Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>C(O)(=O)C>[N+:1]([C:27]1[CH:28]=[C:23]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:24]=[CH:25][C:26]=1[OH:29])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
40 ml of nitric acid (d=1.18) was added dropwise to a solution of 10 g of p-octadecylphenol dissolved in 300 ml of acetic acid at 10° to 40° C. After one hour, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water, then with aqueous sodium bicarbonate solution, followed by drying. After the solvent was evaporated, the residued crystals were recrystallized from n-hexane. 2-Nitro-4-octadecylphenol of m.p. 71° C. was obtained in an amount of 8.4 g.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S-:4].[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S:4][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Fc1ccc([S-])c(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Sc2ccc(F)cc2F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of potassium 2,4-difluorothiophenoxide (5.5 g) in N,N-dimethylformamide (9 ml) was added dropwise to a solution of 4'-chloro-3'-nitroacetophenone (5 g) in toluene (50 ml). The mixture was stirred at room temperature for 2 hours, washed with water, dried and evaporated to dryness. The residue was washed with a mixture of hexane and ethanol to give crystals of 4'-(2,4-difluorophenylthio)-3'-nitroacetophenone (7.4 g).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:22])[N:6]=1)[CH2:3][CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]2[NH:30][CH:31]=[N:32][C:25]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:32]1[C:25]2[C:26](=[N:27][CH:28]=[CH:29][C:24]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13](=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:22])[N:6]=2)[CH2:3][CH3:4])[NH:30][CH:31]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (27 mg, 0.091 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (21 mg, 0.14 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 4A).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]([O:28]C)=[O:27])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>C1COCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:10]([C:26]([OH:28])=[O:27])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 80 °C

Procedure:
To a solution of methyl 1-benzyl-4-(benzyloxy)-2-oxo-1,2-dihydro-1,5naphthyridine-3-carboxylate (0.65 g, 1.62 mmol) in THF (20 mL) was added sodium hydroxide (16.2 mL, 1 N) and the solution was heated to 80° C. and after 1.5 hours the reaction was completed. The reaction was allowed to cool and then the THF was removed leaving the product in water. The water was acidified with 1N HCl to adjust the pH to 3 and the resulting crude solids were collected by vacuum filtration and taken on as is.
Reaction SMILES: C([Li:5])CCC.[CH:6]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:8])[CH3:7].C[Si](CC(OCC)=O)(C)C.N1C2C(=CC=CC=2)C=CC=1OCCCCCCCCCC(=O)C>C1COCC1>[CH:6]([N-:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:8])[CH3:7].[Li+:5]
Reactant: CC(C)NC1CCCCC1
Reactant: [Li]CCCC
Agent: CC(=O)CCCCCCCCCOc1ccc2ccccc2n1
Agent: CCOC(=O)C[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(C)[N-]C1CCCCC1
Product: [Li+]
Reaction time: 16 h

