Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14](Br)[CH:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.O.C(Cl)Cl.[Cu]I>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:29]#[N:30])=[C:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(CCC)C1CC2CN(C(=O)c3ccccc3)C3=C2C(C1)C(Br)C=C3
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of (±)-1-benzoyl-6-bromo-4-(di-n-propylamino)hexahydrobenz[cd]indole (5.5 g, 12.5 mmol) in DMF (100 mL) under a N2 atmosphere was added 3.4 g (37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The reaction mixture was then stirred at 140° C. for 6 hr. The reaction mixture was poured onto ice, diluted with water, CH2Cl2 added and stirred for 30 minutes. The mixture was filtered through a Celite pad and the filtrate was extracted twice with CH2Cl2. The organic solution was washed twice with saturated NaCl solution. The CH2Cl2 solution was dried over MgSO4 and then evaporated to provide 4 g of a solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2Cl2 as eluent gave 3 g (62%) of product.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]([CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[N:7][N:8]([CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:9]3=[O:12])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: O=c1c2cc(Br)ccc2cnn1Cc1cccnc1
Reactant: Oc1ccc(Cl)cc1
Product: O=c1c2cc(Oc3ccc(Cl)cc3)ccc2cnn1Cc1cccnc1

Procedure:
The titled compound was prepared from 7-bromo-2-(3-pyridylmethyl)-1 (2H)-phthalazinone and 4-chlorophenol in the same manner as in Example 1 (1) c).
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(Cl)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-chlorophenylboronic acid (156 mg), tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give the title compound (59 mg, yield 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cl-].[CH3:14][O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=1[O:15][CH3:14])[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: COc1ccccc1C=[N+]1CCCCC1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Cl-]
Product: COc1ccccc1C(c1c(O)ccc2cc(Br)ccc12)N1CCCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-bromo-2-naphthol and 1-(2-methoxy-benzylidene)-piperidinium chloride, which had been prepared in accordance with example 32.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].BrBr.C(O)(=[O:15])C.C([O-])(=O)C.[Na+]>>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:15])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C(O)c1ccc([N+](=O)[O-])s1
Yield: 98.5 %

Procedure:
As an example, a trial performed with 5-nitro-2-formyl-thiophene and bromine in a medium maintained at pH=4.6 by means of a acetic acid/sodium acetate mixture provided crude 5-nitro-2-thenoic acid in a yield of 98.5% or the pure acid in a yield of 81%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:15][CH2:14][CH2:13][NH:12][C:11](=S)[CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]([C:35]([NH:37][NH2:38])=O)([F:34])([F:33])[F:32].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.CCOCC.C1(C)C=CC=CC=1.O.CC(=O)OCC.[Hg](OC(C)=O)OC(C)=O>[CH2:1]([C@@H:8]1[CH2:15][CH2:14][CH2:13][N:12]2[C:35]([C:31]([F:34])([F:33])[F:32])=[N:37][N:38]=[C:11]2[CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1OC(F)(F)F)N1CC(=S)NCCC[C@H]1Cc1ccccc1
Reactant: NNC(=O)C(F)(F)F
Agent: CC(=O)O[Hg]OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1OC(F)(F)F)N1Cc2nnc(C(F)(F)F)n2CCC[C@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of compound 31n (150 mg, 0.33 mmol) in THF (15 mL) was cooled to 0° C., treated with Hg(OAc)2 (118 mg, 0.36 mmol) and CF3CONHNH2 (173 mg, 1.65 mmol), stirred for 2 h, diluted with Et2O (20 mL), filtered through Celite and evaporated. A solution of the residue in toluene/H2O (30:1, 15 mL) was treated with TsOH.H2O (250 mg, 1.32 mmol) and stirred at 75° C. for 12 h. The mixture was diluted with EA (30 mL) and washed with saturated K2CO3. The aqueous layer was extracted with EA (20 mL). The combined organic layers were dried over Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by Preparative HPLC to give compound 31 as a white solid (113 mg, 64% yield). 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=7.5 Hz, 1H), 7.68 (t, J=8.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.15-7.10 (m, 3H), 6.76-6.70 (m, 2H), 5.71 (d, J=18.0 Hz, 1H), 4.97 (m, 1H), 4.90 (d, J=8.0 Hz, 1H), 4.26 (dd, J=15.0, 8.0 Hz, 1H) 4.21 (m, 1H), 2.59 (dd, J=13.0, 10.5 Hz, 1H), 2.33 (dd, J=13.0, 5.0 Hz, 1H), 2.12-1.90 (m, 2H), 1.70-1.60 (m, 2H). MS (ESI+) m/z: 535 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][C:20]=2[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([F:32])[F:31])[CH:25]=2)[CH:23]=1)(=[O:13])=[O:12])(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[NH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:15]2[CH:16]=[CH:17][N:18]=[CH:19][C:20]=2[CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([F:32])[F:31])[CH:25]=2)[CH:23]=1)(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(-c2cccc(C(F)F)c2)cc2cnccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCCNS(=O)(=O)c1cc(-c2cccc(C(F)F)c2)cc2cnccc12
Reaction time: 8 h
Yield: 95 %

