Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])(C1C=CC(C)=CC=1)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.N12CCCN=C1CCCCC2>CN(C=O)C>[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[CH2:22]([OH:23])[CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: OCCOCCOCCOCCO
Temperature: 70 °C

Procedure:
To a stirred solution of 31.96 g (0.092 mol) of 2a in 400 mL of anhydrous DMF was added 14.2 g (1.05 equiv.) of phthalimide and 14.4 mL (1.05 equiv.) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The solution was heated at 70° C. for 18 h then concentrated in vacuo. The crude yellow oil was purified by flash chromatography using 1600 mL of silica gel and eluting with 25% EtOAc-50% EtOAc-75% EtOAc in hexane, then EtOAc, then 10% MeOH-20% MeOH in EtOAc to afford 23.8 g (80%) of 3a as an oil. Upon standing, 3a became a waxy white solid. 1H NMR (300 MHz, CDCl3) d 7.84-7.78 (m, 2H), 7.70-7.66 (m, 2H), 3.86 (t J=5.6 Hz, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.64-3.51 (m, 12H), 2.67 (bs, 1H); 13C NMR (75 MHz, CDCl3) d 168.2, 133.8, 132.0, 123.1, 72.4, 70.5, 70.4, 70.2, 70.0, 67.8, 61.6, 37.2.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][C:16]([N:18]([C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:32])[CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[OH:24])=[O:17]>CC(C)=O>[Cl:14][CH2:15][C:16]([N:18]([C:25]1[C:26]([CH3:32])=[CH:27][CH:28]=[CH:29][C:30]=1[CH3:31])[CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24])=[O:17]
Reactant: Cc1cccc(C)c1N(C(=O)CCl)C1CCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: Cc1cccc(C)c1N(C(=O)CCl)C1CCCC1=O
Yield: 82.7 %

Procedure:
A 4.5-ml (0.004-mol) sample of Jones Reagent (26.72 g chromium trioxide in 23 ml of concentrated sulfuric acid diluted with H2O to 100 ml) was added dropwise to a vigorously stirred solution of 4.4 g (0.016 mol) 2-(N-chloroacetyl-2,6-dimethylphenylamino)cyclopentanol in 100 ml acetone. The acetone solution was decanted from the solids, dried over magnesium sulfate, treated with silica and evaporated under reduced pressure to give 3.7 g of pale yellow oil. The oil was chromatographed on silica gel using mixtures of ethyl ether/hexane as eluant. 2-(N-chloroacetyl-2,6-dimethylphenylamino)cyclopentanone was eluted with 25% ethyl ether/hexane, as a white solid. This product melted at 79°-82° C. after recrystallization from hexane. This product is tabulated in Table I, as Compound No. 1-A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]#[C:5][CH:6]([OH:9])[CH2:7][CH3:8].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:10])[C:4]#[C:5][C:6](=[O:9])[CH2:7][CH3:8]
Reactant: CCC(O)C#CC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)C#CC(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of 4-Hydroxy-hex-2-ynoic acid methyl ester (1.50 g, 10.55 mmol) in dichloromethane (30 mL) was added Des-martin periodinane (6.0 g, 14.14 mmol) and stirred at room temperature for 18 hours. Additional periodinane (4.5 g) was added to the reaction mixture and stirred at room temperature for 6 hours. Aqueous NaHCO3 was added to reaction mixture, and precipitate was filtered and washed with dichloromethane. Aqueous phase was extracted with dichloromethane, and combined organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated under vacuum to afford 1.48 g (100%) of title compound. C7H8O3 (140.04)
Reaction SMILES: N1([O:10][C:11]2[C:12]3[O:19][CH:18]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)[C:13]=3[N:14]=[CH:15][N:16]=2)C2C=CC=CC=2N=N1.[CH3:33][S:34]([C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:10][C:11]2[C:12]3[O:19][CH:18]=[C:17]([CH:20]4[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]4)[C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:39][CH:38]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCC(c2coc3c(On4nnc5ccccc54)ncnc23)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2coc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc23)CC1
Reaction time: 2 h
Yield: 91.8 %

