Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[OH-].[Na+].[CH2:17]([NH2:19])[CH3:18].Cl>C1COCC1.C(#N)C>[CH2:17]([NH:19][S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH3:18]
Reactant: CCN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCNS(=O)(=O)c1ccc(F)c(C(=O)O)c1

Procedure:
To a 5 ml Biotage microwave reaction tube was added 5-(chlorosulfonyl)-2-fluorobenzoic acid (0.4 g, 1.68 mmol) and a Teflon covered magnetic stir-bar followed by 2.5 ml of THF. To the resulting mixture was added 10N aqueous NaOH (0.369 ml, 3.38 mmol) with stirring. After formation of a cloudy suspension, ethylamine (0.838 ml, 1.68 mmol) was added as a 2M solution in THF. The reaction vessel was capped and heated to 110° C. for 1.1 min in a Biotage Initiator 8 microwave set at high absorbance. Reaction mixture was then diluted with 4 ml acetonitrile and acidified with 6M aqueous HCl (0.670 ml, 4.02 mmol). Water was removed from the mixture by adding excess anhydrous Na2SO4 and subsequent filtration. The filtered was washed with acetonitrile and DMF. The combined filtrates were concentrated with rotary evaporation, yielding the crude 5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid.
Reaction SMILES: [F:1][C:2]([F:22])([CH:7]([O:11][C:12](=[O:21])[C:13]([F:20])([F:19])[CH:14]([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].FC(F)([CH:41]([OH:45])[CH:42]([CH3:44])[CH3:43])C(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)=O>>[F:1][C:2]([F:22])([CH:7]([O:11][C:12](=[O:21])[C:13]([F:19])([F:20])[CH:14]([O:18][C:41](=[O:45])[C:42]([CH3:44])=[CH2:43])[CH:15]([CH3:16])[CH3:17])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(F)C(OC(=O)C(F)(F)C(O)C(C)C)C(C)C
Reactant: CC(C)C(O)C(F)(F)C(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)F
Product: C=C(C)C(=O)OC(C(C)C)C(F)(F)C(=O)OC(C(C)C)C(F)(F)C(=O)OC
Yield: 49 %

Procedure:
Reaction was conducted by the same procedure as Example 11 aside from using methyl 2,2-difluoro-3-(2,2-difluoro-3-hydroxy-4-methylpentanoyloxy)-4-methylpentanoate in Example 11-1 instead of 2,2,3,3,4,4,5,5-octafluoropentyl 2,2-difluoro-3-hydroxy-4-methylpentanoate in Example 11-3. Subsequent purification was conducted by silica gel column chromatography instead of vacuum distillation. The target compound, methyl 2,2-difluoro-3-(2,2-difluoro-3-methacryloyloxy-4-methylpentanoyloxy)-4-methylpentanoate was obtained in a yield of 49%.
Reaction SMILES: [CH3:1][O-].[Na+].[C:4]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][O:19]S(C)(=O)=O)[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.C1COCC1>[C:4]([O:8][C:9](=[O:10])[NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][O:19][CH3:1])[CH2:14][CH2:13]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
A solution of sodium methoxide in methanol (6.0 mL of a 25% solution, ˜27.0 mmol) was added to a solution of trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (1.50 g, 4.88 mmol) in THF (15 mL) and methanol (15 mL). The mixture was heated at reflux for 6.75 hours. The cold mixture was concentrated under vacuum to remove most of the solvent then diluted with water (10 mL). The mixture was then cautiously neutralised with 1M hydrochloric acid then extracted with DCM (3×20 mL). The combined organic phase was dried over magnesium sulphate and concentrated under vacuum. The residue was purified by chromatography on silica gel (eluting with 9:1 cyclohexane:ethyl acetate) to afford 1.07 g (90%) of trans (4-methoxymethyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCl3): δ 4.36 (br s, 1H), 3.37 (br s, 1H), 3.32 (s, 3H), 3.18 (d, 2H), 2.07-1.97 (m, 2H), 1.84-1.75 (m, 2H), 1.56-1.45 (m, 1H), 1.44 (s, 9H), 1.16-0.96 (m, 4H).
Reaction SMILES: [C:1](=[O:15])(OC1C=CC=CC=1)[O:2][CH2:3][C:4]([NH:6][CH3:7])=[O:5].[CH2:16]([NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>ClCCl>[CH2:16]([NH:26][C:1](=[O:15])[O:2][CH2:3][C:4]([NH:6][CH3:7])=[O:5])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CNC(=O)COC(=O)Oc1ccccc1
Reactant: CCCCCCCCCCN
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)OCC(=O)NC

