Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].[Br:17]NC(=O)CCC(N)=O>CN(C)C=O.CCOC(C)=O>[Br:17][C:11]1[C:10]([O:14][CH3:15])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]2=[O:16]
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Reactant: NC(=O)CCC(=O)NBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(ccc(OC)c2Br)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-butyl-5-methoxy-1-indanone (1.869 g, 8.56 mmol) in anhydrous dimethylformamide (8.6 mL) was treated with N-bromosuccinamide (1.676 g, 9.42 mmol). The resulting mixture was stirred under a nitrogen atmosphere and at room temperature for 14 hours, and then heated in an oil bath at 50° C. for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with water (4×50 mL) and brine (50 mL), dried over MgSO4, and evaporated under vacuum to a dark amber oil (2.468 g). The crude product was purified by column chromatography on EM silica gel 60 (230-400 mesh, 620 mL dry, packed under CH2Cl2), using CH2Cl2 as eluting solvent, to afford 4-bromo-2-butyl-5-methoxy-1-indanone (1.267 g, contains approx. 3% of the 6-bromo isomer) as a pale tan solid. Earlier fractions afforded the 6-bromo isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[S:13](=[O:16])(=[O:15])[NH2:14].N[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>C(O)CCCC>[Br:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:21]2[CH2:22][CH2:23][CH:18]([N:8]3[C:6](=[O:7])[C:5]4[C:4](=[CH:3][C:2]([Cl:1])=[C:12]([S:13]([NH2:14])(=[O:16])=[O:15])[CH:11]=4)[C:9]3=[O:10])[CH2:19][CH2:20]2)=[CH:30][CH:29]=1
Reactant: NC1CCN(Cc2ccc(Br)cc2)CC1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Solvent: CCCCCO
Product: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(C1CCN(Cc3ccc(Br)cc3)CC1)C2=O

Procedure:
Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide (6.48 g., 0.025 mole) and 4-amino-1-(4-bromobenzyl)piperidine (6.7 g., 0.025 mole) in n-pentanol according to the procedure of Example 1(a) afforded the 1,3-dioxoisoindole product. Purification of the crude product by triturating with n-heptane and crystallization from DMF-methanol afforded 6.9 g. (54%) of 2-[1-[(4-bromophenyl)methyl]-4-piperidinyl]-6-chloro-2,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide, m.p. 246°-247° (dec.).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][O:13]C)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[N:10]=[C:9]([CH2:11][CH2:12][OH:13])[CH:8]=[C:7]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1nc(CCO)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2-tert-Butyl-4-(2-methoxy-ethyl)-6-piperazin-1-yl-pyrimidine (2.78 g, 9.99 mmol) in DCM (150 mL) was added BBr3 (3.75 g, 14.98 mmol) at 0° C. Then the mixture was stirred overnight at room temperature. The mixture was quenched with saturated aqueous NaHCO3 solution. The organic phase was separated out and dried over Na2SO4, filtered and concentrated. The crude title compound was used in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCOCC1)c1cccc3c1N2CC3
Temperature: 25 °C

Procedure:
A mixture of 7.88 g (0.0250 mole) of 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 21.8 g (0.250 mole) of morpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for three hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 250 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filterd, and concentrated in vacuo to 8.6 g (90%) of product. Recrystallization from a hot solution of dichloromethane (80 ml) to which methanol (80 ml) was added provided the analytical sample, mp 216°-218° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2=[O:24].[CH3:25][NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:26]([CH3:25])[CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:11][CH:10]=3)[C:5](=[O:24])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: CNCc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(N(C)Cc3cccnc3)cc2c1=O
Temperature: 110 °C
Yield: 32.9 %

