Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[C:44]([F:46])[CH:43]=[C:42]([F:47])[C:41]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>CN(C=O)C.ClCCl.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>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[C:40]([F:39])=[CH:45][C:44]([F:46])=[CH:43][C:42]=3[F:47])=[O:16])=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OB(O)c1c(F)cc(F)cc1F
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (990 mg, 1.8 mmol), 2,4,6-trifluorophenylboronic acid (634 mg, 3.6 mmol), potassium phosphate (2.2 g, 10.8 mmol), tetrakis(triphenylphosphine)palladium (416 rag, 0.4 mmol) in dry DMF (25 mL) and heat at 100° C. for 3 hours. Purify reaction by SCX column. Additional purification is done by silica get chromatography using a 1-3% gradient of methanol in dichloromethane to yield 320 mg (35%) of the title compound: mass spectrum (ion spray) m/z=534 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[F-].[Cs+].O.[CH3:12][C:13]1[N:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=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>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([C:16]2[CH:15]=[N:14][C:13]([CH3:12])=[N:18][CH:17]=2)[CH:7]=1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: Cc1ncc(-c2cc(Cl)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g, 1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mL water. The mixture was flushed with nitrogen gas for 30 minutes and Pd(PPh3)4 (22.05 g 19.08 mmol) was added. The resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes, heated to reflux, and a nitrogen-flushed solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (140 g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours. The resulting dark red solution was refluxed under an atmosphere of nitrogen for 16 hours. After this time the mixture was cooled to RT and 300 mL of water was added. The mixture was then cooled to 5° C. and stirred for 40 minutes. The resulting precipitate (6-chloro-2′-methyl-4,5′-bipyrimidine, compound 2039) was collected by filtration, washed with 50 mL water, followed by washing with 150 mL EtOAc. The filtrate was separated into two layers and the aqueous layer extracted with EtOAc (2×1 L). The combined organics were dried over Na2SO4, concentrated under reduced pressure, diluted with 300 mL of DCM, and purified by medium pressure silica gel chromatography (0-100% EtOAc/DCM). Fractions containing pure product were concentrated under reduced pressure and the concentrate treated with 400 mL of hexanes to produce compound 2039 as a solid. This material was combined with the solid product previously collected and treated with 400 mL of 1:1 THF/DCM. The resulting suspension was heated and transferred to a filtration funnel containing a plug of Florisil®. The plug was washed with additional 1:1 THF/DCM to dissolve any remaining solid material and then washed with 4:1 EtOAc/DCM (2×1 L). The combined filtrates were concentrated under reduced pressure to produce a pink solid which was triturated with 500 mL hexanes, collected by filtration, and dried under reduced pressure to provide 6-chloro-2′-methyl-4,5′-bipyrimidine (compound 2039, 88.8 g, 68% yield): LC-MS=207.01 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 2.85 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=O)[CH:16]=[CH:17][CH:18]=1.[H][H]>C(OCC)(=O)C.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)C=Cc2cccc(OCc3ccc4ccccc4n3)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CCCc2cccc(OCc3ccc4ccccc4n3)c2)cc1

Procedure:
A solution of 4-(3-(3-(2-quinolinylmethyloxy)phenyl)-1-oxo-2-propen-l-yl)benzonitrile (0.008 mol) in ethyl acetate (150 ml) is shaken under 50 psi of hydrogen gas in the presence of 10% palladium an carbon catalyst (1.0 g). The reaction is filtered through a celite pad and evaporated to give 4-(3-(3(2-quinolinylmethyloxy)phenyl)propyl)benzonitrile.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[O:35])=[CH:37][CH:38]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C[C@H]1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCO
Product: C[C@H]1COCCN1C(=O)c1ccc(N)nc1
Reaction time: 18 h
Yield: 30.1 %

