Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].O>CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-].ClCCl>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reaction time: 8 h

Procedure:
Ethyl N-(3-nitroquinolin-4-yl)-β-alaninate (62.0 g, 214 mmol, prepared as described in Part A of Example 22) was treated with sodium hydrosulfite (130.59 g, 750.04 mmol), potassium carbonate (117 g, 847 mmol), and ethyl viologen dibromide (0.802 g, 2.14 mmol) according to a modification of the method described in Part A of Example 8. After the reaction was stirred overnight, additional water (100 mL), dichloromethane (100 mL) and sodium hydrosulfite (20.0 g, 11.5 mmol) were added, and the reaction was stirred for three additional hours. The organic layer was separated; washed sequentially with water, saturated aqueous sodium bicarbonate, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to provide 40.2 g of ethyl N-(3-aminoquinolin-4-yl)-β-alaninate.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[C:10]([Cl:16])[CH:9]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>O>[Cl:14][C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([Cl:16])[C:11]=1[O:15][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3c(Cl)cc(N)cc3Cl)c2cc1OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
Sodium hydride (60 wt %, 0.36 g) was added to dimethyl sulfoxide (10 ml), and the mixture was stirred at 50° C. for 30 min and was then cooled to room temperature. 4-Amino-2,6-dichlorophenol (1.59 g) was added to the cooled mixture, and the mixture was stirred at room temperature for 10 min. Next, 4-chloro-6,7-dimethoxyquinoline (1.00 g) was added thereto, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (1/1) to give 0.35 g (yield 22%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][OH:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:27]I>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([CH2:23][O:24][CH3:27])[N:12]2[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC1CCC(c2ccc(F)cc2)N1S(=O)(=O)c1ccc(C)cc1
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred and cooled (0° C.) solution of (2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol in THF (10 ml) was added sodium hydride (147 mg, 3.66 mmol, 60%) and the reaction mixture was stirred at room temperature for 1 h. Subsequently methyl iodide (0.34 ml, 5.5 mmol) was added at 0° C. and stirring was continued for 3 h at room temperature. Aqueous work-up and crystallization from ethyl acetate/hexane yielded the title compound as a white solid (0.53 g, yield 79%), m.p. 152° C. and MS: m/e=364.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][C:14]([CH3:16])=O.C(N(CC)CC)C>CO>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][NH:11][C:14]1([CH3:16])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)NCc1ccccc1
Reactant: CC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)NCC(=O)N1Cc1ccccc1

Procedure:
To a solution of N1-benzylglycinamide (3.00 g, 14.95 mmol) in MeOH (25 mL) were added acetone (5.50 mL, 74.75 mmol) and triethylamine (1.67 mL, 11.96 mmol). The solution was stirred and heated to reflux overnight under an atmosphere of nitrogen. The solvent was removed in vacuo, and the resulting orange oil was purified by flash column chromatography on silica gel using a gradient elution of 0-7% (MeOH/NH3)/CH2Cl2. Collection and concentration of the appropriate fractions afforded the product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 5H), 4.44 (s, 2H), 3.55 (s, 2H), 1.26 (s, 6H); ES MS (M+1)=205.