Procedure:
Compound D (75 mg, 0.19 mmol, 1.0 eq), N-methyl-N-(3-pyridylmethyl)amine (47 mg, 0.38 mmol, 2.0 eq), cesium carbonate (88 mg, 0.27 mmol, 1.4 eq), tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol, 0.080 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg, 0.023 mmol, 0.12 eq) were dissolved in toluene (1.9 mL) in a sealed vial and heated at 110° C. overnight. The reaction was cooled, filtered over Celite® and washed with 5% methanol in DCM. The organics were concentrated and purified using reverse phase chromatography to afford 27 mg (33%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 8.28 (s, 1H), 7.68 (dd, J=6.9, 4.9 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.47 (t, J=8.7 Hz, 2H), 7.40 (d, J=3.0 Hz, 1H), 7.34-7.30 (m, 1H), 7.21 (dd, J=9.3, 3.0 Hz, 1H), 6.80 (d, J=9.3 Hz, 1H), 4.70 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.12 (s, 3H), 1.23 (t, J=7.1 Hz, 3H); ES-MS [M+1]+: 432.3.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10][NH2:11])[CH:6]=[CH:7][C:8]=1[F:9].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][NH:11][C:12](=[O:14])[CH3:13]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
A solution of (3-bromo-4-fluorophenyl)methanamine hydrochloric acid salt (500 mg, 2.079 mmol) in pyridine (6 mL) was stirred on ice and treated with acetic anhydride (0.235 mL, 2.495 mmol). The resulting solution was stirred at rt for 17 h, then was concentrated. The residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, rinsed with water and dried to provide N-(3-bromo-4-fluorobenzyl)acetamide as a white solid (435 mg, 85%). 1H NMR (400 MHz, chloroform-d) δ 7.47 (dd, J=6.6, 2.2 Hz, 1H) 7.20 (ddd, J=8.6, 4.6, 2.2 Hz, 1H) 7.07 (t, J=8.3 Hz, 1H) 5.84 (br. s., 1H) 4.38 (d, J=5.9 Hz, 2H) 2.04 (s, 3 H). Mass spectrum m/z 246, 248 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].CCO>>[O:19]1[CH:20]=[CH:21][C:17]([CH2:16][O:15][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)=[CH:18]1
Reactant: CCOC(=O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reaction time: 24 h

Procedure:
The 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid ethyl ester 96 obtained above is mixed with a 1M-solution of KOH in EtOH (35 ml, 35 mmol) and stirred for 24 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:22])[O:5][C:6]1[CH:7]=[C:8]([OH:21])[CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:24]1[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:21][C:8]1[CH:9]=[C:10]([C:24]2[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[CH:27][CH:28]=2)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:22])[CH2:3][O:2][CH3:1])[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nccs1
Reactant: COC[C@H](C)Oc1cc(O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
3-[(1S)-2-Methoxy-1-methylethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.30 g, 10.7 mmol) synthesized in Example (38c) and t-butyl 2-bromo-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (4.10 g, 12.5 mmol) synthesized in Example (1g) were dissolved in a mixed solvent of 1,4-dioxane (100 mL) and water (25 mL), and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride dichloromethane complex (400 mg, 0.490 mmol) and potassium carbonate (7.20 g, 52.1 mmol) were added, followed by stirring at 50° C. for 4 hours under nitrogen atmosphere. After the reaction solution was cooled to room temperature, water (200 mL) was added, and extraction was carried out with ethyl acetate (400 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=25%-40%) to afford the desired compound (3.72 g, yield 81%) as a pale yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].C1COCC1.CCOC(C)=O>CCO.[Pd]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([S:2][CH3:1])[C:4]=1[C:5]#[N:6]
Reactant: CSc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1cccc(N)c1C#N
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-(methylthio)-6-nitrobenzonitrile (Example 104c) (1.5 g, 7.73 mmol) in EtOH (150 ml)/THF (50 ml)/EtOAc (50 ml) was added 200 mg of 10% Pd/C. The reaction mixture was hydrogenated on part shaker overnight. After the filtration, the filtered solution was dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with EtOAc/Hexane to give the title compound (79%). 1H NMR (400 MHz, CDCl3) δ 2.51 (s, 3H), 4.47 (s, 2H), 6.53-6.51 (m, 1H), 6.58 (d, J=8.0 Hz, 1H), 7.27-7.21 (m, 1H).
Reaction SMILES: N1(C2N=[C:9]([CH2:14][C:15]([O-])=O)NC(=O)C=2)CCOCC1.[Na+].[N:19]1([C:25]2[N:30]=[C:29]([CH2:31][C:32](=[O:48])[N:33]3[C:41]4[C:36](=[C:37](C5C=CC=CN=5)[CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34]3)[NH:28][C:27](=[O:49])[CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH:14]1([CH:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:33]2[C:32](=[O:48])[CH2:31][C:29]2[NH:28][C:27](=[O:49])[CH:26]=[C:25]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:30]=2)[CH2:15][CH2:9]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccn3)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1C1CC1
Yield: 160.9 %

