Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:21]2[CH:20]=[C:19](B(O)O)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:33][C:34]1[CH:46]=[CH:45][C:44]2[C:43]3[C:38](=[CH:39][C:40](Br)=[CH:41][CH:42]=3)[C:37]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:36]=2[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:33][C:34]1[CH:35]=[C:36]2[C:44]([C:43]3[CH:42]=[CH:41][C:40]([C:19]4[CH:18]=[CH:17][C:16]5[C:15]6[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=6)[C:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:21]=5[CH:20]=4)=[CH:39][C:38]=3[C:37]2([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:45][CH:46]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(B(O)O)cc21
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCCCCCCC)(CCCCCCCC)c3cc(Br)ccc3-4)cc21
Temperature: 90 °C
Reaction time: 48 h
Yield: 63.8 %

Procedure:
A mixture of 9,9-bis(n-octyl)fluoren-2-yl-boronic acid (2a) (2.0 g, 4.60 mmol), 2,7-dibromo-9,9-bis(n-octyl)fluorene (3a) (4.0 g, 7.32 mmol), Pd(PPh3)4 (50 mg, 0.043 mmol), Na2CO3 (2.0 M aqueous solution, 12.0 mL, 24.0 mmol), and toluene (20 mL) is stirred at 90° C. for 2 days. After the mixture is cooled to room temperature, 200 mL of petroleum ether is added to the reaction mixture. The organic portion is separated and washed with brine before drying over anhydrous MgSO4. The solvent is evaporated off, and the solid residues are purified by column chromatography on silica gel with petroleum ether to afford 7-bromo-9,9,9′,9′-tetra-n-octyl-2,2′-bifluorene (4a) as a white solid (2.52 g, 66%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:36][O:37][C:38]([C:40]1[C@@H:41]2[N:55]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:44]([CH2:45][C:46]=1OS(C(F)(F)F)(=O)=O)[CH2:43][CH2:42]2)=[O:39]>CCO.O.C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:36][O:37][C:38]([C:40]1[C@@H:41]2[N:55]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C@H:44]([CH2:45][C:46]=1[C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:43][CH2:42]2)=[O:39]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Br)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1=C(c2ccc(Br)nc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 40.4 %

Procedure:
6-Bromopyridine-3-boronic acid (5.00 g, 24.8 mmol), Pd(OAc)2 (278 mg, 1.24 mmol) and PPh3 (650 mg, 2.48 mmol) were suspended in EtOH (67 mL). A sol. of Na2CO3 (3.15 g, 29.7 mmol) in water (25.3 mL) was added. A sol. of compound A1 (10.3 g, 24.8 mmol) in THF (25 mL) was added, and the mixture was heated to reflux for 4 h. 6-Bromopyridine-3-boronic acid (5.00 g, 24.8 mmol) was added again, and 1 h later Pd(OAc)2 (278 mg, 1.24 mmol) and PPh3 (650 mg, 2.48 mmol) and Na2CO3 (3.15 g, 29.7 mmol) were added. The mixture was stirred at reflux for 1 h, and was allowed to cool to rt. The solvents were removed under reduced pressure. EtOAc was added, and the mixture was washed with aq. sat. NaHCO3 (2×), with aq. sat. NH4Cl, and with brine. The org. layer was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 20:80) yielded the title compound (4.24 g, 40%). LC-MS: tR=1.01 min, ES+: 423.19.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([NH:5][C:6]1[C:7]2[N:14]=[N:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1)=[O:4].[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:5]([C:6]1[C:7]2[N:14]=[N:13][N:12]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[C:8]=2[N:9]=[CH:10][N:11]=1)[C:3](=[O:4])[CH:2]([CH3:15])[CH3:1]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)C(=O)Nc1ncnc2[nH]nnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)N(COCC[Si](C)(C)C)c1ncnc2c1nnn2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide (3, 1.5 g, 7.27 mmol) in dimethylformamide (20 mL), sodium hydride (0.26 g, 10.91 mmol) was added portion wise in 10 min at 0° C. The above suspension was stirred for 10 min at 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (1.82 g, 10.91 mmol) was added at the same temperature under nitrogen. The reaction was stirred at room temperature for 6 h. After completion, the reaction mass was quenched with saturated aqueous solution of ammonium chloride and crude was extracted with dichloromethane (2×50 mL). The organics were then separated, dried (magnesium sulfate) and concentrated to dryness under vacuum and the crude was purified by flash chromatography eluting with 5% ethyl acetate in hexane. Concentration of the desired fractions provides 2-methyl-N-(2-trimethylsilylethoxy)-N-[3-(2-trimethylsilylethoxyl)triazolo[4,5-d]pyrimidin-7-yl]propanamide (4) as transparent viscous oil. Yield: 1.1 g, 44%; MS (ESI) m/z 467.42 [M+1]+.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[F:20][C:21]1[CH:43]=[CH:42][C:24]([CH2:25][NH:26][C:27]([C:29]2[S:33][C:32]([C:34]3[CH:39]=[N:38][CH:37]=[C:36](I)[N:35]=3)=[N:31][C:30]=2[CH3:41])=[O:28])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:43]=[CH:42][C:24]([CH2:25][NH:26][C:27]([C:29]2[S:33][C:32]([C:34]3[CH:39]=[N:38][CH:37]=[C:36]([N:12]([CH3:11])[CH2:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[N:35]=3)=[N:31][C:30]=2[CH3:41])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: CNCc1ccncc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccncc3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 78 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with methyl-pyridin-4-ylmethyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide, the title compound was obtained in 78% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.63 (s, 1H), 8.51 (d, J=8.0 Hz, 2H), 8.14 (s, 1H), 7.27-7.36 (m, 4H), 6.99-7.08 (m, 2H), 6.18 (bs, 1H), 4.86 (s, 2H), 4.54 (d, J=4.0 Hz, 2H), 3.21 (s, 3H), 2.68 (s, 3H); MS (ES+) m/z 449.2 (M+1), Rt=1.30 min.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[NH:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].[CH2:28]1[O:30][CH2:29]1.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>CC#N>[CH3:4][C:2]([O:5][C:6](=[O:27])[C@H:7]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[N:8]([CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:28][CH2:29][OH:30])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Reactant: C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN(CCO)[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: -80 °C
Yield: 77.3 %