Procedure:
Lithium N-isopropyl-N-cyclohexylamide was prepared at -78° in anydrous THF from n-butyl lithium (6.1 mmol) and N-isopropyl-N-cyclohexylamine (1.00 ml). Ethyl trimethylsilylacetate (1.1 ml) was added, followed after 10 minutes by addition of the above ketone in THF. The reaction mixture was left at room temperature for 16 hours and worked-up in the usual manner. Excess ethyl trimethylsilylacetate was removed in vacuo and purification by column chromatography on silica (9:1, hexane: ether) gave (2E/Z)ethyl 3-methyl-12-(2-quinolinyloxy)dodec-2-enoate (0.33 g). This was converted to the title compound by analogy with Stages c and d of EXAMPLE I.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][OH:8])([CH3:6])([CH3:5])[CH3:4].[CH:9]([N:12]=[N:13][C:14]1(Cl)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:11])[CH3:10].[OH-].[Na+]>>[CH:9]([N:12]=[N:13][C:14]1([O:8][O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)([CH3:11])[CH3:10]
Reactant: CC(C)(C)OO
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N=NC1(OOC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 24.7 grams (0.11 moles) of 25% potassium hydroxide in an erlenmeyer flask equipped with a magnetic stirrer, thermometer and addition funnel was added 14.0 grams (0.14 moles) of 90% tert.-butylhydroperoxide while holding the temperature below 30° C. with a cold water bath. After the addition was complete, the reaction was stirred for 30 minutes at room temperature, cooled to 18° C. and with rapid stirring 18.85 grams (0.1 mole) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise from the addition funnel over 40 minutes while holding the reaction temperature at 20° C.± 2° C. After the addition was complete, the reaction was stirred for 10 minutes at 15° C., cooled to 0° C. and stirred an additional 30 minutes. At this point, 3.2 grams (0.04 mole) of 50% sodium hydroxide was added, the reaction stirred an additional 10 minutes, poured into 100 ml of ice water and the product extracted into 100 ml of pentane. The pentane solution was separated, washed with 50 ml portions of water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the pentane evaporated at 0° C. under reduced pressure on a rotating evaporator. The product was a light yellow liquid weighing 18.7 grams (77% crude yield). It was stored in a dry ice chest to prevent decomposition and it was not shock sensitive. The infrared spectrum was in agreement with the structure of 1-isopropylazo-1-(tert.-butylperoxy)cyclohexane (absence of the carbon-chlorine band of the starting material at 800-825cm-1 and the presence of a tert.-butylperoxy band around 885 cm-1.) The presence of a weak OH band at 3350cm-1 indicates that a small amount of 1-isopropylazo-1-hydroxycyclohexane also formed.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:3]1=[O:25].CCN(C(C)C)C(C)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N>[CH2:18]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][N:6]=2)[CH2:11][CH:2]([NH:1][S:41]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:43])=[O:42])[C:3]1=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)cnc2N1Cc1ccccc1
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
To a solution of 1J (120 mg, 0.36 mmol) in CH3CN (4 mL) at RT was added DIPEA (94 μL, 0.54 mmol), followed by benzenesulfonyl chloride (51 μL, 0.4 mmol). After 5 min, white precipitates formed. The reaction was stirred for additional 15 min. The product was collected by filtration and the solid washed with CH3CN (2-3 mL) to give the title compound as a white solid (100 mg, 71%). LC/MS (method A): retention time=3.96 min, (M+H)+=470. 1H NMR (CD3SOCD3, 400 MHz): δ8.60 (d, J=2.3 Hz, 1H), 8.35 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.94 (dd, J1=7.1 Hz, J2=1.5 Hz, 2H), 7.70 (dd, J1=8.5 Hz, J2=1.3 Hz, 2H), 7.66-7.69 (m, 1H), 7.61-7.64 (m, 2H), 7.54 (t, J =7.5 Hz, 2H), 7.34-7.46 (m, 1H), 7.25 -7.34 (m, 5H), 5.16 (dd, J1=47.0 Hz, J2=15.2 Hz, 2H), 4.44-4.50 (m, 1H), 3.20 (dd, J1=15.9 Hz, J2=6.0 Hz), 3.06-3.13 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N+:41]([O-])([OH:43])=[O:42]>CC(O)=O>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([N+:41]([O-:43])=[O:42])[CH:33]=[CH:32][C:31]=3[O:36][CH3:37])[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: COc1ccccc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc([N+](=O)[O-])cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.75 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (example 143) (159.4 mg, 0.276 mmol) in HOAc (5 mL) was added HNO3 (1.5 mL). After 45 minutes, additional HNO3 (1.5 mL) was added. 45 minutes later, the reaction was quenched by pouring into ice water (30 mL). The mixture was extracted with EtOAc (75 mL), and the organic layer was washed with 1 N NaOH, saturated NaHCO3, and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (8 to 40% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-nitro-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.11 (25% EtOAc/hexanes). LCMS=623.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 8.34 (m, 1H), 8.10 (m, 1H), 7.85 (d, J=6.9 Hz, 1H), 7.61-7.71 (m, 4H), 7.40 (m, 1H), 7.11 (m, 1H), 5.66 (d, J=8.0 Hz), 5.28 (d, J=8.2 Hz), 4.89-4.94 (m, 1H), 3.74-4.09 (m, 5H), 0.61 (d, J=6.6 Hz), 0.47 (d, J=6.5 Hz).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6](=[C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.Cl.O>O1CCCC1.[Cl-].[Na+].O>[CH:15]1([CH:12]2[CH2:13][CH2:14][C:9](=[C:6]3[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC1(OC)CCC(=C2CCC(C3CCCCC3)CC2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(=C2CCC(C3CCCCC3)CC2)CC1
Yield: 107.8 %

