Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:7]=[N:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=3)=[N:4][CH:3]=2)=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: CCCc1ccc(CBr)cc1
Reactant: CCCCCCc1ccc(-c2ncc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2ncc(OCc3ccc(CCC)cc3)cn2)cc1

Procedure:
A mixture of 10.2 g of 5-hydroxy-2-(4-n-hexyl-phenyl)-pyrimidine, 8.6 g of 4-n-propylbenzyl bromide, 8.6 g of potassium carbonate and 50 ml of dimethylformamide are warmed at 90° for 10 hours. Conventional work-up gives 2-(4-n-hexylphenyl)-pyrimidin-5-yl p-n-propylbenzyl ether.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:48]([OH:50])[CH3:49])[CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[C:34]([C:39]1([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40]1)[N:33]=2.ClCCl.C([O-])(O)=O.[Na+]>>[F:23][C:24]1[CH:25]=[C:26]([C:48](=[O:50])[CH3:49])[CH:27]=[CH:28][C:29]=1[C:30]1[S:31][C:32]2[C:37]([N:38]=1)=[CH:36][CH:35]=[C:34]([C:39]1([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:40][CH2:41]1)[N:33]=2
Reactant: CC(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
Dess-Martin periodinane (0.266 g, 0.627 mmol) was added to a solution of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanol (0.204 g, 0.522 mmol) in dichloromethane (15.00 mL, 0.522 mmol), and the reaction mixture was stirred at ambient temperature for 65 min. Saturated aqueous NaHCO3 was added and the reaction stirred for 5 min. The organic layer was dried and concentrated in vacuo, and purified by silica gel chromatography: ISCO 40 g column, 20-40% (3% Et3N in EtOAc)/hexanes to give 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)ethanone. MS (ESI) m/z: Calculated: 388.1; Observed: 389.0 (M++1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH2:43])=[O:42])[CH:39]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH2:43])=[O:42])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C
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: O
Solvent: C1COCCO1
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(CC(N)=O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetamide (7.2 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in 1,4-dioxane (0.2 mL) and water (0.1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with methanol, and purified with RP-HPLC (pH=10 to afford the desired product (1.5 mg). LCMS (M+H)+: m/z=462.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH2:14])[CH2:4][O:3]1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>CCCCC.ClCCl>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[NH:24][C:25]([NH:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:7][C@H:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:26]
Reactant: CC1(C)OC[C@H](N)[C@H](c2ccccc2)O1
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCCCC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccc(Cl)cc2Cl)[C@H](c2ccccc2)O1
Yield: 59 %

Procedure:
To a solution of 102 mg (0.49 mmol) of (4S,5S)-amine 1 in pentane (3 mL) was added a solution of 74 mg (0.39 mmol) of 2,4-dichlorophenyl isocyanate in dichloromethane (0.1 mL). A white precipitate was observed and collected via filtration. The crude solid was dissolved in dichloromethane (˜4 mL) and washed with 0.1 N HCl (˜4 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated to yield 91 mg (59%) of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)O1.Cl[C:30]1[CH:35]=[N:34][N:33]2[C:36]([C:39]3[CH:40]=[C:41]([NH:45][C:46]([NH:48][CH2:49][C:50]([F:53])([F:52])[F:51])=[O:47])[CH:42]=[CH:43][CH:44]=3)=[CH:37][N:38]=[C:32]2[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[F:53][C:50]([F:51])([F:52])[CH2:49][NH:48][C:46]([NH:45][C:41]1[CH:40]=[C:39]([C:36]2[N:33]3[N:34]=[CH:35][C:30]([C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:19][CH2:20]5)=[N:13][CH:14]=4)=[CH:31][C:32]3=[N:38][CH:37]=2)[CH:44]=[CH:43][CH:42]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (46.3 mg, 0.119 mmol, Aldrich, Cat. No. 654337), N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (40.0 mg, 0.108 mmol, Example 30, Step 3), tetrakis(triphenylphosphine)palladium(0) (6.25 mg, 0.00541 mmol) and sodium carbonate (34.4 mg, 0.324 mmol) in dioxane (1 mL) and water (0.3 mL) was degassed and recharged with nitrogen three times, and heated and stirred at 110° C. for 3 h. