Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[NH4+:14].C[O-].[Na+]>CO>[NH2:14][C@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@@H](N)CC(=O)OC
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
Ru(OAc)2((R)-dm-segphos) (1.21 g, 1.28 mmol), methyl 3-oxopentanoate (50.0 g, 384 mmol), ammonium acetate (29.6 g, 384 mmol) and methanol (500 mL) were placed in a 1 L stainless steel autoclave under nitrogen atmosphere, and then the mixture was stirred under a hydrogen pressure of 3 MPa at 80° C. for 16 hours. After completion of the reaction, the solvent was removed by evaporation. To the residue, toluene (500 mL) was added, and then a 28% solution of sodium methoxide in methanol (66.7 g, 346 mmol) was added at room temperature. After the additions, the mixture was stirred at room temperature for 1 hour, and then the precipitate was filtered off. The filtrate was evaporated and the residue was then distilled to give methyl (3R)-3-aminopentanoate (32.0 g, colorless oil) in 63.5% yield. The enantiomeric excess of the product obtained above was determined to be 98.4% ee by HPLC analysis using a CHIRALCEL OD-H column after conversion into methyl (3R)-3-(4-nitrobenzoylamino)pentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:11])[O:12][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
4-Chloroaniline (2.3531 g) was dissolved in pyridine (20 ml), and to the solution was added dropwise ethyl chloroformate (2.116 ml) under ice-cooling. After the mixture was stirred for 1.5 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (3.6875 g, quantitative yield).
Reaction SMILES: O[C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>>[NH:15]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc2ccccc2cc1O
Reactant: Nc1ccccc1
Agent: Cl
Product: O=C(O)c1cc2ccccc2cc1Nc1ccccc1
Temperature: 170 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
A mixture of 3-hydroxy-2-naphthoic acid (Aldrich cat. #H4600-7) (376 g, 2.0 mol) and aniline (376 ml, 4.1 mol) was heated at 170° C. with stirring under nitrogen for 16 hours. The resulting mixture, when hot, was poured into 1N HCl (2.5 ml), heated to 100° C., and stirred at this temperature for 5 minutes. The mixture, when hot, was filtrated and the solid was washed with 0.2N HCl (600 ml). The wet material was boiled and mechanically stirred with 0.5N sodium carbonate solution (6.0 ml) for 10 minutes, cooled and filtered. The reddish filtrate was treated dropwise with 5N HCl with stirring to ~ pH 7. The resulting yellow precipitate was collected, washed with small amount of water and crystallized from ethanol (400 ml) to give 3-anilino-2-naphthoic acid (36 g, 7%). Rf 0.6 (silica gel, EM Art. 5715, 20% methanol/chloroform). MS (EI): m/z 264 (M).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[C:11]=2[O:22][C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.B(Br)(Br)Br.CO>ClCCl>[F:9][C:7]1[CH:6]=[C:5]([C:10]2[C:11]([O:22][C:23]3[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:36][CH:37]=3)=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:4]=[C:3]([F:2])[CH:8]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)cc(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)cc(F)c3)ccc2c1
Yield: 96.8 %

Procedure:
Dissolve 1-(2-{4-[2-(3,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-piperidine hydrochloride (410 mg, 0.76 mmol) in dichloromethane (10 mL) and cool in an ice bath. Add boron tribromide (0.22 mL, 2.28 mmol) and stir for 2.5 hours. Add methanol (5 mL), warm to ambient temperature, dilute with dichloromethane and wash with saturated aqueous sodium bicarbonate, dry with solid magnesium sulfate, filter and remove solvent under vacuum. Chromatograph on silica gel with dichloromethane/methanol mixtures to give 350 mg of the title compound (96%).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11]>C(O)(=O)C.[Pt]=O>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[CH:23]1[CH:14]([CH2:15][C:16]2[C:21]([NH:22]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CC2Cc3ccccc3NC12
Yield: 76.7 %