Reaction SMILES: [Mg].[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.Cl>C1(C)C=CC=CC=1>[CH2:6]([O:2][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([Br:7])=[CH:9][CH:10]=3)[CH2:15][CH:16]=2)=[CH:9][CH:10]=1)[CH2:5][CH2:4][CH3:3]
Reactant: C1CCOC1
Reactant: O=C1CCC(c2ccc(Br)cc2)CC1
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCOCCc1ccc(C2=CCC(c3ccc(Br)cc3)CC2)cc1
Temperature: 110 °C

Procedure:
Metallic magnesium (6.9 g, 0.28 mol) was introduced into a completely dried 1 l three-neck flask and the inside of the vessel was completely dried by passing dry nitrogen gas through it, followed by adding anhydrous tetrahydrofuran (50 ml) and a trace of iodine. An anhydrous tetrahydrofuran solution (146 ml) of 4-brom-1-(β-butyloxyethyl)-benzene (X1V) (73 g, 0.28 mol) was gradually added with stirring, while the temperature was maintained at 30°~35° C., followed by further reaction at the same temperature for 1.5 hour. The reaction liquid was ice-cooled to reduce the inner temperature down to 5° C. or lower, followed by adding an anhydrous tetrahydrofuran solution (146 ml) of 4-(p-bromophenyl)-cyclohexanone (X111) (72 g, 0.28 mol) obtained in Step G, at such a rate that the inner temperature did not exceed 10° C. After reaction at room temperature for 30 minutes, a small amount of 6 N--HCl was added to make the contents weakly acidic, followed by adding toluene (200 ml), separating the toluene layer from the aqueous layer, subjecting the aqueous layer to extraction with toluene (50 ml), combining the toluene layers together, washing the combined layers with water and removing toluene by concentration of the layers. To the resulting residue were added toluene (200 ml) and potassium hydrogen sulfate (10 g) and the mixture was heated and placed under reflux at 110° C. for one hour. After cooling, the toluene solution was washed with water to make it neutral, followed by removing toluene by concentration of the solution. The resulting raw crystals were recrystallized from ethanol (200 ml) to obtain 1-[p-(β-butyloxyethyl)-phenyl]-4-(p-bromophenyl)-cyclohexene (XV) (57.5 g) having a melting point of 86.5°~89.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](F)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([S:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=S(=O)(F)c1cccc(Br)c1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a stirred solution of 3-bromophenylsulfonyl fluoride (D1) (1 g, 4.18 mmol) in dry THF (20 ml) at −78° C., under argon was added phenylmagnesium bromide (1 M, 1.4 ml, 4.18 mmol) dropwise. The reaction was left to warm to room temperature overnight and then quenched with ammonium chloride (50 ml), extracted with ethyl acetate (3×40 ml) and the combined organic extracts dried (Na2SO4). Solvents were evaporated in vacuo to give a colourless solid (1.09 g, 88%).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Br[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>C(COC)OC.CCOCC>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(Oc2nccs2)CC1
Reaction time: 1 h
Yield: 85 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 5.67 g) in dimethoxyethane (40 ml) was added a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (23.9 g) in dimethoxyethane (60 ml) over 30 minutes, and the mixture was stirred for an additional 1 hour. To the mixture was added 2-bromothiazole (15.0 g), and the mixture was refluxed for 4 hours. After cooling, the resulting pale brown suspension was diluted with ether (300 ml) and the mixture was filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (eluent; 15% ethyl acetate in n-hexane) to give the title compound (22.1 g) as a yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:24]#[N:25])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])C.[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27]>CCO>[C:26]([O:30][C:31](=[O:37])[C:32]([CH3:36])([CH3:35])[CH2:33][NH:34][C:4]([C:6]1[N:7]=[C:8]([C:24]#[N:25])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH:10]=2)=[O:5])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccnc3)ccc2c1O
Yield: 80.1 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-(pyridin-3-yloxy)-isoquinoline-3-carboxylic acid ethyl ester (19 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (25 mg) in EtOH (0.3 mL) was microwaved at 140° C. for 1 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (21 mg). LC MS ESI+: 463 (M+1)+.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C([Cl:18])=O.CN(C)C=O>O1CCCC1>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([Cl:18])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)O)c2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoic acid (139 mg, 0.742 mmol) in tetrahydrofuran (7.0 mL) were added oxalyl chloride (80 μL, 0.929 mmol) and N,N-dimethylformamide (about 20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyanocyclopropyl)benzoyl chloride as a pale-brown oil.