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=597.2.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:28])[CH2:26][CH3:27])=[C:21]([OH:29])[C:20]=3[CH3:30])[CH:12]=2)=[N:6][CH:5]=1.[OH-].[Li+].O.Cl>O1CCCC1>[OH:29][C:21]1[C:20]([CH3:30])=[C:19]([CH:24]=[CH:23][C:22]=1[C:25](=[O:28])[CH2:26][CH3:27])[O:18][CH2:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][N:6]=1
Reactant: CCC(=O)c1ccc(OCc2cccc(Oc3ccc(C(=O)OC)cn3)c2)c(C)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(OCc2cccc(Oc3ccc(C(=O)O)cn3)c2)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
Dissolve 6-[3-(3-hydroxy-2-methyl-4-propionyl-phenoxymethyl)-phenoxy]-nicotinic acid methyl ester (0.10 g, 0.24 mmol) in tetrahydrofuran (2 mL). Add lithium hydroxide (0.007 g, 0.29 mmol) and water (0.5 mL). Stir at ambient temperature for 2 hrs. Add 1 N hydrochloric acid (5 mL) and extract with ethyl acetate (3×10 mL). Combine the organic extracts, dry over magnesium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purification using 5% isopropyl alcohol/chloroformchloroform to 10% isopropyl alcohol/chloroform as gradient eluent gives the title compound (0.06 g, 58%): MS (m/z): 406.1 (M−1). 1H NMR (acetone-d6) 13.00 (s, 1H), 8.76 (s, 1H), 8.40 (dd, J=1.7 Hz, 8.4 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 5.36 (s, 2H), 3.09 (q, J=7.2 Hz, 2H), 2.14 (s, 3H), 1.20 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(C2C=C(F)[CH:24]=[CH:23][C:22]=2[C:28]([C:30]2[CH:35]=[CH:34][C:33](F)=[CH:32][C:31]=2C2CC2)=[O:29])CC1.C(=O)([O-])[O-].[K+].[K+].[ClH:46]>CS(C)=O.CO.C(OCC)C>[ClH:46].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:33]3[CH:32]=[CH:31][C:30]([C:28]([CH:22]4[CH2:23][CH2:24]4)=[O:29])=[CH:35][CH:34]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)C2CCNCC2)CC1
Reactant: O=C(c1ccc(F)cc1C1CC1)c1ccc(F)cc1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOCC
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccc(C(=O)C4CC4)cc3)CC2)CC1
Temperature: 140 °C

Procedure:
To 1-isopropyl-4-(piperidine-4-carbonyl)-piperazine (D1)(0.25 g) and cyclopropyl-4-fluorophenyl ketone (0.3 g), dissolved in DMSO (5 ml) was added potassium carbonate (0.37 g). The reaction was heated to 140° C. for 2 h. After cooling the mixture, the inorganics were filtered off. The filtrate was diluted with MeOH (20 ml) and then poured onto a 10 g isolute SCX column which was washed with MeOH (50 ml). The product was eluted with 10% ammonia in MeOH (50 ml), and then further purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.88 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base which was dissolved in MeOH (4 ml) and treated with 1N HCl in diethyl ether (2 ml) to give the title compound (E105) as a solid (51mg). 1H NMR δ [DMSO-d6]: 0.93 (4H, m) 1.27 (6H, d, J=6.4 Hz), 1.5-1.8 (2H, m), 2.77-3.14 (7H, m), 3.38-3.48 (2H, m), 3.92-4.56 (4H, m), 6.98 (2H, d, J=9.2 Hz), 7.89 (2H, d, J=9.2 Hz), 10.6 (1H, br s). MS electrospray; (+ve ion) 384 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH:35]([CH3:41])[CH3:36])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: CC(C)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 140 mg, 0.42 mmol) was dissolved in methylene chloride and a 2.0 M solution of oxalyl chloride in methylene chloride (154 mg, 0.47 mmol) was added. The reaction stirred at 25° C. for 1 h. The reaction was chilled to 0° C. under nitrogen and 2,6-lutidine (113 μL, 0.98 mmol) was added dropwise. The reaction became golden brown, the ice bath was removed and the reaction continued to stir at 25° C. for 30 min. 1-Iso-butyl-1H-pyrazol-3-ylamine (59 mg, 0.42 mmol) was dissolved in methylene chloride and added dropwise to the reaction. The solution continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride, washed with water and saturated aqueous brine solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1-iso-butyl-1H-pyrazol-3-yl)-propionamide (117 mg, 61%) as a white foam: ESI-LRMS m/e calcd for C22H30ClN3O3S [M+] 451.2, found 452.