Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([O:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)[CH:34]=[C:33]([F:44])[C:32]=1[C:45]1[N:50]=[C:49]([C:51](O)=[O:52])[CH:48]=[CH:47][C:46]=1[F:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:51]([C:49]3[CH:48]=[CH:47][C:46]([F:54])=[C:45]([C:32]4[C:31]([F:30])=[CH:36][C:35]([O:37][CH:38]5[CH2:43][CH2:42][CH2:41][O:40][CH2:39]5)=[CH:34][C:33]=4[F:44])[N:50]=3)=[O:52])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(OC4CCCOC4)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (30 mg, 0.074 mmol), 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylic acid (26 mg, 0.074 mmol) and HATU (56 mg, 0.15 mmol) in DMF (0.3 mL) and DIPEA (39 μL, 0.22 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and the resulting mixture was extracted with EtOAc (2 times). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to afford an amide intermediate, 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.CON(C)[C:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:13]=1[CH3:19].[NH4+].[Cl-]>C1COCC1>[CH3:19][C:13]1[C:12]([C:11]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=2)=[O:20])=[CH:17][CH:16]=[C:15]([CH3:18])[N:14]=1
Reactant: CON(C)C(=O)c1ccc(C)nc1C
Reactant: Cn1cncc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cncn2C)c(C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 5-bromo-1-methyl-1H-imidazole (360 mg, 2.24 mmol) was added THF and the solution was cooled to 0° C. To this clear homogeneous solution was added isopropyl magnesium chloride-LiCl complex (1.3 M, 2.3 mL, 2.98 mmol) which resulted in a white suspension. The reaction mixture was stirred at 0° C. for 30 min, and a THF (2 mL) solution of N-methoxy-N,2,6-trimethylnicotinamide (522 mg, 2.69 mmol, Intermediate 40, step a) was introduced and the mixture was allowed to warm to room temperature for 3 hours and then heated to 50° C. for 20 hours. The contents were cooled to room temperature, poured into a saturated NH4Cl solution and extracted with EtOAc (4×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography on silica gel (25-50% Acetonitrile-DCM increasing gradient to 5% MeOH-DCM) afforded the title compound as a pale yellowish solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:21]2[O:22][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:24][N:25]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:49]=[CH:48][CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][NH:45]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH:45]1[C:46]2[C:42](=[C:41]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])=[C:4]([C:21]4[O:22][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:24][N:25]=4)[CH:3]=3)[CH:49]=[CH:48][CH:47]=2)[CH:43]=[CH:44]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(Br)cc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cccc5[nH]ccc45)cc32)cc1
Temperature: 100 °C
Yield: 29.8 %

Procedure:
A stirred mixture of 6-bromo-1-[(4-methylphenyl)sulfonyl]-4-[5-(4-morpholinylmethyl)-1,3,4-oxadiazol-2-yl]-1H-indazole (75 mg, 0.145 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (52.8 mg, 0.217 mmol), 1,1′-bis(diphenylphosphino)-ferrocene palladium dichloride (5.29 mg, 7.23 μmol) and tripotassium phosphate (92 mg, 0.434 mmol) in 1,4-dioxane (2 ml) and water (0.2 ml) was heated at 100° C. in the microwave (Biotage initiator) for 30 mins. The mixture was poured into water (40 ml) and extracted into ethyl acetate (2×30 ml). The combined extracts were washed with water (30 ml), dried (frit) and evaporated. The residual solid was purified on a silica (5 g) cartridge using ether and ethyl acetate/ether (2:1) as the eluent. The appropriate fractions were evaporated to dryness to give the title compound as a cream coloured solid (24 mg).
Reaction SMILES: [F:1][C:2]([F:28])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)=[N:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.P([N:52]=[N+:53]=[N-:54])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(O)(C)C>[F:28][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:18][C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([N:52]=[N+:53]=[N-:54])=[O:24])=[CH:21][CH:20]=3)=[N:16][N:15]=2)=[CH:12][CH:13]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2nnc(-c3ccc(OC(F)(F)C(F)(F)F)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoic acid (217 mg, 0.54 mmol) in isopropanol (5.4 mL) was added triethylamine (0.09 mL, 0.65 mmol) and diphenyl phosphorazidate (0.13 mL, 0.60 mmol) and the reaction was stirred at room temperature for 16 hours. The white precipitate that had formed was filtered and dried in a vacuum oven to provide 4-(5-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzoyl azide as a white solid (145 mg, 63%): mp 140° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 8.32 (m, 4H), 8.24-8.17 (m, 2H), 7.68 (d, J=8.9 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −85.25, −86.89; ESIMS m/z 426 ([M+H]+).
Reaction SMILES: [C:1]([NH:11][NH2:12])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17](S(O)(=O)=O)=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([C:24]2[O:3][CH:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[NH:11][N:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NNC(=O)C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NN=C(c2ccccc2)OC1c1ccccc1
Yield: 482.6 %

