Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]2[C:15]3=[C:16]4[C:21](=[CH:22][CH:23]=[C:14]3[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:12]2=[O:33])[N:20]=[CH:19][CH:18]=[CH:17]4)=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[C:34]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:13]2[C:14]3[C:15](=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[CH:19][CH:18]=[CH:17]4)[C:11]3([CH2:34][O:1][C:2]4[CH:3]=[C:4]5[C:5](=[CH:9][C:10]3=4)[CH2:6][CH2:7][O:8]5)[C:12]2=[O:33])=[CH:26][CH:27]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: COc1ccc(CN2C(=O)C(c3cc4c(cc3O)OCC4)c3c2ccc2ncccc32)cc1
Product: COc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3c2ccc2ncccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 3′-(4-methoxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,1′-pyrrolo[3,2-f]quinolin]-2′(3′H)-one was obtained (9%) as a yellow solid: mp 169-170° C.; 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.10 (m, 1H), 7.92 (m, 1H), 7.43-7.28 (m, 4H), 6.92-6.86 (m, 2H), 6.51 (s, 1H), 6.44 (s, 1H), 5.17-5.06 (m, 2H), 4.97-4.88 (m, 2H), 4.58-4.49 (m, 2H), 3.79 (s, 3H), 3.09-2.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.1, 162.2, 161.0, 159.3, 148.0, 144.6, 140.2, 130.9, 128.8, 127.8, 127.6, 124.8, 122.4, 120.4, 119.8, 118.9, 114.4, 113.9, 93.4, 79.6, 72.4, 58.5, 55.3, 43.9, 29.0; MS (ES+) m/z 451.0 (M+1).
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[C:5]([N:7]=[C:8]([S-:10])[S-:9])#[N:6].[K+].[K+].[OH:13]O>>[OH:13][C:5]1[N:7]=[C:8]([S:10][CH2:1][CH:2]=[CH2:3])[S:9][N:6]=1
Reactant: OO
Reactant: N#CN=C([S-])[S-]
Reactant: C=CCCl
Agent: [K+]
Product: C=CCSc1nc(O)ns1

Procedure:
77 g of allyl chloride and 195 g of potassium N-cyanodithioimidocarbonate were condensed and the reaction product was oxidized with 100 ml of 30% hydrogen peroxide to obtain 63 g of 3-hydroxy-5-allylthio-1,2,4-thiadiazole melting at 84° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.O>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[S:6][C:5]([NH2:7])=[N:4][N:3]=2)[CH2:16][CH2:17]1
Reactant: Nc1nnc(Br)s1
Reactant: C1COCCN1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(N2CCOCC2)s1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine, K2HPO4 (5.7 g), and 5.3 ml of morpholine in 20 ml of DMF is heated at 80° C. under nitrogen for 18 hours, then diluted with 50 ml of water. The clear solution is placed in a continuous extractor and extracted with a brisk flow of dichloromethane for 18 hours. The solution is dried over MgSO4 and concentrated under reduced pressure, with toluene azeotropes to remove DMF. Recrystallization of the residual solid from 50 ml of acetonitrile and 100 ml of toluene affords 3.92 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=3)[C:9]=2[O:21][CH2:22]OC)=[CH:4][CH:3]=1.Cl.O1CCOCC1.FC1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([CH3:18])=[CH:16][C:11]3[C:10](=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[CH:12]=3)[C:9]=2[O:21][C:22]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=2)=[CH:6][CH:7]=1
Reactant: COCOc1c(-c2ccc(F)cc2)c(C)cc2cc(OC)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccc(F)cc3)c(C)cc2c1
Yield: 71.6 %

Procedure:
2-(4-Fluoro-phenyl)-6-methoxy-1-methoxymethoxy-3-methyl-naphthalene (203) (0.31 g, 0.95 mmol), 4 N HCl/Dioxane (5 mL), 4-fluorobenzaldehyde (0.132 mL, 1.23 mmol), Cs2CO3 (0.838 g, 2.57 mmol) and DMSO (3 mL) were reacted as described above to give 0.263 g (72%) of the title compound (204) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.24 (s, 3H), 3.93 (s, 3H), 6.69 (d, J=8.8 Hz, 2H), 6.92-6.97 (m, 2H), 7.07-7.15 (m, 4H), 7.59-7.68 (m, 4H), 9.80 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH2:23]1[CH:25](C(O)C#N)[CH2:24]1.[H][H]>CO.[Pd].C(Cl)(Cl)Cl>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:23]4[CH2:25][CH2:24]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: N#CC(O)C1CC1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5