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (dd, J=6.7, 2.2 Hz, 6H, 2×CH3), 1.06-1.20 (m, 2H, CH2), 1.44-1.94 (m, 8H, 4×CH2), 2.07-2.31 (m, 1H, CH), 3.26 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 3.76 (d, J=7.2 Hz, 2H, NCH2), 6.64 (d, J=2.3 Hz, 1H, Ar), 7.23 (d, J=2.3 Hz, 1H, Ar), 7.45 (dd, Jo=8.2, Jm=1.8 Hz, 1H, Ar), 7.59 (d, Jm=1.8 Hz, 1H, Ar), 7.80 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]([F:18])=[C:3]([C:14]([F:17])([F:16])[F:15])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][SiH2]C(C)(C)C>CO>[F:1][C:2]([F:18])=[C:3]([C:14]([F:15])([F:16])[F:17])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: CC(C)(C)[SiH2]OCCCCC(=C(F)F)C(F)(F)F
Solvent: CO
Product: OCCCCC(=C(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.59 g (11.28 mmol) 6,6-difluoro-5-trifluoromethyl-1-tert-butylsilyloxy-5-hexene in 50 ml methanol was treated with a teaspoon full of ion exchange resin and the mixture stirred for 3 hours at room temperature. The ion exchange resin was then filtered off and washed with methanol. The filtrate was carefully concentrated in a rotary evaporator (bath temperature=35° C.; 200 mbar). The residue was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[C:9]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:10][C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([CH:22]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[N:18][CH:17]=1)=[O:14].[CH3:38][N:39]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40]1>COCCOC.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>[CH3:38][N:39]1[CH:43]=[C:42]([C:8]2[C:9]([CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:10][C:11]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:12]([CH:22]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)=[O:14])[CH:41]=[N:40]1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Reactant: Cn1cc(B(O)O)cn1
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: COCCOC
Product: Cn1cc(-c2cc(C(=O)Nc3ccnnc3)c(OCc3ccccc3)cc2CN2CCOCC2)cn1
Temperature: 120 °C

Procedure:
Na2CO3 (0.25 ml, 0.25 mmol) and palladium tetrakis (8.61 mg, 7.45 μmol) was added to 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 1; 60 mg, 0.12 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (18.76 mg, 0.149 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. in a microwave for one hour and the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a white solid. 8 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][N:15]=[CH:16][C:9]=12.[OH-].[K+].[I:24]I>CN(C=O)C>[Cl:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][N:15]=[C:16]([I:24])[C:9]=12
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]ncc12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]nc(I)c12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 4-(5-chloro-2-methyl-4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (21.0 g, 68.9 mmol) in DMF (100 mL) was added freshly ground (mortar/pestle) potassium hydroxide (11.6 g, 207 mmol) flakes followed immediately by iodine (26.2 g, 103 mmol) under N2 at 25° C. The dark reaction was heated to 50° C. for 6 hours. The mixture was quenched by addition of aqueous 10% NaHSO3 (75 mL). The suspension was further diluted by addition of water (100 mL) and filtered. The resulting precipitate washed with water, dried by toluene azeotrope, and then left under high vacuum for 2 days. The beige powder (26.5 g, 69%) was carried forward without further purification.
