Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[CH:7]=[C:2]([Br:1])[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[C:5]2=[O:8])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(Br)c[nH]c(=O)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(Br)c(C)c([N+](=O)[O-])c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirred solution of 5-bromo-4-methyl-3-nitro-2-pyridone (0.60 g, 2.5 mmol) in DMF (15 mL) was added sodium hydride (60% suspension in oil, 0.103 g). After 30 minutes, 4-methoxybenzyl chloride (0.35 mL) was added, and the mixture was stirred overnight at rt. Ethyl acetate was added and the organic phase was washed with water, dried (Na2SO4), filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane 1/1)) gave 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-nitro-2-pyridone (0.60 g, 1.7 mmol, 68%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([Cl:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([Cl:11])[CH:3]=1
Reactant: Clc1cc(Br)c2nc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1cnc2c(Br)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 109c (3.5 g, 15 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.14 g, 30 mmol) and iodomethane (1.4 mL, 22.7 mmol). The reaction was stirred at room temperature for overnight. Water (50 mL) was added to quench the reaction and the resulting mixture was extracted with ethyl acetate (5 mL×3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with petroleum ether/ethyl acetate (from 4:1 to 1:2) to afford 109d as a white solid (1.4 g, 38%). LCMS: [M+H]+ 245/247. 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[CH3:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][NH:28]1.O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:9][S:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[C:6]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]2[CH3:26])[N:7]=1
Reactant: C[C@H]1COCCN1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCCC2)nc(Cl)n1
Temperature: 6 °C
Reaction time: 0.5 h
Yield: 72.1 %

Procedure:
To a cooled (ice/water bath) solution of 2,4-dichloro-6-(cyclohexylsulfonylmethyl)pyrimidine (1.65 g, 5.34 mmol) in DCM (25 mL) was added triethylamine (0.820 mL, 5.88 mmol). The resulting solution was treated, dropwise over 8 minutes, with a solution of (3S)-3-methylmorpholine (609 mg, 6.02 mmol) in DCM (5 mL). The mixture was stirred at 6° C. for 30 minutes. The cooling bath was then removed and reaction mixture left to stir overnight. Water (25 mL) was then added and reaction mixture stirred for 5 minutes. The organic layer was then separated, dried (MgSO4) and evaporated to give a crude brown oil, which was purified by flash silica chromatography, elution gradient 25 to 75% ethyl acetate in isohexane, to give the desired material (1.440 g).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN([CH:12]=[N:13][C:14]1[C:15]([C:24]([O-:26])=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)C.C(O)(=O)C>O1CCCC1.O>[O:26]=[C:24]1[C:15]2[C:14](=[CH:23][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:16]=2)[NH:13][CH:12]=[C:7]1[C:6]#[N:8]
Reactant: CC#N
Reactant: CN(C)C=Nc1cc2ccccc2cc1C(=O)[O-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2cc3ccccc3cc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5.6 g (30 mmol) of 3-amino-2-napthoic acid in 30 mL of N,N-dimethylformamide dimethyl acetal is refluxed for 6 hours. Removal of the solvent yields 7.06 g (86.4%) of methyl 3-{[(dimethylamino)methylidene]amino}-2-naphthoate as a dark oil residue. To a solution of 20.8 mL (52 mmol) of n-butyllithium (2.5M in hexane) in 18 mL of tetrahydrofuran (THF) is added dropwise a solution of 5.97 mL (114 mmol) of acetonitrile in 100 mL of THF at −78° C. After completion of addition, the suspension is stirred for 15 minutes. To this is added 7.02 g (26 mmol) of 3-{[(dimethylamino)methylidene]amino}-2-naphthoate in 50 mL of THF dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour. Then 7.8 g (130 mmol) of acetic acid is added dropwise. The reaction mixture is warmed up to room temperature and diluted with water. The precipitate is collected by filtration and washed with water and ethyl acetate. After drying in vacuo, this yields 3.80 g (67%) of the product as a yellow solid, mp>260° C.
Reaction SMILES: [Br-].[Br-].[Br-].B.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
Boran tri-bromide in DCM (10 mL) was added to a stirred solution of 7-methoxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (35A: 1.1 g, 4.104 mmol) in DCM (20 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (10% methanol in DCM). The reaction mixture was quenched with methanol and concentrated. The concentrate was partitioned between water and DCM. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (3% methanol in DCM) afforded 850 mg of the product (77% yield).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([S:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([S:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Reactant: CCCCSc1ccc(CCN)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCSc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 55.5 %

