Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:9]=2)[C:4](=[O:16])[NH:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1
Reactant: FC(F)(F)c1ccncc1Br
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1c1cnccc1C(F)(F)F
Yield: 3.9 %

Procedure:
3-Methyl-7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-43d: 60 mg, 0.26 mmol) was reacted with 3-bromo-4-(trifluoromethyl)-pyridine (88 mg, 0.39 mmol), 1,4-dioxane (5 mL), copper iodide (14 mg, 0.078 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (3.7 mg, 0.026 mmol) and potassium phosphate (166 mg, 1.78 mmol) to afford the crude product. Purification by column chromatography on silica gel (1.5% methanol in CHCl3), followed by preparative HPLC afforded 3.8 mg of the product (3.8% yield).
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C)C=O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:9]2[CH2:10][CH2:11][C@H:6]([N:19]=[N+:20]=[N-:21])[CH2:7][CH2:8]2)=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](c2ccc(F)cc2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](c2ccc(F)cc2)CC1

Procedure:
A mixture of 4.22 g. of trans 4-(p-fluorophenyl)cyclohexanol methanesulfonate (obtained as in Example 17) and an equal weight of sodium azide in 45 ml. of dimethylformamide is heated at about 95° C. for about 12 hours. The mixture is taken to dryness on a rotary evaporator and the residue dissolved in water and benzene. The organic layer is washed with water and brine to yield cis 4-(p-fluorophenyl)cyclohexan-1-ylazide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[C:18]([CH2:19][OH:20])=[CH:22][CH:23]=[C:24]([O:26][CH3:27])[N:25]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)n1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CO)c(Nc2cccc(CNC(=O)OC(C)(C)C)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
To a mixture of the compound (300 mg) obtained in Example 452, triethylamine (101 mg) and tetrahydrofuran (8 ml), a tetrahydrofuran solution (1 ml) of ethyl chlorocarbonate (109 mg) was added under ice cooling and the resulting mixture was stirred at 0° C. for 15 min. The reaction mixture was filtered and a tetrahydrofuran solution (2 M, 0.8 ml) of lithium borohydride was added to the filtrate under ice cooling. The reaction mixture was stirred at 0° C. for 30 min and thereafter a 1 N aqueous sodium hydroxide solution was added under ice cooling. Further, the reaction mixture was stirred at 0° C. for 5 min and then ether and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:methylene chloride=1:10) to give 199 mg of the titled compound (yield, 69%).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:6]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:23])[OH:19])=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)Oc1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of tert-butyllithium (1.7 M in pentane, 12 ml, CAUTION-PYROPHORIC) was added dropwise to a stirring solution of 4-bromophenyl tert-butyl ether (2.33 g) in tetrahydrofuran (20 ml) at -70° C. After a further 5 minutes the resulting solution of anion was added dropwise to a solution of triisopropyl borate (6 ml) in tetrahydrofuran (10 ml) at -70 ° C. After the addition was complete the reaction mixture was allowed to warm to room temperature. After 20 minutes a solution of saturated aqueous ammonium chloride (25 ml) and ether (25 ml) was added. The layers were separated and the aqueous phase washed with ether (50 ml). The combined organic extracts were washed with dilute hydrochloric acid (5%, 25 ml) and were then dried over anhydrous magnesium sulfate. The solution was filtered and concentrated under reduced pressure to give a white solid. This was purified by column chromatography over silica eluting with ether then methanol to give the sub-title compound as a white solid (0.69 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].I[CH:18]([CH3:20])[CH3:19].BrC(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH:18]([CH3:20])[CH3:19])[CH:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(C)c2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c2c1ccn2C(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A cooled (ice/water bath) solution of methyl 7-methyl-1H-indole-4-carboxylate (260 mg, 1.374 mmol) in DMF (20 mL) was added sodium hydride (43.4 mg, 1.718 mmol). After 10 minutes 2-iodopropane (0.151 mL, 1.512 mmol) was added and the reaction was stirred for 16 h. LCMS showed reaction only 10% complete. Added sodium hydride (43.4 mg, 1.718 mmol) followed by 2-iodopropane (0.151 mL, 1.512 mmol). After 2 hours LCMS showed reaction was 15% compete. Added more sodium hydride (43.4 mg, 1.718 mmol) and let stir for 5 minutes, then added more 2-bromopropane (0.142 mL, 1.512 mmol). Heated to 70° C. for 16 h. LCMS showed reaction 50% complete. Concentrated reaction mixture. Added DCM and washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (Biotage; 0% to 100% DCM:Hex; 25 g-HP-silica gel column) to give 137 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.60 (m, 6H), 2.78 (s, 3H), 3.94-4.02 (m, 3H), 5.17 (dt, J=13.20, 6.66 Hz, 1H), 6.96 (d, J=7.83 Hz, 1H), 7.28 1H, 7.40 (d, J=3.28 Hz, 1H), 7.81 (d, J=7.58 Hz, 1H). MS(ES) [M+H]+ 232.1
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.C([O:35][CH:36](OCC)/[CH:37]=[CH:38]/B1OC(C)(C)C(C)(C)O1)C.C(=O)([O-])[O-].[Na+].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOC.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]=4)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][O:10][C:6]=2[C:5](/[CH:38]=[CH:37]/[CH:36]=[O:35])=[CH:4][N:3]=1
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2coc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1nc2ccccc2n1C
Yield: 36.9 %

