Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1.[I:15]Cl.CC(O)=O>C(O)(=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:12]([I:15])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([S:13][CH3:14])[CH:3]=1
Reactant: ClI
Reactant: CCOC(=O)c1ccc(N)cc1SC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(I)c(N)cc1SC
Temperature: 60 °C
Yield: 62.4 %

Procedure:
To a pre-heated 60° C. solution of ethyl 4-amino-2-(methylthio)benzoate (65 mmol) in acetic acid (150 mL) was added ICl/AcOH solution (1M, 72 mL, 72 mmol) dropwise during 40 min and the temperature was maintained at 60° C. for 3 h. After cooling to rt the reaction was diluted with EtOAc (500 mL) and washed with 5% sodium thiosulfate solution (3×100 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-20% EtOAc/Hexanes) to afford ethyl 4-amino-5-iodo-2-(methylthio)benzoate (13.67 g, 53% yield). For ethyl 4-amino-2-(methylthio)benzoate: LC-MS m/z 212 [M+H]+. For ethyl 4-amino-5-iodo-2-(methylthio)benzoate: LC-MS m/z 338 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 6.47 (s, 1H), 4.49 (br s, 2H), 4.31 (q, J=7.2 Hz, 2H), 2.38 (s, 3H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[BH4-].[Na+].C(O)(=O)C.O>O1CCCC1CCO>[CH:1]1([CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][OH:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C=CC2CC2)s1
Agent: OCCC1CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OCc1ccc(C=CC2CC2)s1
Yield: 96.2 %

Procedure:
5-(2-Cyclopropylvinyl)thiophen-2-aldehyde described in Preparation Example 148 (960 mg, 5.39 mmol) was dissolved in a mixture solvent of tetrahydrofuran-ethanol (2:1) (30 mL), sodium borohydride (100 mg, 2.64 mmol) was added under stirring on an ice bath, and the solution was stirred for 30 minutes. Acetic acid (0.5 mL) and water (10 mL) were added sequentially to the reaction solution, which was then extracted with ethyl acetate (50 mL). The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, and the title compound (930 mg, 5.19 mmol, 96.2%) was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[C:11]([CH3:13])([CH3:12])[C@@H:8]([CH2:9][CH2:10]1)[CH:7]=[C:6]2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:16][C:15]=1[O:31][CH3:32])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:32][O:31][C:15]1[CH:16]=[C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:6]1[C@:5]2([CH2:3][OH:2])[C:11]([CH3:13])([CH3:12])[C@H:8]([CH:7]=1)[CH2:9][CH2:10]2
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(CO)C3(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Solution of methyl ester 11a 0.790 g (1.79 mmol) in THF 20 ml was cooled to 0° C. After addition of LiAlH4 3.58 ml (3.58 mmol, 1M solution in diethyl ether) the reaction was allowed to warm up to ambient temperature and stirred for 18 hrs. The reaction worked up with a small amount of saturated MgSO4 solution and extracted with ethyl acetate. The organic phase was washed with brine and water, dried over MgSO4 and concentrated in vacuo. The product was purified by silica gel column chromatography (petroleum ether/ether) to give oil 0.460 g (62%), which solidified upon standing at −20° C. to give a yellow solid. mp 49-51° C.; 1H NMR (300 MHz, CDCl3) δ ppm 6.52 (s, 2H), 5.90 (d, J=3.24 Hz, 1H), 3.75 (s, 6H), 3.65 (m, 2H), 2.35 (t, J=3.39, 1H), 2.25 (dd, J=7.29, J=5.01, 1H), 1.93 (m, 1H), 1.53-1.59 (m, 5H), 1.27 (s, 6H), 1.21 (s, 3H), 1.0-1.19 (m, 7H), 0.94 (s, 3H), 0.85 (t, J=6.71 Hz, 3H). Exact mass calculated for C27H42O3 m/e 414.31. found 414.87. Anal. calcd. for C27H42O3: C, 78.21; H, 10.21. Found: C, 78.31; H, 10.31.