Procedure:
To a solution of noroxymorphone (2 g, 6.14 mmol) in methanol (20 ml) was added cyclopropylcarboxaldehyde (0.63 ml, 8.43 mmol). 5% Palladium on carbon catalyst (1 mole % Pd) was added and the mixture was hydrogenated at 50° C. under 3 bar hydrogen pressure for 1 hour. On completion, the catalyst was filtered off and the reaction liquors diluted with chloroform (20 ml) and washed with water (3×20 ml). Evaporation of the solvent yielded naltrexone alkaloid.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH:7]([N:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][C:14](SC)=[CH:15][CH:16]=2)[C:11]1=[O:29])([CH3:9])[CH3:8].O1CCOC[CH2:31]1.O>O>[CH:7]([N:10]1[N:19]=[C:18]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[C:17]2[C:12](=[CH:13][C:14]([S:3]([CH3:31])(=[O:5])=[O:2])=[CH:15][CH:16]=2)[C:11]1=[O:29])([CH3:9])[CH3:8]
Reactant: O=S([O-])OO
Reactant: C1COCCO1
Reactant: CSc1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Agent: [K+]
Solvent: O
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(S(C)(=O)=O)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
Oxone (0.88 g, 1.4 mmol) was added in one portion to a stirred solution of 2-iso-propyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-methylsulfanyl-2H-phthalazin-1-one (0.12 g, 0.36 mmol) in a 4:1 mixture of dioxane/water (1.2 ml) and the reaction mixture was stirred at RT for one hour. The reaction mixture was diluted with water (5 ml) and the solution was extracted with EtOAc (3×75 ml), the organic layers were combined, dried (MgSO4), filtered and concentrated under vacuum to give a dark brown solid. Flash column chromatography (elution: 96% DCM, 4% MeOH) gave the title compound (0.032 g, 25% yield) as a light yellow solid (Example H-2). 1H-NMR: (400 MHz, D6-DMSO) 11.99 (1H, br s), 9.44 (1H, s), 8.76-8.68 (2H, m), 8.39 (1H, d), 6.36 (1H, s), 5.32-5.18 (1H, m), 3.36 (3H, s), 2.25 (3H, s), 1.34 (6H, d) MS (ESI+)=(M+H)+ 362.16.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=2[CH3:34])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:31]=[CH:32][C:33]=3[CH3:34])[CH2:24][CH2:23]2)=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCCC2)CC1

Procedure:
Example 134 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, 1H, J=8.9, 6.3 Hz), 7.32 (s, 1H), 7.23–7.18 (m, 2H), 7.06 (dd, 1H, J=8.5, 3.0 Hz), 7.01–6.92 (m, 2H), 5.99–5.93 (m, 1H), 3.24 (q, 2H, J=5.9 Hz), 2.85–2.79 (m, 3H), 2.59–2.50 (m, 1H), 2.44 (septet, 1H, J=7.0 Hz), 2.41–2.37 (br, 1H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.07–2.01 (m, 2H), 1.81–1.69 (m, 4H), 1.61–1.37 (m, 10H), 1.17 (d, 6H, J=7.0 Hz); ESMS m/e: 556.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)N1CCOCC1.[C-:18]#[N:19].[K+].[OH-].[Na+]>O>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([CH:3]([CH:2]([CH3:1])[CH3:17])[C:18]#[N:19])=[CH:15][CH:14]=1
Reactant: CC(C)C(c1ccc(O)cc1)N1CCOCC1
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(C#N)c1ccc(O)cc1
Yield: 97 %