Procedure:
A mixture of N-[4-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-benzimidazole-2-carboxamide (1.50 g, 2.78 mmol) in 1,2-dimethoxyethane (30 mL) and water (15 mL) was reacted 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.42 g, 5.56 mmol), sodium carbonate (1.17 g, 11.12 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) at 80° C. for 18 hours. Additional 2-[(E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 3.90 mmol), sodium carbonate (0.508 g, 4.80 mmol) and tetrakis triphenylphosphine palladium (0) (0.19 g, 0.17 mmol) was added and the mixture was heated for another 24 hours. Additional tetrakis triphenylphosphine palladium (0) (0.32 g, 0.27 mmol) was added and the mixture was heated for another 24 hours after which time all starting material was consumed. The solvent was removed in vacuo and the residue was triturated with water (30 mL) for 3 hours. The solid was collected by filtration and dried in vacuo. The crude product was suspended in acetone (60 mL) and water (8 mL) and reacted with p-toluenesulfonic acid monohydrate (0.10 g, 0.52 mmol) at ambient temperature for eighteen hours. The acetone was removed in vacuo and the precipitate was filtered, washing with water. The precipitate was triturated with 2-propanol (30 mL) for 1 hour. The solvent was removed an the residue was partitioned between dichloromethane (20 mL) and water (40 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (0.48 g, 31%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.19 (s, 1H), 9.64 (d, 1H), 8.52 (dd, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.86 (d, 1H), 7.75-7.82 (m, 2H), 7.47 (t, 1H), 7.39 (t, 1H), 7.32 (d, 1H), 7.21 (dd, 1H), 6.93 (dd, 1H), 4.25 (s, 3H), 4.04 (s, 3H), 1.86 (s, 3H); RP-HPLC (Conditions g) Rt 12.21 min.; MS: MH+ 468.
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]1[C:24]([O:26]CC)=O)=O)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:24]1(=[O:26])[NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]12
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCN2CCNCC12
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 3-ethyl 4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1,3-piperazinedicarboxylate (D77, 2.492 g, 6.21 mmol) in dichloromethane (30 mL) kept at 0° C. was added TFA (10 mL) dropwise. The solution was kept at 0° C. for 2 h, and then at room temperature for 6 h. The deprotected product was isolated by SCX and the resulting solution was evaporated at 50° C. to induce cyclization. The target product was purified by reverse phase chromatography (Oasis HLB 6 g×4 columns, eluted with water), obtaining 372 mg of the title compound.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCCCC)cc3)s2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 32.5 %

