Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6]CCO)=[O:5])=[CH2:3].[CH:10]1[C:15]([N:16]=[C:17]=[S:18])=[CH:14][C:13]2[C:19]([O:21][C:22]3([C:32]4[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=4[O:30][C:24]4[CH:25]=[C:26]([OH:29])[CH:27]=[CH:28][C:23]3=4)[C:12]=2[CH:11]=1)=[O:20]>O>[C:4]([OH:6])(=[O:5])[C:2]([CH3:3])=[CH2:1].[CH:10]1[C:15]([N:16]=[C:17]=[S:18])=[CH:14][C:13]2[C:19]([O:21][C:22]3([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=4[O:30][C:31]4[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:32]3=4)[C:12]=2[CH:11]=1)=[O:20]
Reactant: C=C(C)C(=O)OCCO
Agent: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: O
Product: C=C(C)C(=O)O
Reaction time: 1 h

Procedure:
The rate of release of a macromolecule trapped in the voids between hydrogel particles in an aggregate can be controlled by modifying the ionic character of the particles. Thus, particles were produced of approximately 40 nm diameter using 90:10 HEMA:MAA. A solution of 1 mg/mL of FITC-BSA in a suspension of 60 mg/ml hydrated copolymer nanoparticles in 20 mL milli-Q water was prepared. The solution/suspension was spun in a centrifuge at 50,000×G for 1 hr at room temperature. The resulting aggregate, which was yellow, was removed and the percent loading was determined by subtracting the FITC-BSA remaining in solution from the original solution concentration. The loading of this aggregate was calculated to be approximately 7% by weight. The aggregate was washed with five 10 mL aliquots until the washings contained no further FITC BSA as determined by UV-Visible spectroscopy. The aggregate (2.1 g) was placed in 21 mL of phosphate buffered saline (PBS, pH 7.4, NaCl concentration=120 mmol/L) at 37° C. and was shaken at 60 cycles per second on an orbital shaker. Periodic aliquots were removed and analyzed by UV-Visible spectroscopy. FIG. 11 shows the release of FITC-BSA from the aggregate over time. Variations in the mole percent methacrylic acid in the hydrogel particles of the aggregate result in distinct changes in the rate of FITC-BSA release.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.Br[CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1>C(#N)C>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:40][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(C(=O)OC)cc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 64.3 %

Procedure:
The 4-[(S)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (0.51 g, 1.29 mmol) was dissolved in 10 mL of dry acetonitrile. Sodium iodide (20 mg, 0.13 mmol) was added and the reaction was stirred under nitrogen at room temperature during the addition of triethylamine (0.72 mL, 5.16 mmol), followed by methyl 4-(bromomethyl)benzoate (0.59 g, 2.58 mmol). The reaction mixture was stirred under nitrogen overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over Na2SO4/MgSO4 and concentrated under reduced pressure. The residual light yellow oil was purified by chromatography on silica gel (50% EtOAc in CH2Cl2) to give 0.45 g (0.83 mmol) of methyl 4-{(2R, 5S)-4-[(S)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl}-benzoate as a white amorphous solid.
Reaction SMILES: C1(C[O:8][C:9](=[O:36])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([OH:35])[CH:11]=2)C=CC=CC=1.C(N(CC)CC)C.[C:44](Cl)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([O:35][C:12]1[CH:11]=[C:10]([C:9]([OH:8])=[O:36])[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOc1cc(OC(C)=O)cc(C(=O)O)c1
Yield: 115.2 %