Procedure:
Camptothecin (500 mg, 1.43 m-mol) is suspended in acetic acid (100 ml). Platinum oxide (100 mg) is added to the suspension and the mixture is subjected to catalytic reduction (1.5 hours, absorption of about 140 ml of hydrogen) at room temperature under atmospheric pressure. After removing the catalyst by filtration, the reaction mixture is evaporated until dryness under reduced pressure. The residue is taken up in chloroform (200 ml) and washed with a 5% aqueous solution of sodium hydrogen carbonate (100 ml) and then with a saturated solution of sodium chloride (100 ml). The chloroform phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure until dryness. The residue is purified by column chromatography (chloroform) on silica gel (20 g) whereby 285 mg (conversion rate: 56.3%; yield: 76.7%) of the objective compound is obtained as yellowish white crystals. Unreacted starting materials (113 mg in crude state) is recovered. M.P. (dec.) 240°-242° C. (from methanol)
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[Br:16])(=O)=O.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCCC>CN(C=O)C.O>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][NH:23][CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[Br:16]
Reactant: CS(=O)(=O)OCc1cc([N+](=O)[O-])ccc1Br
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-nitrobenzyl methanesulfonate from Step B (0.42 g, 1.35 mmol) and 3,5-bis-trifluoromethyl benzylamine (0.33 g, 1.35 mmol) in DMF (10 ml) at 0° C., potassium carbonate (0.37 g, 2.69 mmol) was added. The mixture was stirred at 0° C. for 2h. TLC analysis (EtOAc/hexane=2:8) showed completion of the reaction. Water (50 ml) was added. The mixture was extracted with EtOAc (3×40 ml). The combined organic layers were washed with brine, and dried over sodium sulfate. The title compound was obtained by flash column chromatography using 2:8 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 8.35 (d, J=2.5 Hz, 1H), 8.03 (dd, J=8.5, 2.5 Hz, 1H), 7.88 (s, 2H), 7.81 (s, 1H), 8.76 (d, J=8.5 Hz, 1H), 4.00 (s, 4H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C@@:11]([NH:33][C:34](=[O:46])[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[F:10].[CH3:47][S:48](Cl)(=[O:50])=[O:49].Cl>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([NH:33][C@:11]([C:6]2[CH:7]=[CH:8][C:9]([F:10])=[C:4]([CH2:3][NH:2][S:48]([CH3:47])(=[O:50])=[O:49])[CH:5]=2)([C:19]2[CH:24]=[C:23]([O:25][C:26]([F:31])([F:30])[CH:27]([F:28])[F:29])[CH:22]=[C:21]([F:32])[CH:20]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:46])=[CH:36][C:37]=1[C:42]([F:45])([F:44])[F:43]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)—N-(1-(3-(aminomethyl)-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide hydrochloride (Example 269, 30 mg, 0.04 mmol) in DCM (2 mL) at rt was added TEA (6.8 μL, 0.05 mmol) followed by methanesulfonyl chloride (3.4 μL, 0.04 mmol). The reaction mixture was stirred at rt for 1 h and then poured into 1 N HCl. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO column chromatography (4 g, 0-40% EtOAc/hexane) to yield (R)-4-fluoro-N-(1-(4-fluoro-3-(methylsulfonamidomethyl)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 271) as a clear, colorless film (12 mg, 41%). 1H NMR (400 MHz, CDCl3) 7.95 (dd, J=6.57, 2.02 Hz, 1H), 7.86 (m, 1H), 7.22 (m, 7H), 7.07 (t, J=8.97 Hz, 1H), 6.93 (m, 3H), 6.71 (m, 3H), 5.88 (m, 1H), 4.55 (t, J=6.32 Hz, 1H), 4.30 (t, J=5.81 Hz, 2H), 3.97 (m, 1H), 3.83 (m, 1H), 2.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[CH2:10]=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:9])[C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:10]
Reactant: COC(=O)[C@H]1CCCN1
Reactant: C=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CCCN1C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
(2R)-proline methylester (1.20 g, 10.0 mmol) was dissolve in DMF (30 mL), and formalin (37% in water, 1.12 mL, 15.0 mmol) and NaBH (OAc)3 (4.20 g, 20.0 mmol) were added portionwise. After 12 h, the reaction material was concentrated in vacuo, and the residue was diluted with NaHCO3 (30 mL). The organic material was extracted with EtOAc, and the organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=4/1) to give the title compound (1.33 g, 93.0%).
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.[Br-].[CH2:32]([Zn+])[CH2:33][CH2:34][CH3:35]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[CH2:32]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][CH2:17]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCC[Zn+]
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: C1CCOC1
Product: CCCCc1ccc2oc(=O)cc(NC3CCN(CC=Cc4ccccc4)CC3)c2c1
Temperature: 160 °C
Yield: 13 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(dppf)Cl2 (˜5 mol %), and CuI (˜6 mol %) in dry THF (0.5 mL) followed by n-butyl zinc bromide (0.273 mL, 0.138 mmol (0.5M in THF)) dropwise. The solution was heated in the microwave for 10 minutes at 160° C., filtered, and was purified by Prep HPLC to give 2.5 mg (10%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 417 (M+H)+; 1H NMR (300 MHz, MeOH) δ ppm. 96 (t, 3H), 1.33-1.42 (m, 2H), 1.61-1.69 (m, 2H), 1.91-2.03 (m, 2H), 2.41 (br d, 2H), 2.72 (t, 2H), 3.24 (br t, 2H), 3.73 (br d, 2H), 3.96 (m, 3H), 5.42 (s, 1H), 6.30-6.40 (m, 1H), 6.95 (d, 1H), 7.23-7.54 (m, 8H), 7.86 (d, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH:9]=[CH2:10])(C)(C)C.Cl>CO.O1CCOCC1>[Cl:17][C:13]1[CH:12]=[C:11]([C@@H:8]([NH2:7])[CH:9]=[CH2:10])[CH:16]=[CH:15][CH:14]=1
Reactant: C=C[C@H](NC(=O)OC(C)(C)C)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C=C[C@H](N)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
(S)-tert-Butyl(1-(3-chlorophenyl)allyl)carbamate: To a solution of Intermediate 9A (1.38 g, 5.08 mmol) in MeOH (10 mL) was added 4 N HCl (6.35 mL, 25.4 mmol) in dioxane and the resulting reaction was stirred at rt for 1 h. After this time, the reaction mixture was concentrated and coevaporated with toluene (2×). The crude product was then triturated with ether, filtered and washed with additional ether to give (S)-1-(3-chlorophenyl)prop-2-en-1-amine (0.8 g, 94%) as a beige solid. MS (ESI) m/z: 150.8 (M+H—NH3)+. The beige solid was dissolved in ACN (25 mL) and TEA (4 mL, 28.7 mmol) and to this solution was added Boc2O (1.415 mL, 6.09 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water followed by brine. The crude product was then purified by silica gel chromatography to give the desired product, Intermediate 9B (546 mg, 40%) as a clear oil. MS(ESI) m/z: 290.0 (M+Na)+.
Reaction SMILES: C[Si](I)(C)C.[OH:6][NH:7][C:8](=[O:42])[C@H:9]([NH:25][S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)(=[O:28])=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O.CO>C(#N)C>[OH:6][NH:7][C:8](=[O:42])[C@H:9]([NH:25][S:26]([N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)(=[O:28])=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: O=C(NCCCC[C@@H](NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1)C(=O)NO)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: NCCCC[C@@H](NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1)C(=O)NO
Temperature: 25 °C
Yield: 43.5 %