Procedure:
Under an argon atmosphere, the tert-butyl 4-{4-[(1H-benzo[d][1,2,3]triazol-1-yl)oxy]furo[3,2-d]pyrimidin-7-yl}piperidine-1-carboxylate (10 mg, 0.023 mmol) obtained in Step 7 of Example 1 and 4-(methylsulfonyl)phenol (4 mg, 0.023 mmol) were dissolved in anhydrous N,N-dimethyl formaldehyde (0.5 mL), potassium carbonate (5 mg, 0.035 mmol) was added, stirring was conducted at room temperature for 2 hours, water was added, followed by extraction with toluene. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (hexane:ethyl acetate=1:2) to give the titled compound (10 mg, 89%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8](C)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](I)[CH3:21]>>[CH3:19][N:2]([CH3:1])[C:3]([C:4]1([N:5]2[CH:9]=[CH:8][C:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:6]2)[CH2:17][CH2:21][CH2:20]1)=[O:18]
Reactant: CCI
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Product: CN(C)C(=O)C1(n2ccc(-c3ccccc3)n2)CCC1

Procedure:
Following the procedure of Example 95, but substituting α-(3-bromopropyl)-N,N-dimethyl-3-phenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and without addition of ethyl iodide there was obtained N,N-dimethyl-1-(3-phenylpyrazol-1-yl)cyclobutanecarboxamide having a boiling point of 170°/0.1 mm.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:10]1[C:11]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[OH-].[Na+]>O1CCCC1.CO.O>[C:34]([O:33][C@@H:9]([C:10]1[C:11]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15]([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH:14]=[CH:13]2)[CH2:8][OH:7])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc2nc(-n3ccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc2nc(-n3ccnc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 45 °C
Yield: 98.2 %

Procedure:
To a solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-7-methylquinolin-6-yl)ethyl pivalate (39.2 mg, 0.075 mmol) in tetrahydrofuran and methanol (5:1, 1 mL) was added 1 M sodium hydroxide (2 mL) and the reaction was heated to 45° C. overnight. The reaction was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude extract was co-evaporated two times with acetonitrile to give a clear white oil (32.1 mg). LCMS-ER+ (m/z): [M+H]+ calcd for C25H27ClN3O2: 436.17. found: 436.86.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH:5]([C:14]([O:17]CC)(F)[F:15])([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].C(F)C>C(C(Cl)=O)(C(F)(F)F)C(F)(F)F.C(OCC)C>[CH:5]([C:14]([F:15])=[O:17])([C:6]([F:8])([F:7])[F:9])[C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(F)(F)C(C(F)(F)F)C(F)(F)F
Agent: CCF
Agent: O=C(Cl)C(C(F)(F)F)C(F)(F)F
Agent: [Al+3]
Solvent: CCOCC
Product: O=C(F)C(C(F)(F)F)C(F)(F)F
Yield: 36.7 %