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 3-fluoro-4-nitrophenol (2.96 g, 18.81 mmol) in DMF (18.81 mL) was added 1-(chloromethyl)-4-methoxybenzene (2.55 mL, 18.81 mmol) and potassium carbonate (5.20 g, 37.6 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The mixture was diluted with EtOAc (100 mL), washed with water, and the aqueous layer was back-extracted with EtOAc (25 mL). The combined organic layers were washed with 1 M aqueous NaOH (20 mL) and then with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The yellow solid was triturated with ether (20 mL), and the solid was collected, rinsing with ether (5 mL). The title compound was obtained as a yellow solid (4.39 g, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:19](OC)(OC)OC>CN(C=O)C>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[CH:19]1
Reactant: COC(OC)OC
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2ncn(CC(OC)OC)c12
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.4 g, 1.6 mmol) from Step C above in DMF (15 mL) was added trimethyl orthoformate (0.5 mL, 4.7 mmol) and the reaction was heated to reflux and stirred overnight. The reaction mixture was washed with water, extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give the crude material which was purified by column chromatography (silica gel, 0% to 100% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-1H-benzo[d]imidazole-7-carboxylate: 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.90 (dd, J=8.0, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 1.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 4.64 (d, J=5.0 Hz, 2H), 4.48 (t, J=5.0 Hz, 1H), 3.91 (s, 3H), 3.22 (s, 6H); MS (ESI+) m/z 264 (M+H).
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[CH:12]=[CH:11][C:10]=1[C:29](=[O:32])[CH2:30][CH3:31])=O)(C)(C)C.[ClH:33]>O1CCOCC1.C(OCC)C>[ClH:33].[NH2:8][C:9]1[C:10]([C:29](=[O:32])[CH2:30][CH3:31])=[CH:11][CH:12]=[C:13]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[N:14]=1
Reactant: CCC(=O)c1ccc(NC2CCCN(C(=O)OC(C)(C)C)C2)nc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC(=O)c1ccc(NC2CCCNC2)nc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
380 mg (0.85 mmol) of tert-butyl 3-({6-[(tert-butoxycarbonyl)amino]-5-propanoylpyridin-2-yl}amino)piperidine-1-carboxylate (Example 26A) were dissolved in 10 ml of a solution of hydrochloric acid in dioxane (4 M), and the mixture was stirred at RT for 20 h. After the reaction had gone to completion, the reaction mixture was diluted with diethyl ether (100 ml), and the recipitate was filtered off and washed with diethyl ether (100 ml) and dried. This gave 170 mg (70% of theory) of the product as a solid.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:17]([NH2:20])(=[S:19])[CH3:18]>C(O)C>[CH3:18][C:17]1[S:19][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:20]=1
Reactant: CCOC(=O)C(Br)C(=O)c1ccc(C)cc1
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1-c1ccc(C)cc1
Yield: 40.9 %

Procedure:
A solution of 4.4 g of ethyl 2-bromo-3-(4-methylphenyl)-3-oxopropanoate in 30 ml of anhydrous ethanol is added with 1.4 g of thioacetamide and the mixture is refluxed for 4 hours. The solvent is evaporated and the residue is dissolved in H2O and alkalinized to pH 10 with 10% NaOH, extracted 2 times with ether and the organic phase is washed with brine, dried and evaporated to dryness under reduced pressure. The residue is purified by F.C. (eluent 90:10 hexane:ethyl acetate) and 1.65 g of a light yellow solid are obtained (41% yield). 1H NMR (CDCl3), δ: 1.28 (t, 3 H), 2.39 (s, 3 H), 2.73 (s, 3 H), 4.26 (q, 2 H), 7.23 (d, 2 H), 7.62 (d, 2 H).