Procedure:
Trimethylsilyl iodide (0.026 ml, 0.19 mmol) was added to a solution of N-hydroxy-6-(benzyloxycarbonyl)amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-hexanoamide (103 mg, 0.19 mmol) [prepared as described in Example 17, Step 3] in acetonitrile (2 ml) at 0° C. The reaction mixture was allowed to warm to RT, and additional trimethylsilyl iodide (0.47 mmol, 0.065 ml) was added in 0.5 equiv. portions over 2.5 h. Methanol (1.0 ml) was added and the reaction mixture was concentrated in vacuo. The residue was chromatographed (SiO2, 2%-10% methanol/methylene chloride) to give N-hydroxy-6-amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoamide (43.5%) as tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]([N:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=2[N:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:57]1[CH:62]=[CH:61][N:60]=[CH:59][C:58]=1[N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>CN(C=O)C>[C:7]1([CH:6]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([N:66]4[CH2:65][CH2:64][N:63]([C:58]5[CH:59]=[N:60][CH:61]=[CH:62][N:57]=5)[CH2:68][CH2:67]4)=[O:23])=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)O)ccc21
Reactant: c1cnc(N2CCNCC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(C(=O)N3CCN(c4cnccn4)CC3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-ethoxy-3-oxo-1-phenylpropyl)-1H-benzimidazole-5-carboxylic acid (70 mg, 207 μmol) in DMF (4 mL) was added N,N-diisopropylethylamine (40 μL, 229 μmol) and TBTU (80 mg, 249 μmol). The solution was stirred at room temperature for 0.5 hour, 1-(2-pyrazinyl) piperazine (41 mg, 249 μmol) was added, and stirring continued at room temperature for 24 hours. The solution was evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5) to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.33 min, MH+ 485].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:32])=[O:31]
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)ccc1Oc1cncc(Cl)c1
Yield: 92 %