Procedure:
The above ethyl ether, 43 g (0.175 mol), in a 100 ml flask equipped as described in Example 6 was mixed with 1 g (0.0075 mol) of AlCl3. The mixture was refluxed for 17 hours. Material condensed in the attached Dry Ice-acetone trap was combined with residual material in the flask and distilled in a low-temperature still. An amount of 30.8 g of unreacted (CF3)2CHCF2OC2H5 was recovered, together with 9.1 g (26.3% yield) of (CF3)2CHCOF, 2.2 g of C2H5F and 0.1 g of (CF3)2CHCOCl. No improvement in product yield was obtained when the reactants were heated in a sealed tube at 120° for 4 hours.
Reaction SMILES: C(OCC)(=O)C.[ClH:7].[C:8]1([C@H:14]([CH3:26])[C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)C>C(OCC)(=O)C>[ClH:7].[C:8]1([C@H:14]([CH3:26])[C:15]([NH:17][NH2:18])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H](C(=O)NNC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@H](C(=O)NN)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4 N hydrogen chloride-ethyl acetate (2 mL) was added to a suspension of tert-butyl N′-((S)-2-phenylpropionyl)hydrazinecarboxylate (470 mg) in ethyl acetate (4 mL), and the reaction solution was stirred at room temperature overnight. Diethyl ether (6 mL) was added to the reaction solution, and the precipitated powder was collected by filtration. The resulting solid was dried under reduced pressure to obtain 280 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([SH:9])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl>CCOCC>[C:1]([N:4]1[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:7])([CH3:8])[S:9][C@@H:18]1[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)(C)S
Agent: Cl
Solvent: CCOCC
Product: CC(=O)N1[C@@H](c2ccc(F)cc2)SC(C)(C)[C@@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A solution containing 5.74 g (30 mmoles) of N-acetyl-D-penicillamine and 3.2 ml of 4-fluorobenzaldehyde in 20 ml of ether saturated with gaseous hydrogen chloride is stirred. After 5 to 6 minutes an oil separates which becomes crystalline after 30 minutes on rubbing. The precipitate is filtered out and washed with ether to give the title acid in a yield of 7.81 g (87.1%) which can be recrystallized from ethyl acetate, m.p. 144°-146° C., [α]D20 =+206.9°.
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([F:15])[C:3]=1C=NO.[C:19](OCC)(=[O:21])C>C(O)C.C(O)(=O)C.[Ni]>[F:15][C:4]1[CH:3]=[C:2]([CH:19]=[O:21])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(C=NO)c1F
Reactant: CCOC(C)=O
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(C=O)cc1F
Reaction time: 1 h
Yield: 56 %

Procedure:
tert-Butyl 4-amino(hydroxyimino)methyl-2-fluorobenzoate (WO 2011/016469) (3.90 g, 17.6 mmol) was dissolved in ethanol (40 mL) and acetic acid (40 mL). Raney nickel (ca. 10 g) was added to the mixture at room temperature, and the resulting mixture was stirred for 1 hour under hydrogen flow. After the insoluble material was removed by filtration through Celite, water was added to the filtrate, and the resulting mixture was extracted three times with ethyl acetate, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and then water and a saturated aqueous solution of sodium hydrogen carbonate were added to the mixture. The resulting mixture was extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→2:1, v/v) to give the title compound (2.21 g, yield: 56%).
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([NH:1][CH:2]=[C:3]([C:8](=[O:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:21]
Reactant: COC(=O)C(=CN)C(C)=O
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=CNC(=O)C(Cl)(Cl)Cl)C(C)=O

Procedure:
Methyl 2-aminomethylene-3-oxobutanoate (1.4 g) in methylene chloride (20 ml) was treated with triethylamine (2.0 ml) and trichloroacetyl chloride (2.0 ml) while stirring at 20°-25° C. The mixture was stirred for 4 hours at 20° C. to give a solution of the title compound, which was used immediately to prepare the dihydropyran of Example 15 without isolation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1B(O)O>>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:4]1[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1ccco1
Reactant: Nc1cccc(Cl)n1
Product: Nc1cccc(-c2ccco2)n1
Yield: 85.8 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from 2-amino-6-chloropyridine (925.64 mg; 7.20 mmol; 1.0 eq.) and 2-furanboronic acid (1.21 g; 10.8 mmol; 1.5 eq.). The crude was purified by flash chromatography (EtOAc/c-Hex, gradient from 25:75 to 40:60) to give the title compound (990 mg; 86%). HPLC, Rt: 1.33 min. (purity 99.9%). LC/MS, M+(ESI): 161.0.
Reaction SMILES: N1CCCCC1.[CH2:7]([CH2:10][NH2:11])[CH:8]=[CH2:9].[OH:12][C:13]1([CH:25]([CH3:38])[CH2:26]C2C=C(S([O-])(=O)=O)C=CC=2C)[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:7]([CH2:10][NH:11][CH2:38][CH:25]([C:13]1([OH:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:26])[CH:8]=[CH2:9]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CC(C)C1(O)CCCCC1c1ccccc1
Reactant: C=CCCN
Solvent: C1CCNCC1
Product: C=CCCNCC(C)C1(O)CCCCC1c1ccccc1