Procedure:
In a four-necked flask cooled to −80° C. equipped with a mechanical stirrer, a thermometer, and a jacketed dropping funnel N-[2-(1,1-dimethylethoxy)-2-oxoethyl]-L-tryptophan 1,1-dimethylethyl ester (5 g; 13.35 mmol) was dissolved in CH3CN (25 mL). In the dropping funnel, cooled at −80° C., ethylene oxide (13 mL; 0.26 mol) was collected from the cylinder and then quickly dropped into the solution. Solid ytterbium triflate (0.83 g; 1.34 mmol) was added and after removal of the cooling bath the temperature was allowed to rise to r.t. The reaction was monitored by HPLC (Chromatographic method of Example 3, A)). After 15 h the solution was diluted with H2O (50 mL) and extracted with Et2O (150 mL). After evaporation of the solvent the crude was purified by flash chromatography (silica gel; n-hexane/ethyl acetate, 7:3 v/v) giving the desired product (4.32 g; 10.32 mmol).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=O)[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]1[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[O:1]=[C:2]1[CH2:6][CH2:5][C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:3]1[CH:17]=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(=O)CC1
Reaction time: 4 h

Procedure:
6 Parts of 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid is dissolved in 71 parts of ethanol and cooled to about 10° as 1.88 parts of triethylamine is added. The solution is stirred as 1.5 parts of sodium borohydride dissolved in 100 parts of water is added dropwise at 10°-15°. After stirring at about 15° for 4 hours, the mixture is acidified with dilute aqueous acetic acid and the oily precipitate is extracted with ethyl acetate. The organic solution is washed with dilute aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to an orange oil. Then the oil is taken up in benzene and chromatographed on silicic acid as the column is eluted with benzene containing increasing amounts of ethyl acetate. A fraction eluted with 30% ethyl acetate is crystallized from ethyl acetate-hexane to give pale yellow crystals of 3-oxo-2-styrylcyclopent-1-eneheptanoic acid, melting at about 118°-120°. That compound displays, in chloroform, absorption peaks in the infrared spectrum at about 2940 and 1700 reciprocal centimeters and an absorption band, in methanol, in the ultraviolet spectrum at about 288 millimicrons with a molecular extinction coefficient of about 24,400. That compound is represented by the following structural formula ##SPC18##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[N:9](COCC[Si](C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[OH-].[Na+]>FC(F)(F)C(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]2[C:26]([CH3:39])=[CH:27][C:28]([O:31][CH2:32][C:33]([CH3:37])([CH3:38])[C:34]([OH:36])=[O:35])=[N:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[CH:10][N:9]=1
Reactant: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(C(F)(F)F)[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.9 %