Procedure:
Suspend {2-[7-(3-difluoromethylpheny)-isoquinoline-5-sulfonylamino]-ethyl}-carbamic acid tert-butyl ester in ethyl acetate (11 mL), and add an excess of 4 M HCl in 1,4-dioxane. Stir overnight, filter the precipitate, wash with dichloromethane, and dry under vacuum to give the desired compound as a white solid (0.092 g, 95% yield): 1H NMR (CD3OD): δ9.92 (s, 1H), 9.10 (d, J=7.0 Hz, 1H), 9.04 (m, 2H), 8.80 (d, J=7.0 Hz, 1H), 8.09 (m, 2H), 7.74 (m, 2H), 6.94 (t, J=52.1 Hz, 1H), 3.25 (m, 2H), 3.15 (m, 2H). Load the product onto ion exchange resin and elute with 1N NH3 in methanol and concentrate to dryness to give the free base. (Used in example 97).
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[OH:15].CCN(CC)CC.[C:23](ON1C(=O)CCC1=O)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl.CCOC(C)=O>[CH2:26]([O:25][C:23]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[OH:15])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)OCc2ccccc2)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.6 %

Procedure:
To a stirred mixture of Compound 249A (1.40 g, 6.47 mmoL) in 10 mL of CH2Cl2 was added Et3N (1.08 mL, 7.76 mmoL), followed by Cbz-OSu (1.69 g, 6.80 mmoL). The reaction mixture was stirred at room temperature for 16 hrs and then diluted with 300 mL of EtOAc. The organic layer was washed with 5% citric acid solution (2×40 mL), 5% K2CO3 solution (2×40 mL) and brine (40 mL) and dried (MgSO4). The residue was filtered and concentrated in vacuo to afford 2.25 g (yield: 99%) of Compound 262A. It had an analytical HPLC retention time=3.02 min. (Phenomenox S5 C18-HC 4.6×50 mm column, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=351.
Reaction SMILES: [I:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[CH2:17]([O:24][C:25]1[C:30]([CH2:31]Cl)=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25]1[C:30]([CH2:31][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([I:1])[C:3]([O:13][CH3:14])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:29]([CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2c(c1I)C(=O)NCC2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1I)C(=O)N(Cc1c(C)cc(C)nc1OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.6 %