Procedure:
(±)-2-[2-(2-Cyclopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is prepared by following the procedure described in example 1 using 0.90 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.60 g of (±)-2-cyclopropylindoline (reference example 12d) and 0.86 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.56 ml of pyridine and 10 ml of N,N-dimethylformamide. After purification by chromatography on a 100 g column of 20-45 μm silica, elution being carried out with a 90/10 v/v dichloromethane/methanol mixture, 0.88 g of (±)-2-[2-(2-cyclopropyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one is obtained in the form of a cream foam, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C(#N)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Cl:20])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(N)cc1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCCc1ccc(NC(=O)CCCCl)cc1
Temperature: 50 °C
Yield: 52.2 %

Procedure:
17.9 gm (0.1 mol) of p-aminophenethyl acetate were dissolved in 180 ml of acetonitrile, 27.6 gm (0.2 mol) of potassium carbonate were added to the solution, and then, while stirring, 17.0 gm (0.12 mol) of 4-chlorobutyric acid chloride were added dropwise. The resulting mixture was stirred for 2 hours at room temperature, thereafter heated to 50° C and then vacuum-filtered to remove precipitated inorganic salts. The solvent was distilled out of the filtrate in vacuo, and the residue was recrystallized from isopropanol, yielding 14.8 gm (52.2% of theory) of p-(4-chlorobutyramido)-phenethyl acetate, m.p. 83° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:21]1[NH:26][C:25](=[O:27])[C:24]([CH:28]([NH:30][C:31](=O)[CH2:32][CH2:33][CH3:34])[CH3:29])=[N:23][N:22]=1)[CH3:2].O=P(Cl)(Cl)Cl>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[C:21]1[NH:22][N:23]2[C:31]([CH2:32][CH2:33][CH3:34])=[N:30][C:28]([CH3:29])=[C:24]2[C:25](=[O:27])[N:26]=1)[CH3:2]
Reactant: CCCC(=O)NC(C)c1nnc(-c2cc(S(=O)(=O)N3CCN(CC)CC3)ccc2OCC)[nH]c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)c2c(=O)nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)ccc3OCC)[nH]n12
Temperature: 80 °C
Yield: 65.5 %

Procedure:
The compound of formula III (0.51 g, 1 mmol) was added with POCl3 (2 mL), and the mixture was heated for 2 hours at 80° C. The excess phosphorous oxychloride was evaporated of under reduced pressure, and the residue was slowly poured into chopped ice. The solution was adjusted to a pH of 8 with sodium carbonate, and extracted with dichloromethane (40 mL). The organic phase was washed with saturated saline (15 mL), and dried over anhydrous sodium sulfate. Then, 20 mL of ethanol was added therein, and the solution was decolorized by activated carbon, filtrated, and evaporated to remove some of the solvent therefrom. Ethyl acetate was then added therein to perform a recrystallization. Finally, the crystal was separated to obtain 0.32 g of product with a yield of 65%. 1H NMR (CDCl3, 300 MHz) δ: 1.01 (3H, t), 1.04 (3H, t), 1.62 (3H, t), 1.86 (2H, m), 2.42 (2H, q), 2.54 (4H, t), 2.64 (3H, s), 2.99 (2H, t), 3.07 (4H, m), 4.34 (2H, q), 7.15 (1H, d), 7.88 (1H, dd), 8.48 (1H, d), 9.52 (1H, s).
Reaction SMILES: [H][H].[CH2:3]=[CH:4]CCCC.[CH2:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH2:14].[CH:15]([CH:17]1CC[CH2:20][CH2:19][CH2:18]1)=[CH2:16]>>[CH2:3]=[CH2:4].[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]=[CH:15][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CC1CCCCC1
Reactant: [H][H]
Agent: C=CCCC=C
Solvent: C=CCCCC
Product: C=C
Reaction time: 0.1 h