Procedure:
In trifluoroacetic acid (1.0 mL) and water (0.05 mL) was dissolved 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (268 mg), and the solution was stirred at room temperature for 10 hours. The solution was neutralized by adding 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with a saturated brine, and the organic layer was separated and concentrated under reduced pressure. Ether was added to the obtained residue, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 3-[(5-{3-chloro-4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (133 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:4]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([O:26][CH3:27])[CH:18]=2)[N:3]=1.O.NN>C(O)C.O1CCCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:4]2[C:5]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:14])=[O:15])=[CH:11][CH:12]=3)=[CH:6][C:2]([Cl:1])=[N:3]2)=[CH:18][C:19]=1[O:26][CH3:27]
Reactant: COc1cc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-n2nc(Cl)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1N
Yield: 98.3 %

Procedure:
To a solution of 3-chloro-1-(3-methoxy-4-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (900 mg) in ethanol (30 ml) and tetrahydrofuran (30 ml) were added active carbon (3 g), hydrazine monohydrate (2 ml) and ferric chloride (50 mg). The mixture was refluxed for 2 hours, and filtered. The filtrate was evaporated in vacuo and partitioned between water and dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give 1-(4-amino-3-methoxyphenyl)-3-chloro-5-[4-(methylsulfonyl)phenyl]pyrazole (820 mg).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH:18]([CH3:20])[CH3:19].O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:18]([C:6]1[N:5]([CH2:4][CH:3]=[O:2])[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cccc2nc(C(C)C)n(CC=O)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate from Step A above in methylene chloride and water was added trifluoroacetic acid and the reaction was stirred at room temperature for 1.5 h and then heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure to remove the excess trifluoroacetic acid, diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure to give methyl 2-isopropyl-1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate: 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.87 (dd, J=8.1, 0.9 Hz, 7.68 (dd, J=7.5, 0.9 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 5.44 (s, 2H), 3.84 (s, 3H), 3.22-3.17 (m, 1H), 1.34-1.27 (m, 6H); MS (ESI+) m/z 261 (M+H).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH2:6])=[O:5])[NH2:3].[F:7][CH:8]([F:12])[C:9](O)=O>C1(C)C=CC=CC=1>[F:7][CH:8]([F:12])[C:9]1[NH:6][C:4](=[O:5])[N:2]([CH3:1])[N:3]=1
Reactant: O=C(O)C(F)F
Reactant: CN(N)C(N)=O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)[nH]c1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.5 %

Procedure:
20 ml of toluene was added to 500 mg (5.61 mmol) of 2-methyl semicarbazide (produced in the same manner as in Reference Production Example 6), and to this mixture was added 808 mg (8.41 mmol) of difluoroacetic acid, and the mixture was stirred for 10 hours under reflux with heating. The reaction solution was cooled to room temperature, then, concentrated, and the residue was subjected to silica gel thin layer chromatography (eluant: chloroform/methanol=9/1 (v/v)), to obtain 305 mg of 5-difluoromethyl-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one having a melting point of 141.2° C. in the form of colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 5 ml of acetonitrile is mixed with 145 mg (0.73 mmol) of (3-bromopropyl)benzene and 100.76 mg (0.73 mmol) of potassium carbonate and then stirred under reflux for 12 h. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. 278 mg (0.45 mmol, 93% of theory, content 86%) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.FC(F)(F)C(O)=O.[CH3:32][NH:33][C:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]1)=[O:35].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:38]3[CH2:39][CH2:40][CH2:41][C@@H:36]([C:34]([NH:33][CH3:32])=[O:35])[CH2:37]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: CNC(=O)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
In a 2 mL microwave vial were placed N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 437 mg, 1.3 mmol) and (R)—N-methylpiperidine-3-carboxamide, trifluoroacetate salt (585 mg, 2.2 mmol). To the sealed vial were then added NMP (6 ml) and diisopropylethylamine (0.67 ml, 3.85 mmol), and the mixture was then heated in the microwave at 100° C. for 15 minutes. After cooling to room temperature, the reaction mixture was filtered by syringe filter and was then directly purified by preparatory HPLC (25-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder (510 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ=10.96 (br. s., 1H), 8.11 (br. s., 1H), 8.00 (d, J=8.1 Hz, 3H), 7.61 (d, J=8.1 Hz, 2H), 7.35 (s, 1H), 6.39 (br. s., 1H), 4.48-4.25 (m, 2H), 3.29 (t, J=11.1 Hz, 1H), 3.08 (br. s., 1H), 2.61 (s, 3H), 2.60 (m, 1H), 2.08 (s, 1H), 1.94 (br. s., 1H), 1.83 (br. s., 1H), 1.73 (br. s., 2H), 1.46 (s, 6H); ESI-MS: m/z 437.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[NH2:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[S:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:12]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[S:14][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3F)cs2)CC1
Yield: 26.4 %

