Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]([S:14]([CH3:16])=[O:15])[Na]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CCO>[CH3:16][S:14]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:15])=[O:12]
Reactant: CS(=O)O[Na]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 120.2 %

Procedure:
To a mixture of 4-nitrobenzyl chloride (1 g, 5.8 mmol) and TBAI (0.11 g, 0.29 mmol) in EtOH (12 mL) was added NaOSOCH3 (0.77 g, 6.38 mmol). After heating at reflux for 2 h, the mixture was cooled to room temperature, and the precipitates were collected by filtration to give 1-(methylsulfonylmethyl)-4-nitrobenzene (1.5 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=2[C:17]([F:20])([F:19])[F:18])[CH2:5][CH2:4]1)[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[C:24]([F:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([CH2:9][N:6]3[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[O:30])=[C:24]([F:32])[CH:23]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(Br)cc3F)cc2C(F)(F)F)CC1
Temperature: 26 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A suspension of 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (247 mg, 0.858 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (200 mg, 0.858 mmol) in DCM (35 mL). HOBt (197 mg, 1.287 mmol), EDC (247 mg, 1.287 mmol) and Et3N (0.359 mL, 2.57 mmol) was added and the mixture was stirred at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf=0.6) were combined and concentrated to yield a light yellow solid of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol, 96.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.98-7.91 (m, 1H), 7.79-7.67 (m, 2H), 7.40-7.27 (m, 3H), 3.74 (s, 2H), 3.61 (s, 2H), 2.58-2.39 (m, 11H), 1.09 (s, 4H); ES-LCMS m/z 502.0 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7].[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[N+:14]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30]([CH:32]4[CH2:33][CH2:34]4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1cccc([N+](=O)[O-])c1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1cccc([N+](=O)[O-])c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-nitrophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 450.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15](=O)[NH:14][CH:13]=[N:12]2.P(Cl)(Cl)([Cl:21])=O.C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl.O>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:18])[N:11]2[C:16]=1[C:15]([Cl:21])=[N:14][CH:13]=[N:12]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(=O)[nH]cnn12
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cnn(C)c2Br)c2c(Cl)ncnn12
Temperature: 105 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (10.00 g, 32.35 mmol) in toluene (100 mL) was treated with phosphorus oxychloride (9.05 mL, 97.1 mmol). After drop-wise addition of N,N-diisopropylethylamine (28.2 mL, 162 mmol), the mixture was heated at 105° C. for 24 hours. The reaction was allowed to cool to room temperature, and then was diluted with dichloromethane (20 mL) and added over 10 minutes to a solution comprised of triethylamine (30 mL), toluene (50 mL) and water (80 mL), while keeping the internal temperature below 36° C. After an additional 20 minutes of stirring, the phases were separated, and the aqueous layer (pH ˜7) was extracted with toluene (100 mL). The combined organic layers were washed with aqueous citric acid solution (1 M, 150 mL), then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to provide the product as a solid. Yield: 9.80 g, 29.9 mmol, 92%. LCMS m/z 328.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.78 (s, 3H), 3.97 (s, 3H), 7.75 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6].[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([SH:32])[CH:26]=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[C:20]([N:24]1[C:29](=[O:30])[C:28]([Cl:31])=[C:27]([S:32][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][C:2]([F:19])([F:1])[CH:3]([F:9])[O:4][C:5]([F:8])([F:7])[F:6])=[CH:12][CH:13]=2)[CH:26]=[N:25]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: FC(OC(F)(F)F)C(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(SCc2ccc(OC(F)(F)C(F)OC(F)(F)F)cc2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
1.4 g of 4-(1,1,2-trifluoro-2-trifluoromethoxy-ethoxy)-benzyl bromide (Example 4) and 1 g of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone are added to a suspension of 0.8 g of potassium carbonate in 10 cc of dimethylformamide. The resulting reaction mixture is stirred for 1 hour at room temperature, is diluted with ether, is washed with diluted HCl and brine; the washed solution is thoroughly dehydrated, the solvent is evaporated off and the so obtained raw reaction product is chromatographed on silica gel with 9/1 hexane/ethyl acetate. 1.4 g of pure product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[C:17]([O:23]C)=[N+:18]([O-:22])[CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[C:17](=[O:23])[N:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1c(COc2ccc(-c3ccc(Br)cc3)cc2)ccc[n+]1[O-]
Agent: Cl
Solvent: CO
Product: O=c1c(COc2ccc(-c3ccc(Br)cc3)cc2)cccn1O