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(CN[C@@H]2C[C@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
A mixture of (trans)-2-phenylcyclopropanamine hydrochloride (0.25 g, 1.50 mmol) and 4-cyanobenzaldehyde (0.22 g, 1.65 mmol) in CH2Cl2 (8 mL) and water (0.5 mL) was vigorously stirred at room temperature for 10 min. Then, NaBH(OAc)3 (0.41 g, 1.95 mmol) was slowly added and stirring continued for 1.5 h. The reaction mixture was washed with an aqueous saturated solution of NaHCO3 (10 mL), the organic layer was dried over anhydrous Na2SO4, filtered and, after removal of the solvent, the residual oil was purified by column chromatography on silica gel (1% MeOH/CH2Cl2) affording 0.07 g of 4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile [Rf=0.6 (5% MeOH/CH2Cl2), colorless oil, 19% yield].
Reaction SMILES: N1C=CN=CC=1[N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.ClCC([N:18]1[CH2:22][C:21](F)(F)C[C@H:19]1[C:25]#[N:26])=O.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl>C(#N)C.C(OCC)C>[N:18]1[CH:19]=[CH:25][N:26]=[CH:21][C:22]=1[CH:12]1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8][NH:7]1
Reactant: NC1CCN(c2cnccn2)CC1
Reactant: N#C[C@@H]1CC(F)(F)CN1C(=O)CCl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: NC1CCNC(c2cnccn2)C1
Temperature: 55 °C
Reaction time: 8 h
Yield: 145.5 %

Procedure:
63 mg of 1-(2-pyrazinyl)-4-amino-piperidine (0.32 mmol) and 62 mg (2S)-1-(2-chloroacetyl)-4,4-difluoro-2-pyrrolidine carbonitrile (0.32 mmol) and 285 mg of polymer-bound 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PBEMP) (0.73 mmol) are dissolved in 20 ml dry acetonitrile and stirred at 55° C. for 8 hours. The resin is removed by filtration, the filtrate is concentrated by vacuum and the residue is purified by column chromatography using chloroform—methanol (9:1) as eluent to result an oil, which is treated with hydrochloric acid in diethylether result in 83 mg (60%) of title compound, as white crystals. M.p.: 158-160° C. 1H-NMR (400 MHz, DMSO-d6): δ 1.54 (m, 2H), 2.15 (m, 2H), 2.80-2.95 (m, 4H), 4.20-4.25 (m, 4H), 4.55 (d, 2H,), 5.20 (t, 1H), 7.00 (d, 1H), 7.87 (dd, 1H), 8.50 (d, 1H); 9.38 (br, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([CH3:19])=[N:7][C:8]3[C:13]([N:14]=2)=[C:12]([C:15](=[O:17])[CH3:16])[C:11]([F:18])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:42][CH2:16][C:15]([C:12]1[C:11]([F:18])=[CH:10][CH:9]=[C:8]2[C:13]=1[N:14]=[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)[C:6]([CH3:19])=[N:7]2)=[O:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(F)ccc2nc(C)c(NC3CC3)nc12
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2ccc(F)c(C(=O)CBr)c2nc1NC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a stirred solution of 1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (283b) (1.44 g, 5.55 mmol) in DCM (13.88 mL) at 0° C. was added TEA (0.91 mL, 6.54 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (Sigma-Aldrich) (1.40 mL, 6.11 mmol). The overall mixture was stirred at 0° C. for 1 h, while under inert atmosphere. The reaction mixture was treated with saturated NaHCO3 (20 mL) and the layers were separated. The aq. layer was extracted with DCM (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. m/z (ESI, +ve) 374 (M+H). The residue was treated with THF (13.88 mL) and water (1.6 mL). The resulting mixture was chilled to 0° C. in an ice/water bath. NBS (Alfa Aesar, Ward Hill, Mass.) (0.99 g, 5.55 mmol) was added into the mixture and the overall mixture was stirred at 0° C. for 30 min. The mixture was diluted with DCM (40 mL) and saturated NaHCO3 (10 mL). The layers were separated and the aq. layer was extracted with DCM (3×). The organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography through a