Procedure:
To a solution of 8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53b, 2.08 mg, 5.22 mmol) in anhydrous DMF (30 mL) was added NaH (420 mg, 10.4 mmol, 60% in oil) at 0° C. under N2 atmosphere for 30 minutes. 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 1.89 g, 7.83 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 14 hours. The mixture was quenched with H2O (60 mL) and extracted with EtOAc (4×80 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep.HPLC to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-iodo-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (53c, 2.5 g, 91%) as a yellow solid.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7](=[O:20])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH2:16][C:17]#[CH:18])=[CH:10][C:9]=1[Cl:19])C#C.Cl>CO>[Cl:19][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]#[CH:18])[C:12]([F:14])=[CH:13][C:8]=1[C:7]([OH:20])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1cc(Cl)c(C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a mixed solution of 30 ml of methanol and 30 ml of an aqueous 15% sodium hydroxide solution, 19 g of the obtained 2-chloro-5-fluoro-4-(2-propynyloxy)benzoic acid 2-propynyl ester was added, followed by stirring at 50° C. for 2 hours. The reaction mixture was acidified by adding hydrochloric acid and the obtained solid was collected by filtration. The solid was washed with a mixed MTBE-hexane solvent, and 10 g of 2-chloro-5-fluoro-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: C([Cu])#N.[F:4][C:5]1[CH:6]=[C:7]([Mg]Br)[CH:8]=[CH:9][CH:10]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25]I)[C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([F:4])[CH:6]=2)[C:23]=1[CH3:24])[C:17]([O:19][CH3:20])=[O:18]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: COC(=O)c1cc(Br)c(C)c(CI)c1
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)c(Cc2cccc(F)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a THF (0.1 M) suspension of CuCN (2 eq.) was added at −78° C. 3-fluorophenyl magnesium bromide (0.5 M solution in THF, 4 eq.) over a period of 5 min. The resulting mixture was stirred at −78° C. for 20 min and then at 0° C. for another 20 min. The now yellow suspension was re-cooled to −78° C. before methyl 3-bromo-5-(iodomethyl)-4-methylbenzoate (1 eq.) from the previous step was added. The resulting mixture was stirred at −78° C. for 20 min, 0° C. for another 20 min and finally at RT for 16 h. The crude reaction mixture was quenched with a 3:1 (v/v) mixture of sat. aq. NH4Cl:conc. NH4OH and then extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Further purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[C:61]1([N:67]2[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]2)[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.[ClH:73]>C1COCC1.CO>[ClH:73].[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:70]1[CH2:71][CH2:72][N:67]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:68][CH2:69]1)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N6CCN(c7ccccc7)CC6)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol) and 1-phenylpiperazine (21 mg, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 5 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative TLC (silica gel, 90:10 dichloromethane/methanol) to afford a dark red solid. The solid was dissolved in methanol (1 mL) and treated with HCl (1.25 M solution in methanol, 0.5 mL) at 0° C. The solution was concentrated and triturated with diethyl ether to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-2-(4-phenylpiperazine-1-carbonyl)-6,6a-dihydrobenzo[a]tetracene-7,9,12,14(5H,14aH)-tetraone hydrochloride as a mixture of diastereomers (9.0 mg, 25%) and as a red solid: 1H NMR (500 MHz, CD3OD) δ 8.10 (s, 1H), 7.60-7.20 (m, 5H), 6.70 (s, 1H), 6.20-6.10 (m, 0.3H), 6.04-5.95 (m, 0.7H), 5.49 (s, 1H), 4.96-4.85 (m, 1H), 4.18-4.08 (m, 1H), 4.05-3.89 (m, 1H), 3.78-3.62 (m, 7H), 3.54 (s, 3H), 3.61-3.52 (m, 2H), 3.51-3.41 (m, 7H), 3.27-3.16 (m, 1H), 3.09-2.90 (m, 1H), 3.16 (s, 3H), 1.30-1.20 (m, 3H); MS (ESI−) m/z 826 (M−H); HPLC 94.2% (AUC), tR 11.89 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].C(=O)([O-])OC.[Cl:25][C:26]1[C:32]([OH:33])=[CH:31][C:29]([NH2:30])=[C:28]([F:34])[CH:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:25][C:26]1[C:32]([OH:33])=[CH:31][C:29]([NH:30][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]([O:18][CH3:19])[CH:7]=3)[N:12]=[CH:11][C:10]=2[C:15]#[N:16])=[C:28]([F:34])[CH:27]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: COC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCl

Procedure:
By using the above method, starting with 3 g of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 2.46 g of the methyl carbonate of 4-chloro-2-fluoro-5-hydroxy-aniline, and 1.18 g of pyridine hydrochloride in 31 ml of 2-ethoxyethanol, 2.2 g of the title compound was obtained as a tan solid: mass spectrum (electrospray, m/e) M+H 421.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([OH:11])[CH2:9][CH2:10]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C2(O)CC2)c(F)c1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a stirred solution of 1-(4-amino-2-fluorophenyl)cyclopropanol (0.7 mg, 4.19 mmol, 1.0 eq) in acetone (10 mL) was added pyridine (0.33 mL, 4.19 mmol, 1.0 eq) and phenyl chloroformate (0.5 mL, 4.19 mmol, 1.0 eq) and stirred at 0° C. to RT for 1 h. The solvent was evaporated, the residue diluted with water (10 mL×2), extracted with EtOAc (25 mL), brine (10 mL) and dried over Na2SO4 and evaporated under vacuum; the resulting residue was purified by CC using EtOAc/PE (1:4 as eluent to get phenyl 3-fluoro-4-(1-hydroxycyclopropyl)phenylcarbamate (0.9 g, 75%, off white solid; TLC system: EtOAc/PE (1:1), Rf: 0.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH:36]=O)=[CH:30]3)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:36][C:31]4[NH:32][C:33]5[C:29]([CH:30]=4)=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:35][CH:34]=5)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc3cc(OCCN4CCCC4)ccc3[nH]2)c1