Procedure:
To a solution of (S)-3-methylmorpholine (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 256a (1.0 g, 30%) as white solid. MS-ESI: 222.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2([CH3:27])[CH2:26][CH2:25]2)[CH:19]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2([CH3:27])[CH2:26][CH2:25]2)[CH:19]=1
Reactant: CC1(c2cc(Br)ccn2)CC1
Reactant: CC(=O)Nc1nc(C)cs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C3(C)CC3)c2)s1
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 2-acetamido-4-methylthiazole [7336-51-8] (60.4 mmol), cesium carbonate (110 mmol), tri-tert-butylphosphinium tetrafluoroborate (10.99 mmol), palladium (II) acetate (5.49 mmol) and 4-bromo-2-(1-methyl-cyclopropyl)-pyridine (Step 1.4) (54.9 mmol) in DMF (230 mL) was stirred for 3.5 h at 100° C. After cooling to rt, the reaction mixture was filtered and then concentrated. The residue was diluted with a saturated solution of NaHCO3 and extracted with EtOAc (3×). The combined organic phases were successively washed with a saturated solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a pale yellow solid. HPLC: tR=4.37 min (method B); LC-MS: tR=1.47 min, [M+H]+ 288; TLC: Rf=0.26 (1:2 Hex/EtOAc).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([I:9])[CH:8]=1)[NH2:5].[CH3:10][Si:11]([CH3:27])([CH3:26])[CH2:12][CH2:13][O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOCC>[CH3:26][Si:11]([CH3:10])([CH3:27])[CH2:12][CH2:13][O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[NH:5][C:4]1[CH:3]=[C:2]([I:1])[CH:8]=[C:7]([I:9])[CH:6]=1
Reactant: C[Si](C)(C)CCOC(=O)NCCCCCC(=O)O
Reactant: Nc1cc(I)cc(I)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOC(=O)NCCCCCC(=O)Nc1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
3,5-Diiodoaniline [Dininno, F.; Guthikonda, R. N.; Schmitt, S. M. 1994 U.S. Pat. No. 5,292,879 A] (1 g, 2.90 mmol), 6-(2-Trimethylsilanyl-ethoxycarbonylamino)-hexanoic acid (1 g, 3.77 mmol) in DMF (12 ml) were added DIPEA (0.9 ml, 5.8 mmol) and HATU (1.65 g, 4.35 mmol). The mixture was stirred for overnight at room temperature. The reaction mixture was diluted with Et2O. To the mixture was added sat.NaHCO3 and then separated. The aqueous phase was extracted with Et2O (3×40 ml). The combined extraction were washed with 5% HCl (30 ml), H2O (50 ml), sat.NaHCO3 (30 ml), and Brine (30 ml), and finally dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by silica gel column with (Hexane:EtOAc=6:4) to afford 21 (1 g, 59%) as a colorless powder. 1H NMR (300 MHz, (CD3)2SO): δ 0.09 (S, 9H), 0.84 (t, J=2.1 Hz, 2H), 1.34 (m, 2H), 1.40 (m, 2H), 1.50 (m, 2H), 2.41 (t, J=1.8 Hz, 2H), 2.47 (m, 2H), 2.89 (m, 2H), 4.01 (t, 2H), 6.92 (bt, 1H), 7.68 (m, 1H), 7.99 (m, 2H); 13C NMR (75 MHz, (CD3)2SO): δ −0.72, 18.0, 25.2, 26.4, 29.9, 36.9, 61.9, 96.4, 127.0, 139.0, 142.3, 156.9, 172.2; IR (film): 3326, 2853, 2361, 1687, 1541, 1450, 1249, 837 cm−1; MS:(ESI)) [M+Na]+ 624.9
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14]Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C-:19]#[N:20].[K+]>O.CO.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][C:19]#[N:20])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)CBr)cn2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Cn2cc(C(=O)CC#N)cn2)cc1
Yield: 96.9 %

Procedure:
According to Scheme 5 Step 1: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (9.70 mmol, 3.00 g) and potassium cyanide (14.6 mmol, 948 mg) in 120 mL of water/MeOH/THF (1:1:1) was stirred for 30 minutes at room temperature. The reaction mixture was diluted with water (150 mL) and the aqueous phase was extracted with DCM. The organic phase was dried over MgSO4, was filtered and was concentrated to yield 3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-3-oxopropanenitrile (9.40 mmol, 2.40 g, 97%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[S:7]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18]C)=[O:17])[CH2:8]1>O.CO>[S:7]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([OH:18])=[O:17])[CH2:8]1
Reactant: COC(=O)c1ccc(OC)c(OC2CCSC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1OC1CCSC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A solution of potassium carbonate (7.4 g) in water (72 mL) is added, dropwise, to a stirred solution of methyl 3-(tetrahydrothiophen-3-oxy)-4-methoxybenzoate (11.8 g) in methanol (200 mL) at room temperature. After the addition is complete, the solution is stirred and heated at 60-70° C. for 5 hours and allowed to stand at room temperature overnight. The solution is evaporated, the residue is dissolved in water, acidified with glacial acetic acid and the precipitate formed is collected and dried, to give 3-(tetrahydrothiophen-3-oxy)-4-methoxybenzoic acid (7.4 g). m.p. 177-179° C. [Elemental analysis: C,55.3; H,5.5; calculated: C,56.7; H,5.55%].
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:27](S(C3C=CC=CC=3)(=O)=O)[C:13]3=[N:14][CH:15]=[CH:16][C:17](B4OC(C)(C)C(C)(C)O4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1.Br[C:39]1[C:40]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[N:41][N:42]([CH3:44])[CH:43]=1>>[CH3:1][N:2]([CH3:37])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:27][C:13]3=[N:14][CH:15]=[CH:16][C:17]([C:39]4[C:40]([C:45]5[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=5)=[N:41][N:42]([CH3:44])[CH:43]=4)=[C:12]3[CH:11]=2)=[CH:6][CH:5]=1
Reactant: CN(C)Cc1ccc(-c2cc3c(B4OC(C)(C)C(C)(C)O4)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: Cn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CN(C)Cc1ccc(-c2cc3c(-c4cn(C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc3[nH]2)cc1