Procedure:
A solution of 3-(4′-bromo-biphenyl-4-yloxymethyl)-2-methoxy-pyridine 1-oxide (0.045 g, 0.12 mmol) from Step C in MeOH (1 mL) was treated with 2N HCl (1.5 mL) at reflux for 1 h. The reaction mixture was concentrated under the reduced pressure and the resulting material (Compound 41) was washed with water and Et2O/hexanes (1:5) to give the titled compound. MS: 372, 374 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1]
Reactant: Br
Reactant: Nc1cccc(Cl)c1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc(Br)c1Cl
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
32.7 g 2,3-Dichloroaniline (0.20 mole) is added to a mixture of 168.5 g of 48% aqueous HBr (1.0 mole, 5.0 equivalents) and 40 ml water at 30-40° C. The mixture is stirred for 15 minutes at 30-40° C. and then heated to 45° C. Then 2.9 g Cu(I)Br (0.02 mole, 0.10 equivalent) is added and the mixture is stirred for 15 minutes at 45° C. After this, an aqueous solution of NaNO2 (40% solution in water, 35.6 g, 0.21 mole, 1.0 equivalents) is added via subsurface feeding over a period of 2 hours at 45° C. The reaction mixture is stirred for 30 minutes at 45° C. After this, the reaction mixture is heated to 60-65° C. The organic phase containing the reaction product is separated from the aqueous phase and is cooled to ambient temperature, leading to solidification of the reaction product. The remaining liquid is discarded and the crude product is washed twice with 10 ml water and dried under vacuum. 40.0 g (80% of theory) of 1-bromo-2,3-dichlorobenzene is obtained in the form of a light brown solid (purity: 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:16](Cl)(=[O:19])[CH2:17][CH3:18].C[O-].[Na+].Cl>O.C(O)C.N1C=CC=CC=1>[C:10]1([C:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:16](=[O:19])[CH2:17][CH3:18])[S:3][CH:4]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1c(-c2ccccc2)csc1N
Reactant: CCC(=O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1scc(-c2ccccc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-amino-4-phenylthiophene-3-carboxylic acid amide (3.0 g, 13.8 mmol) and anhydrous pyridine (12 ml) was treated with propionyl chloride (1.32 ml, 15.2 mmol) and stirred at ambient temperature for 3 hours. The excess pyridine was removed in vacuo to give a residue, which was treated with ethanol (50 ml) and sodium methoxide (2.24 g, 41.4 mmol) and the resultant mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with water (300 ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 4-phenyl-2-propionylaminothiophene-3-carboxylic amide.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:19])[CH2:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.Cl.ClC1C=CSC=1C(=O)CN.ClC1C=CC(C(Cl)=O)=CC=1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:19][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])=[CH:8][N:9]=2)=[CH:16][CH:15]=1
Reactant: O=C(NCC(=O)c1sccc1Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: NCC(=O)c1sccc1Cl
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: Clc1ccc(-c2ncc(-c3sccc3Cl)o2)cc1

Procedure:
N-[2-(3-Chloro-thiophen-2-yl)-2-oxo-ethyl]-4-chloro-benzamide: The title compound was prepared from 2-(3-chloro-thiophen-2-yl)-2-oxo-1-ethylamine hydrochloride (0.05 g, 0.235 mmol) and 4-chloro-benzoyl chloride (0.02 mL, 0.235 mmol) by a procedure similar to Example 97a to yield 0.048 g (72.7%) of white solid. 1H NMR (CD3OD): 7.77 (m, 3H), 7.43 (d, J=8.4 Hz, 2H), 7.36 (t, 1H), 7.05 (d, J=5.4 Hz, 1H), 4.75 (d, J=9.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Yield: 97 %