Procedure:
The procedure of Example II is followed except that piperidine is replaced by allylmethylamine. Starting with 12 g allylmethylamine and 30 g of tosylate (Compound III), 5.9 g of product is obtained.
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH:37]=O.O>O1CCCC1.C(O)C.[Pd]>[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:37][C:36]1[CH:35]=[C:34]([F:33])[CH:41]=[C:40]([F:42])[CH:39]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: [Br-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1cc(F)cc(CCC2OCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To 95.0 g (221 mmol) of dried 1,3-dioxolan-2-ylmethyl triphenylphosphonium bromide was added 800 ml of tetrahydrofuran (hereinafter abbreviated as “THF”), and the mixture was cooled to 0° C. 25.0 g (223 mmol) of potassium-t-butoxide was gradually added thereto at that temperature and the mixture was stirred for one hour. To the resulting mixture was added dropwise a solution of 25.0 g (176 mmol) of 3,5-difluorobenzaldehyde in 50 ml of THF and the mixture was stirred at 0° C. for one hour and then stirred at room temperature for 12 hours. 500 ml of water was added thereto and the reaction product was extracted with toluene. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluting solvent: toluene) and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in 600 ml of ethanol and the resultant solution was hydrogenated with 5% palladium/carbon as a catalyst and filtered to separate the catalyst. The solvent was distilled off under reduced pressure to afford 30.9 g (154 mmol) of 1-(1,3-dioxolan-2-ylethyl)-3,5-difluorobenzene. (Yield: 87.5%)
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:41])([CH3:40])[O:14][Si:15]([CH3:39])([CH3:38])[O:16][Si:17]([CH3:37])([CH3:36])[O:18][Si:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)([CH3:21])[CH3:20])=[CH:6][CH:5]=1)([O-])=O.[H][H]>>[NH2:1][C:4]1[CH:43]=[CH:42][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:40])([CH3:41])[O:14][Si:15]([CH3:39])([CH3:38])[O:16][Si:17]([CH3:37])([CH3:36])[O:18][Si:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=2)([CH3:20])[CH3:21])=[CH:6][CH:5]=1
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)CCCCOc1ccc(N)cc1
Yield: 99.6 %

Procedure:
2.26 g of the above 2b (3.38 mmol) and 15 mL of a 10 wt % Pd/C ethyl acetate solution (0.0209 g) were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material of 1,7-bis(4-aminophenoxybutyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3c) (2.05 g, 99% of yield) represented by the following formula. Various measurements were carried out with regard to the obtained 1,7-bis(4-aminophenoxybutyl)-1,1,3,3,5,5,7,7-octamethyltetrasiloxane (3c), and results are shown below.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15](I)[CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[CH:18]=[C:17]([CH:10]([NH2:11])[C:6]2([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:7][CH2:8][CH2:9]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(I)c1
Reactant: N#CC1(N2CCCC2)CCC1
Product: NC(c1cccc(F)c1)C1(N2CCCC2)CCC1

Procedure:
The title compound, yellow, oil, MS: m/e=249.2 [(M+H)+], was prepared in accordance with the general method of intermediate K from 1-pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) and 3-fluoro-iodobenzene.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:11]O)(=[O:10])[CH3:9]>>[C:8]([OH:11])(=[O:10])[CH3:9].[C:8]([OH:11])(=[O:10])[CH3:9].[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OO
Solvent: Ic1ccccc1
Product: CC(=O)O
Temperature: 30 °C

