Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][N:16]([CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:15][N:16]([CH3:24])[C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[NH:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: CN(C)c1cccc(N)c1
Product: Cc1cc(Nc2cccc(N(C)C)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and N,N-dimethyl-m-phenylenediamine (51 mg, 0.243 mmol) similar to Example 13 and isolated as a dark green oil (49 mg, 66%). 1H NMR (CDCl3): 8.82-8.79 (m, 1H), 8.47 (d, J=7.8 Hz, 1H), 7.84-7.78 (m, 1H), 7.37-7.21 (m, 3H), 6.68-6.66 (m, 3H), 6.58-6.54 (m, 1H), 2.96 (s, 6H), 2.46 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:14].Br[C:16]1([C:20]([O:22]CC)=[O:21])[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:14][C:16]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17]1
Reactant: CCCC(=O)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OC2(C(=O)O)CCC2)c(Cl)c1Cl
Temperature: 65 °C

Procedure:
A mixture of 2,3-dichloro-4-butyrylphenol (7 g, 0.03 mole), ethyl 1-bromocyclobutanecarboxylate (10.23 g, 0.049 mole) and potassium carbonate (7.5 g, 0.054 mole) in N,N-dimethylformamide (60 ml) was stirred and heated at 65° C. for 18 hours. The reaction mixture was poured into ice water and the resulting mixture was extracted with ether. The ether extract was washed with a 1% sodium hydroxide solution, then with water and finally dried over MgSO4. The ether was evaporated in vacuo and the residue treated with acetic acid (60 ml) and 5% hydrochloric acid (15 ml). The mixture was stirred and refluxed overnight. The solvents were evaporated in vacuo. The residue was chromatographed over a column containing silica gel (140 g) using methylene chloride/tetrahydrofuran/acetic acid 50/1/1 as the eluent. The pertinent fractions were united, treated with toluene and evaporated in vacuo to obtain 1-(2,3-dichloro-4-butyrylphenoxy)cyclobutane-1-carboxylic acid as a liquid whose identity was confirmed by NMR and purity by thin layer chromatography.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].B.[OH-:10].[Na+].OO>O.O1CCCC1>[CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: [OH-]
Reactant: C=CCCCCC=C
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCCCO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture containing 1.7 liter of anhydrous tetrahydrofuran (distilled from sodium/benzophenone ketyl) and 600 g (5.4 mol) of distilled 1,7-octadiene (Aldrich Chemical Co. Inc.) was prepared under nitrogen. Borane in tetrahydrofuran (1 M, 600 ml, 0.60 mol) was added dropwise to the mixture over a 1.0 hr period while the mixture was maintained at 25° C. The resultant solution was stirred for 1 hr at room temperature and then 25 ml of water was added thereto followed by 300 ml of 3 M sodium hydroxide. These additions were followed by 300 ml of 30% aqueous hydrogen peroxide while maintaining the mixture at 30° to 40° C. The mixture was stirred for 15 min and the phases which formed were separated. The aqueous phase was extracted 3 times with an equal volume of pentane. The combined pentane extracts were washed with 200 ml of 10% aqueous sodium bisulfite, then with saturated aqueous sodium chloride and then dried over magnesium sulfate. The mixture was filtered and the filtrate was evaporated and distilled to yield the title compound (bp 62°-64° C., 20 mm) as a colorless oil having the following physical characteristics:
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a mixture of ethyl 3-{[(6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-3-yl)carbonyl]amino}propanoate (366 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (287 mg, 83%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([NH2:29])[CH2:5][C:6]1[C:15]([CH2:16][P:17]([O:22]CC)([O:19]CC)=[O:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:27][CH3:28])=[C:11]([O:25][CH3:26])[CH:12]=2)[N:7]=1>Cl>[NH2:29][CH:4]([CH2:5][C:6]1[C:15]([CH2:16][P:17]([OH:19])([OH:22])=[O:18])=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:27][CH3:28])=[C:11]([O:25][CH3:26])[CH:12]=2)[N:7]=1)[C:3]([OH:30])=[O:2]
Reactant: CCOP(=O)(Cc1cc2cc(OC)c(OC)cc2nc1CC(N)C(=O)OC)OCC
Agent: Cl
Product: COc1cc2cc(CP(=O)(O)O)c(CC(N)C(=O)O)nc2cc1OC

