Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[CH:23]=[C:22]([CH3:39])[C:18]=1[C:19](Cl)=[O:20].OC1C=C(C)C(C(OC)=O)=C(C)C=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[C:17]([CH3:16])=[CH:25][C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)=[CH:23][C:22]=1[CH3:39]
Reactant: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Cl
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(N)c1
Agent: COC(=O)c1c(C)cc(O)cc1C
Product: Cc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Nc1cc(C(C)(C)C(=O)O)ccc1Cl
Yield: 47.5 %

Procedure:
By the same procedures as a series of Example 18 and Example 19 using the compound (121 mg) prepared in Example 16 and 2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride (211 mg) (the compound prepared by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2,6-dimethylbenzoate.), the title compound (132 mg) having the following physical data was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][C:12]([C:14](=[O:16])[NH2:15])=[C:11]([C:17]2[CH:38]=[CH:37][C:20]3[C:21]4[N:25]([CH2:26][CH2:27][O:28][C:19]=3[CH:18]=2)[CH:24]=[C:23]([C:29]2[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=2)[N:22]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].C([N+](CC=C)(CC=C)CC=C)C=C.C([N+](CC=C)(CC=C)CC=C)C=C>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl>[CH:34]([N:30]1[C:29]([C:23]2[N:22]=[C:21]3[N:25]([CH2:26][CH2:27][O:28][C:19]4[CH:18]=[C:17]([C:11]5[CH2:10][CH2:9][NH:8][CH2:13][C:12]=5[C:14]([NH2:15])=[O:16])[CH:38]=[CH:37][C:20]=43)[CH:24]=2)=[N:33][CH:32]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Agent: C=CC[N+](CC=C)(CC=C)CC=C
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CNCC3)cc1OCC2
Yield: 82 %

Procedure:
5-Carbamoyl-4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was stirred in TFA (1 mL) and DCM (2 mL) for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with diethyl ether to give a solid. The solid was then treated with tetra allylammonium carbonate (polymer bound) (1.84 g, 4.68 mmol) in methanol and DCM for 30 min. The resin was filtered off and the filtrate concentrated in vacuo to give 4-[2-(2-Isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide (0.40 g, 82%). 1H NMR 300 MHz (CDCl3) δ: 8.52-8.46 (1 H, m), 7.88 (1 H, s), 7.71-7.69 (1 H, m), 7.08 (1 H, dd, J=8.30, 1.82 Hz), 6.98 (1 H, d, J=1.79 Hz), 6.01-6.00 (1 H, m), 4.52-4.47 (4 H, m), 3.75 (2 H, s), 3.15 (2 H, t, J=5.82 Hz), 2.51 (2 H, m), 1.60 (6 H, d, J=6.62 Hz).
Reaction SMILES: Br[CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29]>CN(C=O)C.O>[CH2:6]([CH:2]1[O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][C:3]1=[O:4])[CH3:7]
Reactant: CCC(Br)C(=O)O
Reactant: Nc1ccccc1O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCC1Oc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromobutanoic acid (11 mmol, 2145 mg) in DMF (10 ml) was added EDC (12 mmol, 2.3 g) and HOBt (5 mmol, 675 mg) followed by the addition of 2-aminophenol (10 mmol, 1091 mg). The reaction mixture was stirred at room temperature for 2 h, diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. To the crude product in DMF (5 ml) was added K2CO3 (1.6 g) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 1N HCl, Sat. NaHCO3, dried over Na2SO4 and evaporated to dryness. Purification by column chromatography gave the desired product as a white solid. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=178; tR=2.36.
Reaction SMILES: [N+:1]([C:4]([CH3:12])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].CCOCC.[CH3:18][Li].[N+:20](C([N+]([O-])=O)([N+]([O-])=O)[N+]([O-])=O)([O-:22])=[O:21]>C1COCC1>[N+:1]([C:4]([N+:20]([O-:22])=[O:21])([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:18])[CH3:12])([O-:3])=[O:2]
Reactant: CC(=Cc1ccccc1)[N+](=O)[O-]
Reactant: [Li]C
Reactant: O=[N+]([O-])C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(c1ccccc1)C(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: -40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4.03 g (0.025 mol) of 2-nitro-1-phenyl-1-propene dissolved in 30 ml of dry THF (cooled to -40° C. with an acetronitrile-dry ice bath) and under a positive nitrogen atmosphere was added with stirring 22 ml (0.05 mol) of a 5% ether solution of methyllithium. The resulting solution was stirred for 1 h at -40° C. followed by the addition of 4.9 g (0.025 mol) of tetranitromethane. The solution was then allowed to warm to room temperature and stirred an additional hour. The resulting product was isolated and purified as described in Example 1 above, yielding 3.4 g (60% yield) of an analytically pure white crystalline product, mp 76°-78° C. A similar procedure was used for the preparation of derivatives wherein R3 (see structure above or scheme) was CH3 (CH2)3 and R2 was H and wherein R3 was CH3 and R2 was CH3 (see scheme).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>CCOC(C)=O>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: CCOC(=O)COc1cccc(N)c1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)c1

