Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([C:23]1[S:27][C:26](C=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N+](C1C=C([N+]([O-])=O)C=CC=1S(O)(=O)=O)([O-])=O.C1(C)C=CC=CC=1>O>[CH2:15]([C:23]1[S:27][C:26](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH2:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(C=O)s1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)O)c([N+](=O)[O-])c1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC1=CCC(=Nc2ccc(CCC(=O)OCC)cc2)S1

Procedure:
A solution of 8.6 g. ethyl 4-aminohydrocinnamate, 9.77 g. 5-octyl-2-thiophenecarboxaldehyde and a few crystals of 2,4-dinitrobenzenesulfonic acid in 250 ml. toluene is refluxed under a Dean-Stark trap for 17 hours, whereupon the theoretical amount (0.8 ml.) water has been collected. The toluene is evaporated to yield ethyl 3-[4-(5-octyl-2-thienylideneamino)phenyl]propionate as a crystalline mass.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[O:45]=[C:46]1[CH2:51][CH2:50][CH2:49][CH:48]([C:52](O)=[O:53])[CH2:47]1>C(OCC)(=O)C.CN(C=O)C>[CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:52]([CH:48]2[CH2:49][CH2:50][CH2:51][C:46](=[O:45])[CH2:47]2)=[O:53])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(NC(=O)C2CCCC(=O)C2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
4-Isopropoxyaniline (117 mg, 0.774 mmol), HATU (294 mg, 0.774 mmol) and diisopropylethylamine (0.27 mL, 1.548 mmol) were added in that order to a DMF (3 mL) solution of 3-oxo-1-cyclohexanecarboxylic acid (100 mg, 0.703 mmol), and stirred at room temperature for 5 hours. Ethyl acetate was added to the reaction liquid, and washed with distilled water and saturated brine. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give the intended product (194 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.C([O-])=O.[NH4+]>[Pd].CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)(=[O:17])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:28][CH:29]=1
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a clear solution of methyl 3-[(4-methoxyphenethyl)-(3-nitrobenzenesulfonyl)-amino]-propionate in 5/1 methanol/ethyl acetate (30 mL) was added 10% Pd/C (300 mg) and ammonium formate (1.79 g, 28.4 mmol). After being stirred at room temperature for 24 h, the catalyst was filtered off through a pad of celite and the filtrate was concentrated. The residue was partitioned between methylene chloride (100 mL) and water (100 mL). Aqueous layer was extracted with another 100 mL of methylene chloride. Combined organic layer was washed with water (100 mL) and brine, dried over Na2SO4, filtered, and concentrated to give methyl 3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)-amino]-propionate (2.8 g, 7.1 mmol) as a yellow gummy product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](Cl)=[O:20]>>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:19]([C:15]2[S:16][CH:17]=[CH:18][C:14]=2[CH3:13])=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: COC(=O)C1(N)CCCCC1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2sccc2C)CCCCC1
Yield: 46.7 %

Procedure:
581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, and 482 mg (3 mmol) of 3-methyl-2-thiophenecarbonyl chloride was used instead of phenylacetyl chloride in the process according to Reference Example 1 to obtain 394 mg (47%) of the title compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.C(OCC)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Diisopropylethylamine (0.9 ml, 5.5 mmol) was added in one portion to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in THF (10 ml) at room temperature. To this mixture was added benzyl chloroformate (0.78 ml, 5.5 mmol) drop wise and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time the mixture was diluted with ethyl acetate (50 ml) and washed with water (100 ml), saturated NaHCO3 (100 ml) and HCl (100 ml, 2M). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 50% heptane, 50% ethyl acetate) to give the title compound (1.2 g, 73% yield) as a colourless oil. Tr=2.08 min m/z (ES+) (M+Na+) 357.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18](Cl)[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:27])[C:15]=2[CH:14]=[CH:13][CH:12]=1>[Cu]>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[C:18]([NH:4][C:3]4[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=4[Cl:1])[CH:19]=[CH:20][CH:21]=3)[C:16](=[O:27])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Agent: [Cu]
Product: O=C1c2cccc(Nc3cc(Cl)ccc3Cl)c2C(=O)c2cccc(Nc3cc(Cl)ccc3Cl)c21