Procedure:
A solution of 4-(4'-cyclohexylcyclohexylidene)cyclohexanone dimethyl ketal (0.016 mol) and 1.0N HCl (100 ml) in tetrahydrofuran (125 ml) was left at room temperature for 2.5 hours at which time TLC indicated hydrolysis to be complete. Water and brine were added to the reaction solution and the mixture was extracted with ether (4×). The pooled ether extracts were washed with brine, dried (Na2SO4), filtered, and concentrated to give 4.49 g of white solid. This solid was chromatographed (790 g of 40-63 μm silica gel, 4.5 l of 5% ethyl acetate-hexane followed by 10% ethyl acetate-hexane) with 4-(4'-cyclohexylcyclohexylidene)cyclohexanonedimethylketal (0.56 g, 10%) eluted first followed by the title compound. Recrystallization of the title compound from hexane gave colorless crystals, mp 81°-81.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([O:13][CH2:14][CH2:15][NH2:16])=[CH2:12].C1C=CC=CC=1.[BH4-].[Na+]>O>[CH:11]([O:13][CH2:14][CH2:15][NH:16][CH:8]([CH3:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH2:12]
Reactant: C=COCCN
Reactant: CC(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: C=COCCNC(C)Cc1ccccc1
Yield: 64 %

Procedure:
A solution of 40.2 g. (0.3 mole) of phenylacetone, 26.2 g. (0.3 mole) of 2-aminoethyl vinyl ether and 200 cc. of anhydrous benzene were heated under reflux under a DeanStart water separator until the theoretical amount of water was removed (ca. 4 hours). At the end of this time, the benzene was removed under vacuum and the resulting crude imine was taken up in 450 cc. of dry methanol. To this solution was added 22.6 g. (0.6 mole) of sodium borohydride in small portions over a period of 1/2 hour. After the addition was complete, the reaction mixture was refluxed for 3 hours. The methanol was removed under vacuum and 300 cc. of water, 150 cc. of 20% potassium hydroxide and 60 g. of potassium hydroxide were added successively and the resulting oil was extracted with ether. After drying the ether solution over anhydrous magnesium sulfate, filtering and concentrating the resulting oil, it was distilled. 32.5 g. (64% yield) of the product as a colorless oil was obtained, b.p. 100°-102°/1.5 mm; ND25 1.5070.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([OH:23])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].ClC1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[O:23][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Product: CCOC(=O)c1cc(Oc2ccc([N+](=O)[O-])c(F)c2)ccn1
Temperature: 120 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To ethyl 4-chloropyridine-2-carboxylate (19.4 g) were added 3-fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml), followed by heating and stirring under a nitrogen atmosphere at 120° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature. Ethyl acetate (400 ml) and a saturated aqueous solution of sodium hydrogencarbonate (400 ml) were added thereto, followed by stirring at room temperature for 27 hr. Stirring was stopped and the aqueous layer was separated. To the organic layer was added again a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 2 days. Stirring was stopped and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (300 ml). The organic layers were combined and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=2:1, 1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound as a brown oil (12.9 g, 40.2%).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=O)[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:15])=O>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:15])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Product: CCCCc1nc(C)cc(Cl)n1