Procedure:
To a stirred and ice bath cooled solution of 5.0 g (0.01 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid phenylmethyl ester in 7.5 ml of methylene chloride and 2.8 ml (0.02 mol) of triethylamine was added 0.86 ml (0.012 mol of acetyl chloride. The reaction mixture was stirred in an ice bath for 1 hour, at room temperature for 2 hours and then was washed with 1N HCl, with NaHCO3 solution, dried and concentrated at reduced pressure to a solid. Trituration with methanol and filtration gave 5.17 g (96% yield, mp 55°-56°) of 3-acetyloxy-5-(octadecyloxy)benzenecarboxylic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1.C1CCN2C(=NCCC2)CC1>CC(O)C>[CH2:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2cccc(O)c2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a solution of quinoline-2,8-diol (5.0 g, 31.1 mmol) in i-PrOH (50 mL) was added BnBr (5.31 g, 31.1 mmol) and DBU (2.02 g, 5.32 mmol). The mixture was stirred at 80° C. for 16 h. The mixture was evaporated and to the residue was added DCM (100 mL), and this solution was washed with 0.5 N NaOH (50 mL), 10% HCl (50 mL), and H2O (50 mL). The organic layer was evaporated to give the desired compound (6.6 g, yield 85%). 1HNMR (CDCl3, 400 MHz) δ: 9.16 (br. s., 1H), 7.74 (d, J=9.8 Hz, 1H), 7.49-7.36 (m, 5H), 7.20-7.10 (m, 2H), 7.09-7.03 (m, 1H), 6.67 (d, J=9.5 Hz, 1H), 5.19 (s, 2H).
Reaction SMILES: C(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:21][O:22][C:23](=[O:35])[C@@H:24]([CH2:33][OH:34])[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>[C:29]([O:28][C:26]([NH:25][C@H:24]([CH2:33][O:34][CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][O:36]1)[C:23]([O:22][CH3:21])=[O:35])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: C1=COCCC1
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](COC1CCCCO1)NC(=O)OC(C)(C)C
Yield: 95.3 %

Procedure:
To a 2 L three neck flask fitted with a magnetic stirbar, under argon, was added CH2Cl2 (500 mL), PPTs (pyridinium-p-toluene sulfonate) (2 g, 0.008 mol). After dissolving the PPTs by stirring, N-(tert-butoxycarbonyl)-D-serine methyl ester 1 (97.9 g, 0.446 mol) was added to give a clear yellow solution. DHP (3,4-dihydro-2H-pyran) (105 mL, 1.16 mol) was added in one portion. The clear yellow solution was stirred at room temperature over 60 hr to give a slightly cloudy yellow mixture. The mixture was evaporated to give an off-white solid. Ethyl acetate (650 mL) was added to the residue and stirred for 20 minutes to dissolve. The solution was washed with 1.2M HCl (1×500 mL) to pH 4, sat. NaHCO3 (1×600 mL plus 1λ300 mL) to pH 7, brine (1×500 mL), dried over MgSO4 (20 g), filtered and concentrated under reduced pressure to give 129 g (96%) of product 2 as a waxy white solid. 1H NMR (60 MHz, CDCl3) δ 5.2-5.7 (br m, 1H), 3.4-4.8 (m, 9H), 1.4-1.8 (m, 15H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:20]([C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Product: O=Cc1ccc(C(F)(F)F)cc1Oc1ccccc1
Yield: 78 %

Procedure:
Preparation analogous to Example 12 from 2-fluoro-4-trifluoromethyl-benzaldehyde and phenol. Yield: 78%, light-coloured crystals, crystallised from hexane; melting point: 57°-59° C.; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.71; 1H-NMR (CDCl3, 200 MHz): 7.08-7.50 (m, 7H); 8.05 (d, 1H); 10.60 (s, 1H). MS: 266/265 (M+), 217, 188.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]#[N:10].[ClH:11].CCOCC>C(Cl)Cl>[ClH:11].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([S:3][CH2:1][CH3:2])=[NH:10]
Reactant: N#Cc1cccs1
Reactant: CCS
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCSC(=N)c1cccs1
Temperature: 25 °C