Reaction SMILES: C([O:3][P:4]([CH2:24][N:25]1[C:29](=[O:30])[CH2:28][NH:27][C:26]1=[O:31])([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])C.Br[Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:31]=[C:26]1[NH:27][CH2:28][C:29](=[O:30])[N:25]1[CH2:24][P:4]([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[OH:5]
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CNC1=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)CNC1=O
Yield: 97.8 %

Procedure:
60 mg (0.13 mmol) of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester were dissolved in 1 ml of dichloromethane and the solution was stirred at room temperature for 3 hours in the presence of 1 ml of bromotrimethylsilane and 0.1 ml of trifluoroacetic acid. The solvent was removed by evaporation. The residue was treated three times with acetone/water (9:1) and the solvent was removed by evaporation each time. Finally, the product was triturated with diethyl ether to yield 55 mg of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a foam.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[CH3:14][C:15]([CH3:22])([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>CCO.[OH-].[Na+].CCOC(C)=O>[C:15]([C:16]1[CH:17]=[C:18]([NH2:19])[N:12]([C:9]2[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:11][CH:10]=2)[N:13]=1)([CH3:22])([CH3:21])[CH3:14]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reaction time: 0.08 h

Procedure:
4-(methylsulfonyl)phenylhydrazine hydrochloride (1.133 g, 5.09 mmol) and 4,4-dimethyl-3-oxopentanenitrile (0.697 g, 5.57 mmol) were weighed into a 100 mL RBF. 0.2 M HCl in EtOH (42 mL) was added and the suspension was heated to reflux for 27 h, during which time all solids gradually dissolved to give a yellow solution. The solution was diluted with 1 M NaOH(aq) (˜16 mL) to pH 12-13, EtOAc (70 mL) was added and the biphasic system was vigorously stirred for 5 min. The organic layer was isolated, dried (MgSO4), filtered and concentrated to give a yellow crystalline solid. Yield: 1.42 g (95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N+:29]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)([O-:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].N1C=CN=C1>C(Cl)Cl.C1(C)C=CC=CC=1.O.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])(=[O:21])=[O:22])[N:11]([CH2:36][C:35]3[CH:38]=[CH:39][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=3)[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=S(=O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2c(S(=O)(=O)C(F)(F)C(F)F)nc(-c3ccc(F)cc3)c2-c2ccc(F)cc2)cc1
Temperature: 75 °C

Procedure:
4.20 g (0.01 mole) of 4,5-bis-(4-fluorophenyl)-2-[(1,1,2,2-tetrafluoroethyl)sulfonyl]-1H-imidazole, prepared according to the method described in U.S. Pat. No. 4,190,666, 2.7 g (0.0125 mole) of 4-nitrobenzylbromide, 1.73 g (0.0125 mole) of anhydrous powdered potassium carbonate, and 50 ml of dimethylformamide were combined in a round bottom flask and stirred and heated under nitrogen in an oil bath at 75° C. for 20 hours. The reaction mixture was cooled to room temperature and poured into 500 ml of water. The product was extracted with methylene chloride. The methylene chloride solution was washed several times with water to remove dimethylformamide, dried over sodium sulfate, filtered, and evaporated on a rotary evaporator. The remaining oil was triturated with ether, which caused the product to crystallize. The white solid was filtered, washed with ether, and dried to yield 4.9 g, m.p. 169°-170°. The product was freed from a small amount, usually less than 1% of 4,5-bis-(4-fluorophenyl)-2-[ (1,1,2,2-tetrafluoroethyl)sulfonyl]-1H-imidazole by dissolving it in a small amount of methylene chloride and putting the solution through a preparative liquid chromatography apparatus using toluene to elute. After evaporating the toluene from the main fraction on a rotary evaporator, 4.4 g of product, m.p. 176°-177° was obtained. A mass spectrum of the product showed it to have a m/e of 555.4 and also showed it to contain no measurable starting imidazole, m/e 420.3.