Procedure:
α-Amino-3-(diethylphosphonomethyl)-6,7-dimethoxy-2-quinolinepropanoic acid methyl ester (0.09 g, 0.2 mmol) was refluxed in 6M HCl (15 ml) for 6 h. The mixture was concentrated and dissolved in water. After removal of some undissolved material by filtration, 38 mg of the title compound, α-amino-6,7-dimethoxy-3-(phosphonomethyl)-2-quinolinepropanoic acid was precipitated by addition of acetonitrile. 1H NMR(D2O, 400 MHz: δ 3.22 (dd, 2H), 3.66 (m, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 4.15 (m, 1H), 7.22 (s, 1H), 7.37 (s, 1H), 8.53 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1)[CH2:5][N:6]1[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]1.[CH3:20][C:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)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>[CH3:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)[CH2:5][N:6]2[CH2:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7]2)[CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)C1CN(Cc2cc(Br)cc([N+](=O)[O-])c2)C1
Reactant: Cc1cc(B(O)O)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2cc(-c3ccnc(C)c3)cc([N+](=O)[O-])c2)C1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 59.8 %

Procedure:
To a rt solution of 79.D (2.42 g, 7.4 mmol) and 2-methylpyridin-4-ylboronic acid (available from CombiPhos Catalysts, Inc.) (2.52 g, 18.4 mmol) in DMF (22 mL) was added saturated aqueous Na2CO3 (5 mL) followed by bis(triphenylphosphine)palladium(ii) chloride (265 mg, 0.37 mmol) After being purged with N2 for 15 mins, the mixture was stirred at 50° C. under N2 atmosphere for 3.5 hrs. The reaction solution was cooled, diluted with water (35 mL), treated with acetic acid to pH=7, and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, brine dried over MgSO4, and filtered. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-6% MeOH/CH2Cl2 for elution gave the title product 79.E as pale yellow solid (1.51 g, 60%).
Reaction SMILES: C(NC(C)C)(C)C.[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])[CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[I:24]I>O1CCCC1>[F:8][C:9]1[C:10]([CH:15]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])[CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[I:24]
Reactant: Cc1ccc(C)n1C(C)c1ncccc1F
Reactant: II
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C)n1C(C)c1nccc(I)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A dry 250 ml 3-neck roundbottom flask equipped with a thermometer, rubber septum, magnetic stirrer, and nitrogen inlet was charged with 30 ml of anhydrous tetrahydrofuran and 2.1 ml (14.67 mmole) of dry diisopropylamine. The stirring solution was cooled to −78° C. After which 9.5 ml (15.11 mmole) of 1,6 n-butyllithium in hexanes was added over 10 minutes by syringe. The solution was stirred 30 minutes longer and 3.2 g (14.67 mmole) of N-[(3-Fluoropyrid-2-yl)eth-2-yl]-2,5-dimethylpyrrole in 30 ml of dry tetrahydrofuran was added dropwise via syringe over 30 minutes, keeping the internal temperature below −65° C. After stirring 30 minutes longer, a solution of 4.0 g (15.80 mmole) of iodine in 30 ml of dry tetrahydrofuran was added by canula over 10 minutes. The mixture was warmed to room temperature (a color change, quenching, occurred at −30° C.) and stirred overnight under nitrogen. The solution was diluted to 200 ml with ethyl ether, extracted with aqueous saturated sodium bicarbonate (IX), brine (IX), and dried over sodium sulfate. Filtration and concentration gave a dark solid which was purified by flash silica gel chromatography (20% ethyl acetate in hexanes) to give the titled compound as a white solid, 3,9 g (77%): mp 156-158° C.; IR (KBr, cm−1) 3000, 2950, 1574, 1408, 752; 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, 1H) 7.85 (t, 1H), 5.60 (s, 2H), 4.05 (t, 2H), 3.00 (dt, 2H), 2.10 (s, 6H); MS (FD) m/e 344 (Mt). Anal. Calc'd. for C13H14FIN2: C, 45.37; H, 4.10; N, 8.14. Found: C, 45.07; H, 4.03; N, 8.06.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=1[CH:11]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:1](=[O:8])[O:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(F)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: O=C1OC(c2cc(F)ccc2OCc2ccccc2)c2ccccc21
Temperature: -78 °C
Reaction time: 18 h

Procedure:
To the Grignard Solution A cooled to −78° C., a solution of 2-benzyloxy-5-fluoro-benzaldehyde (879 mg, 3.82 mmol, 1.0 eq.) in THF (10 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour and further at r.t. for 18 hours. The reaction was carefully quenched with 1M aq. NH4Cl soln. (50 mL) and AcOEt (100 mL) was added. The resulting suspension was filtered through celite and the filter cake was rinsed with water and AcOEt. The layers were separated and the aq. phase was extracted with AcOEt (2×150 mL). The comb. org. phases were washed with sat. aq. NaCl soln. (1×100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane to Heptane+45% AcOEt) to yield (±)-3-(2-benzyloxy-5-fluoro-phenyl)-3H-isobenzofuran-1-one as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH:1]1([C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:28]5[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)(=[O:25])=[O:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:9]([CH3:27])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)Cl)cc3)nc21
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(S(=O)(=O)N4CCCNCC4)cc3)nc21
Yield: 37 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 181 was used in place of the compound obtained in Example 48, and homopiperazine was used in place of N-methylpiperazine. In this manner, 64 mg (37%) of the captioned compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](SC)[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(O)(=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[C:8]3[C:9](=[CH:11][S:12][CH:13]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccc(Cl)cc2Nc2cscc21
Solvent: CC(=O)O
Product: CN1CCN(C2=Nc3ccc(Cl)cc3Nc3cscc32)CC1