Procedure:
Polymerization was conducted in the same manner as in Example 7 except that 0.0547 MPa of hydrogen was charged, 11 mL of 1-hexene and 3 mL of 1,5-hexadiene were charged as addition polymerizable monomers instead of vinylcyclohexane, and 1.5 μmol of dimethylsilylene(tetramethylcyclopentadienyl)(3-tert-butyl-5-methyl-2-phenoxy)titanium dichloride instead of isopropylidene(cyclopentadienyl)(3-tert-butyl-5-methyl-2-phenoxy)titanium dichloride, and 7.5 μmol of dimethylaniliniumtetrakis(pentafluorophenyl) borate were used, the charging temperature was changed to 80° C. and the polymerization time was changed to 6 minutes. As a result of the polymerization, 53 g of an ethylene/1-hexene/1,5-hexadiene ternary copolymer was obtained having a melt viscosity η*190 of 1.20×103 Pa·se, a fusion heat quantity ΔH of 123 kJ/kg, a melting temperature of 113° C., and a Mw/Mn of 2.2. The resulted ethylene-based copolymer had a tensile impact strength TI of 890 kJ/m2 and a melt tension MT of 7.2 cN The results are shown in Table 5.
Reaction SMILES: [ClH:1].FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C(NC[C@H]3CCNC3)=O)SC=12.[F:41][C:42]1[CH:71]=[C:70]([NH:72][C:73]([NH:75][C:76](=[O:84])[CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[S:74])[CH:69]=[CH:68][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]([NH:56][CH2:57][CH2:58][N:59](C)[C:60](=O)OC(C)(C)C)=[O:55])[S:53][C:46]=12>>[ClH:1].[F:41][C:42]1[CH:71]=[C:70]([NH:72][C:73]([NH:75][C:76](=[O:84])[CH2:77][C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)=[S:74])[CH:69]=[CH:68][C:43]=1[O:44][C:45]1[CH:50]=[CH:49][N:48]=[C:47]2[CH:51]=[C:52]([C:54]([NH:56][CH2:57][CH2:58][NH:59][CH3:60])=[O:55])[S:53][C:46]=12.[ClH:1]
Reactant: CN(CCNC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(C(=O)NC[C@H]4CCNC4)sc23)c(F)c1
Product: CNCCNC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1

Procedure:
Following the procedure described above for the synthesis of 137a but replacing compound 135b with compound 138, title compound 137b was obtained as an HCl salt in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.49 (s, 1H), 11.83 (s, 1H), 9.39(t, J=5.2 Hz, 1H), 8.80(bs, 1H), 8.62(d, J=5.6 Hz, 1H), 8.39 (s, 1H), 8.04(d, J=11.6 Hz, 1H), 7.97(bs, 1H), 7.58-7.50 (m, 2H), 7.37-7.31 (m, 4H), 7.31-7.24 (m, 1H), 6.80(d, J=5.6 Hz, 1H), 3.78-3.71(m, 0.5H), 3.61(q, J=6.0 Hz, 1H), 3.21-3.24 (m, 0.5H), 3.18-3.04 (m, 2H), 2.60(t, J=4.8 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:20]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:19](OC)[CH:18]=[CH:17][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:7].[CH2:29](N(CC)CC)C.Cl.[OH-].[Na+]>CS(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][N:8]2[C:2]([O:1][CH3:29])=[CH:3][C:4]3[C:5](=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2=[O:7])=[CH:16][CH:15]=1
Reactant: CCN(CC)CC
Reactant: CCCCCOc1c(OC)ccc(C(=O)NCCc2ccncc2)c1CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCOc1cccc2c(=O)n(CCc3ccncc3)c(OC)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.2 %