Procedure:
To a solution of 0.40 g (1.10 mM) of 2-(4-octylphenyl)-5-(4-hydroxyphenyl)thiazole in 20 ml of N,N-dimethylformamide (DMF), 0.40 g (1.10 mM) of potassium hydroxide was added, followed by stirring for 45 minutes at 100° C. To the mixture, 0.36 g (1.70 mM) of hexyl iodide was added at 100° C. under stirring, followed by further stirring for 6 hours and 16 minutes at 120° C. After the reaction, the reaction mixture was poured into 100 ml of water and extracted with ethyl acetate. The organic layer was washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized from ethanol to obtain 0.16 g of 2-(4-octylphenyl)-5-(4-hexyloxyphenyl)thiazole (Yield: 32.3%). ##STR43##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=O.C(C1C=C(C=C(C)C=1O)C#[N:19])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[C:5]#[N:19]
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: COc1cc(C=O)cc(Cl)c1O
Product: COc1cc(C#N)cc(Cl)c1O

Procedure:
The title compound is prepared from commercially available 3-chloro-4-hydroxy-5-methoxy-benzaldehyde in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile); LC-MS: tR=0.82 min; 1H NMR (CDCl3): δ3.98 (s, 3H), 6.36 (s, 1H), 7.04 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][CH:17]3[C:18](=O)[NH:19][C:20]=2[CH:21]=1)[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[CH:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][CH:17]3[C:18](=[S:43])[NH:19][C:20]=2[CH:21]=1)[CH2:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(c1ccc2c(c1)NC(=O)C1CCCC21)N(Cc1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCC(c1ccc2c(c1)NC(=S)C1CCCC21)N(Cc1cccc(Cl)c1)C(=O)OC(C)(C)C

Procedure:
A solution of 260 mg (0.55 mmol) of 7-[1-(N-tert-butoxycarbonyl-3-chlorobenzylamino)propyl]-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 597 mg (1.48 mmol) of Lawesson's reagent in 30 ml of THF is refluxed for 1 hour. After concentration by evaporation in a vacuum, the residue is purified by column chromatography with hexane-ethyl acetate: 230 mg of product.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=O.[CH2:9]([NH2:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O>[CH3:6][CH:4]1[N:19]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1](=[O:8])[CH2:2][CH2:3]1
Reactant: CCCCCCCCCCN
Reactant: CC(=O)CCC(=O)O
Solvent: O
Product: CCCCCCCCCCN1C(=O)CCC1C
Temperature: 150 °C

Procedure:
The feedstock used in examples 78 through 86 was 25% of the ammonium salt of levulinic acid, 25% decylamine, and 41% water, by weight. The temperature and pressure of the reactions were maintained at 150° C. and 6.9 MPa. Water was used as the solvent medium for the reactions. The results are set forth in the following table.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[I-:17].[Na+]>CC(C)=O.O>[I:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: CCOC(=O)c1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCI)cc1
Yield: 94.3 %

