Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:20][C:18]1[N:19]=[C:14]([NH:12][CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Temperature: 130 °C
Yield: 92.2 %

Procedure:
A mixture of quinolin-6-ylmethanamine (3.6 g, 22.76 mmol), 3,5-dibromopyrazin-2-amine (5.75 g, 22.76 mmol) and triethyl amine (4.61 g, 45.5 mmol) was heated with microwave irradiation at 130° C. for 5 h. The reaction mixture was diluted with CH2Cl2 and water and the organic layer was separated, washed with aqueous NH4Cl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography with EtOAc:hexanes to provide 6.93 g (92%) of the title compound. LCMS (method A): [MH]+=330, tR=4.89 min.
Reaction SMILES: [CH2:1]([C:5]1([CH:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:11][CH:12]=[O:13])[CH2:8][CH2:7][CH2:6]1)[CH2:2]CC.C([Si](OC(C1(CC)CCC1)C#C)(C)C)(C)(C)C>CCOC(C)=O.CCCCCC>[Si:15]([O:14][CH:9]([C:5]1([CH2:1][CH3:2])[CH2:8][CH2:7][CH2:6]1)[CH2:10][CH2:11][CH:12]=[O:13])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCCCC1(C(CCC=O)O[Si](C)(C)C(C)(C)C)CCC1
Agent: C#CC(O[Si](C)(C)C(C)(C)C)C1(CC)CCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC1(C(CCC=O)O[Si](C)(C)C(C)(C)C)CCC1

Procedure:
The title compound was prepared according to the procedure described for intermediate 2.6 from tert-butyl {[1-(1-ethylcyclobutyl)prop-2-ynyl]oxy}dimethylsilane. (intermediate 21.5). Rf 0.6 (EtOAc/hexanes 1/4).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:24](=[O:26])[CH3:25])=[CH:15][CH:16]=1)[CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CN(C)C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (551 mg) in THF (50 ml) were added triethylamine (0.42 ml) and acetic anhydride (0.26 ml), and the resulting mixture was stirred at room temperature for 3 hours. After evaporation of THF, the residue was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to obtain N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]acetamide (472 mg) as light yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([C:23]#[C:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CSc1nc(N)nc(-c2ccco2)c1C#Cc1ccccc1
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
Following the method of Thorand and Krause (J. Org. Chem. 1998, 63, 8551), to a stirred solution of 500 mg (1.50 mmol) 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine in 10 ml dry degassed THF under argon at room temperature were added 211 mg (0.30 mmol) bis(triphenylphosphine)palladium(II) chloride, 10 mg (0.04 mmol) triphenylphosphine, 0.25 ml (2.28 mmol) phenylacetylene and 0.31 ml (2.22 mmol) triethylamine. Stirring was continued for 30 minutes then 3.0 mg (0.02 mmol) copper(I) iodide was added and the reaction mixture stirred for an additional 72 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (1/4-1/1 ethyl acetate/hexane) afforded 161 mg (35%) 4-furan-2-yl-6-methylsulfanyl-5-phenylethynyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 307 (M+, 100), 306 ([M—H]+, 52), 230 (38).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:24]([O:26]C)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=4[CH3:31])[C:24]([OH:26])=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Temperature: 60 °C

Procedure:
To a mixture of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoate (1 g, 2.4 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH and heated to 60° C. for 5 h. The mixture was cooled to ambient temperature and then in an ice-water bath, quenched slowly with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.850 g (90%). This acid was also prepared by the coupling of 2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate with 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (Cs2CO3, (Ph3)4Pd, H2O/1,4-dioxane (1:5), 90° C.) in a similar manner as described. 1H NMR (400 MHz, DMSO-d6): δ 2.32 (s, 3H), 2.82-2.83 (d, 3H, J=4.6 Hz), 7.36-7.48 (m, 6H), 7.56-7.57 (d, 1H, J=1.44 Hz), 7.75-7.77 (d, 1H, J=8.48 Hz), 7.81-8.03 (m, 2H), 8.46-8.48 (d, 1H, J=4.7 Hz), 12.92 (s, 1H). LCMS: (ES+) m/z=404.0 (M+H).
Reaction SMILES: Cl.Cl.[C:3]([O:11][CH2:12][CH2:13][NH2:14])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.ClC1C=C(Cl)C(Cl)=CC=1[CH:24]([Cl:32])[CH2:25][N:26]([N:30]=[O:31])[C:27](=O)[O-:28].C(Cl)(Cl)Cl.C(OCC)(=O)C>N1C=CC=CC=1>[Cl:32][CH2:24][CH2:25][N:26]([N:30]=[O:31])[C:27]([NH:14][CH2:13][CH2:12][O:11][C:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:10])=[O:28]
Reactant: NCCOC(=O)c1cccnc1
Reactant: O=NN(CC(Cl)c1cc(Cl)c(Cl)cc1Cl)C(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=NN(CCCl)C(=O)NCCOC(=O)c1cccnc1

