Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[C:7]2([CH2:12][CH2:11][N:10]([CH2:13][CH2:14]CCN3C(=O)C4C=CC=C5C=4C(=CC=C5)C3=O)[CH2:9][CH2:8]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1.BrCC[CH2:41][CH2:42][CH2:43][N:44]1[C:53](=[O:54])[C:52]2[CH:55]=[CH:56][CH:57]=[C:50]3[C:51]=2[C:46](=[CH:47][CH:48]=[CH:49]3)[C:45]1=[O:58].BrCCCCN1C(=O)C2C=CC=C3C=2C(=CC=C3)C1=O>>[ClH:1].[O:2]=[C:3]1[C:7]2([CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:41][CH2:42][CH2:43][N:44]3[C:53](=[O:54])[C:52]4[CH:55]=[CH:56][CH:57]=[C:50]5[C:51]=4[C:46](=[CH:47][CH:48]=[CH:49]5)[C:45]3=[O:58])[CH2:11][CH2:12]2)[N:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:5][NH:4]1
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: Cl
Agent: O=C1c2cccc3cccc(c23)C(=O)N1CCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
Following the procedure of part (b) of example 26 but substituting 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione for the 2-(4-bromobutyl)-1H-benz[de]isoquinoline-1,3(2H)-dione, one obtains the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:43]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:46]3[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: O=C(O)C1Cc2cc(Cl)ccc2O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(Cl)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid (1 g, 5 mmol) in N,N-dimethylformamide (10 ml) was added EDAC.HCl (1.45 g, 7.56 mmol, 1.5 eq), HOBt (1.02 g, 7.55 mmol, 1.5 eq), triethylamine (1.52 g, 15.0 mmol, 3 eq) and tert-butyl piperazine-1-carboxylate (935 mg, 5.02 mmol, 1 eq). The resulting solution was stirred overnight at room temperature, quenched with water (200 ml), and then extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (3×100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 10%-20% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford tert-butyl 4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate as a off-white solid (1.2 g, 65%). (ES, m/z): [M+H]+ 367; 1H NMR (300 MHz, CDCl3): δ 7.05-7.22 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 5.38-5.45 (m, 1H), 3.75-3.90 (m, 3H), 3.25-3.70 (m, 7H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH2:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CCO.CC(N(C)C)=O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][NH:35][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reaction time: 18 h
Yield: 81.2 %

Procedure:
2,4-Dichloro-5-nitro-pyridine (500 mg, 2.59 mmol) was dissolved in EtOH-DMA (15 mL, 1:1). To this solution was added diisopropylethyl amine (0.99 mL, 5.7 mmol) followed by 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (611 mg, 2.85 mmol). The reaction was stirred for 18 h, then concentrated in vacuo. The crude residue was rediluted in EtOAc and poured into H2O. The aqueous phase was separated and extracted two more times with EtOAc. The organic layers were combined, dried (Na2SO4), decanted and concentrated. The crude residue was purified by SiO2 flash chromatography eluting with 2% CH3OH—CH2Cl2 to afford 4-[(2-chloro-5-nitro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester as a yellow foam (780 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH2:14]S)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.C(OCC)(=[O:25])C>C(Cl)Cl.CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][CH:14]=[O:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)CCCS)cc1
Reactant: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)CCC=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A: To a solution of 5.0 g (22 mmol) of 3-[(4-methoxyphenyl)sulfonyl]propan-1-ol from example 13 and 12.1 mL (8.8 g, 87 mmole) of triethylamine in 25 mL of methylene chloride at zero° C., was added a solution of 13.8 g (87 mmol) of sulfur trioxide-pyridine complex in 25 mL of DMSO. After 1 hour, the reaction mixture was added to 300 mL of ice, ethyl acetate was added, the organic layer was separated and washed with water, 5% potassium hydrogen sulfate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 4.1 g of 3-[(4-methoxyphenyl)sulfonyl]propan-1-al. suitable for the next reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[N:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C=O)C>[N:8]1([C:6]2[N:5]=[C:4]([N:13]([CH3:15])[CH3:14])[N:3]=[C:2]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[N:7]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CN(C)c1nc(Cl)nc(-n2ccnc2)n1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: CN(C)c1nc(-n2ccnc2)nc(-n2cncn2)n1
Reaction time: 4 h
Yield: 17.5 %

Procedure:
The obtained 2-chloro-4-(1-imidazolyl)-6-dimethylamino-1,3,5-triazine (113 mg, 0.503 mmol) was dissolved in DMF (1 ml), added with 1,2,4-triazole (149 mg, 2.15 mmol) and stirred at 110° C.-120° C. for 4 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was added with ethyl acetate and water, and then shaken for mixing. The organic layer was separated from the mixture, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography, using ethyl acetate and methanol (9:1) as eluant, to obtain 22.7 mg (yield: 17.6%) of the titled compound as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:26][C:25]3[C:17]([F:16])=[C:18]([C:22]([F:27])=[CH:23][CH:24]=3)[C:19]([NH2:21])=[O:20])[N:4]=2)=[CH:10][CH:11]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(Cl)cc2)nc1COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.3 %