Reaction SMILES: C(#N)C.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[OH:18].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:18][C:6]1[CH:7]=[C:8]([S:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([CH3:11])=[CH:10][C:5]=1[CH3:4]
Reactant: BrCCCCCCBr
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: Cc1cc(C)c(SCC(F)(F)F)cc1OCCCCCCBr
Temperature: 25 °C
Yield: 97 %

Procedure:
To 60 ml of acetonitrile were added 1.14 g (4.83 mmol) of 2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenol, 4.71 g (19.31 mmol) of 1,6-dibromohexane, 0.73 g (5.28 mmol) of potassium carbonate and catalytic amount of tetra-n-butylammonium bromide. The mixture was refluxed for 3 hours under heating. The mixture was allowed to cool to room temperature, and insoluble matters were removed by filtration. Then the solvent of filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=40:1˜20:1), to obtain 1.87 g (yield: 97%) of an intended product.
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH2:15][NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH:12]=[CH:11][C:10]=2[Cl:25])=[O:7])=[CH:4][N:3]=1.[CH3:28][NH:29][CH3:30]>C1COCC1>[Cl:25][C:10]1[CH:11]=[CH:12][C:13]([CH2:15][NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:26]=[CH:27][C:2]([N:29]([CH3:30])[CH3:28])=[N:3][CH:4]=1
Reactant: C[C@@H](NCc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccccc1
Reactant: CNC
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(NC(=O)c2ccc(N(C)C)nc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.6 %

Procedure:
To a solution of (R)-6-chloro-N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)nicotinamide 48 (0.175 g, 0.44 mmol) in THF (3 mL) at 0° C. was added dimethylamine (5.0 mL, 153 mmol). The reaction mixture was warmed to room temperature, stirred for 20 h, quenched with saturated NaHCO3, and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave (R)—N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)-6-(dimethylamino)nicotinamide 49 (0.118 g, 66% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.37 (d, J=6.5 Hz, 3H), 3.19 (s, 6H), 3.60 (d, J=13.5 Hz, 1H), 3.66 (d, J=13.5 Hz, 1H), 3.81 (q, J=6.6 Hz, 3H), 6.57 (d, J=8.6 Hz, 1H), 7.00 (dd, J=8.2, 2.2 Hz, 1H), 7.25-7.37 (m, 7H), 8.00 (dd, J=9.0, 2.5 Hz, 1H), 8.27 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H). Mass spectrum: calculated for C23H25ClN4O 408.2. found 409.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:21]1([CH:19]([CH3:20])[CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(CCCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CCOc1ccc(C2(C#N)CCOCC2)cc1)N1CCCC1
Yield: 9.4 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.0 g, 4.9 mmol), 1-(3-chloro-1-methyl-propyl)-pyrrolidine (780 mg, 3.90 mmol), DMF (20 ml) and K2CO3 (2.71 g, 19.60 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. and purified by preparative HPLC, eluting with acetonitrile/water/0.1% TFA as a gradient, to provide the title compound (120 mg, 9%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 2H), 6.93 (d, 2H), 4.15-3.98 (m, 4H), 3.89 (td, 2H), 2.75-2.51 (m, 5H), 2.22-1.74 (m, 10H), 1.17 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11](Cl)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[S:10][C:9]([C:11]([NH:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C(Cl)c1cc2ncnc(Cl)c2s1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1cc2ncnc(Cl)c2s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
To a stirred solution of 22 (500 mg, 2.15 mmol) in anhydrous DCM (20 mL) at 0° C. under nitrogen was added 4-(2-aminoethyl)-morpholine (307 mg, 2.36 mmol). The reaction mixture was allowed to warm to the room temperature over 3 hours and was stirred for additional 14 hours, treated with saturated aqueous solution of NHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. The residues was purified by flash chromatography on silica gel (eluents MeOH-DCM, 5:95, then 1:9) to afford the title compound 23 (458 mg, 65% yield) as a white solid 1H NMR (400 MHz, CDCl3) δ(ppm): 9.13 (t, J=5.6 Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 3.60-3.54 (m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.54-2.48 (m, 2H), 2.46-2.40 (m, 4H).