Procedure:
To a stirred solution of ethanethiol (28.4 g, 0.45 mols) in methylene chloride (500 ml) at 10° C. under nitrogen was added 2-thiophenecarbonitrile (50.0 g, 0.45 mols). This solution was treated with a slow stream of HCl gas for 6 h. The reaction mixture was then allowed to warm to room temperature for 18 h. Ether (200 ml) was added and a white solid crystallized. The solid 2-thiophenecarboximidothioic acid, ethyl ester, hydrochloride was collected by filtration and air dried (65.8 g), m.p. 196-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:16]=C.C[OH:19]>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH3:14])([CH3:15])[C:10](=[O:13])[N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[CH:16]=[O:19]
Reactant: C=Cc1cc2c(nc1OC)C(C)(C)C(=O)N2C
Reactant: CO
Solvent: ClCCl
Product: COc1nc2c(cc1C=O)N(C)C(=O)C2(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A 65 mg (0.28 mmol) solution of 5-methoxy-1,3,3-trimethyl-6-vinyl-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one in 16 ml of methylene chloride and 4 ml of methanol was cooled to −70° C. Ozone (via an ozone generator) was bubbled into the solution until a blue color was achieved. The reaction mixture was stirred at −70° C. for 30 minutes and warmed to room temperature. Approximately 0.5 ml of dimethyl sulfide was added and the reaction was evaporated. This residue (0.6 g) was used directly in the next step. 1H NMR (CDCl3) δ 10.20 (s, 1H). Mass spectrum: m/e =235 (p+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=O)[CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[CH3:8])=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCn1ncc(C(=O)O)c1C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
A dry flask was charged with 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid (0.159 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1-Ethyl-5-methyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.236 g, 0.61 mmol, 59%).
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].CO[Si](CC[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N+:55]=1C)(OC)OC.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[NH+:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:54]=1
Reactant: CO[Si](CCc1cccc[n+]1C)(OC)OC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: c1cc[nH+]cc1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.44 g of tetraethoxysilane, 22.05 g of methyltriethoxysilane, 0.59 g of the 30% methanol solution of trimethoxysilylethylmethylpyridinium trifluoroacetate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.12 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-17):
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:2](=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccccc1O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(O)cccc2c1O
Temperature: 25 °C
Yield: 5.6 %

Procedure:
A mixture of 2-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 240° C. for 90 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to room temperature and the resulting solid is collected and washed with hexanes. The crude solid is recrystallized from acetone to yield 0.650 g of ethyl 4,8-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.349 g of the desired product as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1.[C:28]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[O:2][CH3:1])=[CH:35][CH:34]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCCc1nc(OC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(OC)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 75.1 %

Procedure:
To a suspension of 4′-[(2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 4-tert-butoxyphenylboronic acid (0.54 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.51 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.53 g, 75%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:30])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]1[C:17]([CH3:29])=[N:18][N:19]2[C:24]3[NH:25][CH2:26][CH2:27][C:23]=3[C:22]([CH3:28])=[N:21][C:20]=12.[CH2:31]([S:35](Cl)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34].O>ClCCl>[CH2:31]([S:35]([N:25]1[C:24]2[N:19]3[N:18]=[C:17]([CH3:29])[C:16]([C:9]4[C:8]([CH3:30])=[CH:13][C:12]([CH3:14])=[CH:11][C:10]=4[CH3:15])=[C:20]3[N:21]=[C:22]([CH3:28])[C:23]=2[CH2:27][CH2:26]1)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]
Reactant: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCN4)c(C)c1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCS(=O)(=O)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Reaction time: 2 h
Yield: 27.3 %

Procedure:
Triethylamine (0.091 mL, 0.652 mmol) was added to a solution of 3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (100 mg, 0.326 mmol) prepared in Example 72 in dichloromethane (5 mL). Butanesulfonyl chloride (0.047 mL, 0.358 mmol) was added dropwise at room temperature, followed by stirring for two hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried over MgSO4, and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give the title compound (38 mg, 27%) as white crystals from a fraction of ethyl acetate-hexane (1:4 v/v).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]=[N:9][OH:10])[CH2:3]1.[CH2:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[C:12]#[CH:13]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[C:12]([CH2:11][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[O:10][N:9]=2)[CH2:3]1
Reactant: CN1CCCC(C=NO)C1
Reactant: C#CCN1CCCC1=O
Product: CN1CCCC(c2cc(CN3CCCC3=O)on2)C1
Yield: 50.1 %