Procedure:
To a solution of 4-Bromomethyl-2-(4-chloro-phenyl)-5-methyl-oxazole (0.12 g, 0.42 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.072 g, 0.42 mmol) and potassium carbonate (0.203 g, 1.20 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.01 g, 6%). 1H NMR (DMSO-d6, 400 MHz): δ 2.49 (s, 3H), 5.09 (s, 2H), 7.11 (m, 1H), 7.38 (m, 1H), 7.60 (d, J=8.40 Hz, 2H), 7.85 (br s, 1H), 7.95 (d, J=8.40 Hz, 2H) and 8.13 (br s, 1H). MS ES+ (379.25), HPLC (method I) Rt=16.71 min.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)=[C:6]([F:21])[CH:5]=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(=[O:25])=[O:24].Cl[C:35]([O:37][CH3:38])=[O:36].C(OCC)C>C(Cl)Cl.O>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[S:23]([N:22]([C:3]1[CH:4]=[CH:5][C:6]([F:21])=[C:7]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[CH:11][N:10]([CH2:19][CH3:20])[N:9]=2)[C:2]=1[F:1])[C:35](=[O:36])[O:37][CH3:38])(=[O:24])=[O:25]
Reactant: COC(=O)Cl
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(C(=O)OC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
N-{2,4-difluoro-3-[1-ethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-2,5-difluorobenzenesulfonamide (80 mg, 0.168 mmol) was suspended in 3.5 mL of DCM and TEA (18.7 mg, 25.8 μL, 0.185 mmol) was added. Methyl chloroformate (17.5 mg, 13.0 L, 0.185 mmol) was added to the solution so obtained, and the reaction mixture was stirred at room temperature for 3 hours, diluted with DCM, and poured in water. The organic layer was washed three times with water, once with brine, dried over Na2SO4 and concentrated to dryness. The solid so obtained was taken up with ethyl ether and filtered (72 mg, 80% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:19](Cl)(Cl)=[O:20]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([N:17]=[C:19]=[O:20])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: CC#N
Product: Cc1nc(N=C=O)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 85 °C

Procedure:
5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) (1.74 mmol, 0.5 g) is added to acetonitrile (15 ml) and treated with phosgene (20% solution in toluene, 6.99 mmol, 3.7 ml). The reaction mixture is heated to reflux (85° C.) for 30 minutes. After cooling to room temperature the solvent is removed in vacuo to leave 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole as an orange solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:8]([OH:10])=[O:9])=[N:5][S:6][CH:7]=1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[NH2:2][C:3]1[C:4]([C:8]([O:10][CH3:15])=[O:9])=[N:5][S:6][CH:7]=1
Reactant: Nc1csnc1C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)c1nscc1N

Procedure:
A suspension of 52.0 g of 4-amino-3-isothiazolecarboxylic acid hydrochloride [prepared by the method of K. Gewald and P. Billman, Liebigs Ann. 1542 (1979)] in 300 ml methanol was cooled in an ice-bath and 10 ml of thionyl chloride was added dropwise. The reaction mixture was refluxed 3 hours, cooled and the solvent evaporated. The residual solid was collected, washed with ether and dried giving 47.5 g of methyl 4-amino-3-isothiazolecarboxylate hydrochloride, m.p. 170°(d).
Reaction SMILES: B(F)(F)F.CSC.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:31]3[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([O:38]C)[CH:32]=3)=[N:25][N:26]([CH2:28][C:29]#[N:30])[CH:27]=2)=[CH:19][N:18]=1)(=[O:10])[CH3:9]>ClCCl>[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:31]3[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([OH:38])[CH:32]=3)=[N:25][N:26]([CH2:28][C:29]#[N:30])[CH:27]=2)=[CH:19][N:18]=1)(=[O:10])[CH3:9]
Reactant: COc1cc(C)cc(-c2nn(CC#N)cc2-c2ccc(-c3ccccc3C(C)=O)nc2)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)c1ccccc1-c1ccc(-c2cn(CC#N)nc2-c2cc(C)cc(O)c2)cn1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (50.7 mg, 0.12 mmol) prepared in Example 67 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL), and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (27 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[N:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][I:20]>CC(C)=O>[I-:20].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[N+:12]([CH3:19])([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1cccc(C23CCCCC2N(C)CC3)c1
Solvent: CC(C)=O
Product: COc1cccc(C23CCCCC2[N+](C)(C)CC3)c1
Product: [I-]

