Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[H-].[Na+].[C:13](=O)([O:16]C)[O:14][CH3:15].Cl.[Na+].[Cl-]>C1COCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:13](=[O:16])[O:14][CH3:15])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: COC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(C)cc(OC)n1
Reaction time: 0.5 h

Procedure:
2-Amino-4-methoxy-6-methylpyrimidine (50 g) was added portion wise to 50% sodium hydride (42.8 g) in 1 L dry THF. After stirring for 1/2 hour, dimethyl carbonate (58.5 g) was added dropwise with cooling. The mixture was stirred under nitrogen for ~16 hours at ambient temperature. Concentrated HCl (80 ml) was added slowly and using external cooling a pot temperature of ~25° C. was maintained. Saturated aqueous NaCl (80 ml) was then added. The solvents were decanted from the precipitated solids and dried over Na2SO4. Filtering and evaporating the solvents afforded the crude material which was recrystallized from hexane. 54 g m.p. 89-92.5° C. The infrared spectrum showed characteristic absorption bonds at 3400 and 1760 cm-1.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>COCCOC>[CH2:14]([N:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]1[CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(C)=O
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 20 °C

Procedure:
Ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 3.2 9 of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 16.4 cm3 of triethyl phosphonoacetate and 9.5 g of 3-hydroxy-2benzyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and then with 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (75/25 and then 67/33 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 8.7 g of ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous yellow oil. (Rf=0.35, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2OS(C)(=O)=O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl.CO>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: -30 °C
Reaction time: 4 h
Yield: 55.7 %

Procedure:
To a solution of 3-methanesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3c) in dichloromethane (7 parts) cooling at -25° to -20° C. under nitrogen are added pyridine (2 equivalents) and phosphorus pentachloride (1.7 equivalents). After stirring at -15° to -10° C. for 4 hours, the mixture is diluted with methanol (12 parts) cooled at -40° to -30° C. After stirring for 30 minutes at -30° C. and for 2.5 hours at 0° to 5° C., the mixture is cooled to -30° C., mixed dropwise with triethylamine (8.1 equivalents) and let stand overnight at 0° to 5° C. The mixture is diluted with dichloromethane and ice-water and stirred for 20 minutes at 0° to 5° C. The formed organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield: 55.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:18][CH:17]=2)=[S:12])=[C:5]([CH3:38])[CH:4]=1.Br[CH2:40][C:41](OC)=[O:42]>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:41](=[O:42])[CH2:40][S:12]/[C:11]/2=[N:13]/[N:14]=[CH:15]\[C:16]2[CH:17]=[CH:18][C:19]([C:22]3[N:26]=[CH:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[N:23]=3)=[CH:20][CH:21]=2)=[C:5]([CH3:38])[CH:4]=1
Reactant: COc1cc(C)c(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Reactant: COC(=O)CBr
Solvent: CCO
Solvent: O
Product: COc1cc(C)c(N2C(=O)CS/C2=N/N=C\c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C)c1
Temperature: 70 °C
Yield: 76.1 %

Procedure:
To a solution of (E)-N-(4-methoxy-2,6-dimethylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazine-carbothioamide (250 mg, 0.462 mmol) in EtOH (5 mL) was added methyl bromoacetate (100 mg, 0.65 mmol), and the mixture was heated to 70° C. for 4 h. The mixture was allowed to cool to room temperature and diluted with water (1 mL). The precipitate was vacuum filtered, giving the title compound as a white solid (204 mg, 76%): mp 188-190° C.; 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.33 (s, 1H), 8.22 (d, J=8.1 Hz, 2H), 7.90-7.70 (m, 4H), 7.39 (d, J=8.7 Hz, 2H), 6.72 (s, 2H), 4.01 (s, 2H), 3.87-3.73 (s, 3H), 2.18 (s, 6H); ESIMS m/z 581 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.Cl.[O:28]([NH2:30])[CH3:29]>CCO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:19]2[C:18](=[N:30][O:28][CH3:29])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CCCc2[nH]cc(C(=O)Nc3ccccc3F)c21
Temperature: 120 °C
Yield: 72.7 %