Procedure:
A solution of 136 mg (0.65 mmol) of 2-(methylamino)-2-oxoethyl phenyl carbonate and of 133 mg (0.85 mmol) of decylamine in 2 ml of dichloromethane is stirred at ambient temperature for 18 h.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.O>[OH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][C:4]2[C:16]([CH3:18])([CH3:17])[CH2:15][CH2:14][C:12]([CH3:20])([CH3:13])[C:3]=2[CH:2]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: OCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CCCO)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 14 g (103 mmol) of 3-phenyl-1-propanol and 18.2 g (123 mmol) of 2,5-dichloro-2,5-dimethylhexane in 100 mL of dichloromethane was added 15 g (113 mmol) of aluminum chloride. After the addition of aluminum chloride was complete, the reaction was heated to reflux. After 16 hours, the reaction mixture was cooled to room temperature and 100 mL of water was added, followed by 100 mL of 1N HCl. The reaction mixture was stirred for 2 hours, filtered through a Celite pad and the layers were separated. The aqueous layer was extracted with diethyl ether and the combined organic fractions were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford 13.45 g (53%) of 2-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:13][CH3:14])([CH2:24][OH:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCC(CC)C(=O)OC
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
5.2 ml (0.037 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 12.9 ml (0.035 mol) of n-butyllithium (2.7 M in heptane) in 17 ml of THF, and the mixture is stirred at 20° C. for 15 min. Within approx. 10 min, 5 g (0.032 mol) of methyl 2-ethylhexanoate are added dropwise at 20° C., and the mixture is stirred at 20° C. for a further 30 min and subsequently admixed with 2.9 g (0.097 mol) of paraformaldehyde. After stirring at 20° C. for 2 hours, a saturated aqueous solution of ammonium chloride (20 ml) is added and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 20 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The yield of pure product is 77% (GC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28]O)[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[NH:30]1[CH2:36][C:34](=[O:35])[NH:33][C:31]1=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:33]4[C:34](=[O:35])[CH2:36][NH:30][C:31]4=[O:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: OCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1CNC(=O)N1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CNC(=O)N1CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethanol (prepared as described in Example 4/50 mg, 0.12 mmol), hydantoin (36 mg, 0.36 mmol) and triphenylphosphine (94 mg) were dissolved in a 1:1 mixture of THF and DMF (1.2 ml). Ditertbutyl azodicarboxylate (69 mg, 0.3 mmol) was added at 0° C. and mixture was stirred at room temperature for 3 hours. After evaporation, the crude mixture was purified by preparative HPLC (column beta-basic, Hypercil 5 μm, 21×100 mm) eluting with a mixture of water and acetonitrile containing 2g/l of ammonium carbonate (gradient) to give the title compound (15 mg, 25%); NMR Spectrum: 3.88 (t, 2H), 3.96 (s, 2H), 4.37 (t, 2H), 5.29 (s, 2H), 7.24 (d, 1H), 7.36-7.38 (m, 1H), 7.58 (d, 1H), 7.78 (dd, 1H), 7.88 (t, 1H), 8.09 (s, 1H), 8.17 (s, 1H), 8.21 (s, 1H), 8.34 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23].N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:31]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=4)=[O:32])[C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 3-bromo-8-(2,6-dichloro-3-methylaminobenzyloxy)-2-methylimidazo[1,2-a]-pyridine (68 mg) and pyridine (0.5 ml) in dichloromethane (2 ml) was added 4-nitrophenyl chloroformate (40 mg) at ambient temperature. After stirring for 1 hour, the mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane twice. The organic layers were combined, washed with water twice and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(4-nitrophenoxycarbonyl)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (84 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].C([O-])(=O)C.[NH4+].[N+:16]([CH3:19])([O-:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
To a solution of 4-chloro-3-fluorobenzaldehyde (8 g, 50.5 mmol) and ammonium acetate (9.72 g, 126 mmol) in acetic acid (168 mL) was added nitromethane (8.16 mL, 151 mmol). The reaction mixture was heated at reflux for 5 h and cooled down. Water (100 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid was filtered, washed by water, and dried under vacuum. The solid was purified by flash chromatography (0-20% EtOAc/heptane) to yield clean product 4.2 g in 41% yield. 1H NMR (400 MHz, CDCl3) δ ppm 7.92 (d, J=13.7 Hz, 1H), 7.54 (d, J=13.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.33 (dd, J=2.0, 9.3 Hz, 1H), 7.31-7.28 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A solution of indole (5.6 g 48 mmol,) in DMF at 0° C. was treated with sodium hydride (1.84 g, 48 mmol), stirred for 10 minutes at room temperature, treated with methyl 4-(bromomethyl)benzoate (10 g, 44 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give a solid residue. The resultant residue was purified by column chromatography (silica, EtOAc:hexanes, 30%) to give the title product in 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 266 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:28][CH2:29][CH3:30])=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:31](Cl)([Cl:33])=[O:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:31]([Cl:33])=[O:32])[C:10]([C:20]3[C:21]([O:28][CH2:29][CH3:30])=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C27H27N6O3SCl2 [(M+H)+] 585.1237, observed 585.1236.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:24]([O-])([N+]([O-])=O)=[O:25]>>[Cl:1][CH2:2][CH2:3][N:4]([N:24]=[O:25])[C:5]([N:7]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: COCC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: COCC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 33.4 %