Procedure:
If, analogously to the above example, 2,5-dichloroaniline is condensed with 1,5-dichloroanthraquinone in the presence of a mixture of 0.5 part of copper powder and 0.5 part of copper-I chloride as the catalyst, instead of the copper-I iodide/picoline complex, only 12 parts of 1,5-bis-(2,5-dichloroanilino)anthraquinone are obtained, corresponding to a yield of only 23%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[CH3:29][C:30]1([CH3:33])[CH2:32][O:31]1.B(F)(F)F.CCOCC.[Li]C(C)(C)C>C1COCC1>[C:18]1([C:4]2[CH:3]=[C:2]([CH2:29][C:30]([OH:31])([CH3:33])[CH3:32])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CC1(C)CO1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Agent: CC(C)[Mg]Cl
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (prepared in Example 11, step (g)) (0.10 g, 0.27 mmol) in 1.5 mL of THF at −40° C. was added 0.15 mL of i-PrMgCl (0.30 mmol, 2 M solution in THF) and the solution was stirred at this temperature for 15 min. The mixture was then cooled to −78° C. and 2,2-dimethyl-oxirane (0.12 mL, 1.3 mmol) was added followed by boron trifluoride etherate (0.044 mL, 0.35 mmol) and t-BuLi (0.41 mL, 0.69 mmol, 1.7 M solution in pentane). After stirring for 30 min at −78° C. the mixture was quenched with satd NH4Cl (10 mL), extracted with EtOAc (2×10 mL) and the organic layer was dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE column with 50% EtOAc/hexanes to give 0.015 g (15%) of a white solid: 1H-NMR (DMSO-d6, 400 MHz): δ 14.25 (s, 1H), 9.71 (s, 1H), 8.33 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.14 (dd, J=8.2, 1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 5.74 (s, 1H), 4.63 (t, J=5.2 Hz, 1H), 3.61 (m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.23-2.11 (m, 4H), 1.76-1.62 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H24N4O2, 365.2 (M+H), found 365.1.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:12]=2)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:63]([CH2:65][C:66](O)=[O:67])#[N:64]>ClCCl>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([C@@H:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:66](=[O:67])[CH2:65][C:63]#[N:64])[CH2:22]3)[N:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:2]=4[F:1])=[CH:10][CH:9]=3)[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)ccc3F)cc1)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)ccc4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.5 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-[4-(2,5-difluoro-phenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (300 mg, 0.71 mmol, 1.00 equiv) in dichloromethane (30 mL), HATU (400 mg, 1.05 mmol, 1.5 equiv), triethylamine (220 mg, 2.17 mmol, 3.0 equiv), and 2-cyanoacetic acid (90 mg, 1.06 mmol, 1.5 equiv). The resulting solution was stirred for 10 h at 25° C. and then washed with water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10/1) to give 200 mg (58%) of 3-[(3R)-3-[4-amino-3-[4-(2,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[C:20](Cl)(=[O:22])[CH3:21]>C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][C:13]=1[C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1cccc(-c2ccccc2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(-c2ccccc2)ccc1C(C)=O
Yield: 97.8 %