Procedure:
A solution of 2-aminoethyl nicotinate dihydrochloride (1.25 g, 52 mmol) and 2,4,5-trichlorophenyl-N-(2-chloroethyl)-N-nitrosocarbamate (2 g, 6 mmol) in 40 mL of pyridine was stirred under nitrogen at room temperature for 24 hours. The reaction was monitored by thin layer chromatography (silica, 1:1 chloro form/ethyl acetate, Rf 0.26). The solvent was removed in vacuo and the residue was chromatographed on a silica gel column by eluting, first with benzene to remove unreacted nitrosocarbamate and trichlorophenol by-product, and then with chloroform, to give the desired product. The resultant oil solidified in the freezer. It melted at 63°-64° C. and had the formula ##STR152##
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([CH3:28])[C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:29])[C:3]=1[CH2:30][OH:31].C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].C(Cl)(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:7]([N:8]([CH3:28])[C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)=[CH:6][CH:5]=[C:4]([Cl:29])[C:3]=1[CH2:30][O:31][S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: CN(C)C(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CO)c2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COS(C)(=O)=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a stirred solution of 2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(dimethylcarbamoyl)cinnamoylglycyl]amino]benzene (300 mg) and triethylamine (78.5 mg) in dichloromethane (3 ml) was dropwise added mesyl chloride (81.4 mg) under ice-cooling, and the mixture was stirred for 10 minutes at the same temperature and for 30 minutes at ambient temperature. Chloroform was added thereto, and the mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo to give 2,6-dichloro-1-methanesulfonyloxymethyl-3-[N-methyl-N-[4-(dimethylcarbamoyl)cinnamoylglycyl]amino]benzene (330 mg) as colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O.CCCCCC>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: Brc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
A solution of 2-bromophenol (17.3 g) in dimethylformamide (200 mL) was treated with potassium carbonate (15.2 g) followed by benzyl bromide (17.1 g, 11.9 mL). After stirring for 3 hours at the room temperature, the reaction mixture was diluted water and hexane. The aqueous layer was extracted with hexane; and the organic layers were washed (water, 1N sodium hydroxide, brine), dried and evaporated to give the product as a colorless oil (22.94 g). This material was fractionally distilled under reduced pressure to afford the bromobenzene (16.52 g); bp 110°-145° C. (1333 Pa); NMR (CDCl3): 5.17 (s, 2), 6.65 (d of t,1, J=8, J=1), 6.92-6.96 (d of d, 1, J=8, J=1), 7.19-7.26 (m, 1), 7.33-7.42 (m, 3), 7.46-7.50 (m, 2), 7.55 (d of d, 1, J=9, J=2). This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:15][CH:16]=2)[CH2:11][C@H:10]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@H]1Cc2cc(Br)ccc2N(Cc2ccccc2)C1)c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(N[C@H]1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
The title compound was also prepared using the following procedures: To a solution of 87C (510 mg, 1.11 mmol) in THF/MeOH (2.1, 15 mL) was added phenylboronic acid (272 mg, 2.22 mmol), followed by K2CO3 (613 mg, 4.44 mmol) and PXPd (30 mg, 0.056 mmol). The reaction mixture was stirred at 60° C. for 2 h, then additional amount of phenylboronic acid (54 mg, 0.44 mmol) and PXPd (16 mg, 0.028 mmol) were added. After 2 h at 60° C., same amount of phenylboronic acid and PXPd were added again to the reaction mixture to push completion of the reaction. After stirring at 60° C. for one more hour, the reaction was allowed to cool to RT and concentrated. The residue was partitioned between water and CH2Cl2, and the aqueous phase extracted with CH2Cl2 (50 mL×2). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified using chromatography (silica gel) eluting with EtOAc/hexane (0-60%) to afford the title compound (260 mg, 51%) as a white solid.
Reaction SMILES: [C:1]([N:4]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[CH:25]([NH:38][CH2:39][CH2:40][CH2:41]CC(OCC)=O)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[K+].[CH2:50]([OH:52])[CH3:51]>>[C:50]([N:38]([CH:25]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:39][CH2:40][CH2:41][CH2:2][C:1]([N:4]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[O:3])(=[O:52])[CH3:51]
Reactant: CCOC(=O)CCCCNC(c1ccccc1)c1ccccc1
Reactant: CC(=O)N(CCCCC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CC(=O)N(CCCCC(=O)N(CCCCC(=O)O)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-acetyl-5-benzhydrylaminovaleric acid and ethyl 5-benzhydrylaminovalerate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-(N-acetyl-5-benzhydrylaminopentanoyl)-5-benzhydrylaminovaleric acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[C:3]([CH3:19])=[C:2]([NH:28][C:27]2[CH:29]=[C:30]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:31]=[CH:32][C:26]=2[N:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1cc(-c2cccnc2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2cccnc2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-2-(2-fluorophenyl)-3-methylquinoline (64 mg, 0.23 mmol), 2-morpholino-5-(pyridin-3-yl)aniline (60 mg, 0.23 mmol) and a 4.0M solution of HCl in dioxane (0.06 mL, 0.23 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 2-(2-fluorophenyl)-3-methyl-N-(2-(4-morpholinyl)-5-(3-pyridinyl)phenyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (1H, dd, J=4.7, 1.6 Hz), 8.19 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=8.2 Hz), 7.59-7.76 (4H, m), 7.54 (1H, d, J=7.4 Hz), 7.47 (1H, d, J=8.2 Hz), 7.31-7.36 (1H, m), 7.10-7.24 (4H, m), 6.65 (1H, br. s.), 3.97 (4H, t, J=4.7 Hz), 3.09-3.30 (4H, m), 2.26 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=491.0 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.O.C(OCC)(=O)C>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C1CCc2cc(F)c(F)cc21
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 84.8 %