Procedure:
The title compound was prepared using the alternative procedure described in Example 3. In this manner, 0.1 g of the aniline of Example 1 was combined with 2,4-dichloro-6-methylbenzenesulfonyl chloride and polyvinyl pyridine to provide 0.162 g (92%) of the title sulfonamide after chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH2:61])[CH:58]([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C@@H:57]([NH:61][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH:16]=[CH:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH:58]([CH3:60])[CH3:59])=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Reactant: CC(C)[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)C(C)C)ccc1C(=O)N1CC=CC1
Yield: 60 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methylpropylamine in tetrahydrofuran. Yield: 60%; Rf value: 0.50 (silica gel; dichloromethane/methanol=9:1); C24H25ClN4O2 (436.94); mass spectrum: (M+H)+=437/439 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25](Cl)=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[K+].[Br-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][NH:8][C:25](=[O:26])[CH2:24][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC

Procedure:
prepared from 3,4-dimethoxyphenethylamine and 3,4-dimethoxyphenylacetyl chloride; mp 125° C. (lit.17 123-125° C.); IR (KBr) 3327, 3064, 3007, 2916, 2840, 1642, 1608, 1591; 1H NMR δ 2.67 (t, 2H), 3.40-3.47 (m, 4H), 3.83 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 5.30 (brs, 1H), 6.52-6.86 (m, 6H); 13C NMR δ 35.6, 41.2, 43.5, 56.3, 56.4, 70.5, 111.7, 112.2, 115.8, 121.1, 127.5, 127.9, 128.5, 129.1, 131.1, 131.6, 137.3, 148.1, 149.5, 158.5, 171.8.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[C:17]2[C:12](=[C:13]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[O:11][C:10](=[O:26])[CH:9]=1.[Cl:27][C:28]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([Cl:36])[C:29]=1[NH2:30].OP([O-])(O)=O.[K+]>CS(C)=O>[CH:21]1([O:20][C:13]2[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[C:17]3[C:12]=2[O:11][C:10](=[O:26])[CH:9]=[C:8]3[NH:30][C:29]2[C:31]([Cl:36])=[CH:32][CH:33]=[C:34]([CH3:35])[C:28]=2[Cl:27])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(Cl)c(N)c1Cl
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)ccc(C)c3Cl)cc(=O)oc2c1OC1CCCC1
Reaction time: 14 h

Procedure:
Potassium t-butoxide (35 mg, 0.3 mmol) was added to a solution of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (29 mg, 0.1 mmol, Example 7, Step 1), 2,6-dichloro-3-methylaniline (26 mg, 0.15 mmol), and DMSO (1 mL). After 14 h, the reaction was poured into 1M KH2PO4 (20 mL), and extracted with ethyl acetate (20 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silica gel chromatography (4:1→0:1; hexanes:ethyl acetate) to give 8-(cyclopentyloxy)-4-(2,6-dichloro-3-methylphenylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 7.95 (d, 1H), 7.58 (d, 1H), 7.48 (d, 1H), 7.18 (d, 1H), 4.82 (m, 1H), 4.33 (s, 1H), 3.90 (s, 3H), 2.40 (s, 3H), 1.90-1.45 (m, 8H); MS (ESI): 433.9.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:29])=[CH:5][CH2:6][O:7][C:8]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]2[C:11]([C:12](=[O:28])[C:13]([CH3:27])=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:15]2)=[CH:10][CH:9]=1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C.O>[CH3:27][C:13]1[C:12](=[O:28])[C:11]2[C:16](=[C:17]([C:18](=[O:20])[CH:19]=[CH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]([O:7][CH2:6][CH:5]=[C:4]([CH3:29])[CH3:3])=[CH:9][CH:10]=2)[O:15][C:14]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(=O)c(C)c(-c3ccccc3)oc12
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(3-methylbut -2-enyloxy)-8-acetyl-3-methylflavone (2.71 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.3 g of product m.p. 83-84° C., 1H-NMR (CDCl3)δ:1.67 (s, 3H); 1.70 (s, 3H); 2.18 (5, 3H); 4.68 (d, 2H, J=6.4 Hz); 5.30-5.38 (m, 11H); 7.00 (d, 1H, J=16 Hz); 7.02 (d, 11, J=8.9 Hz; 7.24 (d, 1H, J=16 Hz); 7.30-7.45 (m, 6H); 7.48-7.54 (m, 4H);8.30 (d, 1H, J=8.9 Hz).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:26]4[C@H:25]([CH3:24])[CH2:29][O:28][C:27]4=[O:30])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)OC[C@H]4C)cn3)CC2)c(C)c1
Yield: 80.3 %

Procedure:
Using (5-bromopyrazin-2-yl) [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (130 mg) described in Preparation Example 232 and (R)-4-methyloxazolidin-2-one (35 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (110 mg) was obtained.