Procedure:
4-(6-Chloropyrimidin-4-yloxy)phenylamine (663 mg, 3.00 mmol) and phenyl isocyanate (393 mg, 3.30 mmol) were stirred in dimethylformamide (5 ml) at room temperature for 18 hours. The reaction solution was poured into water and the precipitated crystals were filtered out, washed with water and ethanol and blow-dried to obtain the title compound (988 mg, 2.91 mmol, 97%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](O)[CH:9]=2)[N:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1ccc2cc(O)ccc2n1
Reactant: ClCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc2cc(COCc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyano-6-hydroxyquinoline (100 mg) in 10 mL of acetone was added potassium carbonate (122 mg). After stirring at RT for three minutes, the solution was put on ice. Benzyl chloromethyl ether (122 μL) was added through a needle and the resultant solution was stirred on ice for 2 hours. The solvent was then removed under vacuum and the residue was purified by flash chromatography with dichloromethane. 157 mg was obtained.
Reaction SMILES: [CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](=[O:31])[CH:17]=[C:16]1[CH2:32]O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.CN(C=O)C>[CH:1]([O:14][N:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:18](=[O:31])[CH:17]=[C:16]1[CH2:32][N:38]1[C:34](=[O:44])[C:35]2[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:37]1=[O:39])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CO)cc2=O)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(OC(c3ccccc3)c3ccccc3)c(CN3C(=O)c4ccccc4C3=O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
To a solution of 1-(benzhydryloxy)-2-(hydroxymethyl)-5-((4-methoxybenzyl)oxy)pyridin-4(1H)-one (Intermediate 291, 2 g, 4.51 mmol), phthalimide (0.664 g, 4.51 mmol) and triphenylphosphine (1.178 g, 4.51 mmol) in THF (20 mL) at room temperature was added diisopropyl azodicarboxylate (2.397 mL, 12.18 mmol). Reagents are insoluble. DMF (10 mL) was added. The reaction was stirred at room temperature overnight. The reaction mixture was filtered and concentrated onto silica gel. Silica gel chromatography (0%-4% methanol/dichloromethane) did not offer separation of desired product from impurities. Fractions were combined and repurified. Silica gel chromatography (0%-30% acetone/dichloromethane) afforded the title compound (1.66 g, 64.3%) as a light yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.O1CCCC1>C(N(CC)CC)C>[C:4]([NH:6][C:7](=[S:8])[O:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)N=C=S
Reactant: OCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)OCc1ccc(Cl)cc1
Yield: 58.2 %

Procedure:
90 g of ethoxycarbonyl isothiocyanate were added dropwise to a mixture of 85 g of p-chlorobenzyl alcohol, 600 ml of tetrahydrofuran and 4 ml of triethylamine and the mixture was refluxed for 24 hours and was then evaporated to dryness under reduced pressure. The residue was added to isopropyl alcohol and the precipitate formed was recovered by vacuum filtration to obtain 95 g of p-chlorobenzyl N-carbethoxy-thiocarbamate melting at 95° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[NH:10][C:9](=[O:23])[C:8]=3[C:7]=2[CH:24]=1.[CH2:25]([O:27][C:28](=[O:47])[C@H:29]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[NH:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)[CH3:26].C(N(CC)CC)C>CN(C=O)C>[O:23]=[C:9]1[C:8]2[C:7]3[CH:24]=[C:3]([CH2:2][NH:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([NH:30][C@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:47])[CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:39])=[CH:33][CH:34]=4)[CH:4]=[CH:5][C:6]=3[CH:15]=[CH:14][C:13]=2[N:12]=[C:11]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[NH:10]1
Reactant: CC(C)(C)C(=O)Nc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(NC(=O)C(C)(C)C)[nH]c(=O)c4c3c2)cc1)C(=O)OCC

Procedure:
To a hot solution of N-(1,2-dihydro-9-methyl-1-oxobenzo[f]quinazolin-3-yl)pivalamide (0.94 g, 3.0 mmol) in benzene (250 ml) under nitrogen were added N-bromosuccinimide (0.57 g, 3.2 mmol) (Kodak) and 2,2'-azobisisobutyronitrile (AIBN) (35 mg, 0.21 mmol) (Kodak). The solution was stirred at reflux for 1.5 hours and then concentrated in vacuo to give crude N-(9-bromomethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-3-yl)pivalamide. The pivalamide and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.5 g, 7.8 mmol)(Aldrich) in DMF (10 ml) were stirred under nitrogen at 105°-110° C. for 5 minutes and then allowed to cool. Triethylamine (0.5 ml, 3.6 mmol) was added and the solution was concentrated under high vacuum. The residue was purified by chromatography on silica gel (130 g) eluting with ethyl acetate:methylene chloride (1:19->2:3), followed by recrystallization of the solid from ethanol/diethyl ether. This was filtered and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-1-oxo-3-pivalamido-benzo[f]quinazolin-9-yl)methyl)amino)benzoyl)-L-glutamate (0.32 g) as a white solid. The filtrate was concentrated and the residue purified by chromatography and crystallization to give an additional 0.243 g. 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.16 (t, J=7 Hz, 3H, ester CH3), 1.28 (s, 9H, t-butyl), 1.87-2.13 (m, 2H, glu CH2), 2.39 (t, J=7 Hz, 2H, glu CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 4.07 (q, J=7 Hz, 2H, ester CH2), 4.30-4.40 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 -CH2), 6.63 (d, J=9 Hz, 2H, Ar), 7.04 (t, J=6 Hz, 1H, ArNH), 7.53 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.62 (d, J=9 Hz, 2H, Ar), 7.99 (d, J=8 Hz, 1H, Ar) 8.21 (d, J=8 Hz, 1H, glu NH), 8.22 (d, J=9 Hz, 1H, Ar), 9.75 (s, 1H, Ar), 11.25 (s, 1H, N2H), 12.30 (br s, 1H, NH). Mass spectrum (CI-CH4) 630 (M+1, 6.5%), 243 (100%). Anal. Calculated for C34H39N5O7 : C, 64.85; H, 6.24; N, 11.12. Found: C, 64.74; N, 6.25; N, 11.10.
Reaction SMILES: [F:1][C:2]1[CH2:7][C:6](F)([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](F)([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3]=1[F:26].CC(C1C=CC(O)=CC=1)(C1C=CC(O)=CC=1)C.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[F:1][C:2]1[CH2:7][CH:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:4][C:3]=1[F:26]
Reactant: O=C(c1ccccc1)C1(F)CC(F)=C(F)CC1(F)C(=O)c1ccccc1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)C1CC(F)=C(F)CC1C(=O)c1ccccc1
Temperature: 130 °C