Procedure:
A solution of 5,6-difluoro-1-indanone (535 mg) and morpholine (554 mg) in 1-methyl-2-pyrrolidinone (6.0 mL) was stirred at 100° C. for 7 hours. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (elution solvent: heptane-ethyl acetate system) to obtain 635 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:6][CH:7]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[C:3]([O-:5])=[O:4].C([Br:28])C1C=CC=CC=1>CCOCC>[BrH:28].[CH3:20][C:2]([CH3:1])([CH2:6][CH:7]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[C:3]([OH:5])=[O:4]
Reactant: CCC(C)(C)CC(CC(C)(C)C(=O)[O-])N1CCCCC1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: Br
Product: CCC(C)(C)CC(CC(C)(C)C(=O)O)N1CCCCC1
Temperature: 105 °C

Procedure:
A mixture of 28.3 parts of 2,2,6,6-tetramethyl-4-piperidinyl-n-octanoate and 8.55 parts of benzyl bromide was stirred and heated at 105° C. for 72 hours. Ether was added to the cooled reaction mixture and the 2,2,6,6-tetramethyl-4-piperidinyl-n-octanoate hydrobromide formed during the reaction was filtered off. The ether solvent was removed by distillation under reduced pressure and the residue distilled under reduced pressure to give 16.40 parts of 1-benzyl-2,2,6,6-tetramethyl-4-piperidinyl-n-octanoate having a boiling point of 180° C. at 0.1 mm of Hg and the following elemental analysis by weight:
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8]([Cl:10])[C:7]([S:11][CH2:12][CH3:13])=[C:6]([Cl:14])[N:5]=1)([CH3:3])[CH3:2].C(OO)(=[O:17])C.[OH2:20]>C(O)(=O)C.C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([Cl:14])[C:7]([S:11]([CH2:12][CH3:13])(=[O:17])=[O:20])=[C:8]([Cl:10])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)OO
Reactant: O
Reactant: CCSc1c(Cl)nc(C(C)C)nc1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1c(Cl)nc(C(C)C)nc1Cl
Temperature: 40 °C
Reaction time: 24 h

