Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[O:9]1[C:5]2[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]3[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=3)=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: Brc1ccc2c(c1)CCO2
Product: FC(F)(F)c1ccc(CCNc2ccc3c(c2)CCO3)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (2,3-dihydro-benzofuran-5-yl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 309.0 [M+H]+) was prepared from 5-bromo-2,3-dihydro-1-benzofuran instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:24][C:25]1([NH2:29])[CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:29][C:25]2([CH3:24])[CH2:28][CH2:27][CH2:26]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC1(N)CCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)CCC1
Temperature: 90 °C
Yield: 77.7 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41.6 mg, 0.094 mmol), 1-methylcyclobutanamine hydrochloride (ChemBridge, San Diego, Calif.; 34.3 mg, 0.282 mmol), and DIPEA (0.098 mL, 0.564 mmol) in DMSO (0.8 mL), heating at 90° C. for 19 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-((1-methylcyclobutyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26.4 mg, 0.073 mmol, 78% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (1H, br. s.), 7.89 (1H, d, J=6.8 Hz), 7.56 (1H, d, J=7.2 Hz), 7.32 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=1.8 Hz), 7.01 (1H, s), 6.98 (1H, br. s.), 3.45 (2H, td, J=6.8, 2.2 Hz), 2.92 (2H, t, J=6.7 Hz), 2.56 (3H, s), 2.42-2.49 (2H, m), 2.21-2.30 (2H, m), 1.86-2.00 (2H, m), 1.69 (3H, s). m/z (ESI, +ve) 362.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:48]I.O>CN(C=O)C>[C:1]([O:5][C:6](=[O:45])[N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)[CH3:48])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (1.05 g, 1.64 mmol) was dissolved in anhydrous DMF (10 mL) and cooled to 0° C. under argon. NaH (78.8 mg, 1.97 mmol, 60% dispersion in mineral oil) was added and the mixture stirred at 0° C. for 30 minutes. Methyl iodide (164 uL, 2.63 mmol) was added and the reaction was allowed to warm to room temperature at which point the solution was maintained for 18 hours. The reaction mixture was then poured into H2O and extracted twice with EtOAc. The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated to a yellow oil which was further purified by silica gel chromatography (10 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: hexanes, B: EtOAc, B: 0% for 5 min, B: 0% to 10% over 10 min; B: 10% for 10 min; B: 10% to 30% over 15 min; B: 30% for 10 min; detection at 214 nm) to give 1.05 g (1.63 mmol, 99%) of the title compound as a yellow oil. MS (ESI) 653.2
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=[C:4]([CH2:13][O:14][CH2:15][CH3:16])[N:3]=1.C(O)(=[O:19])C>[OH-].[Na+]>[CH2:15]([O:14][CH2:13][C:4]1[NH:3][C:2](=[O:19])[C:11]2[C:6](=[N:7][CH:8]=[C:9]([CH3:12])[N:10]=2)[N:5]=1)[CH3:16]
Reactant: CC(=O)O
Reactant: CCOCc1nc(N)c2nc(C)cnc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1nc2ncc(C)nc2c(=O)[nH]1
Reaction time: 1 h

Procedure:
A suspension of 7.4 g (0.0338 mole) of 4-amino-2-ethoxymethyl-6-methylpteridine in 148 ml of 5% aqueous sodium hydroxide is brought slowly to 85° C. and maintained at this temperature for 2 hours. A further 592 ml of 5% aqueous sodium hydroxide are then added and heating is continued at 85° C for 1 hour. After cooling, the solution obtained is acidified with acetic acid to pH 5.5, and is then extracted with dichloromethane. The organic extracts are dried over sodium sulphate and concentrated to dryness under reduced pressure. The solid residue is recrystallized from acetone in the presence of Norit. Yld: 4.9 g (66%), m.p. 181°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][C:13](O)=O>>[CH3:12][C:13]1[NH:11][S:8](=[O:9])(=[O:10])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CC(=O)O
Product: CC1=Nc2ccccc2S(=O)(=O)N1
Yield: 91 %

Procedure:
2-Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91%) of 3-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method A (using dimethylamine as amine). M.p. 260–261° C.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH3:35])[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: C[C@H](N)C(=O)N(C)C
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](C)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
From 4.48 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 61-2 (16.0 mmol, crude form) as starting materials, respectively 1.75 g (Isomer A, colorless amorphous) and 1.64 g (Isomer B, colorless powder) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH:10]=[O:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=1)[CH3:2].CC(=CC)C.Cl([O-])=[O:21].[Na+].O.OP([O-])(O)=O.[Na+].Cl>O1CCOCC1.O1CCCC1.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([C:10]([OH:21])=[O:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)n1
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc([N+](=O)[O-])c(C(=O)O)n1
Reaction time: 18 h
Yield: 122.5 %