Procedure:
52 g of SnCl4 are added dropwise at 5°, while stirring vigorously, to a solution of 36.8 g of 3-methoxy biphenyl and 15.6 g of acetyl chloride in 700 cc of benzene. The mixture is stirred over night at 23°. The reaction mixture is washed twice with 2 N sodium hydroxide and twice with water. Extraction is again effected twice with toluene. The organic phases are combined, dried over anhydrous sodium sulphate and concentrated. 44 g of a crude product are obtained, which are chromatographed on a 20-fold quantity of silica gel. Solvent for absorption and elution: methylene chloride. The crude fractions are crystallized from ether/petroleum ether, whereby 4-acetyl-3-methoxy biphenyl, having an M.P. of 74°-75°, is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.C(N(CC)[C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])C>C1COCC1>[F:28][C:27]([F:30])([F:29])[C:26]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1)=[O:31]
Reactant: CCN(CC)C(=O)C(F)(F)F
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
tert-Butyl 1-(4-bromophenyl)ethylcarbamate (6.35 g, 21.2 mmol) was dissolved in dry THF (100 ml) and cooled to −78° C. under an atmosphere of nitrogen. n-Butyllithium (21 ml, 52.9 mmol, 2.5M in hexanes) was added dropwise under 10 minutes and the reaction was stirred at −78° C. for 3 hours. A solution of diethyl trifluoroacetamide (5.0 g, 29.6 mmol) in 10 ml dry THF was added dropwise and the reaction was stirred 1.5 hours at −78° C. Reaction was quenched with NH4Cl (sat) (50 ml) and H2O (50 ml) and allowed to reach room temperature. The aqueous phase was separated and extracted with EtOAc (100 ml). The combined organics were washed with NH4Cl (sat) (2*100 ml), H2O (100 ml), dried over MgSO4, filtered and evaporated. Unreacted starting material was removed by precipitation from MeOH/H2O (9/1). The mother liquor was evaporated and the residue purified by flash chromatography using Pet. Ether/EtOAc (7:1→5:1) as eluent to give 3.09 g (46%) of the title compound as white solids.
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].CN(C=[O:25])C>>[CH2:1]([C:8]([OH:25])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)C(O)(Cc1ccccc1)C(=O)OCC
Temperature: 40 °C

Procedure:
A mixture of diethyl benzylpropanedioate (41 g) and CsF (49.8 g) in 90 mL of DMF was heated at 40° C. with vigorous air bubbling for 3 days. The resulting mixture was diluted with ethyl acetate (800 mL) and washed with water (3×1 L). The organic layer was concentrated and then purified by Biotage silica gel column chromatography (5-20% ethyl acetate in hexanes) to give the title product as a colorless oil. 1H NMR (300 MHz, CDCl3) δ: 7.22-7.26 (m, 5H), 4.23 (q, J=7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H), 1.26 (t, J=7.2 Hz, 6H).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[C:8]([C:23]#[N:24])[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].O.CP(C)C.C(OCC)(=O)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[CH:7]=[C:8]([C:23]#[N:24])[C:9]2[CH:10]=[CH:11][CH:12]=[N:13][C:14]=2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(3-fluorophenyl)quinoline-5-carbonitrile (0.020 g, 0.063 mmol) in tetrahydrofuran (0.2 mL) and water (0.0455 mL, 2.52 mmol) was added 1.0 M trimethylphosphine in tetrahydrofuran (0.076 mL, 0.076 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The LCMS of the crude, showed two peaks with the same desired mass, and was used directly in the next step (18 mg, 98%). LCMS calculated for C18H15FN3 (M+H)+: m/z =292.1; Found: 292.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([N:40]=[C:41]=[O:42])[CH:37]=[CH:38][CH:39]=1>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([O:33][CH3:32])[CH:35]=4)=[O:42])=[C:3]([F:31])[CH:4]=3)[C:16]=12
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)Nc2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2F)c1
Reaction time: 19 h

Procedure:
trans-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (77 mg, 0.182 mmol) was suspended in pyridine (1 mL). A solution of 3-methoxyphenylisocyanate (30 mg, 0.200 mmol) in pyridine (1 mL) was added to the reaction mixture and stirring was continued for 19 hours. The reaction mixture was concentrated under reduced pressure to yield the crude product as a pale yellow oil (149 mg). The crude material was purified on RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300 A, 15 μm, 40×100 mm column) to afford trans-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methoxyphenyl)urea as a white solid (76 mg, 0.133 mmol). HPLC-RT: 12.33 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=574.2.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]1([CH:28]([OH:44])[CH2:29][O:30][CH2:31][CH2:32][O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.[O:45]1[CH:50]=[CH:49][CH2:48][CH2:47][CH2:46]1>C(Cl)Cl>[C:18]1([CH:28]([O:44][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50][O:45]2)[CH2:29][O:30][CH2:31][CH2:32][O:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2cccc3ccccc23)cc1
Reaction time: 0.17 h