Procedure:
Carboxylic acid (149)(50 mg, 0.21 mmol) was coupled to aniline (64)(42 mg, 0.21 mmol) using Method C. During this reaction, partial hydrolysis occurred. The residue was re-dissolved in EtOAc (2 ml) and the organic layer was washed with 1M HCl (2×1 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)(=[O:20])[CH3:19]
Reactant: O=C1Nc2cc(CCO)ccc2C2CCCC12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCc1ccc2c(c1)NC(=O)C1CCCC21

Procedure:
A solution of 560 mg (2.4 mmol) of 7-hydroxyethyl-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 10 ml of pyridine is stirred with 5 ml of acetic anhydride for 24 hours at room temperature. The batch is concentrated by evaporation in a vacuum and purified by column chromatography on silica gel with hexane-ethyl acetate: 500 mg of product.
Reaction SMILES: [CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(#N)C>[CH2:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:18](=[O:19])[CH2:17][CH2:16][C:15]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:20])=[CH:10][C:9]=2[F:21])=[C:5]([O:24][CH3:25])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N3C(=O)CCC3=O)cc2F)c(OC)c1
Reactant: C1COCCN1
Solvent: CC#N
Product: CCc1ccc(Oc2ccc(NC(=O)CCC(=O)N3CCOCC3)cc2F)c(OC)c1
Temperature: 30 °C
Reaction time: 72 h
Yield: 87.3 %

Procedure:
To 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione (40.4 mg, 0.12 mmol) were added acetonitrile (120 μL) and morpholine (20 μL, 0.24 mmol). The reaction mixture was stirred at 30° C. for 3 days under argon, then concentrated, dissolved in ethyl acetate, washed with saturated NH4Cl and extracted with ethyl acetate. Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title product (45.1 mg; 87%) after purification by preparative TLC (dichloromethane/methanol: 9/1).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[NH:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=1)[NH2:28]>>[CH3:25][N:23]([CH3:24])[S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][CH:34]=4)[N:28]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:21])=[O:22]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N(C)C)c2)ccc1=O
Reactant: CC(=O)Nc1cccc(NN)c1
Product: CC(=O)Nc1cccc(-n2nccc2-c2nn(-c3cccc(S(=O)(=O)N(C)C)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzenesulfonamide (A-12) and N-(3-hydrazino-phenyl)-acetamide according to the method described for example 91. MS: M=479.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1.C([O-])(=O)C.[Na+].[C:30]([C:38]1[CH:50]=[CH:49][C:41]([O:42][CH:43]([CH2:47][CH3:48])[C:44](Cl)=[O:45])=[CH:40][CH:39]=1)([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:31]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:44](=[O:45])[CH:43]([O:42][C:41]3[CH:40]=[CH:39][C:38]([C:30]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:31])=[CH:50][CH:49]=3)[CH2:47][CH3:48])[CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11]1
Reactant: Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Reactant: CCC(Oc1ccc(C(C)(C)CC(C)(C)C)cc1)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC(C)(C)C)cc1)C(=O)Nc1ccc(Cl)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1
Temperature: 25 °C
Yield: 863.6 %