Procedure:
To a stirred solution of the compound prepared in Example 423 (1.66 g) in dioxane (40 mL) at room temperature was added 2-methyl-2-butene (2.0 mol/L; 25.811 mL) in tetrahydrofuran. To the resulting stirred solution was added a solution of sodium chlorite (4.2095 g) and sodium phosphate monobasic monohydrate (4.2039 g) in water (28 mL). The resulting two-phase mixture was vigorously stirred at room temperature. The color of the reaction mixture lightened considerably over the first 30 minutes. After 18 hours, the reaction mixture was diluted with ethyl acetate (50 mL) and transferred to a separatory funnel. The aqueous layer was acidified with concentrated hydrochloric acid to about pH 1.5, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried, evaporated and dried further under high vacuo to provide the title compound (2.2 g) as a pale orange oil with the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Yield: 71.8 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (compound 42.1, 9.00 g, 28.9 mmol) in pyridine (50 mL). With stirring, phosphoroyl trichloride (7.93 mL, 84.8 mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and carefully quenched by slow addition of aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with aqueous sodium bicarbonate (2×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100 to 1:10) to yield the title compound as a colorless oil (6.1 g, 72%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2=[O:1])(=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: c1ccccc1
Product: O=C1CCc2c1cccc2C(=O)c1ccccc1
Reaction time: 5 h

Procedure:
To 100 ml. of dry benzene are added 17.6 g. of 1-oxoindan-4-carboxylic acid and 22.9 g. of phosphorus pentachloride and, after stirring for 1.5 hours, 40 g. of aluminum chloride is added. The mixture is stirred for 5 hours, after which the product is poured into dilute hydrochloric acid and extracted with ether. The organic layer is dried and distilled free of the solvent under reduced pressure. The crystalline residue is recrystallized from cyclohexane. The described procedure gives 4-benzoylindan-1-one which melts at 87°-89° C.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]([OH:18])=[O:17])[NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+].[CH3:21]O>O>[OH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([C:16]([O:18][CH3:21])=[O:17])[NH:13]2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc2ccc(O)cc2[nH]1

Procedure:
0.144 ml (2.70 mmol) of concentrated sulfuric acid is added, at ambient temperature, to a solution of 5.98 g (33.75 mmol) of 6-hydroxy-1H-indole-2-carboxylic acid in 350 ml of methanol. The mixture is refluxed for 9 days and the reaction mixture is then concentrated to dryness under reduced pressure. The residue obtained is taken up in water and alkalinized to pH9 with a 38% potassium hydroxide solution, and the product is then extracted 6 times with ethyl acetate. The organic phases are combined and then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure, to give 5.81 g of methyl 6-hydroxy-1H-indole-2-carboxylate in the form of a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([Br:13])=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Br:13][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([CH3:14])[CH:16]=2)=[N:12][CH:11]=1
Reactant: Cc1cncc(B(O)O)c1
Reactant: CCOC(=O)c1cc(Br)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2cncc(C)c2)ncc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution ethyl 2,5-dibromoisonicotinate (1-2, 1.5 g, 4.86 mmol) in degassed dimethylformamide (24 mL) at 25° C. was added (5-methylpyridin-3-yl)boronic acid (0.665 g, 4.86 mmol), PdCl2dppf (0.355 g, 0.486 mmol), cesium carbonate (4.75 g, 14.6 mmol) and water (0.262 mL, 14.57 mmol). The reaction flask was purged with nitrogen, sealed and stirred at 50° C. overnight. The crude reaction mixture was partitioned between water and EtOAc, separating layers and washing the organic layer with saturated sodium bicarbonate solution and brine. The solvent was removed by rotary evaporation and the crude product was purified by normal phase column chromatography (0 to 50% EtOAc in hexanes) to afford the product (1-3) as a white solid. ESI+MS[M]+C14H13BrN2O2=321.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH2:16][CH2:15]2)=O)=[CH:5][CH:4]=1>O>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1([C:12]2[C:7]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: COc1ccc(CCNC(=O)C2(c3ccccc3Cl)CC2)cc1
Solvent: O
Product: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CC1)=NCC2

Procedure:
A mixture of N-[2-(4-methoxyphenyl)ethyl]-1-(2-chlorophenyl)cyclopropanecarboxamide (2 g, prepared in a similar manner to that described in Example D8) and polyphosphate ester (20 ml) was gently heated for 12 hours. The mixture was poured into water and washed with ether, then ethyl acetate. The aqueous phase was basified with aqueous ammonia solution and extracted with ethyl acetate. The extract yielded a solid which was recrystallised from cyclohexane to give 1-[1-(2-chlorophenyl)cyclopropyl]-7-methoxy-3,4-dihydroisoquinoline.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(CC)C>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH:48]([CH3:53])[CH2:49][CH3:50])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCC(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C)NC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and sec-butylamine (12.12 uL, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (3.2 mg, 9%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[NH:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35])=[O:5]
Reactant: OCCNCCO
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(CCO)CCO