Procedure:
0.82 g of pyridinium p-toluenesulfonate was added to a solution of 6.3 g of 1-(1-naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 2.97 ml of 3,4-dihydro-2H-pyran dissolved in 63 ml of methylene chloride at room temperature. The resulting mixture was stirred at the same temperature for 20 minutes and further at 35°-40° C. for 10 minutes. The reaction mixture was cooled, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.53 g of colorless, oily 1-(1-naphthyl)-1-(tetrahydropyran-2-yloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:17])[N:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2O)[CH:7]=1.[OH2:18]>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:17])[N:6]([CH2:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[CH:7]=1
Reactant: O=c1ncc(Cl)cn1CCc1ccccc1O
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccccc1

Procedure:
A solution of 5-chloro-1-(2-hydroxyphenethyl)pyrimidin-2-one (251 mg) in pyridine (6 ml) was added to the stirred suspension obtained by adding chromium trioxide (408 mg) to pyridine (4 ml). After 21/2 hours the mixture was diluted with water (10 ml) and the products were extracted with ethyl acetate (150 ml). The extract was washed with N-hydrochloric acid (2×25 ml) and water (50 ml), dried (MgSO4) and evaporated to a solid (271 mg). Crystallisation of this from ethanol followed by purification of the mother liquor material by preparative-layer chromatography gave the title pyrimidinone (48 mg), whose p.m.r. spectrum (in deuteriodimethylsulphoxide) and t.l.c. characteristics were identical to those of authentic material (vide supra).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH:20]([Cl:22])[CH3:21].O>CN(C=O)C>[Cl:22][CH:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:6]1[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(Cl)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(CCCC(C)Cl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-methyl-2,4(1H,3H)-pyrimidinedione (thimine, 500 mg) and K2CO3 (548 g) in dry DMF (15 mL) was stirred for 1 hour at room temperature. 1-bromo-4-chloropentane (0.548 mL) was then added and the mixture was stirred at room temperature for 4 hours. Water was then added and the resulting mixture was extracted with dichloromethane. The aqueous phase was acidified to pH 7 with aqueous 2% HCl solution and extracted with DCM. The organic phases were dried and concentrated in vacuo. The crude product was purified by a silica SPE cartridge eluting with DCM/MeOH from 98/2 to 95/5 to give the title compound (100 mg).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:13])=[N-]>CCOCC>[CH:1]1([CH2:7][C:8]([O:10][CH3:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CC1CCCCC1
Solvent: CCOCC
Product: COC(=O)CC1CCCCC1
Temperature: 0 °C
Yield: 72.4 %

Procedure:
To an ice-cooled and stirred solution of cyclohexylacetic acid (9.34 g, 0.066 mol) in 30 ml of ether was slowly added an excess solution of diazomethane in ether. After concentration of ether, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl cyclohexylacetate (7.45 g, 0.048 mol, yield 72.4%, b.p. 86°-88° C./12 mmHg), which was assigned the structure by the following data:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][CH3:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:17]1([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:24]([CH3:23])[CH2:25][CH2:26][NH:27][CH3:28])[CH:3]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: CNCCNC
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CNCCN(C)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), N,N′-dimethyl-ethane-1,2-diamine (0.37 mL, 3.4 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-{3-[methyl-(2-methylamino-ethyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 80%) as a white solid: LC/MS m/e calcd for C22H29N3O2 (M+H)+: 368.50, observed: 368.1.