SiliCycle SiliaSep pre-packed silica-gel column (120 gram), eluting with a gradient of 0-25% EtOAc in DCM, to provide 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (283c) (1.19 g, 3.52 mmol, 63% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (dd, J=9.00, 5.87 Hz, 1H), 7.65-7.84 (m, 1H), 7.32 (t, J=9.39 Hz, 1H), 5.18 (s, 2H), 2.69-2.91 (m, 1H), 2.51 (s, 3H), 0.76-0.95 (m, 2H), 0.60-0.76 (m, 2H). m/z (ESI, +ve) 338/341 (M+H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH2:20][OH:21])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:22]([O-:24])=[O:23])[C:7](=[O:25])[C:6]=1[CH2:26]Cl)([CH3:4])([CH3:3])[CH3:2].[OH:28][CH2:29][CH2:30][SH:31].C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[O:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH2:20][OH:21])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:22]([O-:24])=[O:23])[C:7](=[O:25])[C:6]=1[CH2:26][S:31][CH2:30][CH2:29][OH:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCS
Reactant: CC(C)(C)c1on(-c2ccc(S(=O)(=O)CCO)cc2[N+](=O)[O-])c(=O)c1CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1on(-c2ccc(S(=O)(=O)CCO)cc2[N+](=O)[O-])c(=O)c1CSCCO

Procedure:
15 g of 5-t-butyl-4-chloromethyl-2-(4-(2-hydroxyethylsulfonyl)-2-nitrophenyl)-4-iso-oxazolin-3-one was dissolved in 150 ml of tetrahydrofuran, 2.8 g of 2-hydroxyethanethiol and 4 g of triethylamine were added and the mixture was reacted at room temperature for a period of 5 hours. After reaction, the solvent was removed by distillation, ethyl acetate and water (150 ml:100 ml) were added and the mixture was partitioned. The organic layer was recovered, the solvent was removed by distillation and the residue obtained was used without further refinement in step 6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:13][C:3]1[C:2]([Cl:1])=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:5][N:4]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1noc(-c2cccnc2)c1Cl
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2cccnc2)c1Cl
Yield: 64 %

Procedure:
4-Chloro-3-hydroxy-5-(3-pyridyl)isoxazole (0.49 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.54 g, 63%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[CH:14]([OH:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH:3]1[C:15]2[CH:14]([O:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
0.8 g of sodium hydride (60% dispersion in mineral oil) was added over 5 minutes under ice-cooling to a solution of 3.64 g of 9-fluorenol and 3 ml of ethyl bromoacetate in 40 ml of N,N-dimethylformamide. After stirring for 50 minutes, the reaction mixture was poured into ice-cold 5% HCl and extracted with ether. The organic layer was washed with a saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: methylene chloride-hexane) to give 2.28 g of ethyl 9-fluorenyloxyacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([O:23][CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[N:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[N:35]=2)=[O:40])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CC(C)n1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)c1nn(C(C)C)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxy-phenylamine and 4-(4-Fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carboxylic acid using the procedure for example 1. mp=216-218° C.; LCMS m/z=602 (M+1); 1H NMR (CDCl3) δ: 11.02 (s, 1H), 8.66 (d, 1H, J=8.5 Hz), 8.50 (d, 1H, J=5 Hz), 7.54 (s, 1H), 7.43 (s, 1H), 7.30-7.27 (m, 3H), 6.83 (dd, 1H, J=3.5, 10 Hz), 6.75 (d, 1H, J=2.5 Hz), 6.53 (d, 1H, J=5 Hz), 5.09 (m, 1H), 4.05 (s, 6H), 3.86 (s, 3H), 1.53 (d, 6H, J=6.5 Hz)