Reaction SMILES: [CH3:1][C:2]([NH:38]C(=O)OC(C)(C)C)([CH3:37])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:7](=[O:32])[NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[C:13]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[C:10]1=[O:31])=[O:4].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:38][C:2]([CH3:1])([CH3:37])[C:3]([NH:5][C@H:6]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:7]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[C:13]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:25][C:26]2[CH:30]=[CH:29][S:28][CH:27]=2)[C:10]1=[O:31])=[O:32])=[O:4]
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)C[C@@H](NC(=O)C(C)(C)N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-methyl-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxopropan-2-ylcarbamate (2.8 g) was dissolved in ethanol (28 mL), and concentrated hydrochloric acid (7.5 mL) was added thereto. The mixture was heated at 70° C. while being stirred for 30 minutes, and then neutralized with saturated aqueous sodium bicarbonate solution under cooling on ice. Subsequently, the resultant mixture was extracted with chloroform and water, and the aqueous layer was further extracted with chloroform. The organic layers were combined. The combined organic layer was washed with saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby the title compound (2.30 g) was yielded.
Reaction SMILES: CN1C(C)=C(C(O)=O)C(=O)N1C1C=CC=CC=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:33][C:34]1([CH3:56])[S:38][C@@H:37]2[C@H:39](NC([C@H](N)C3C=CC=CC=3)=O)[C:40](=[O:41])[N:36]2[C@H:35]1[C:53]([OH:55])=[O:54]>CN(C)C=O.CCOCC>[CH3:33][C:34]1([CH3:56])[S:38][C@@H:37]2[CH2:39][C:40](=[O:41])[N:36]2[C@H:35]1[C:53]([OH:55])=[O:54]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Temperature: -10 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
2,3-Dimethyl-1-phenyl-3-pyrazolin-5-one-4-carboxylic acid (0.186 g, 0.8 mmol) in dry dimethyl formamide (D.M.F) (4 ml) was treated with triethylamine (0.12 ml, 0.8 mmol). The solution was cooled to -10° C. and isobutyl chloroformate (0.10 ml, 0.76 mmol) added dropwise. After 1 hour at -10° C., solids were removed by filtration and the solution added to ampicillin (anhydrous) (0.28 g, 0.8 mmol) premixed with triethylamine (0.12 ml, 0.8 mmol) in D.M.F. (10 ml) at -40° C. The solution was allowed to warm to 0° C., stirred for 90 minutes and poured into excess dry ether, with stirring. The precipitate was isolated and partitioned between ethyl acetate and water. The pH was adjusted to 7.5 (bicarbonate addition); the aqueous layer separated and acidified to pH 1.5 (HCl(5N)). Extraction with ethyl acetate, drying (Na2SO4) and evaporation gave the title product as the free penicillanic acid (0.09 g, 20%), δ((CD3)2CO) 1.50, 1.58 (2×3H, 2s, (CH3)2), 2.68 (3H, s,=C--CH3), 3.34 (3H, s, --NCH3), 4.36 (1H, s, C3 -proton), 5.53 (1H, d, J 4 Hz, C5 -proton), 5.71 (1H, d of d, J 4, 8 Hz, C6 -proton), 5.94 (1H, d, J 8 Hz, --CHCON--), 7.53 (10H, complex, aryl protons), 8.20 (1H, d, J 8 Hz, --NH--), 9.78 (1H, d, J 8 Hz, --NH--), 6.5-9 (1H, br, --CO2H). The free acid was converted to the sodium salt by addition, to an acetone solution of the free acid, of a solution of sodium ethylhexanoate (0.084 ml, 1.9N) in methyl isobutyl ketone, further addition of ether, and filtration of the precipitate. The sodium salt (2) showed vmax (nujol) 1780, 1760, 1690, 1655, 1600 cm-1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Br:16][C:17]1[CH:18]=[C:19]([CH2:20][NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:22]=[CH:23][CH:24]=1
Reactant: NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-bromobenzylamine hydrobromide (222 mg, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate. Yield: 142 mg. To a solution of tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((3-bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((3-Bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 49 mg; 13C-NMR (CD3OD, rotamers): δ 26.6, 28.2, 40.2, 43.9, 44.0, 51.8, 54.1, 54.6, 113.76, 113.84, 114.1, 114.2, 122.2, 125.0, 125.5, 126.7, 127.1, 129.2, 129.5, 129.7, 129.8, 129.9, 130.0, 130.5, 130.6, 140.8, 141.8, 159.1, 173.3, 173.7.