Procedure:
Following the procedure described in Intermediate 100 and Intermediate 21 using N,N-dimethyl-1-{4-[1-(phenylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanamine and 4-bromo-1-methyl-3-(4-nitrophenyl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 453.2.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl.CCOC(C)=O>[CH3:52][S:53]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)(=[O:55])=[O:54]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CO)cc(C(F)(F)F)c3)c2)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(COS(C)(=O)=O)cc(C(F)(F)F)c3)c2)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.211 g, 0.361 mmol) in 6 mL of DCM with DIEA (0.19 mL, 1.08 mmol) at 0° C., methanesulfonyl chloride (0.037 mL, 0.469 mmol) is added and the reaction stirred for 3 h. At that point the reaction is diluted with EtOAc, washed with saturated sodium bicarbonate, brine and the organic layer is dried over sodium sulfate. Concentration provides a mixture of the title compound and tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-a]pyrimidine-7(8H)-carboxylate (3:7), which is carried on to next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH3:22])[CH3:21])[N:15]=1)[CH:8]=[C:7]2[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C.[Br:37][C:38]1[C:46]2[C:41](=[N:42][CH:43]=[N:44][C:45]=2Cl)[NH:40][N:39]=1.C(OCC)(=O)C>O1CCCC1>[Br:37][C:38]1[C:46]2[C:41](=[N:42][CH:43]=[N:44][C:45]=2[N:27]2[CH2:28][CH2:29][CH:24]([NH:23][C:7]3[C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=4)[CH:10]=[C:9]([C:14]4[CH:19]=[CH:18][N:17]=[C:16]([N:20]([CH3:22])[CH3:21])[N:15]=4)[CH:8]=3)[CH2:25][CH2:26]2)[NH:40][N:39]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCNCC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c2c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 58.7 %

Procedure:
To a solution of 4-(6-methoxy-4-(piperidin-4-ylamino)naphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (143) (196 mg, 0.43 mmol) and triethylamine (0.5 ml) in anhydrous tetrahydrofuran (8 ml) was added 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (122 mg, 0.52 mmol). The mixture was stirred at 50° C. for 24 hours before being poured into ethyl acetate (150 ml) washed with water (300 ml) and the organic layer dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow foam that was crystallized from dichloromethane and ethyl acetate to give 4-(4-((1-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)amino)-6-methoxynaphthalen-2-yl)-N,N-dimethylpyrimidin-2-amine (144) as a yellow solid (145 mg) M.p.=167-172° C. 1H NMR (DMSO-d6) 400 MHz δ 8.4-8.33 (m, 2H), 7.9-7.8 (m, 2H), 7.52 (m, 2H), 7.24-7.2 (m, 1H), 7.15-7.12 (m, 1H), 5.9-5.74 (m, 1H), 4.56-4.53 (m, 2H), 3.95 (s, 1H), 3.9 (s, 3H), 3.41-3.26 (m, 2H), 3.22 (s, 6H), 2.28-2.25 (m, 2H), 1.97-1.75 (m, 2H), LCMS m/e 574 and 576 (M+) Calculated for C27H28BrN9O.CH2Cl2: C, 51.00; H, 4.59; N, 19.12; found C 51.00, H 4.39, N 18.85.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:35]1([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C.O>[C:35]1([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][NH:49][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([OH:11])=[C:2]([I:1])[CH:3]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccc(O)c(I)c1
Reactant: NCCCCCCCCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCCCCCCCc1ccccc1)c1ccc(O)c(I)c1
Reaction time: 4 h
Yield: 99 %