Procedure:
6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:20]=[CH:21][C:22]3[N:26]=[C:25]([CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[O:29])[NH:24][C:23]=3[CH:35]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>C(#N)C>[OH:1][C:2]1([C:19]2[CH:20]=[CH:21][C:22]3[N:26]=[C:25]([CH2:27][C:28]([O:30][CH2:31][CH2:32][CH2:33][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[O:29])[NH:24][C:23]=3[CH:35]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cc1nc2ccc(C3(O)c4ccccc4C(=O)N3Cc3ccccc3)cc2[nH]1)OCCCCl
Solvent: CC#N
Product: CN1CCN(CCCOC(=O)Cc2nc3ccc(C4(O)c5ccccc5C(=O)N4Cc4ccccc4)cc3[nH]2)CC1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of 3-chloropropyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}acetate (0.25 g, 0.51 mmol) and 1-methyl-piperazine (0.46 mL, 5.10 mmol) in acetonitrile (5.0 mL) was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The aqueous residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Filtration and concentration gave a pale yellow residue, which was freeze-dried from a mixture of acetonitrile-water (1:1, 3.0 mL) to give 3-(4-methylpiperazin-1-yl)propyl {6-[1-hydroxy-3-oxo-2-(phenylmethyl)-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}acetate (0.12 g, 43%). 1H NMR (400 MHz, DMSO-d6): 11.50 (br.s, 1H), 7.70 (d, 1H), 7.49 (m, 3H), 7.23 (t, 1H), 7.15 (m, 6H), 6.84 (d, 1H), 4.49 (d, 1H), 4.16 (t, 4H), 4.10 (d, 1H), 3.34 (s, 6H), 2.36 (m, 3H), 2.18 (s, 3H) open, 2.16 (s, 3H) closed, 1.78 (m, 1H); MS (EI) for C31H34N6O4: 555 (MH+).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[C:18](OCC)=[O:19])[CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:16])[C:6]=2[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.52 g, 4.47 mmol) in THF (20 mL) at 0° C. was slowly added a 1.5 M solution of diisobutylaluminum hydride in toluene (6.26 mL, 9.39 mmol). The solution was allowed to warm slowly to ambient temperature. After approximately 4 hr of stirring, the solution was re-cooled to 0° C. and an additional 6 mL of diisobutylaluminum hydride was added. After approximately 1.5 hr of stirring the mixture was re-cooled to 0° C., quenched with aqueous Rochelle's salt and allowed to stir overnight while warming to ambient temperature. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with Rochelle's salt followed by with brine and then dried over magnesium sulfate and concentrated to afford [5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methanol (1.30 g, 98%). 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.87 (t, J=5 Hz, 1H), 4.10 (d, J=5 Hz, 2H), 3.91-3.83 (m, 1H), 2.42-2.28 (m, 4H), 2.08-1.98 (m, 1H), 1.94-1.84 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].CN(C)CCN(C)C.C=CCC>>[CH3:9][CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: Cc1ccc(C)cc1
Reactant: [Li]CCCC
Agent: C=CCC
Agent: CN(C)CCN(C)C
Product: CCC(C)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 162 mmols of p-xylene were added 7 mmols of n-butyl lithium and 9 mmols of N,N,N',N'-tetramethylethylenediamine, and the mixture was stirred at room temperature for 2 hours, whereupon it turned brilliant orange. The resulting product was placed in an autoclave, and at the same time, 143 mmols of 1-butene was introduced into it. When they were reacted at 80° to 100°C. at an initial pressure of 15 Kg/cm2, the pressure of the inside of the autoclave decreased gradually. After reacting for 5 hours, 3-methyl-4-(p-tolyl) butane was obtained in a selectivity of about 90%. This compound was distilled under reduced pressure to purity it. The resulting product was used in the following Examples.