Procedure:
A solution of 0.7 g. of 6-chloro-10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine in 3.5 ml. of N-methylpiperazine is treated with 1-2 drops of glacial acetic acid and heated undr reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled, and made alkaline with concentrated ammonium hydroxide. The precipitate is collected, washed with water and recrystallized from acetone-petroleum ether (30°-60°C.) to give yellow crystals, m.p. 148°-149°C. (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]3[C:12]([C:15]4[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)=[CH:2]1.ClC(Cl)(Cl)C[O:26][C:27](=O)[NH:28][C:29]1[N:30]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:34]([C:32]1[CH:33]=[C:29]([NH:28][C:27]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([C:3]5[CH:4]=[CH:5][S:1][CH:2]=5)=[CH:7][C:8]4=[N:14][CH:13]=3)=[CH:16][CH:17]=2)=[O:26])[N:30]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:31]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: NCc1ccc(-c2cnc3cc(-c4ccsc4)ccn23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2ccc(-c3cnc4cc(-c5ccsc5)ccn34)cc2)cc1
Temperature: 62 °C
Yield: 21.6 %

Procedure:
Dissolve 4-(7-thien-3-yl-imidazo[1,2-a]pyridin-3-yl)-benzylamine (0.058 g, 0.19 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.093 g, 0.23 mmol) and diisopropylethylamine (0.071 g, 0.55 mmol) in DMSO (3.6 mL). Heat the mixture at 62° C. for 8 hours. After evaporation of solvent, dilute the reaction with water and ethyl acetate. Extract the water phase with ethyl acetate and wash the combined organic layers with saturated aqueous saturated sodium chloride and evaporate to dryness. Purify the residue by silica gel column chromatography (dichlromethane/ethyl acetate gradient) to give 0.023 g (21% yield) of desired compound: MS(ES), m/z 561 (M+1).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([C:36](C)(C)[O:37][SiH2]C(C)(C)C)[CH:30]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:45])[N:25]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][OH:37])[CH:30]=1)[CH3:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(CCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CCc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
TBAF (1M in THF, 2.90 mL, 2.90 mmol) was added to a sol. of {2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (600 mg, 1.45 mmol) in THF (14.2 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc was added, and the mixture was washed with aq. sat. NH4Cl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (435 mg, quantitative yield). LC-MS: tR=0.93 min.
Reaction SMILES: CS([O-])(=O)=O.N[C:7]1[N:15]=[C:14]([C:16]#[C:17][C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:13]=[C:12]2[C:8]=1[N:9]=[C:10]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[N:11]2[CH3:25].N(OCCC(C)C)=O>O1CCCC1>[F:32][C:28]1[CH:27]=[C:26]([C:10]2[N:11]([CH3:25])[C:12]3[C:8]([N:9]=2)=[CH:7][N:15]=[C:14]([C:16]#[C:17][C:18]2([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[N:13]=3)[CH:31]=[CH:30][CH:29]=1
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCCC3)nc21
Agent: CC(C)CCON=O
Agent: CS(=O)(=O)[O-]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2cnc(C#CC3(O)CCCCC3)nc21