Procedure:
Mandelic acid hydrazide (1.66 g) and trimethyl o-benzoate (1.82 g) were heated under stirring in dimethyl formamide (30 ml) at 120° C. for 12 hours in the presence of p-toluene sulfonate monohydrate (0.2 g). The solvent was evaporated, and the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The ethyl acetate layer was washed with water (50 ml×2) and brine (50 ml), and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel chromatography (ethyl acetate/hexane, 1:1), to give the title compound as a white powder (1.28 g, 51%).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>C1COCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a flask charged with dry, freshly ground magnesium turnings (187 mg, 7.7 mmol) and I2 (81 mg, 0.32 mmol) in THF (10 mL) was added a solution of 1,4-dibromobenzene (1.81 g, 7.7 mmol) in THF (10 mL) slowly. The resulting mixture was stirred at rt for 30 min. The resultant pale yellow Grignard solution was cooled to −78° C. and to it was added a solution of 1,4-dioxaspiro[4.5]decan-8-one (1 g, 6.4 mmol) in THF (10 mL) slowly dropwise. The reaction was stirred at −78° C. for 20 min before being allowed to stir and warm to rt for 15 hr. The reaction was quenched with a saturated aqueous NH4Cl solution and extracted with methyl tert-butyl ether. The organic phase was washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 2.2 g of crude orange oil. Purification of the crude material by column chromatography (50 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm) afforded 0.99 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:6]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1.CCOCC>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10]([NH:30][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:9][CH:8]=[CH:7][C:6]=12
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2Br)cc1
Reactant: NC1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(NC4CCCC4)cccc3c2Br)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a solution of 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (1.26 g, 3.9 mmol) in toluene (39 mL) was added successively racemic-BINAP (153 mg, 0.23 mmol), cesium carbonate (1.44 g, 3.9 mmol), cyclopentylamine (1.14 mL, 11.5 mmol), and palladium (II) acetate (35 mg, 0.15 mmol). The resultant mixture was heated at 95° C. for 2.5 hours at which time the reaction was judged complete by thin layer chromatography. The solution was cooled to room temperature and ether was added. The organic layer was washed with water and brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (100:1 to 40:1 hexanes:ether) provided 3-bromo-N-cyclopentyl-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (1.2 g, 83%) as a white crystalline solid upon standing. 1H NMR (CDCl3): δ 8.05 (dd, 2H), 7.22–7.14 (m, 3H), 6.87 (d, 1H), 5.95–5.92 (m, 2H), 4.00 (m, 1H). 2.13 (m, 2H), 1.84–1.67 (m, 6H); 19F NMR (CDCl3) δ −113.44; MS m/z 374 (M+1).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=O)=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:36]([NH:38][CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH3:37].Cl>CS(C)=O.CCOCC.O>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([N:38]([CH2:39][CH2:40][N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:36][CH3:37])=[O:23])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCNCCN(CC)CC
Reactant: O=C(O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCN(CC)CCN(CC)C(=O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 177.8 %