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[O:43])=[CH:36][CH:35]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].[OH:50][C@:51]1([C:92](O)=[O:93])[CH2:68][C@H:67]([O:69][C@@H:70]2[O:84][C@@H:83]([CH3:85])[C@H:73]3[O:74][C@H:75]4[N:80]([C@H:72]3[CH2:71]2)[CH2:79][CH2:78][O:77][C@@H:76]4[O:81][CH3:82])[C:66]2[C:53](=[C:54]([OH:91])[C:55]3[C:56](=[O:90])[C:57]4[C:62]([C:63](=[O:87])[C:64]=3[C:65]=2[OH:86])=[C:61]([O:88][CH3:89])[CH:60]=[CH:59][CH:58]=4)[CH2:52]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:45][CH2:46][N:47]([C:92]([C@@:51]3([OH:50])[CH2:68][C@H:67]([O:69][C@@H:70]4[O:84][C@@H:83]([CH3:85])[C@H:73]5[O:74][C@H:75]6[N:80]([C@H:72]5[CH2:71]4)[CH2:79][CH2:78][O:77][C@@H:76]6[O:81][CH3:82])[C:66]4[C:53](=[C:54]([OH:91])[C:55]5[C:56](=[O:90])[C:57]6[C:62]([C:63](=[O:87])[C:64]=5[C:65]=4[OH:86])=[C:61]([O:88][CH3:89])[CH:60]=[CH:59][CH:58]=6)[CH2:52]3)=[O:93])[CH2:48][CH2:49]2)=[O:43])=[CH:38][CH:39]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)O)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)N1CCN(C(=O)OCc2ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN4C(=O)C=CC4=O)C(C)C)cc2)CC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Step 3 To the intermediate 60 (13.2 mg) a solution of crude (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxylic acid 56 (9.3 mg) in anhydrous dichloromethane (2.6 ml), TBTU (5.3 mg, 0.0165 mmol), and anhydrous triethylamine (2.8 mg, 0.0275 mg) was added. The reaction mixture was stirred at room temperature under argon atmosphere for 15 minutes, until disappearance of the starting material (HPLC-MS analysis). The solvent was then evaporated under vacuum and the crude was purified by flash column chromatography (EtOH:AcOEt=1.5:8.5) on silica gel (230-400 mesh), affording 4.8 mg (red solid, yield calculated on PNU-159682=34%) of 55. MS (ESI): 1295 [M+H]+. Retention time=5.51 min(method 1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2/[C:12](=[O:35])[C:13]3[C:18]([CH2:19]/2)=[C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:16]([OH:34])=[CH:15][CH:14]=3)=[CH:2]1.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:36].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2/[C:12](=[O:35])[C:13]3[C:18]([CH2:19]/2)=[C:17]([CH2:20][N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[C:16]([OH:34])=[CH:15][CH:14]=3)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2C/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Cc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of tert-butyl (E)-4-({2-[(1H-indol-3-yl)methylene]-5-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.063 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 1 hour. The mixture was azeotroped twice with toluene under reduced pressure, and the residual solid was suspended in methylene chloride and thereby washed to obtain (E)-2-[(1H-indol-3-yl)-methylene]-5-hydroxy-4-(piperazin-1-ylmethyl)-2,3-dihydro-1H-inden-1-one dihydrochloride (0.024 g, 85%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[CH:9][C:8]=1[C:18](=[O:20])[CH3:19])(=O)=O.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([N:27]2[CH2:28][CH2:29][CH:24]([OH:23])[CH2:25][CH2:26]2)=[C:8]([C:18](=[O:20])[CH3:19])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2ccccc2c1N1CCC(O)CC1
Temperature: 65 °C
Yield: 80.9 %

Procedure:
A stirred mixture of 2-acetyl-4-chloro-1-naphthyl trifluoromethanesulfonate (0.106 g, 0.301 mmol), 4-hydroxypiperidine (0.0366 g, 0.362 mmol), palladium acetate (1 mg, 0.006 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6 mg, 0.009 mmol), and cesium carbonate (0.14 g, 0.42 mmol) in tetrahydrofuran (6 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over sodium sulfate and evaporated to dryness. The resulting residue was purified on silica gel, eluting with 0 to 60% ethyl acetate in hexane, to give the desired product (74 mg, 81%). LCMS calculated for C17H19ClNO2 (M+H)+: m/z=304.1; Found: 304.0.