Procedure:
A methanesulfonate (470 mg) prepared from 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclohexanol by a conventional method was dissolved in 25 ml of tetrahydrofuran, 0.44 ml of isoamyl nitrite was added thereto and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated to dryness and purified by a silica gel column (eluting with dichloromethane:methanol=95:5) to give 20 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].O.[Cl:10][C:11]([Cl:15])([Cl:14])[CH:12]=[O:13].C(N(CC)CC)C>C(Cl)CCl>[OH:1][C:2]1[CH:7]=[C:6]([CH:12]([OH:13])[C:11]([Cl:15])([Cl:14])[Cl:10])[CH:5]=[CH:4][C:3]=1[OH:8]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To the solution of 440 g of 1,2-dihydroxybenzene dissolved in 1L of ethylene dichloride was added 1036 g of trichloroacetaldehyde monohydrate and then the reaction solution was cooled down to 0° C. 102 g of triethylamine was slowly added dropwise thereto. The reaction solution was warmed to normal temperature, stirred for about 20 minutes, heated to 50° C. and then stirred for further 3 hours while maintaining the same temperature. After the reaction is completed, the reaction mixture was distilled under reduced pressure to remove ethylene dichloride. The residue was dissolved in 4L of ethylacetate, washed successively with 2400 ml of 0.5N-aqueous hydrochloric acid solution and 2L of saturated saline solution, dried over anhydrous magnesium sulfate and then distilled under reduced pressure to remove the solvent to obtain 540 g of the title compound.
Reaction SMILES: C[O:2][PH:3]([CH2:5][CH:6]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[OH-].[Na+]>CO.O>[OH:4][PH:3]([CH2:5][CH:6]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])=[O:2]
Reactant: CO[PH](=O)CC(CCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)C(CCc1ccccc1)C[PH](=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of benzyl 2-((methoxyphosphinyl)methyl)-4-phenylbutanoate (4.02 g, 11.6 mmol) in methanol (20 mL) was cooled in an ice bath and 2.5N aqueous sodium hydroxide (5.1 mL. 12.8 mmol) was added over 10 min. The resulting solution was stirred at 0° C. for 45 min before being diluted with water (150 mL) and washed with a mixture of ether (75 mL) and hexane (25 mL). The aqueous layer was washed with hexane (75 mL), acidified by the addition of 2N aqueous hydrochloric acid (20 mL), and extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were washed in succession with saturated aqueous sodium chloride (50 mL), dried (sodium sulfate), decanted, and evaporated. The residue was dried overnight under vacuum to give crude (±)-benzyl 2-((hydroxyphosphinyl)methyl)-4-phenylbutanoate as 3.67 g of colorless oil (95% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[N+:23]([O-])=O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH2:23])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Oc3cc(C)ccc3[N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Oc3cc(C)ccc3N)cccc2[nH]1
Reaction time: 3 h

Procedure:
134 (1.3 g, 3.82 mmol) is dissolved in 250 ml of ethyl acetate and, after addition of Pd—C (200 mg), the mixture is hydrogenated at room temperature for 3 hours. The mixture is filtrated over celite to remove the catalyst and evaporated.
Reaction SMILES: CC([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[C:15](=[O:17])[O-:16])(C)C.[CH:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27]>>[CH2:7]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:6]1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH:26]=[O:27])[CH:33]=2)=[CH:21][CH:20]=1)[C:15](=[O:17])[O:16][C:8]([CH3:13])([CH3:9])[CH3:7]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)C1c2ccccc2CC1N(Cc1ccc(Br)cc1)C(=O)[O-]
Product: CC(C)(C)OC(=O)N(Cc1ccc(-c2cccc(C=O)c2)cc1)C1Cc2ccccc2C1

Procedure:
The title compound was prepared from 1,1-dimethylethyl[(4-bromophenyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate (Example V-13) and 3-formylphenylboronic acid according to the procedure described in Example VI-16 Step 1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (s, 9H), 3.00 (d, J=8.56 Hz, 4H), 4.51 (br. s., 2H), 7.06-7.19 (m, 4H), 7.34 (d, J=8.03 Hz, 2H), 7.69 (t, J=7.67 Hz, 1H), 7.72-7.77 (m, 2H), 7.86-7.91 (m, 1H), 8.01-8.06 (m, 1H), 8.19-8.24 (m, 1H), 10.10 (s, 1H).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])=[O:27])[CH2:20]2.Cl[C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=[CH:39][N:38]=1>>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:37]2[N:42]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[CH:39][N:38]=2)[CH2:20]1)=[O:27]
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: COc1ccccc1C(=O)N1CC2CNC2C1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: COc1ccccc1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 22 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C23H22N4O, 386.46; m/z found, 387.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[N:9][N:10]([CH2:12][CH2:13][O:14]C3CCCCO3)[CH:11]=2)=[CH:3][CH:2]=1.C(Cl)Cl>>[OH:14][CH2:13][CH2:12][N:10]1[CH:11]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[C:8]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=3)=[O:29])[CH:24]=[CH:25][CH:26]=2)=[N:9]1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn(CCOC3CCCCO3)cc2-c2ccncc2)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(-c2nn(CCO)cc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 1-(3-{4-pyridin-4-yl-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-phenyl)-3-(4-trifluoromethyl-phenyl)-urea (50 mg, 0.09 mmol) in methylene chloride (1 mL) p-toluenesulfonic acid (PTSA) (25.8 mg, 0.13 mmol) was added, the reaction was stirred at room temperature for two days. The solvent was removed under reduced pressure and the product was isolated by silica gel column chromatography (DCM/methanol 93:7).