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diethanolamine. Elementary analysis: as C32H53O4N
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8].[H-].[Na+].[C:34]1(C)[CH:39]=[CH:38][C:37](S(OCCCCCC)(=O)=O)=[CH:36][CH:35]=1>O>[CH2:38]([O:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH3:8])[CH2:39][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OCCCCCC)cc2)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Into 20 ml of anhydrous dimethylformamide were dissolved 1.78 g (5 millimole) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 0.24 g (6 millimole) of 60% sodium hydride was added thereto, followed by stirring at 40° C. for 1 hour. Subsequently, 1.79 g (7 millimole) of hexyl p-toluenesulfonate were added thereto, to subject to reaction at the same temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, extracted with 200 ml of toluene, followed by separation thereof, and the organic phase was washed with water sufficiently, followed by drying over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 1.81 g (yield: 82%) of (+)-2-{4-(1-hexyloxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[OH:25][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:23][NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: NCC(O)c1ccccc1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: O=C(NCC(O)c1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 2-amino-1-phenyl ethanol instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.17 (1H, s) 8.07 (1H, t, J=5.37 Hz) 8.02 (1H, d, J=5.47 Hz) 7.77 (1H, d, J=5.47 Hz) 7.45 (1H, d, J=5.27 Hz) 7.27-7.38 (6H, m) 7.18-7.26 (1H, m) 6.79 (1H, d, J=5.47 Hz) 6.44 (1H, d, J=3.51 Hz) 5.51 (1H, d, J=3.90 Hz) 4.77 (1H, ddd, J=7.86, 4.30, 4.05 Hz) 3.47 (1H, dt, J=13.13, 5.15 Hz)
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:11]([CH2:21][CH2:22][CH3:23])[C:10]([O:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=1.[F:28][C:29]([F:37])([F:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].O>O1CCCC1>[F:28][C:29]([F:37])([F:36])[C:30]([C:7]1[CH:8]=[CH:9][C:10]([O:24][CH2:25][O:26][CH3:27])=[C:11]([CH2:21][CH2:22][CH3:23])[C:12]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)([OH:31])[C:32]([F:35])([F:34])[F:33]
Reactant: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1COC1CCCCO1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Under an argon atmosphere, n-butyl lithium (1.58 mol/L hexane solution 1.55 mL, 2.45 mmol) was dropped at −78° C. into a solution of 2-(6-bromo-3-(methoxymethoxy)-2-propylbenzyloxy)tetrahydro-2H-pyrane (725 mg, 1.75 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at the same temperature for 15 minutes and then stirred at the elevated temperature of −45° C. for 1.5 hours. A tetrahydrofuran (4 mL) solution of hexafluoroacetone was dropped at −78° C., and the mixture was stirred at 0° C. for 5 hours and then stirred at room temperature for 12 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (728 mg, 90%) was obtained as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C(N(CC)CC)C.O.[NH2:32][NH2:33]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:32][NH2:33])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 7.5 h

Procedure:
To a mixture of 4-benzyloxyphenylacetyl chloride (1.1 g) and THF (10 mL) were added triethylamine (1.8 mL) and hydrazine hydrate (0.20 mL) at room temperature, which was stirred at the same temperature for 7.5 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate, and the organic layer was washed with saturated brine. The solvent was evaporated under a reduced pressure, after which the residue was purified by silica gel chromatography (methanol:ethyl acetate=1:30) to obtain the titled compound (0.23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:7](=[O:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:5]2.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][OH:32].C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)(Cl)Cl.CO>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:7](=[O:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:5]2
Reactant: CN(C)CCO
Reactant: O=C1c2c(cc(Br)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)CCOc1cc2c(c(C(F)(F)F)c1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A mixture of 5-bromo-7-trifluoromethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.123 g, 0.3 mmol), 2-dimethylamino-ethanol (0.05 mL, 0.5 mmol), Pd(OAc)2 (0.002 g, 0.006 mmol), and Cs2CO3 (0.195 g, 0.6 mmol) in toluene (3 mL) was stirred at 100° C. for 24 h. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 5-(2-dimethylamino-ethoxy)-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.050 g, 36%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 6H), 2.73 (t, 2H), 4.13 (t, 2H), 4.23 (s, 2H), 4.74 (s, 2H), 7.04-7.38 (m, 6H).