Procedure:
4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide (0.73 mmol), pyridine (2.2 mmol), EtOH (10 ml) and methoxylamine hydrochloride (2.2 mmol) are combined in a sealed tube and heated at 120° C. for 16 hours. The reaction mixture is cooled to room temperature, the solvent is removed in vacuo and the residue is treated with 10 ml of H2O for 5 minutes. The resulting solid is collected by vacuum filtration to yield 160 mg (72%) of 4-methoxyimino-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (2-fluoro-phenyl)-amide as a white solid. 1H NMR (DMSO-d6) δ1.80-1.86 (m, 2H), 2.62-2.73 (m, 4H), 3.81 (s, 3H), 7.10-7.29 (m, 3H), 7.48 (d, 1H), 8.01 (t, 1H), 11.70 (s, 1H), 11.81 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([OH:31])=O)[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.CCCP(=O)=O.Cl.[CH3:48][O:49][C:50](=[O:53])[CH2:51][NH2:52]>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29]([NH:52][CH2:51][C:50]([O:49][CH3:48])=[O:53])=[O:31])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)CN
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1cncc2c1CCN(c1cccc(C(=O)Nc3cccc(C(C)C)c3)c1)C2
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 64.2 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (40 mg, 0.096 mmol), N,N-diisopropylethylamine (0.067 mL, 0.39 mmol), and catalytic DMAP in 2.5 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.069 mL, 0.116 mmol). After 6 min at rt, glycine methyl ester hydrochloride (18.1 mg, 0.144 mmol) was added and the reaction stirred at rt for 4 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc plus 10% MeOH to give the title compound as a light yellow solid (30 mg, 64%). 1H NMR (CDCl3) δ: 8.55 (s, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.53 (d, J=11.4 Hz, 2H), 7.47 (d, J=7.3 Hz, 1H), 7.33-7.40 (m, 1H), 7.20-7.32 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.62 (t, J=5.1 Hz, 1H), 4.47 (s, 2H), 4.24 (d, J=5.3 Hz, 2H), 3.81 (s, 3H), 3.56-3.61 (m, 2H), 3.20 (t, J=5.6 Hz, 2H), 2.85-2.99 (m, 1H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:27])[NH:19][C:18]([CH3:28])=[C:17]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[C:34]1([O:40][CH2:41][CH:42]2[O:44][CH2:43]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO>[OH:44][CH:42]([CH2:41][O:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:43][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[CH:16]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH3:27])[NH:19][C:18]([CH3:28])=[C:17]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCN
Solvent: CO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc([N+](=O)[O-])ccc1OCCCCNCC(O)COc1ccccc1
Yield: 31.9 %