Procedure:
A mixture of 4-(2-methyl-1-morpholinopropyl) phenol (2.35 g; 0.01 mol), potassium cyanide (1.6 g; 0.024 mol) and water (2.5 ml) is heated at 95°-100° C. for 17 hours. The reaction mixture is then cooled down, and added to about 35 ml of 5% sodium hydroxide. The aqueous solution is washed with ether (2×, 20 ml), and then its pH is adjusted to ~2 with 6 N hydrochloric acid. The acidified aqueous solution is extracted with ether (2×, 30 ml), the ethereal extracts are combined, washed with water, dried over magnesium sulfate, and concentrated to afford 1.7 g of title product, a viscous, almost colorless oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[C:19]([OH:21])=O)=[O:7])(C)(C)C.[O:22]([CH2:29]C(Cl)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[C:15]([O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6](=[O:7])[CH2:29][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@H:9]([C:19]([NH:36][CH:33]2[CH2:35][CH2:34]2)=[O:21])[CH2:10]1)([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)ON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NC1CC1
Reactant: O=C(Cl)COc1ccccc1
Product: CC(C)(C)ON=C1C[C@@H](C(=O)NC2CC2)N(C(=O)COc2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(tert-butoxyimino)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and cyclopropylamine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=374.2.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:42]2[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[C:26](=[O:27])[C:25]([C:28]2[CH:29]=[N:30][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:32][CH:33]=2)=[C:24]([CH3:38])[N:23]=[C:22]1[CH2:39][CH2:40][CH3:41]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[C:26](=[O:27])[C:25]([C:28]2[CH:29]=[N:30][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[CH:32][CH:33]=2)=[C:24]([CH3:38])[N:23]=[C:22]1[CH2:39][CH2:40][CH3:41]
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)C)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)nc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogen carbonate (1.01 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[5-(6-isopropoxypyridin-3-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.6 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.29 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 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water 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 amorphous solid (0.49 g, 74%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc(F)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccc(F)cc1
Yield: 78.7 %

Procedure:
N-(4-fluorobenzyloxycarbonyl)-L-prolyl-L-valinol was prepared from 16.1 g (60.2 mmol) p-fluorobenzyloxycarbonyl-L-proline, 8.22 g (60.2 mmol) isobutyl chloroformate, 6.09 g (60.2 mmol) N-methylmorpholine, and 6.21 g (60.2 mmol) L-valinol, substantially according to the mixed anhydride procedure described in Example 1. The resulting crude product (19.46 g) was recrystallized from a mixture of 100 mL ethyl acetate and 200 mL n-hexane to give 16.69 g (47.4 mmol, 78.7%) of N-(4-fluorobenzyloxycarbonyl)-L-prolyl-L-valinol, m.p. 123°-124°. αD25 -60.2° (C=1.02 g/100 mL in acetone). An nmr obtained for this material spectrum verified the assigned structure: 1H NMR (CDCl3 /TMSi), 220 mc, δ0.85, m, 6H (valinol CH3); δ1.9, m, 2H (proline γ-CH2); δ2.2, m, 3H (valinol β-CH and proline β-CH2); δ 3.35, m, 3H (proline δCH2); δ 3.58, m, 2H (CH2OH); δ 4.34, m, H (valinol α-CH); δ 5.0, s, 2H (benzyl CH2); δ 6.30-6.80, m, H (NH); δ 7.03, m, 2H (aromatic); δ 7.35, m, 2H (aromatic).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Temperature: 60 °C
Yield: 89.9 %

Procedure:
A mixture of 2-bromo-4-nitrophenol (Description 6; 14 g, 68.6 mmol), benzyl bromide (14.1 g, 82.4 mmol) and potassium carbonate (47.3 g, 0.343 mol) in dimethylformamide (100 ml) was heated at 60° C. for 3 hours. The mixture was cooled to room temperature and poured into a mixture of ethyl acetate and water. The organic phase was washed with water (3 times) and saturated brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give the title compound (19 g). H NMR (250 MHz, CDCl3) δ 8.48 (1H, d, J 2.8 Hz), 8.18 (1H, dd, J 9.08 Hz, 2.8 Hz), 7.46−7.3 (5H, m), 7.0 (1H, d, J 9.2 Hz), and 5.27 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:33][C:34]([F:41])([F:40])[CH2:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:33][C:34]([F:41])([F:40])[CH2:35][S:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of Example 3 (0.05 g, 0.151 mmol) and triethylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0 mL) was added dropwise 2,2,2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol). The reaction mixture was stirred for 1 hour at room temperature and then purified by flash chromatography (silica gel, 0-5% methanol in dichloromethane) to afford 0.050 g (68%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H) 4.55 (q, J=9.91 Hz, 2H) 6.28 (t, J=2.38 Hz, 1H) 6.86 (d, J=7.54 Hz, 2H) 6.95-7.07 (m, 2H) 7.20-7.31 (m, 5H) 7.40 (d, J=2.78 Hz, 1H) 10.43 (s, 1H) 12.02 (s, 1H). MS (APCI+) m/z 478 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)[CH3:2].F[P-](F)(F)(F)(F)F.[N:19]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:23]2C=CC=CC=2N=N1.[NH2:39][C:40]1[CH:45]=[C:44]([O:46][C:47]2[CH:52]=[CH:51][C:50](CN)=[C:49]([N+:55]([O-:57])=[O:56])[CH:48]=2)[CH:43]=[CH:42][N:41]=1>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([C:9]([NH:39][C:40]2[CH:45]=[C:44]([O:46][C:47]3[CH:52]=[CH:51][C:50]([NH:19][CH3:23])=[C:49]([N+:55]([O-:57])=[O:56])[CH:48]=3)[CH:43]=[CH:42][N:41]=2)=[O:11])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(C(=O)O)CC1
Reactant: NCc1ccc(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCN1CCC(C(=O)Nc2cc(Oc3ccc(NC)c([N+](=O)[O-])c3)ccn2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 1-(ethyl)piperidine-4-carboxylic acid (1 eq) in N,N-dimethyl formamide and N,N-disopropylethylamine (4 eq) was added BOP (2 eq) and the mixture was stirred at ambient temperature until homogeneous. To it was added [4-(2-amino(4-pyridyloxy))-2-nitrophenyl]methylamine (1 eq) and the resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and the resulting ((1-ethyl)(4-piperidyl))-N-{4-[4-(methylamino)-3-nitrophenoxy]}(2-pyridyl))carboxamide was purified by silica gel chromatography. MS: MH+=400.2.
Reaction SMILES: [CH3:1][CH:2]([C:16]([OH:18])=[O:17])[CH:3]([C:13]([OH:15])=O)[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:19][CH:20]([C:31]([OH:33])=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:1][CH:2]([C:16]([O-:18])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:19][CH:20]([C:31]([O-:33])=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH3:30].[C:16]1(=[O:17])[O:18][C:13](=[O:15])[CH:3]=[CH:2]1
Reactant: CCCCC=CCCCCC(C)C(=O)O
Reactant: CCCCC=CCCCC(C(=O)O)C(C)C(=O)O
Product: CCCCC=CCCCCC(C)C(=O)[O-]
Product: O=C1C=CC(=O)O1