Procedure:
The mixture of ethyl 4-(3-chloropropoxy)benzoate (26.5 g), sodium iodide (49.0 g) in acetone (300 ml) was heated under reflux for 24 hr. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with 5% aqueous sodium sulfite, water, saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (34.4 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>O>[Cl:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(Cl)cccc1Nc1ccc(CCO)cc1
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 2,6-dichloronitrobenzene (Norman, M. H.; Chen, N.; et al. PCT Int. Appl., WO 9940091 (1999), Spada, A. P.; Fink, C. A.; Myers, M. R. PCT Int. Appl., WO 9205177 (1992), 6.3 g, 32.8 mmol), 4-aminophenylethyl alcohol (4.9 g, 36 mmol) and sodium acetate (3.2 g, 39.3 mmol) was placed in a sealed tube and heated at 160° C. for 3 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 4.57 g (72%) of the title compound as a red oil: 1H-NMR (CDCl3) δ 7.09-7.28 (6H, m), 6.91 (1H, dd, J=2.0, 7.1 Hz), 3.87 (2H, t, J=6.6 Hz), 2.86 (2H, t, J=6.6 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[C:9][CH3:10].CN(C)C=O.[Cl:17][C:18]1[NH:28][C:21]2[CH:22]=[N:23][N:24]([CH3:27])[C:25](=[O:26])[C:20]=2[N:19]=1>C(OCC)(=O)C>[CH2:7]([N:19]1[C:20]2[C:25](=[O:26])[N:24]([CH3:27])[N:23]=[CH:22][C:21]=2[N:28]=[C:18]1[Cl:17])[C:8]#[C:9][CH3:10]
Reactant: CC#CCBr
Reactant: Cn1ncc2[nH]c(Cl)nc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2cnn(C)c(=O)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.166 g of potassium carbonate and 0.106 μl of 2-butynyl bromide were added to a 10 ml N,N-dimethylformamide solution of 0.184 g of 2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the mixture was stirred at room temperature for 18 hours. 50 ml of ethyl acetate was added to the solution, and the mixture was washed three times with 20 ml of water and then with 20 ml of a saturated sodium chloride solution. The organic liquid was dried over magnesium sulfate, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.175 g of 3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one was obtained from the fraction eluted with hexane-ethyl acetate (4:1), and 0.033 g of 1-(2-butynyl)-2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one was obtained from the fraction eluted with hexane-ethyl acetate (2:3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)=[N:9][N:8]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:5]2=[CH:6][N:7]=1.[O:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26][CH2:25]1>>[O:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=4)=[N:9][N:8]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:5]3=[CH:6][N:7]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: CC1(C)OB(C2=COCCC2)OC1(C)C
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(Br)cc23)n1
Product: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(C4=COCCC4)cc23)n1
Yield: 45 %

Procedure:
Following the Suzuki coupling procedure of Example 10, 5-bromo-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were reacted and purified via silica gel chromatography using a gradient of EtOAc in heptane to afford 68 mg (45%) of 5-(3,4-Dihydro-2H-pyran-5-yl)-3-(6-fluoropyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine. ESI MS m/z 381.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])=[CH:9][N:10]=2)[CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([C:30]3[N:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[N:27]=[CH:28][CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)c(F)c1
Product: Fc1ccc(-n2nccc2-c2ccc3ncc(-c4ccc(F)cc4F)n3c2)cc1

Procedure:
The title compound, white solid (56 mg, 44%), MS (ISP) m/z=391.5 [(M+H)+], mp 168° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(2,4-difluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate K) (0.1 g, 0.324 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.38 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:20])[CH:13](Cl)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:20])[CH:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccc(Cl)cc1)C(=O)OCC
Yield: 84.4 %

Procedure:
A mixture of 38.6 g (0.3 mole) of 4-chlorophenol, 70 g (0.36 mole) of diethylchloromalonate and 69.1 g (0.5 mole) of anhydrous potassium carbonate in 750 ml of acetone was heated at reflux for 48 hr, cooled, filtered and the filtrate concentrated. The residue was diluted with 250 ml of ethyl ether and was washed successively with two 100 ml portions of a 1% NaOH solutoin, once with H2O and once with brine, dried (sodium sulfate) and concentrated to give an oil which gradually crystallized. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 72.6 g (84%) of white solid. An analytical sample, mp 43.5°-45° C. (lit. 1 mp 58°-60° C.), was recrystallized from petroleum ether (60°-110° C.).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[O:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:7]2[C:2]([O:27][C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=4)=[CH:26][CH:25]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9]1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: Fc1ncccc1C1CCCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc(Nc2ccc(Oc3ncccc3C3CCCOC3)cc2)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), 4-(pyridin-2-ylamino)phenol (0.26 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give N-(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 348.1 (M+1). IC50 (uM) 0.012.