Procedure:
The pyrimidinone from Example 3 2-n-butyl-6-methylpyrimidin-4(3H)-one is converted to the title compound upon treatment with phosphoryl chloride as described by Gabriel amd Colman (Ber. 1899, 32, 2921) and by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: [CH2:1]([C:4]1[N:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:9][C:5]=1[C:6](O)=[O:7])[CH2:2][CH3:3].[CH:34]1[C:47]2[C:38](=[N:39][C:40]3[C:45]([C:46]=2[NH:48][C:49]2[CH:50]=[C:51]([NH:57][C:58](=[O:62])[CH:59]([NH2:61])[CH3:60])[CH:52]=[C:53]([CH2:55][OH:56])[CH:54]=2)=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:37]=[CH:36][CH:35]=1>>[CH:44]1[C:45]2[C:40](=[N:39][C:38]3[C:47]([C:46]=2[NH:48][C:49]2[CH:50]=[C:51]([NH:57][C:58]([CH:59]([NH:61][C:6]([C:5]4[CH:9]=[C:10]([NH:15][C:16]([N:18]5[CH2:19][CH2:20][N:21]([C:24]6[CH:25]=[C:26]([O:32][CH3:33])[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=6)[CH2:22][CH2:23]5)=[O:17])[C:11]([O:13][CH3:14])=[N:12][C:4]=4[CH2:1][CH2:2][CH3:3])=[O:7])[CH3:60])=[O:62])[CH:52]=[C:53]([CH2:55][OH:56])[CH:54]=2)=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:41]=[CH:42][CH:43]=1
Reactant: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 41.2 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-propyl-5-{[4-(3,5-dimethoxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[N:10][C:8]=2[N:9]=1)[CH3:2].C(N(CC)CC)C.O>CS(C)=O>[CH2:1]([S:3][C:4]1[N:5]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:28])[F:26])=[CH:19][CH:18]=2)[C:6](=[O:16])[C:7]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10][C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2nc(CO)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCSc1nc2nc(C=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
2-(Ethylsulfanyl)-7-(hydroxymethyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (373 mg) and triethylamine (6 ml) were dissolved in dimethyl sulfoxide (18 ml), sulfur trioxide pyridine complex (1.16 g) was added thereto by several portions, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (299 mg) as a orange solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:29][NH:30][CH2:31][C:32]#[CH:33].C(OS(OCCC)(=O)=O)CC>>[CH3:29][N:30]([CH2:31][C:32]#[CH:33])[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4].[CH2:18]([C:19]([O-:21])=[O:20])[CH2:8][CH3:7]
Reactant: C#CCNC
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Agent: CCCOS(=O)(=O)OCCC
Solvent: CCN(CC)CC
Product: C#CCN(C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Product: CCCC(=O)[O-]

Procedure:
This compound is prepared according to synthesis 111, from 196 mg (0.6 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 242 μL (2.4 mmol) of triethylamine and 45 mg (0.66 mmol) of N-methyl-prop-2-ynyl-amine to give, after esterification according to general method C (using di-n-propylsulfate as the dialkylsulfate) and purification by chromatography on silica (eluent dichloromethane/methanol 97/3) then trituration in diethyl ether, 80 mg (33% in two stages) of 8-(methyl-prop-2-ynyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])[NH:29][CH:28]=1)=[O:26])[CH3:36]
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.5 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (90.4 mg, 76.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.Cl.C(O)C>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 194.4 %

Procedure:
In dichloromethane (50 ml) was dissolved t-butyl 4-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-1-piperidinecarboxylate (1.56 g, 3.21 mmol). Trifluoroacetic acid (5.0 ml) was added dropwise to the resulting solution under ice cooling. The reaction mixture was stirred at room temperature for 2 hours and then, concentrated under reduced pressure. To the residue thus obtained were added dichloromethane (10 ml) and a 1N hydrochloric acid-ethanol solution (10 ml). The resulting mixture was concentrated under reduced pressure to give a white solid. The resulting solid was washed with diethyl ether to give the title compound (1.36 g, 3.12 mmol, 97%) as a white powder.