Procedure:
7.0 Grams (0.02 mole) of 2-[4-(7-chloro-4-quinolylamino)phenyl] acetic acid hydrochloride were dissolved in 150 milliliters of dimethyl sulphoxide by heating the stirred mixture to 50° C. under nitrogen. The solution was cooled to room temperature, 6.48 grams (0.04 mole) of carbonyl diimidazole were added and the mixture was stirred for 21/2 hours under nitrogen. 8.64 Grams (0.06 mole) of triethylethylene diamine was added, the solution was stirred for another 21/2 hrs. and poured into 500 milliliters of water. The mixture was refrigerated overnight and the resulting solid was broken up and stirred with water, but melted at room temperature. The gum was extracted with chloroform and the chloroform layer dried and evaporated to give a yellow oil, which was dissolved in ether. Addition of ethereal HCl gave 9.1 grams (89% yield) of 2-[4-(7-chloro-4-quinolylamino)phenyl]-N-(2-diethylaminoethyl)-N-ethyl acetamide dihydrochloride as a hygroscopic yellow solid, melting point 140°-142° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[H-].[Na+].I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].OS(O)(=O)=O>C1COCC1.CCCCCC>[CH3:1][CH:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCI
Reactant: CC1COC(=O)N1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCN1C(=O)OCC1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
4-Methyl-oxazolidin-2-one (18.0 g, 178 mmol) in THF (100 ml) was added slowly via dropping funnel to a slurry of hexane-washed NaH (60% in mineral oil, 7.12 g, 178 mmol, 1.0 quiv.) in THF (400 ml) upon which H2-evolution was observed. Neat iodopentane (70.51 g, 356 mmol, 2.0 equiv.) was added rapidly and the mixture stirred for 1 h at room temperature, then heated to reflux for 60 h. After cooling to 5° C., 2N H2SO4 (180 ml) was slowly added. The mixture was extracted with MTBE and worked up as usual. Distillation over a Widmer-column at 115° C./0.08 mbar afforded the product as a slightly yellow liquid (20.54 g, 73%).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[C:11]=2[CH3:27])[CH2:4][O:3]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:18]3[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:37])[C:11]=2[CH3:27])[CH2:6][O:7]1
Reactant: Cc1c(OCC2COC(C)(C)OC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2COC(C)(C)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a toluene (45 ml)-methanol (5 ml) solution of the 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (766 mg, 1.92 mmol) obtained in the step (12c), a toluene (0.5 ml)-methanol (0.5 ml) solution of 3-chloroperbenzoic acid (459 mg, 1.73 mmol as the content was regarded as 65%) was added dropwise at −65° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred in the same conditions for one hour and 20 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added. The aqueous layer was extracted with ethyl acetate and chloroform (three times). Organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 30 g, elution solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing the title compound were collected, concentrated to obtain the title compound (688 mg, yield: 86.2%) as a light brown foam.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[NH:5][C:6](=[O:16])[C:7]1[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:9](O)=O)#[N:2].C(OC(=O)C)(=[O:23])C.[OH-].[K+].OO.Cl>>[CH:17]1[C:4]2[N:5]3[C:6](=[O:16])[C:7]4[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=4[C:9]3=[N:2][C:1](=[O:23])[C:3]=2[CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccccc1NC(=O)c1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: OO
Agent: [K+]
Product: O=C1c2ccccc2-c2nc(=O)c3ccccc3n21

Procedure:
A solution of sublimed phthalic anhydride in ethyl acetate is reacted with a solution of anthranilonitrile in ethyl acetate to form 2'-cyanophthalanilic acid. The 2'-cyanophthalanilic acid is then boiled with acetic anhydride to convert the acid to 2'-cyanophthalanil. The 2'-cyanophthalanil is thereafter boiled in a mixture containing 2% potassium hydroxide and 2.4% hydrogen peroxide, cooled and neutralized with hydrochloric acid to cyclicize it and form isoindolo [2,1-a]quinazoline-5,11-dione. A similar procedure is set forth by Bogert and Hand, 24 J. Am. Chem. Soc., 1031 (1902) for preparing 2-methyl-4-ketodihydroquinazoline from N-acetylanthranilonitrile.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[F:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[N:8]=[C:7]([S:9][CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=3)[NH:6][C:5]=2[CH:10]=1
Reactant: COc1ccnc(CCl)c1C
Reactant: Fc1cc2nc(S)[nH]c2cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(CSc2nc3cc(F)c(F)cc3[nH]2)c1C