Procedure:
In 500 ml of methanol were dissolved 5.2 g of diethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and 1.7 g of glycidyl phenyl ether, and the solution thus formed was refluxed under heating for 16 hours. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chlroform-methanol (95:5 v/v). Crude crystals were recrystallized from ethanol to give 2.2 g of diethyl 4-[2-[4-(2-hydroxy-3-phenoxypropylamino)butoxy]-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:6][NH:5][C:4](=[O:7])[CH:3]1[O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[H-].[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[C:24]([N:5]1[CH2:6][C:2]([CH3:21])([CH3:1])[CH:3]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:18])([F:20])[F:19])[CH:10]=2)[C:4]1=[O:7])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)CNC(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CN(C(=O)c2ccccc2)C(=O)C1Oc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirring solution of 4-(4,4-dimethyl-2-oxo-pyrrolidin-3-yloxy)-2-trifluoromethyl-benzonitrile (Product of Example 3, 250 mg, 0.84 mmol) in anhydrous THF (5 mL) was added NaH (40 mg, 1 mmol) under N2 at RT (room temperature). After stirring for 15 minutes, benzoyl chloride was added (0.14 mL, 1 mmol) as a solution in THF (1 mL). After stirring at RT overnight sat. NH4Cl (25 mL) and ethyl acetate (150 mL) were added. The separated organic phase was treated with brine and dried over MgSO4. The solution was then filtered, concentrated down, and purified by column chromatography (small Biotage silica gel column, 2:1 Hex/EA). Combined cleanest fractions to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=3[OH:37])[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=3[OH:37])[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCc1ccc(O)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Solvent: CO
Product: CCc1ccc(O)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)c1
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g, 1.1 mmol) was added to a solution of 6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.3 g, 0.91 mmol Example A(169)) in MeOH (8 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (47 mg, 0.80 mmoL). After 24 hours the reaction mixture was filtered through a glass frit to remove a fine white ppt. The filtrate was concentrated and purified by prep HPLC to give the product (175 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ: 1.07 (t, J=7.6 Hz, 3H), 1.41-1.72 (br m, 8H), 1.97 (m, 1H), 2.10 (m, 1H), 2.41-2.73 (m, 13H), 3.70 (d, J=16.2 Hz, 1H), 3.79 (d, J=16.2 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 7.02 (s, 1H), 9.02 (s, 1H), 10.88 (s, 1H). MS (ESI): 491.20 (M+H+).
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:14][N:13]([CH3:15])[C:9](=[O:10])[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:11][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:29]2[N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[C:31]3[C:36]([N:37]=2)=[CH:35][N:34]=[CH:33][N:32]=3)[CH2:26][CH2:27]1
Reactant: c1ccc(Cn2c(NC3CCNCC3)nc3cncnc32)nc1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(CCN1CCC(Nc2nc3cncnc3n2Cc2ccccn2)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 3.46 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 3.1 parts of N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 80° C. after cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 4.1 parts (71%) of N,N-dimethyl-α,α-diphenyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinebutanamide; mp. 191.6° C. (compound 122).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>C(Cl)Cl.CO>[ClH:26].[ClH:32].[Cl:26][C:21]1[CH:20]=[C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:16]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Reaction time: 0.5 h

Procedure:
Dissolve 4-(4-(3-chloro-4-fluorophenyl)-1-(2-(dimethylamino)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (194 mg; 0.43 mmol) in DCM (5 mL) and methanol (3 mL) and add 4 M hydrogen chloride in dioxane (5 mL; 20 mmol). Stir 30 min and evaporate; add DCM/MeOH and evaporate under vacuum to provide the title compound (245 mg) as a white solid. MS (ES): m/z=351 (M+H).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31](S(O)(=O)=O)=[CH:30][CH:29]=1>C(O)C1C=CC=CC=1>[CH:1]([CH:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:27])[CH2:21][O:22][CH2:23][C:24]([O:26][CH2:38][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:18][CH2:19]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Product: O=C(COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1)OCc1ccccc1

Procedure:
In a similar operation, 3.63 grams (10 millimoles) of [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetic acid, 50 milliliters of benzyl alcohol and 150 milligrams of p-toluenesulfonic acid are mixed together and the resulting mixture heated at reflux temperature for about 6 hours to obtain a product in the reaction mixture. Thereafter, the reaction mixture subjected to reduced pressure to evaporate the alcohol and the residue is dissolved in benzene, the resulting solution washed with bicarbonate solution, dried and the solvent evaporated to obtain a benzyl [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetate product. The molecular weight of benzyl [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetate is 453.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:41](Br)[CH:42]=[CH2:43].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:30])[CH:10]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[S:21]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)(=[O:23])=[O:22])[CH2:43][CH:42]=[CH2:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: COc1cc(CC(=O)OCc2ccccc2)c(S(=O)(=O)N2CCOCC2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCc1ccccc1)c1cc(OC)c(OC)cc1S(=O)(=O)N1CCOCC1
Temperature: -78 °C
Yield: 99.2 %