Procedure:
Forty point four grams of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-aminoanilino)-5-pyrazolone were suspended in 120 ml of ethyl acetate, and to this mixture were added 40 ml of an aqueous solution containing 9.62 g of sodium acetate. At room temperature, 31.1 g of 2-(4-t-octylphenoxy)-butyric acid chloride were added dropwise to the liquid, and the mixture was stirred for another hour at room temperature. The organic phase was separated from the reaction liquid, and the solvent was distilled off under reduced pressure. The residuum was recrystallized from 300 ml of ethanol, whereby 58 g of objective 1-(2,4,6-trichlorophenyl)-3-[2-chloro-5-{2-(4-t-octylphenoxy)butaneamido}anilino]-5-pyrazolone were obtained. Melting point: 163° to 165° C. The structure was confirmed through the procedures of NMR, IR and MASS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][NH:27][CH:28]2[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:29]2)[CH2:17]1.C(#N)C.[CH:48](I)([CH3:50])[CH3:49]>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[C@H:16]1[C@@H:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]2[C@@H:18]([CH2:26][N:27]([CH:48]([CH3:50])[CH3:49])[CH:28]2[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31]2)[CH2:17]1
Reactant: CC(C)I
Reactant: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CC(N(C[C@H]2C[C@@H](n3cnc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C(C)C)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.06 g, 0.1 mmol) was taken up in acetonitrile (2.6 mL, 50 mmol) and isopropyl iodide (0.098 mL, 0.98 mmol) and triethylamine (0.21 mL, 1.5 mmol) were added. The reaction was heated to 80° C. for 12 hours at which point the reaction appeared to stall. Another 15 equivalents triethylamine and another 15 equivalents isopropyl iodide were added and the reaction continued 8 hours more. Reaction appeared to have stalled again so another 15 equivalents each of isopropyl iodide and triethylamine were added. Upon consumption of the starting material the reaction was concentrated and saturated Na2CO3 (20 mls) and DCM (20 mls) was added. The residue was partitioned between the organic layer and the aqueous layer. The aqueous layer was extracted 3 times with DCM, then the combined organics were dried and purified by FC (DCM/7N NH3 in MeOH 97:3). Product was still contaminated with TEA-H+I—, so to a 30 ml solution of the product in DCM was added 20 mls saturated NaHCO3 and 10 mls 1N NaOH. The mixture was stirred for 15 minutes then the aqueous was extracted with DCM 3 times. The combined organics were dried with MgSO4 and solvent removed to yield pure ethyl 3-(3-((((3aR,4R,6R,6aS)-6-(6-((2,4-dimethoxybenzyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate (0.045 g; 70%) as a brown foam/solid with no more amine salts present by NMR. MS (ESI+) for C35H50N6O6 m/z 651.3 [M+H]+.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:9]([OH:13])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:1]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(C)(C)O
Reactant: COC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of 1 equivalent of methyl acetoacetate, 1 equivalent of tertiary butyl alcohol and 100 mg of sulfated tin oxide catalyst prepared according to example 1, in 20 ml of toluene was heated to 110° C. in a two necked round bottom flask provided with a distillation condenser to remove methanol. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction (about 6 hours), the catalyst was filtered and the filtrate was concentrated and chromatographed on a silica gel column (95% petroleum ether and 5% ethyl acetate) to afford t-butyl acetoacetate as a viscous colorless liquid in 50% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc(Cl)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 439.1 (M+H)+.
Reaction SMILES: C(#N)C.[OH:4][CH2:5][CH2:6][O:7][C:8]1[CH:27]=[CH:26][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:10][CH:9]=1.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30]>CN1CCCC1=O>[C:28]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:26][CH:27]=1)(=[O:32])[C:29]([CH3:31])=[CH2:30]
Reactant: O=C(OCCOc1ccc(OCCO)cc1)c1ccc(O)c(Cl)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: C=C(C)C(=O)OCCOc1ccc(OCCOC(=O)c2ccc(O)c(Cl)c2)cc1