Procedure:
A suspension of 23 g of 5,6-difluoro-2-benzimidazolethiol in 740 ml of alcohol was treated with 22.1 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride. A solution of 10 g of sodium hydroxide in 350 ml of water was added dropwise thereto while cooling with ice, the mixture was left to boil at reflux overnight and then concentrated to about 1/3 of its volume in a vacuum. After the addition of 1200 ml of water the crystals were filtered off and thereupon washed thoroughly first with water and then with ether. There was obtained 5,6-difluoro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole of melting point 216°-218°.
Reaction SMILES: [Cl:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:7](=[O:24])[C:8]4[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:9]=4[C:10]([CH3:17])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[Cl-].[NH+]1C=CC=CC=1>O>[Cl:1][C:2]1[C:14]([F:15])=[C:13]2[C:5]([C:6]3[C:7](=[O:24])[C:8]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:9]=4[C:10]([CH3:17])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3c(F)c(Cl)ccc3c1C2=O
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1c(F)c(Cl)ccc21
Temperature: 160 °C
Reaction time: 20 h
Yield: 66.1 %

Procedure:
3-Chloro-4-fluoro-8-methoxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S1-3, 220.0 mg, 0.640 mmol) and pyridinium chloride (800 mg, 6.922 mmol) were mixed with each other, heated to 160° C., and then stirred for 20 hr. The reaction solution was added with water. As a result, black solid was obtained as a precipitate, which was then filtered and subjected to purification by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (139.4 mg, 66%).
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([C:7]([O-:9])=[O:8])[C:4]([O-:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:10]([C:3]([CH2:1][CH3:2])([C:7]([O:9][CH2:2][CH2:1][CH2:3][CH2:10][CH3:11])=[O:8])[C:4]([O:6][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:5])[CH3:11]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOC(=O)C(CC)(CC)C(=O)OCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.4 %

Procedure:
To a stirring solution of diethylmalonate (8.0 g, 50 mmol) in THF (100 mL, 0.5 M) was added sodium hydride (1.2 g, 50 mmol). The solution began bubbling and an exothermic reaction occurred. The reaction eventually turned clear and then pentyl bromide (6.2 mL, 50 mmol) was added. The reaction was refluxed for 20 hours and then cooled to room temperature. Another equivalent of NaH (1.2 g, 50 mmol) was added to the cloudy white mixture which was then stirred for 4 hours at room temperature. Another equivalent of pentyl bromide (6.2 mL, 50 mmol) was added and the reaction was refluxed for 20 hours. The reaction was cooled to room temperature and filtered to remove the precipitated sodium bromide. The mother liquor was collected and concentrated in vacuo to a yellow oil. The crude product was then distilled under vacuum (140° C.) to afford 9.34 g (62%) of pure product.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl-].Cl[CH:13]1N(C)CC[NH+]1C.C(N(CC)CC)C>CO>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1ncccc1C(=O)O
Reactant: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cccnc1N
Yield: 94.8 %

Procedure:
To a mixture of 2-aminonicotinic acid (n) (30.0 g 217 mmol) and 2-chloro1,3-dimethyl imidazolinium chloride (55.2 g 326 mmol) in MeOH (750 ml) was added dropwise triethylamine (91 ml 652 mmol). The resultant mixture was stirred at room temperature for 1 h. The mixture was then evaporated under reduced pressure to afford a residue. The residue was purified by extraction with ethyl acetate (300 ml×2). The combined organic phase was washed with water (200 ml×2) and brine (200 ml). Dried over anhydrous sodium sulfate, filtered and concentrated to give an essentially pure methyl 2-aminonicotinate (31.3 g, yield 94%). This compound was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:32])[C:13]1[CH:18]=[CH:17][C:16]([Sn](CCCC)(CCCC)CCCC)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:34]1[N:35]=[C:36]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH3:51])[CH2:46][CH2:45]2)[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2>C1(C)C(C)=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:50]([N:47]1[CH2:46][CH2:45][N:44]([C:36]2[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:43]=[C:34]([C:16]3[CH:15]=[CH:14][C:13]([C:12](=[O:32])[NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:18][CH:17]=3)[N:35]=2)[CH2:49][CH2:48]1)[CH3:51]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)NCCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(C(=O)NCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 22.5 %

Procedure:
N-(2-Benzyloxyethyl)-4-tributylstannylbenzamide (1.23 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.49 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.13 g) in xylene in nitrogen atmosphere for 3 hr. After cooling, the reaction solution was filtered and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform/methanol system). The resulting product was dissolved in ethyl acetate and extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)carbamoyl]phenyl}isoquinoline (0.17 g) as a pale brown viscous oil.