[n+]([O-])c(C)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a solution of 5-bromo-3-chloro-2,4-dimethylpyridine (441 mg; 2.0001 mmol) in dichloromethane (10 mL; 156.0 mmol) was added 3-chloroperoxybenzoic acid (70%, 0.5547 g; 2.250 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with additional dichloromethane (100 mL), washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-100% ethyl acetate in dichloromethane) to yield 374.1 mg (79%) of the title compound. LCMS (ESI): M+H=236.2; 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 2.47 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:17]1([CH2:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:14][C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:29])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)CNC(=O)Cc1ccccc1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(Cc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and phenylacetylamino-acetic acid (CA [500-98-1]).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])=O.[CH3:20][NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:20][N:21]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8]
Reactant: CNCCc1ccccn1
Reactant: COC1=C(OC)C2C(=O)NC(=O)C2(CCC=O)C=C1
Product: COC1=C(OC)C2C(=O)NC(=O)C2(CCCN(C)CCc2ccccn2)C=C1

Procedure:
Prepared from 2-(2-formyl-ethyl)-5,6-dimethoxy-phthalimide and 2-(2-methylamino-ethyl)-pyridine analogously to Example 4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:35]=[CH:34][C:15]4[N:16]([C:19]5[CH:20]=[C:21]([NH:30][C:31](=[O:33])[CH3:32])[CH:22]=[C:23]([N:25]6[CH:29]=[CH:28][CH:27]=[N:26]6)[CH:24]=5)[CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[CH3:42][S:43]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:35]=[CH:34][C:15]4[N:16]([C:19]5[CH:20]=[C:21]([NH:30][C:31](=[O:33])[CH3:32])[CH:22]=[C:23]([N:25]6[CH:29]=[CH:28][CH:27]=[N:26]6)[CH:24]=5)[CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1)(=[O:45])=[O:44]
Reactant: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(-n2cccn2)cc(-n2cnc3cc(-c4cnn(C5CCN(S(C)(=O)=O)CC5)c4)ccc32)c1
Reaction time: 4 h
Yield: 19 %

Procedure:
To a solution of the compound of Example 128 (80 mg, 0.171 mmol) in DCM (10 ml) was added pyridine (27 mg, 0.34 mmol, 2 eq.) and methanesulfonyl chloride (19 mg, 0.171 mmol, 1 eq.). The mixture was stirred for 4 h and quenched and extracted as in Example 2(b). The solvent was distilled off and the residue was purified by preparative HPLC to give the product in 19% yield (18 mg). 1H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 10.06 (s, 1H), 8.58 (d, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.06-8.00 (m, 3H), 7.89 (s, 1H), 7.83 (d, 1H), 7.78-7.74 (m, 2H), 6.62 (t, 1H), 4.36 (m, 1H), 3.01-2.94 (m, 6H), 2.30 (s, 3H), 2.13 (s, 3H), 2.10-2.01 (m, 2H); LC-MS (ESI): Calculated mass: 544.63; Observed mass: 545.2 [M+H]+ (rt: 0.40 min).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[C:12]([F:19])[CH:11]=1.CN([CH:23]=[O:24])C>C1COCC1>[Br:9][C:10]1[C:11]([CH:23]=[O:24])=[C:12]([F:19])[C:13]([CH2:16][CH2:17][CH3:18])=[CH:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: CCCc1ccc(Br)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1ccc(Br)c(C=O)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
Under a nitrogen atmosphere, LDA (50.7 mL, 56.25 mmol) was slowly added dropwise, at −70° C. or lower, to a THF (100 mL) solution of 4-bromo-2-fluoro-1-propylbenzene (50) (11.1 g, 51.13 mmol). The reaction mixture was agitated at −70° C. or lower for 1 hour, and then DMF (6.15 g, 76.70 mmol) was slowly added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 100 mL of 1N hydrochloric acid aqueous solution, and extracted with 60 mL of toluene 3 times. Combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over magnesium sulfate and a solvent was distilled off by evaporator. The residue was purified by silica gel column chromatography, and thus 6-bromo-2-fluoro-3-propylbenzaldehyde (51) (5.0 g, yield 36%) was obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].P(=O)(O)(O)O.N1CCC[C@H]1C(O)=O.C([O-])(=O)C.[NH4+].[OH-].[NH4+].C1C=CC(C=O)=C(C=O)C=1.B([O-])([O-])[O-].[Na+].[Na+].[Na+].C(N[C@H](C(O)=O)CS)(=O)C.CC1(C)O[C@]2(OC[C@@H]3OC(C)(C)O[C@@H]3C2=O)CO1>O.C(#N)C>[NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(CCCc1ccccc1)C(=O)O
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Solvent: O
Solvent: CC#N
Product: N[C@H](CCCc1ccccc1)C(=O)O
Temperature: 45 °C
Yield: 49.5 %