Procedure:
A 300-ml eggplant type flask was charged with 16.3 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 87 g of 1,4-(2-hydroxyethoxy)benzene and further with 0.8 g of PTD (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was stirred with heating on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. The reaction mixture was poured into ice water followed by extracting with ethyl acetate, drying over anhydrous magnesium sulfate, concentrating and separating with a column using ethylacetate/n-hexane to obtain 29 g of 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester (melting point: 87° to 88° C.). To 50 ml of an acetonitrile solution containing 10 g of the 3-chloro-4-hydroxybenzoic acid 2-[4-(β-hydroxyethoxy)-phenoxy]ethyl ester, 13.9 g of N-methylpyrrolidone and further 8.78 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred at 40° C. for 8 hours to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethylacetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid 2-[4-(β-methacryloyloxyethoxy)phenoxy]ethyl ester (melting point: 105° to 106° C.).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]([F:44])([F:43])[O:31][C:32]1[CH:42]=[CH:41][C:35](/[CH:36]=[CH:37]/[C:38](O)=[O:39])=[CH:34][CH:33]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:38](=[O:39])/[CH:37]=[CH:36]/[C:35]4[CH:34]=[CH:33][C:32]([O:31][C:30]([F:43])([F:44])[F:29])=[CH:42][CH:41]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-4-(trifluoromethoxy)cinnamic acid, by the method of Example 1, step K, giving a solid that was a mixture of cyclohexyl diastereomers by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C31H35F3N4O3: 569 (M+H). Found: 569
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:22])[NH:20][OH:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH:34](=O)[CH3:35].Cl>C(O)C.O.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[S:25]([CH3:28])(=[O:26])=[O:27])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]4[NH:22][CH:34]([CH3:35])[O:21][N:20]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CC=O
Reactant: CS(=O)(=O)N(CCCCO)c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1NC(c2c(-c3ccc(F)cc3)oc3cc(N(CCCCO)S(C)(=O)=O)c(C4CC4)cc23)=NO1
Temperature: 25 °C
Reaction time: 73 h
Yield: 19.9 %

Procedure:
A solution of Example 11D (0.10 g, 0.210 mmol) in ethanol (3 mL) and H2O (3 mL) was treated with acetaldehyde (3 mL, 53.1 mmol) and stirred in a sealed microwave tube at room temperature for 73 hours. The solvent was removed in vacuo leaving a cloudy slurry which was dissolved in ethyl acetate (50 mL) and treated with 5% aqueous HCl (5 mL). The mixture was stirred for 30 minutes at room temperature. The aqueous layer was removed and the ethyl acetate layer was washed with 10 mL 10% aqueous NaCl, dried over anhydrous sodium sulfate (solid), filtered. The solvent was removed in vacuo leaving a clear yellow oil. Purification on a silica gel column (4 g) eluting with a gradient of 99.5/0.5 dichloromethane/methanol to 94/6 dichloromethane/methanol over 25 minutes afforded the title compound (0.021 g, 20%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.56 (s, 1H), 0.84 (m, 2H), 1.07 (dd, J=6.3, 4.5 Hz, 2H), 1.37 (dd, J=5.1, 2.1 Hz, 3H), 1.32-1.48 (m, 2H), 2.37 (ddd, J=12.7, 6.9, 5.5 Hz, 4H), 3.13 (s, 3H), 3.66 (m, 2H), 4.36 (t, J=5.1 Hz, 1H), 5.74-5.80 (m, 1H), 7.22 (s, 1H), 7.30 (s, 1H), 7.42 (t, J=8.9 Hz, 2H), 7.86 (s, 1H), 8.02 (dd, J=9.0, 5.4 Hz, 2H); MS (ESI+) m/z 502 (M+H)+, (ESI−) m/z 500 (M−H)−.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].F[C:32]1[CH:46]=[CH:45][C:35]([C:36]([C:38]2[CH:43]=[CH:42][C:41](F)=[CH:40][CH:39]=2)=[O:37])=[CH:34][CH:33]=1.C1(C)C=CC=CC=1>CN(C)C(=O)C>[CH:1]1[CH:2]=[CH:3][C:4]2[C:10]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])[C:35]1[CH:45]=[CH:46][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Polymerization was carried out similar to the P(BPZ-BNZPH) polymerization, except phenolphthalein (15.0000 g, 47.12 mmol), potassium carbonate (13.02 g, 94.28 mmol), 4,4′-difluorobenzophenone (10.2819 g, 47.12 mmol), toluene (117 g) and N,N-dimethylacetamide 100 g) were used. The yield was about 21.87 g. The number average molecular weight of the polymer was about 40.4K.
Reaction SMILES: [CH2:1]([C:3]([CH2:14][CH3:15])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[C:4]([NH2:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:14]([C:3]([CH2:1][CH3:2])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([NH2:6])=[O:5])[CH3:15]
Reactant: CCC(CC)(C(N)=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-hydroxy-benzeneacetamide (Example 266b, 1.21 g) in DMF (9.93 mL) was treated with potassium carbonate (0.807 g) and benzyl bromide (0.694 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified (SiO2 chromatography eluting with 30-100% ethyl acetate in iso-hexane) to afford the subtitle product (0.77 g).