Procedure:
9.8 g (0.039 mole) of 2-isopropyl-4,6-dichloro-5-ethylthiopyrimidine are dissolved in 50 ml of acetic acid and then 15.2 g (0.08 mole) of peracetic acid are slowly added dropwise to this solution. The exothermic reaction is kept in check by cooling at 40° C. After being stirred for 24 hours at room temperature, the clear solution is diluted with 4 times its volume of water. The precipitate is isolated by filtration and taken up in methylene chloride. The aqueous filtrate is extracted with methylene chloride and the extract is washed with sodium bicarbonate solution until neutral. The combined methylene chloride phases are dried over magnesium sulfate, filtered and concentrated to an oil. The residue (6.3 g) is distilled in a high vacuum in a bulb tube. At an oven temperature of 150° C./3;10-2 mbar, 5.4 g of 2-isopropyl-4,6-dichloro-5-ethylsulfonylpyrimidine distill in the form of a colourless oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Reactant: C1CCNC1
Product: Cc1cc(Nc2cc3cc(N4CCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and Pyrrolidine to give 5 mg of (1-Isopropoxy-6-pyrrolidin-1-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 352 (MH+).
Reaction SMILES: O.[C:2]([C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2/[C:20](=C\OC)/[C:21]([O:23][CH3:24])=[O:22])[CH:8]=1)#[N:3].[Mn]([O-])(=O)(=O)=[O:33].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCCCC)(CCCCCC)CCCCCC)CCCCC>[C:2]([C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:33])[C:21]([O:23][CH3:24])=[O:22])[CH:8]=1)#[N:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Agent: CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a vigorously stirred mixture of water (20 ml) and a solution of (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (3.2 g, 7.94 mmol) in dichloromethane (20 ml) was added potassium permanganate (2.5 g, 15.9 mmol) in one portion and tetra-n-hexylammonium hydrogen sulphate (200 mg). The reaction mixture was stirred overnight (16 hours) and then filtered. The filter was washed through with ether and water and then the combined filtrates were extracted with ether (×3). The ether extracts were washed with water (×3) and brine (×1), dried, filtered and evaporated. The residue was chromatographed (eluent dichloromethaneacetone, 98:2). Recrystallisation (ether-pentane) of the major component afforded methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-ketoacetate (2.105 g, 71%) as a white crystalline solid; mp 96°-97° C.; 1H NMR (CDCl3) δ 3.83(3H,s), 6.61(1H,s), 7.27-7.47(4H,m), 7.67-7.76(3H,m), 8.02(1H,dd), 8.39(1H,s) ppm; IR maxima 2234(CN), 1743(CO, ester); 1688(CO, ketone)cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].C(N(C(C)C)C(C)C)C.[Cl:34][C:35]1[C:36](Cl)=[N:37][CH:38]=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41]>CN(C=O)C.CCOC(C)=O>[Cl:34][C:35]1[C:36]([N:21]2[CH2:22][CH2:23][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([NH:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:14]3=[O:24])[CH2:19][CH2:20]2)=[N:37][CH:38]=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41]
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 1.0 g, 2.8 mmol) in DMF (30 mL) was added N-ethyl-N-isopropylpropan-2-amine (1.1 g, 8.4 mmol) and methyl 5,6-dichloronicotinate (1.7 g, 8.4 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (250 mL) and washed with water (100 mL), and brine (50 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of 1:9 to 1:4 EtOAc:DCM as eluent to yield a solid, which was further precipitated from using isopropanol to give (S)-methyl 5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinate (0.70 g, 47% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[CH2:9][C:10]([CH3:23])([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C@H:3]1[CH2:24][CH2:25][S:26][C:27]1[S:28][CH:29]=[C:30]([C:32]([OH:34])=[O:33])[N:31]=1.[I-].[CH4:36]>>[OH:1][C@H:2]1[CH2:6][CH2:5][C@H:4](/[CH:7]=[CH:8]/[CH2:9][C:10]([CH3:23])([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C@H:3]1[CH2:24][CH2:25][S:26][C:27]1[S:28][CH:29]=[C:30]([C:32]([O:34][CH3:36])=[O:33])[N:31]=1
Reactant: C
Reactant: CCCCCC(C)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)O)cs1)OC1CCCCO1
Agent: [I-]
Product: CCCCCC(C)(C/C=C/[C@H]1CC[C@H](O)[C@@H]1CCSc1nc(C(=O)OC)cs1)OC1CCCCO1

Procedure:
By the same procedure as the reaction of Example 51 using the compound 55 instead of the compound 50 and using methane iodide instead of ethane iodide, the title compound having the following physical data was obtained.