Procedure:
(±)-2-Amino-5-phenylpentanoic acid (35 g) was suspended in water (3 L) and solubilized by adjusting the pH to 12 with 7N sodium hydroxide solution. The pH was readjusted to pH 8 using 1M phosphoric acid with continuous stirring at 45° C. The solution was allowed to cool to 40° C. and L-amino acid oxidase (Sigma, 0.7 unit/mg) was added. The reaction was stirred with good aeration at 37°-40° C. for two weeks. The reaction was monitored using the following High Pressure Liquid Chromatography (HPLC) system: C-18 Waters analytical column, 20% acetonitrile in Buffer (0.624 g/L CuSO4.5H2O, 0.576 g/L L-proline, 2 g/L ammonium acetate, and 1L of water with the pH of the solution adjusted to pH 7 with ammonium hydroxide); 2 mL/minute flow rate; fluorescence detection: Ex 345 nm, Em>415 nm; OPA derivatization: 300 μL of 1N sodium borate pH 9.4, 50 mL of 20 mg ortho-phthalaldehyde (OPA) plus 24 ng N-acetyl cysteine/6 mL 50% methanol/water; incubate 3 minutes at ambient temperature. When the digestion of the L-enantiomer was complete, the reaction mixture was concentrated to 500 mL by removing water in vacuo. The pH was adjusted to 5 and the predpitate was collected by filtration and recrystallization from ethanol-water to afford 17.32 g (99%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH2:16]OC(=O)CC(=O)C)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:29]1[C:33]2[CH2:34][CH2:35][CH2:36][CH2:37][C:32]=2[N:31]=[CH:30]1.[I-].[K+].C(#N)C>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:27](=[O:28])[N:11]2[C:12]([C:24]([O-:26])=[O:25])=[C:13]([CH2:16][N+:31]3[C:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=4[S:29][CH:30]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: c1nc2c(s1)CCCC2
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3csc4c3CCCC4)CS[C@H]12
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 16.3 %

Procedure:
A mixture consisting of 4.0 g of 7β-tert-butoxycarbonylamino-3-(3-oxobutyryloxymethyl]-3-cephem-4-carboxylic acid, 3.0 g of 4,5,6,7-tetrahydrobenzothiazole, 4 g of potassium iodide, 10 ml of acetonitrile and 10 ml of water is stirred at 70° C. for 1.5 hours. To the reaction mixture is added 30 ml of ethyl acetate and the mixture is stirred. After letting the mixture stand, the upper layer is removed by decanting. To the lower layer is added 30 ml of ethyl acetate and the same work-up is repeated twice. The water-layer is subjected to silica-gel column chromatography using 70 g of silica-gel. After washing of the column by using first 200 ml of acetone and then 200 ml of acetone-water (20:1), elution is conducted by acetone-water (3:1). The fractions containing the objective compound are concentrated and lyophilized to give 0.71 g (yield 15%) of the above-identified compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:13])=[C:5]([C:9]([F:12])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:14](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>C1COCC1>[F:13][C:4]1[C:3]([CH2:2][NH:1][C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15])=[CH:11][CH:10]=[C:9]([F:12])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(F)c(C(=O)O)c1F
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(F)c(C(=O)O)c1F

Procedure:
Prepared analogously to 44b with 3-aminomethyl-2,6-difluorobenzoic acid, Piv-Cl, BSTFA and TEA in THF. Yield: 1.2 g (77%); MS: [m+H]+=272; HPLC: Rt=1.38 min (Method MC-6)
Reaction SMILES: [F:1][C:2](=[CH:8][CH2:9][C:10]([F:23])=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7].CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[F:1][C:2](=[CH:8][CH2:9][C:10]([F:23])=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][C:6]([OH:26])=[O:7]
Reactant: CC(C)=O
Reactant: CCCCCC=CCCCCC=C(F)CC=C(F)CCCC=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CCCCCC=CCCCCC=C(F)CC=C(F)CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of the aldehyde prepared in 1I (0.2 g, 0.61 mmoles) in acetone (7 ml) cooled to 0° C. was added dropwise 2.67M Jones reagent until the orange color was stable. The mixture was stirred 15 min. at 0° C. The excess of Jones reagent was reacted with isopropanol. The acetone was evaporated under reduced pressure without heating. The residue was taken with water and extracted three times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to leave an oil. Flash chromatography on silica gel and elution with a 25:75 mixture of ethyl acetate and hexane afforded the expected acid as an oil (0.125 g, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][CH:26]([CH2:35][CH2:36][CH3:37])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>O.CN(C)C=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:14](=[O:16])[NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][CH:26]([F:25])[CH2:35][CH2:36][CH3:37])[CH2:29][CH2:30]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@]1(CC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC(F)CN1CCC(N)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(F)CN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3ccccc3)C[C@H]2C)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
A mixture of (3R*,4S*)-1-benzyl-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidine-3-carboxylic acid obtained in Example 1j (300 mg, 0.9 mmol), the chiral form of 1-(2-fluoropentyl)piperidin-4-amine obtained in Example 1d (182 mg, 0.967 mmol), triethylamine (0.376 ml, 2.7 mmol), PyBOP (656 mg, 1.26 mmol) and N,N-dimethylformamide (4.5 ml) was stirred at room temperature for 61 hours and 30 minutes. Triethylamine (0.207 ml, 1.49 mmol) and PyBOP (360 mg, 0.69 mmol) were further added, followed by stirring for four hours and 30 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate twice. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (161 mg, yield 35.5%).