Procedure:
40.8 g (0.2 mol) of iodobenzene were charged to a 300 ml round bottom flask equipped with thermometer and vented addition funnel. 91.2 g (0.48 mol) of a 40% aqueous solution of peracetic acid was added dropwise to the flask over a 25-minute period while maintaining the flask at 30° C. in a water bath. After about 1 hour a yellowish white solid formed. The reaction mixture was cooled in ice and the solid collected, washed with water and vaccuum dried at 40° C. The iodobenzene diacetate product weighed 40.6 g and had a melting point in the range of 157°-160° C.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([OH:14])([CH3:13])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(C(=O)O)c1ccc(-c2ccccc2)cc1
Reaction time: 3 h
Yield: 72 %

Procedure:
The crude ethyl 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate was saponified by treating with 100 mL of ethanol and 100 mL of 4.0M NaOH solution. The suspension was stirred for 3 hours, after which a clear solution formed The solution was concentrated, diluted with 150 mL of H2O, washed with 2×50 mL of ether, and acidified to pH 1 with 10% HCl solution. The aqueous phase was extracted with 3×100 mL portions of ether and the combined ether extracts were washed with 50 mL of H2O, 50 mL of brine, dried (MgSO4) and concentrated leaving 18.3 g (72% yield) of racemic 2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionic acid as a white solid after was recrystallization from CHCl3 and hexanes.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:9][CH:14]([CH3:15])[CH3:13])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Br
Reactant: CC(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC(C)C)c([N+](=O)[O-])cc1Br

Procedure:
To a mixture of 4-Bromo-5-methyl-2-nitro-phenol from the previous step (0.66 g, 2.84 mmol), 2-propanol (0.262 mL), and triphenylphosphine (894 mg) in 10 mL THF is added diisopropyl asodicarboxylate (0.671 mL) at 22° C. The reaction mixture is concentrated in vacuo. The residue is purified using a SiO2 column (ISCO), affording 1-Bromo-4-isopropoxy-2-methyl-5-nitro-benzene as a bright yellow solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]1[O:31]C(C2CCNCC2)=N[N:34]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O/[N:42]=[C:43](\[CH:45]1[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]1)/N>CN(C=O)C.CCOC(C)=O>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]1[O:31][N:42]=[C:43]([CH:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2)[N:34]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)o2)N1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(/C(N)=N\O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2noc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
CDI (511.3 mg, 3.1 mmol) was added to a solution of crude (2S,5R)-6-(benzyloxy)-2-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (726 mg, 2.6 mmol) in DMF (15 mL). The mixture was stirred at rt for 1 h, then, (E)-tert-butyl 4-(N′-hydroxycarbamimidoyl)piperidine-1-carboxylate (631.8 mg, 2.6 mmol) was added at rt. The mixture was stirred at rt for 2 hrs, and then stirred at 50° C. for another 6 hrs. The mixture was diluted with EtOAc (150 mL) and washed with 1 M HCl (2×), water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (1:5 to 1:1 EtOAc/hexanes) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (968 mg, 76%) as a white solid. ESI-MS (EI+, m/z): 506.2 [M+Na]+. 1H-NMR (400 MHz, CDCl3): δ 7.47-7.36 (m, 5H), 4.99-4.94 (m, 2H), 4.73 (d, J=6.0 Hz, 1H), 3.93 (d, J=9.6 Hz, 1H), 3.72 (s, 1H), 3.08-2.90 (m, 4H), 2.72 (d, J=9.6 Hz, 1H), 2.15 (dd, J=12.0, 5.2 Hz, 1H), 2.09-1.93 (m, 5H), 1.85-1.79 (m, 1H), 1.59-1.50 (m, 2H), 1.40 (s, 9H).