Procedure:
2-(2-Hydroxyethyl)-4-methoxy-3-pentyloxy-N-(2-pyridin-4-ylethyl)-benzamide (90 mg, 233 mmol, 1.0 eq) was dissolved in DMSO (2 ml), and triethylamine (0.3 ml, 2.10 mmol, 9 eq) and sulfur trioxide-pyridine complex (111.2 mg, 0.70 mmol, 3 eq) were successively added under ice-cooling. The mixture was stirred at room temperature for 4 hours. 3N Hydrochloric acid (15 ml) was added to this reaction mixture, and the mixture was stirred at room temperature for 1 hour. Sodium hydroxide was added to make the same alkaline. The solution was extracted twice with ethyl acetate (20 ml). The organic layers were combined, washed with saturated brine (40 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate) and recrystallized from ethyl acetate to give 2-[2-(4-pyridyl)ethyl]-methoxy-5-pentyloxy-2H-isoquinolin-1-one (40.2 mg, 47.1%) as colorless crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>CO.O>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: COC(=O)Cc1ccc2c(c1)CCN2C(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)CCN2
Yield: 73.9 %

Procedure:
A solution of 2 (1.75 g, 7.5 mmol) in a mixture of methanol (100 mL), water (20 mL) and conc. HCl (10 mL) was refluxed for 4 h. The solution was diluted with water (30 mL), concentrated to about 50 mL, basified to pH 8 with K2CO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give methyl indoline-5-acetate 3 as a brown oil (1.06 g, 74%); 1H NMR: δH (90 MHz) 6.80-7.06 (m, 2H), 6.58 (d, J=8 Hz, 1H), 3.64 (s, 3H), 3.52 (t, J=7.2 Hz, 3H), 3.50 (s, 2H) and 2.96 (t, J=7.2 Hz, 2H). The crude product and glutaric anhydride (685 mg, 6 mmol) were dissolved in chloroform (75 mL) and the mixture was stirred at rt overnight, then refluxed for 2 h. The solution was extracted with saturated aq. NaHCO3 solution and the aqueous extract was acidified to pH 2.8 with conc. HCl and extracted with EtOAc. The latter organic extracts were dried and evaporated to give 4 as white crystals (1.24 g, 74%), mp 134-136° C. (EtOAc-hexanes); IR: νmax/cm−1; 1720, 1.625, 1605; 1H NMR: δH (400 MHz) 8.15 (d, J=8 Hz, 1H), 7.07-7.11 (m, 2H), 4.04 (t, J=8.5 Hz, 2H), 3.68 (s, 3H), 3.57 (s, 2H), 3.18 (t, J=8.5 Hz, 2H), 2.52 (t, J=7 Hz, 4H), and 2.06 (quintet, J=7 Hz, 2H). Anal. Calcd for C16H19NO5: C, 56.11; H, 5.07; N,. 10.06. Found: C, 56.18; H, 4.86; N, 10.03.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:25]([NH:29][C:30]3[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=3[CH3:40])=[N:24][CH:23]=[CH:22][C:21]=2[C:20]=1[NH2:41].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:41][C:20]2[C:21]3[CH:22]=[CH:23][N:24]=[C:25]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=4[CH3:40])[C:26]=3[CH:27]=[CH:28][C:19]=2[CH3:18])[C:5]([C:9]2[C:10]3[CH:17]=[CH:16][NH:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(-c2ncnc3[nH]ccc23)c(Cl)n1
Reactant: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(N)c(C)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(C(F)(F)F)cc1Nc1nccc2c(Nc3nc(Cl)ncc3-c3ncnc4[nH]ccc34)c(C)ccc12
Temperature: 70 °C

Procedure:
A mixture of 4-(2,4-dichloropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (89 mg, 335 μmol) and 6-methyl-N1-(2-methyl-5-(trifluoromethyl)phenyl)isoquinoline-1,5-diamine (111 mg, 335 μmol) in DMSO (2 mL) was treated with DIPEA (0.3 mL). The mixture was heated to 70° C. in an oil bath for 2 days. Additional quantities of 4-(2,4-dichloropyrimidin-5-yl)-7H-pyrrolo[2,3-d]pyrimidine (3×20 mg) were added during the course of the reaction. The reaction mixture was cooled to rt and poured onto 50 g of ice with 20 mL of NaHCO3. The resulting suspension was extracted with EtOAc (3×50 mL). The EtOAc solution was washed with brine then dried over Na2SO4 and concentrated. The residue was purified via prep LCMS on silica [4% 1M NH3-MeOH in DCM-EtOAc (5-1)]. The residue was further purified by trituation in MeOH to give the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: 561.2 [M+H]+