Procedure:
A solution of 2-bromo-1-(2-fluorophenyl)ethanone (977 mg, 4.50 mmol), tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.0 g, 4.09 mmol) and potassium carbonate (1.13 g, 8.18 mmol) in dimethylformamide (30 ml) was stirred at 110° C. for 1 hour. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the desired product (391 mg, 26.3%) as an oil.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH:18]([C:20]1[N:25]2[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]2[CH:23]=[CH:22][CH:21]=1)=[O:19]>C1(C)C=CC=CC=1>[CH2:3]([O:2][P:1]([CH:18]([OH:19])[C:20]1[N:25]2[CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=[C:24]2[CH:23]=[CH:22][CH:21]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)c1cn2c(C=O)cccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(C(O)P(=O)(OCC)OCC)cccc2n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
Diethyl phosphite (1.7 g, 12.3 mmol, Aldrich), N,N-diisopropylethylamine (1.63 g, 12.4 mmol, Aldrich) and toluene (60 mL) were combined in a 100 mL flask equipped with a N2 inlet and condensor. After warming this solution to 60° C., the product from Example 54 was added. After stirring at 75°-80° C. for 3 h, all solvent was removed from this mixture and the residue was chromatographed (7.5/92.4/0.1 isopropanol/CH2Cl2 /HOAc) to give 1.2 g (66%) of the title product.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(C#CCO)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)c(CCCO)cn1
Reaction time: 4 h

Procedure:
655 mg of dimethyl 5-(3-hydroxy-1-propinyl)-pyridine-2,4-dicarboxylate (Example 10) are dissolved in 50 ml of methanol and, after addition of the palladium catalyst (10% strength on charcoal) are hydrogenated. The reaction has ended after 4 hours (thin layer control). The catalyst is filtered off and the solution is concentrated in vacuo. The colorless oil is chromatographed on silica gel.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:17][C:18]1([CH3:30])[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH2:29])[CH:26]=[CH:25][CH:24]=2)[CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C:18]1([CH3:30])[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH:29][C:2]3[C:3]4[N:4]([CH:14]=[CH:15][N:16]=4)[N:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:7]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CC1(C)CCN(c2cccc(N)n2)C1
Reactant: Brc1cc(-c2ccccc2)nn2ccnc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)CCN(c2cccc(Nc3cc(-c4ccccc4)nn4ccnc34)n2)C1
Temperature: 100 °C
Yield: 25.3 %

Procedure:
A mixture of 8-bromo-6-phenylimidazo[1,2-b]pyridazine (0.10 g, 0.37 mmol), 6-(3,3-dimethyl pyrrolidin-1-yl)pyridin-2-amine (0.084 g, 0.44 mmol), Pd2(dba)3 (21 mg, 0.037 mmol), BINAP (92 mg, 0.148 mmol) and Cs2CO3 (0.362 g, 1.11 mmol) in dioxane (10 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated and the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:10) to afford N-(6-(3,3-dimethylpyrrolidin-1-yl)pyridin-2-yl)-6-phenylimidazo[1,2-b]pyridazin-8-amine (36 mg, 26%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.68 (s, 1H), 8.87 (s, 1H), 8.19 (d, 1H, J=1.2 Hz), 7.95-7.92 (m, 2H), 7.64 (s, 1H), 7.53-7.40 (m, 4 h), 6.72 (d, 1H, J=7.8 Hz), 6.02 (d, 1H, J=8.1 Hz), 3.51 (t, 1H, J=6.9 Hz). 3.30 (s, 2H), 1.81 (t, 2H, J=6.9 Hz), 1.13 (s, 6H). LC-MS: [M+H]+, 385, tR=2.099 min, HPLC: 96.88% at 214 nm, 97.82% at 254 nm, tR=8.077 min.