Procedure:
The synthesis of polycyclohexenepolyetherketone 28 was conducted in a three-neck flask equipped with a nitrogen inlet, Dean-Stark and condenser. A detailed synthetic procedure for its synthesis is as follows: The flask was charged with the monomer difluoro-4,5-difluoro-4,5-dibenzoylcyclohexene 3 (7.65 mmol, 2.48 g) and bisphenol (BPA) (7.65 mmol, 1.74 g) in N,N-dimethylacetamide (15 mL). Toluene (15 mL) was added, followed by anhydrous potassium carbonate (22.9 mmol, 3.2 g). The reaction mixture was then heated until toluene began to reflux. An optimum reflux temperature range was reached at 130° C. Toluene was periodically removed from the Dean-Stark trap to replace with dry toluene to ensure dehydration. The reaction mixture was maintained at 130° C. for 1-2 h at which point the viscosity increased enormously. The reaction mixture seemed to reach near completion or completion by the dramatic increase in viscosity and was then cooled, a few drops of acetic acid was added, and then diluted with toluene. The polymer solution was coagulated in a large amount of methanol, filtered, and washed with methanol. The white fibrous polymer 28 was redissolved in chloroform, hot filtered through Celite, reprecipitated into a large volume of methanol, filtered and dried in vacuo at 80° C. for 24 h. The yield was essentially quantitative.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8](=[O:14])[CH2:9][C:10]([O:12]C)=[O:11].[Li+].[OH-].O.Cl>C(Cl)Cl.C1COCC1.O>[O:14]=[C:8]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Nc1nccs1
Reactant: COC(=O)CC(=O)Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a solution of 2-aminothiazole (2.0 g, 19.97 mmol) in dry DCM (30 ml) at 0° C. was added TEA (4.03 g, 2 eq, 39.94 mmol) and methyl 3-chloro-3-oxopropanoate (3.0 g, 1.1 eq, 21.97 mmol). The reaction mixture was stirred for 1 hr at room temperature. The reaction mixture was concentrated to dryness, dissolved in EtOAc and washed well with water. The organic phase was collected, dried over anhydrous sodium sulfate then filtered and concentrated. The resultant solid was triturated with Et2O and used directly in the next step with no additional purification (1.1 g, 30% yield). To a solution of the ester 128 (500 mg, 2.49 mmol) in THF/water (1:1, 20 ml) was added LiOH×H2O (209 mg, 2 eq, 4.98 mmol) and the mixture stirred for 2 hrs at room temperature. The mixture was neutralized with 1 M HCl solution and adsorbed onto silica gel. Purification by column chromatography (60% EtOAc in hexanes) afforded the acid 129 as a white solid (320 mg, 69% yield). MS (m/z): 187.2 (M+H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2)#[N:12].Br[CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:30][C:31]([O:33][CH3:34])=[O:32].[Br-]>C1COCC1>[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:23]=[CH:22]2)#[N:12]
Reactant: CCCCCCC(Br)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(CC(=O)OC)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (5.6 ml of 1M solution in THF) in 40 ml THF was added dropwise at 0° C. to a solution of 5-(2-cyanophenyl)indole (5.04 mmoles, 1.1 g) in 100 ml THF and stirred at 0° C. for 30 minutes. Methyl 3-bromononanoate (5.6 mmoles, 1.32 g) in 20 ml THF was added dropwise. The reaction was stirred at room temperature for 12 hours. An additional 5 mmoles of the base and the bromide were added. The reaction was stirred an additional 12 hours, added to ice water and extracted into ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The intermediate was chromatographed over silica gel eluted with 50% ether in hexane to yield 700 mg of methyl 3-[5-(2-cyanophenyl)indol-1-yl]nonanoate.