Procedure:
The procedure according to Example 76 is repeated but using 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2,3-dicarboxylic acid monomer (0.05 mole) as the third comonomer instead of 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylic acid (0.05 mole), to obtain poly(1,1-dimethylethyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylate/12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2,3-dicarboxylic acid/2-hydroxyethyl 12-oxatetracyclo[4.4.0.1.1]dodec-7-ene-2-carboxylate/maleic anhydride) represented by the following Chemical Formula 179:
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH2:24])[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].N1C=CC=CC=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:24][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(N)=O)c2c3cc(NS(C)(=O)=O)ccc3n(C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of methane sulphonyl chloride (30 mg, 0.00027 mol) in dry THF (5 ml). The reaction mixture was stirred for 1 hr THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-methanesulphon-amido-9H-4-carbazolecarboxamide(20 mg), mp>250° C.
Reaction SMILES: [CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2]1.C(Cl)(=O)C(Cl)=O.O[CH:23]1[CH2:27][C:26](=[O:28])[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:24]1[CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>C1C=CC=CC=1.N1C=CC=CC=1.O>[CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][CH2:11][C:12]([O:14][CH:23]2[CH2:27][C:26](=[O:28])[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:24]2[CH:38]=[CH:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:13])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)O)C1
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CC1CCC(C(C)C)C(OCC(=O)OC2CC(=O)C(CCCCCCC(=O)O)=C2C=Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
5 Parts of (-)-menthoxyacetic acid is dissolved in 8.79 parts of benzene and treated with 5.95 parts of oxalyl chloride. The resulting solution then is heated at about 60° for 2 hours and allowed to stand for 1 hour at room temperature. After that time, the solvent is removed under reduced pressure, and the remaining residue is dissolved in benzene and again concentrated to dryness. The crude (-)-menthoxyacetyl chloride thus obtained is dissolved in 8.79 parts of benzene and that solution added to a cold solution of 7.5 parts of 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid dissolved in 9.82 parts of pyridine. That mixture is allowed to stand for about 16 hours at room temperature, then poured into a cold solution of 50 parts of d-tartaric acid in 1,500 parts of water. The solution is extracted with ethyl acetate and the organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The oily residue which remains is dissolved in benzene and chromatographed on silicic acid to yield, after elution with 10% ethyl acetate-90% benzene, crude product. The pure material is obtained upon recrystallization from benzene-hexane to give 3-((-)-menthoxyacetoxy)-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, melting at about 103°-104°, and displaying an optical rotation of about -42.1°. That compound is characterized by infrared absorption maxima, in chloroform, at about 1754, 1710, 1627 and 1124 reciprocal centimeters, an ultraviolet absorption band, in methanol, at about 326 millimicrons with a molecular extinction coefficient of about 37,000, and represented by the following structural formula ##SPC21##