Procedure:
4.6 g of hexahydro-3a-(m-methoxyphenyl)-1-methylindoline are dissolved in 100 ml of acetone, and the solution is treated with 10 ml of methyl iodide. The mixture is boiled at reflux for 10 hours. Thereafter, the solvent is removed by distillation, and the residue is recrystallized from acetone. The hexahydro-3a-(m-methoxyphenyl)-1,1-dimethyl-indolinium iodide obtained melts at 195°-196° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:20][C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:20][C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(CCc2ccccc2)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(CCc2ccccc2)[nH]c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogen carbonate (1.34 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-6-oxo-2-(2-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.71 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.30 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]([C:19]#[N:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:8](OCC)=[O:9])[CH3:2].C(O)C.[H][H].N>[Ni].C(OCC)C.CCCCCC>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:8](=[O:9])[NH:20][CH2:19]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOC(=O)CC1(c2ccccc2)CNC(=O)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (93 g, 321 mmol) and ethanol (400 mL) in a 2 gallon pressure reactor. Add Raney nickel (280 g). Heat to 50° C. and charge with 200 psi of hydrogen. After 15 minutes, vent the reactor and add aqueous concentrated ammonia solution (120 mL). Charge the reactor with 200 psi of hydrogen. After 7 hours, vent the reactor and allow to stand for 18 hours. Filter through a celite pad and rinse the solids with ethanol. Evaporate the filtrate in vacuo to obtain a residue. Combine the residue and 1/5 diethyl ether/hexane (500 mL) and cool to −20° C. After 18 hours, decant and add 1/5 diethyl ether/hexane (500 mL) and cool to −20° C. to give a solid. Collect the solid by filtration and triturate with 1/5 diethyl ether/hexane (500 mL). Filter and dissolve in diethyl ether (300 mL) and add hexane (700 mL) to give a solid. Collect the solid by filtration and dry to give the title compound. Elemental Analysis calculated for C14H17NO3: C 68.00; H 6.93; N 5.66; Found: C 67.63; H 6.99; N 5.81.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[Na+].[Cl-:26]>O>[CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:23][CH2:24]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C:6]=1[F:7].[ClH:26]
Reactant: [Cl-]
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Na+]
Solvent: O
Product: Cl

Procedure:
To demonstrate the release of the ciprofloxacin from the cryogel in a simulated body fluid environment, the cryogel/ciprofloxacin disk was immersed in 1.0 ml portions of 0.9% NaCl in distilled water for 1 hour, after which the procedure was repeated. HPLC analyses of the saline extracts for ciprofloxacin were made. The pH of these saline extracts was found to be 5.5. The initial content of ciprofloxacin in the disk was estimated to be 15 mg. The results are shown in Table 9.
Reaction SMILES: OC(C(C)C)[C:3]([O:5][CH2:6]CCl)=[O:4].[C:12]([O:16][CH3:17])(=[O:15])[CH2:13][OH:14].[C:18](C1C=CC=CC=1)(C)([CH3:20])[CH3:19]>C(OCC)C>[OH:14][CH:13]([CH:18]([CH3:20])[CH3:19])[C:12]([O:16][CH2:17][C:3]([O:5][CH3:6])=[O:4])=[O:15]
Reactant: COC(=O)CO
Reactant: CC(C)C(O)C(=O)OCCCl
Reactant: CC(C)(C)c1ccccc1
Solvent: CCOCC
Product: COC(=O)COC(=O)C(O)C(C)C

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl 2-hydroxy-3-methylbutyrate, 0.25 M methyl glycolate, and 1.0% tert-butylbenzene was added to 0.40 g Lipase P30. After mixing for 10 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-3-methylbutyrate to the title compound was estimated (by GC, Method A) to be <20%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C7H10O5Tms (M--CH3) 247.1001, obsd 247.0973. In identical reactions substituting Lipase AK or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 10 d (Lipase P30=100) were 33 and 0, respectively.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[S:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:23]=[CH:22][S:21][CH:25]=3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cscn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2cscn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(thiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 423.08 g/mol.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:17])[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1OB(O)c2cc(O)cc(F)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (127 mg, 0.50 mmol) in THF (2 mL) was added dropwise a solution of lithium hydroxide (102 mg, 2.5 mmol) in water (3 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h and after cooling to 0° C., acidified to pH=2 by addition of diluted hydrochloride acid, extracted with ethyl acetate (2×15 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (52 mg, Yield: 46%). 1H NMR (400 MHz, DMSO-d) δ 12.12 (s, 1H), 9.91 (s, 1H), 9.37 (s, 1H), 6.94-6.94 (d, J=1.6 Hz, 1H), 6.65-6.68 (m, 1H), 5.46-5.49 (m, 1H), 2.88-2.93 (m, 1H), 2.23-2.29 (m, 1H). MS (ESI) m/z=455 [2M+H]+.
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.S(Cl)(Cl)=O.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:19]([C:14]1[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[C:4](=[O:22])[C:3]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]3[C:1]2=[O:27])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccccc1)c1ccccc1-c1ccccc1CN1C(=O)c2ccccc2C1=O

Procedure:
From 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor 2), after conversion into the acid chloride using thionyl chloride and reaction with benzylamine, 2′-phthalimidomethylbiphenyl-2-carboxylic acid benzylamide was obtained. 1.2 g (2.7 mmol) of the product were dissolved in 55 ml of methanol and treated with 1.35 ml of hydrazine hydrate. After stirring at 40° C. for 1 h, the reaction mixture was concentrated and the residue was taken up in methylene chloride. After filtering off the 2,3-dihydro-phthalazine-1,4-dione formed, the mother liquor was concentrated and the residue was purified by flash chromatography using methylene chloride/methanol 30:1. 0.49 g of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide was obtained.