Procedure:
To a stirred mixture of [4,5-dimethoxy-2-(morpholine-4-sulfonyl)-phenyl]-acetic acid benzyl ester (3.00 g, 6.89 mmol) in anhydrous tetrahydrofuran (50 cm3) under an atmosphere of dry nitrogen cooled to −78° C. in an dry ice/acetone bath was added a 1 M solution of lithium bis(trimethylsilyl)amide (7.60 cm3, 7.60 mmol) in tetrahydrofuran dropwise over 5 minutes. The mixture was warmed to 0° C. in an ice bath for 30 minutes to dissolve all solids and cooled again to −78° C. in an dry ice/acetone bath. Neat allyl bromide (0.720 cm3, 8.27 mmol) was added at −78° C. over 5 minutes and the solution warmed to ambient temperature over 2 hours. Saturated ammonium chloride solution (30 cm3) was added and extracted with ethyl acetate (3×40 cm3). The combined ethyl acetate extracts were washed with brine solution (30 cm3), dried over sodium sulfate, vacuum filtered and the filtrate volatile fractions removed in vacuo to afford the title compound as a golden oil (3.25 g, 99.4%) with a positive ion ESI (M+H)+476.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH2:26][C:27](=[O:29])[CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[C:26](/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)\[C:27](=[O:29])[CH3:28])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CC(=O)Cc1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(=O)/C(=C\c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 3-benzyloxy-4-nitrobenzaldehyde (83, step A) (1.16 g, 4.5 mmol) and 1-phenylpropane-2-one (0.726 g, 5.4 mmol) in toluene (50 mL) is added a catalytic amount of piperidine/glacial acetic acid and the mixture is refluxed for 3 h using a Dean-Stark apparatus. The mixture is cooled to room temperature and concentrated under reduced pressure. The crude material is purified by flash chromatography using a gradient of 15-50% EtOAc/hexane as eluent to give the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]1[CH2:21][S:18](=[O:20])(=[O:19])[O:17][CH2:16]1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:16][CH2:15][CH2:21][S:18]([OH:20])(=[O:19])=[O:17])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCO1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Solvent: CO
Product: O=S(=O)(O)CCCN1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-bromophenyl)-4-piperidinol (2.51 g, 9.8 mmol) in MeOH (25 mL) was added 1,3-propane sultone (1.28 g, 10.7 mmol). The mixture was stirred at reflux for 2 h. Only a small amount of compound precipitated. The resulting suspension was cooled to room temperature with stirring and a solution of 50% MeOH/Acetone was added to precipitate a maximum of compound. The solid was collected by filtration, washed with 50% MeOH/Acetone (2×25 mL) and dried in vacuo. This allowed the isolation of compound G, 2.11 g (57%).
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:28](=[O:29])[N:6]2[CH:7]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8](=C)[CH2:9][S:10][C@H:5]12)=[O:2].[O:30]=[O+][O-].CSC>C(Cl)Cl.CO>[CH:1]([NH:3][CH:4]1[C:28](=[O:29])[N:6]2[C:7]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:8]([OH:30])[CH2:9][S:10][C@H:5]12)=[O:2]
Reactant: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzhydryl 7-formamido-3-methylenecepham-4-carboxylate (40.8 g) in methylene chloride (300 ml) and methanol (1.2 l) was cooled at -74° C. in a dry ice-acetone bath. A theoretical amount of ozone was blown through the solution at -74° C. for 10 minutes with stirring, and nitrogen gas was blown through the solution at -74° C. for 10 minutes. Dimethyl sulfide (20 ml) was added to the solution at -74° C. The mixture was slowly warmed to ambient temperature and evaporated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The eluent was evaporated in vacuo to give benzhydryl 7-formamido-3-hydroxy-3-cephem-4-carboxylate (34.4 g).