Procedure:
To a stirring solution of 3-iodo-4-hydroxy-benzoic acid (2.64 g, 10.00 mmol) in fresh DMF (5 mL) at ambient temperature under an atmosphere of N2 was added EDC (2.11 g, 11.00 mmol), HOBt (1.49 g, 11.00 mmol) and DIPEA (1.94 g, 2.60 mL, 15.00 mmol). The solution was allowed to stir at ambient temperature for 1 hour at which time 8-phenyl-octylamine (2.46 g, 2.39 mL, 12 mmol) was added at one time. The solution was allowed to stir for an additional 4 hours at which time the it was diluted with water (250 mL) and extracted with ethyl acetate (250 mL). The organic phase was washed with water (2×250 mL), saturated aqueous NaHCO3 (250 mL) and saturated aqueous NaCl (250 mL). The solvent was removed in vacuo to yield 4.62 g of crude oil. The crude oil was purified by column chromatography (7:3 hexane:ethyl acetate) to yield 4.47 g (99%) of the desired product as a clear oil, which crystallized upon standing. 1H NMR (CDCl3)6 8.19 (dd, 2H), 7.60 (dd, 1H), 7.20 (m, 4H), 6.97 (dd, 1H), 6.32 (t, 1H), 3.39 (q, 2H), 2.57 (t, 2H), 1.58 (m, 4H), 1.30 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH2:18][CH3:19])[C:13]=3[C:12]([C:20](O)=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(N1CCOCC1)C>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH2:18][CH3:19])[C:13]=3[C:12]([C:20]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Reactant: C1COCCN1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c21

Procedure:
A solution of 4-[(3-chlorophenyl)amino]-1-ethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylic acid (20 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (15 mg), 1-hydroxybenzotriazole hydrate (11 mg), morpholine (11 ul) and N-ethylmorpholine (32 ul) in dimethylformamide (2 ml) was stirred under argon over night. The reaction mixture was diluted with diethyl ether and washed with water. The aqueous layer was acidified with an aqueous 2M hydrochloric acid solution and then extracted three times with diethyl ether. The combined organic layers were washed with brine, dried (MgSO4) and evaporated to afford the title compound as a yellow oil (14 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.[CH3:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:23]=1[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[CH3:1][C:2]1[N:3]([CH2:24][C:23]2[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:22]=2[CH3:21])[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=2[N:6]=1
Reactant: Cc1ccc(C(F)(F)F)cc1CBr
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(F)(F)F)cc1Cn1c(C)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.3 g, 1.090 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 2-methyl-5-(trifluoromethyl)benzyl bromide (0.552 g, 2.179 mmol) and potassium carbonate (0.452 g, 3.27 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (25-55%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (120.1 mg, 0.277 mmol, 25.4% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.53 (s, 3H) 2.88 (s, 3H) 3.15-3.23 (m, 4H) 3.79-3.88 (m, 4H) 5.84 (s, 2H) 7.06 (s, 1H) 7.27 (d, J=2.27 Hz, 1H) 7.51-7.58 (m, 1H) 7.59-7.64 (m, 1H) 7.86 (d, 1H). MS(ES+) m/e 433.8 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].CC([O-])(C)C.[K+].Cl[CH2:16][C:17]1[C:18]([CH3:23])=[N:19][O:20][C:21]=1[CH3:22].O>CN(C=O)C>[CH3:23][C:18]1[C:17]([CH2:16][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1noc(C)c1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(C)c1Cn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To 4-nitro-1H-pyrazole (Example 4-1d) (3.8 g, 34 mmol) in DMF (80 mL) cooled to 0° C., via an ice/water bath, was added t-BuOK (4.2 g, 38 mmol). After addition of the base the ice bath was removed and the mixture was stirred for 30 minutes followed by the addition of 4-(chloromethyl)-3,5-dimethylisoxazole (5 g, 34 mmol). The reaction was refluxed for 16 hours then cooled to ambient temperature. H2O was added to the reaction mixture and the precipitate formed was collected by filtration. The precipitate was washed with additional H2O then dried under high vacuum to afford 3,5-dimethyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)isoxazole (5.8 g, 78%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz):2.23 (s, 3H), 2.46 (s, 3H), 5.08 (s, 2H), 8.02 (s, 1H), 8.08 (s, 1H).