Procedure:
3.6 g of 1-(2-chloroethyl)-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 1.3 g of 1-(2-chloroethyl)-1-nitroso-3-(1-methyl-2-methoxy-ethyl)-3-(D-galactopyranosyl)urea are thereby obtained as yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:13])[NH:8][C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Br[CH2:33][C:34]([C:36]1[CH:40]=[C:39]([CH3:41])[O:38][C:37]=1[CH3:42])=[O:35]>COCCOC>[CH3:42][C:37]1[O:38][C:39]([CH3:41])=[CH:40][C:36]=1[C:34](=[O:35])[CH2:33][N:8]1[C:7](=[O:13])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=[C:9]1[CH3:12]
Reactant: Cc1cc(C(=O)CBr)c(C)o1
Reactant: CCOC(=O)c1cnc(C)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(C)n(CC(=O)c2cc(C)oc2C)c1=O
Yield: 31 %

Procedure:
5-Ethoxycarbonyl-2-methylpyrimid-4-one (3.5 g, 19 mmol) was dissolved in DME (110 mL) and TBAF (28.5 mL, 1 M solution in THF, 28.5 mmol) added dropwise at 0° C. The resulting solution was stirred ten minutes and a solution of 3-bromoacetyl-2,5-dimethylfuran (4.3 g, 20 mmol) in DME (10 mL) was added dropwise. The reaction was stirred at room temperature overnight. The solution was then concentrated in vacuo and partitioned between EtOAc and saturated aqueous NH4Cl. The EtOAc layer was separated and concentrated. The product was purified using flash silica chromatography (EtOAc/hexane=2:8 to 8:2), with the o-alkylated side product eluting at 4:6, and the desired N-alkylated product eluting at 8:2. The N-alkylated product was dried as a yellow solid, isolated in 31% yield; MS: 319 (M+H) and 273.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30]>>[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH:34][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:2])[CH3:30]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Yield: 76 %