Procedure:
The desired compound was prepared by the method of Example 8 from 300 mg (2.11 mmol) of 1-methyl-piperidin-3-carbaldehyde oxime prepared in Example 5 and 520 mg (2 equivalents) of 1-propargyl pyrrolidin-2-one prepared in Example 7, and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 10:1) as eluent to obtain 278.1 mg (50% yield) of 1-[3-(1-methyl-piperidin-3-yl)-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1C)[CH:7]=[O:8])[CH3:2].C([O:15][C:16]1[CH:17]=[C:18](C=[CH:22][C:23]=1O)C=O)C.BrC(CC)CC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:15][CH:16]([CH2:17][CH3:18])[CH2:23][CH3:22])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1C
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(Br)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1OC(CC)CC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMF using K2CO3 as base. MS (ISP): 237.1 [M+H]+.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][O:29]C4CCCCO4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH2:4][CH2:5][C:6](=[O:36])[CH:7]=1>C(O)(=O)C.O>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH2:28][OH:29])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:37])[CH2:4][CH2:5][C:6](=[O:36])[CH:7]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCOC4CCCCO4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCCO)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 65 %

Procedure:
A solution of 4.4 g of 9-fluoro-11β,17,21-trihydroxy-16α-[2-(tetrahydropyran-2-yloxy)ethoxy]pregn-4-ene-3,20-dione, 21-acetate in 60 ml each of acetic acid and water is stirred for 4 hours and the bulk of the solvent removed in vacuo. The residue is dissolved in chloroform and washed with 5% sodium bicarbonate solution. Drying and solvent removal gives an oil which crystallizes from acetone-hexane to give 2.4 g of 9-fluoro-11β,17,21-trihydroxy-16α-(2-hydroxyethoxy)pregn-4-ene-3,20-dione, 21-acetate, melting point 162°-165°C.
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([CH:8]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:11][CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
A solution of 14.2 g (33.9 mmol) of N-(t-butyl)-4-(benzyloxycarbonyl)-1-(t-butyloxycarbonyl)piperazine-2-carboxamide in 100 ml of dichloromethane was treated with 20 ml of trifluoroacetic acid. The resulting solution was stirred at ambient temperature for 3 h, concentrated in vacuo, and treated with 800 ml of ethyl acetate. The solution was washed with 1 N NaOH. The aqueous layer was extracted with two portions of ethyl acetate, and the combined organic layers were washed with saturated brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using first 2% then 4% methanol in chloroform provided 8.42 g (78%) of the desired compound. 1H NMR (CDCl3)δ1.34 (s, 9H), 2.8 (m, 1H), 3.0 (m, 3H), 3.21 (dd, J=9, 4 Hz, 1H), 3.9 (m, 1H), 4.2 (m, 1H), 5.14 (AA', 2H), 6.6 (br, 1H), 7.3-7.4 (m, 5H). Mass spectrum: (M+H)+ =320.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(C3C=CC(O)=CC=3)[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C1(O)C=CC=CC=1>[C].[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 200 °C
Yield: 91 %

Procedure:
Next, 18.7 g (0.060 mole) of the 4,4-bis(4-hydroxyphenyl)cyclohexanecarboxylic acid thus obtained, 2.9 g (0.072 mole) of sodium hydroxide, 100.0 g of phenol, and 0.4 g of 5% palladium-carbon catalyst were charged into a 300-ml stainless steel autoclave. After the air within the autoclave was displaced with nitrogen gas, the reaction mixture was heated at 200° C. for 6 hours. After completion of the reaction, the reaction mixture was filtered to separate unreacted phenol therefrom. The filter cake was dissolved in 50 g of a 20% aqueous solution of sodium hydroxide, and the resulting solution was filtered again to recover the catalyst. In order to precipitate the desired product, the filtrate was brought to pH 1 by the addition of diluted hydrochloric acid. The crystals so formed were collected by filtration, washed with water, and then dried to obtain 11.7 g of 4'-hydroxybiphenyl-4-carboxylic acid in the form of white crystals. Liquid-chromatographic analysis revealed that this product had a purity of 93%, and the greater part of the impurities comprised 4-(4'-hydroxyphenyl)cyclohexanecarboxylic acid. On the basis of the amount of 4,4-bis(4-hydroxyphenyl)cyclohexanecarboxylic acid used, the yield of 4'-hydroxybiphenyl-4-carboxylic acid as corrected for its purity was 85%.