Procedure:
By the same procedure as described in the example 45, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using N,N-diethylethylenediamine. Then, the product was recrystallized using isopropanol and hexane to give the desired compound.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:37][CH2:38][C@H:39]([O:42][C:24]([C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C@H:9]5[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]5)=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:25])[CH2:40][CH2:41]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29]
Reactant: CCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)Cl)cc3)cc2)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(=O)O[C@H]4CC[C@H](c5ccc(CCC)cc5)CC4)cc3)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid chloride obtained was dissolved in 40 ml of benzene and then added dropwise to a solution of 0.90 g of trans-4-(p-propylphenyl)cyclohexanol in 20 ml of pyridine. The mixture was stirred at a bath temperature of 65° C. overnight, then poured into ice-water and extracted with diethyl ether. The extract was washed four times with 25 ml of 3N hydrochloric acid each time, then washed with 25 ml of 2N sodium carbonate solution and several times with water, dried over sodium sulphate and concentrated. The crude 4'-(trans-4-pentylcyclohexyl)-4-biphenylcarboxylic acid trans-4-(p-propylphenyl)cyclohexyl ester obtained was recrystallized once from ethanol containing a small amount of ethyl acetate and once from ethyl acetate. Yield 1.1 g; m.p. (C-S) 131.2° C.; phase transition S-N 143.3° C.; cl.p. (N-I) 337.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([OH:13])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.C(OC([N:39]1[C:43]([CH:44]2[CH2:46][CH2:45]2)=[CH:42][C:41]([NH2:47])=[N:40]1)=O)(C)(C)C>C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:47][C:41]3[NH:40][N:39]=[C:43]([CH:44]4[CH2:46][CH2:45]4)[CH:42]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1C1CC1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 62.7 %

Procedure:
To a solution of 96.8 mg (0.537 mmol) of 2-(1,3-benzodioxol-5-yl)-acetic acid in 3 ml of dichloromethane 360 mg (0.720 mmol) of polystyrene supported dicyclohexylcarbodiimide (loading=2 mmol/g) and 40 mg (0.179 mmol) of tert-butyl-3-amino-5-cyclopropyl-1H-pyrazole-1-carboxylate were added. The mixture was maintained under stirring at room temperature for 96 hours and after that time filtered, washed several times with dichloromethane and evaporated to dryness. The residue was re-dissolved with 3 ml of trifluoroacetic acid 10% V/V in dichloromethane and maintained at room temperature for an hour. The solvent was then evaporated, the residue re-dissolved in dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was evaporated to dryness to give, after trituration with diethylether, 32 mg (63% yield) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:30])[CH:12]([NH:13][C:14](=[O:29])[CH:15]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[NH:16]C(OC(C)(C)C)=O)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:30])[CH:12]([NH:13][C:14](=[O:29])[CH:15]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3cccs3)[C@H]2S1
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3cccs3)[C@H]2S1
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of 2-methyl-7-[N-(tert.-butoxycarbonyl)-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid (2.34 g) in formic acid (10 ml) was stirred for 4 hours at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure from the reaction mixture, and the residue was pulverized by treating with ethyl acetate. The powder (1.79 g) was dissolved in water (40 ml) and the solution was stirred for 30 minutes, and then filtered. The filtrate was lyophilized to give 2-methyl-7-[2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid (1.5 g), mp 145° to 149° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 25 °C

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous cesium carbonate (3.26 g, 10 mmol), 5 ml of dimethylsulfoxide that is dried over 4A molecular sieve, and 15 ml 1,2-dichloroethane are combined and stirred at about room temperature. After 15 hours the mixture is heated to reflux and more cesium carbonate (about 1 more equivalent). HPLC shows the ratio of product to bis alkylated biproduct to starting material is 93.1:6.2: non-detectable. The reaction mixture is cooled to room temperature and diluted with 30 ml of water. The mixture is stirred then the layers separated. The aqueous layer is extracted with 15 ml of methylene chloride and then the combined organics are filtered through sodium sulfate. The filtrate is concentrated in vacuo at about 60° C. to a yellow green oil which solidifies on cooling to give 2.00 g of product. (94.8%). HPLC.