Procedure:
Triethylamine (0.19 g, 1.88 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (0.20 g, 0.93 mmol) in toluene (4 ml). The mixture was stirred at room temperature. Then, 4-butylthiophenethylamine (0.20 g, 0.96 mmol) was added. After stirring for 3 hours, water (20 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-butylthiophenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.20 g, 55%).
Reaction SMILES: C([C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:18])[CH3:17])(=O)C.OO.F[C:30](F)(F)[C:31]([O:33]C(=O)C(F)(F)F)=[O:32]>C(Cl)Cl.O>[C:31]([O:33][C:4]1[C:5](=[O:26])[N:6]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]([CH3:19])=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([CH3:17])[CH3:18])(=[O:32])[CH3:30]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(C(C)=O)c1=O
Agent: OO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2C(C)C)c(OC(C)=O)c1=O

Procedure:
To a stirred solution of 3-acetyl-4-(2-isopropylphenyl)-6-methyl-1-ethoxycarbonylmethyl-2-pyridinone from step 3 above (0.65 g, 1.8 mmol) in CH2Cl2 (150 mL) at 0° C. was added 30% aqueous H2O2 (0.94 mL, 9 mmol) and trifluoroacetic anhydride (1.8 mL, 14 mmol). The resulting solution was refluxed for 1 h and then diluted with CH2Cl2 and water. The organic phase was separated, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.325 g; NMR: OCOCH3 peak at 2.05 ppm; HPLC RT=22.81 min, method B).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CCCCNC(N(CCCC)CCCC)=S.C(N(C(C)C)C(C)C)C>O1CCCC1.O>[CH3:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:8]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: C1CCNC1
Agent: CCCCNC(=S)N(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(Br)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 2a from 4-bromo-2-methylbenzoic acid, pyrrolidine, tBtU and N-ethyl-diisopropylamine in tetrahydrofuran/water 9:1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([CH2:24][NH:25]C(=O)OCC3C=CC=CC=3)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:36])=[CH:13][CH:14]=2)[N:9]=1>[Pd].CCO>[NH2:25][CH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:36])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 3 h

Procedure:
To a mixture of benzyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (610 mg, 1.26 mmol) and EtOH (15 mL) in a round bottom flask was added Pd/C (61 mg, 10% wt Pd on carbon) and the flask was sealed with a septum. The atmosphere in the flask was evacuated, purged with N2, and equipped with a balloon charged with H2. The mixture was then stirred under an H2 atmosphere at ambient pressure for 3 h. After filtration through a plug of Celite, using MeOH as the eluting solvent, the reaction mixture was concentrated to a yellow solid 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (441 mg). LC/MS: nm/z 349.3 (M+H)+ at 1.52 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.45 (m, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.35-7.39 (m, 2H), 6.92-6.96 (m, 2H), 4.52 (d, J=12.5 Hz, 1H), 4.41 (d, J=13.2 Hz, 1H), 3.26-3.29 (m, 2H), 3.02-3.08 (m, 1H), 2.55-2.61 (m, 1H), 2.45-2.48 (m, 1H), 1.84-1.91 (m, 2H), 1.65-1.77 (m, 3H), 1.24-1.36 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[N:9][C:10]=1Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[Cl:21]>>[CH3:1][O:2][N:3]=[CH:4][C:5]1[C:6]([NH2:12])=[N:7][CH:8]=[N:9][C:10]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([Cl:21])[CH:16]=1
Reactant: Nc1ccc(O)cc1Cl
Reactant: CON=Cc1c(N)ncnc1Cl
Product: CON=Cc1c(N)ncnc1Oc1ccc(N)c(Cl)c1

Procedure:
Using the procedure for Example 9, 4-amino-6-chloro-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 9a (0.20 g) and 4-amino-3-chloro-phenol Compound 10a (0.19 g) were reacted to provide 4-amino-6-(4-amino-3-chloro-phenoxy)-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 10b (0.20 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.60 (s, 1H), 7.15 (s, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 5.32 (s, 2H), 3.98 (s, 3H). MS (ESI) m/z: 299 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][S:6][C:5]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[N:11][C:4]=2[NH:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O>C1COCC1>[OH:13][CH2:12][C:10]1[CH:9]=[CH:8][C:5]2[S:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=2[N:11]=1
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CSc2ccc(CO)nc2N1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A solution of 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500 mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to −10° C. and isobutyl chloroformate (0.339 ml) added. After 20 minutes the suspension was filtered through kieselguhr into an ice-cooled solution of sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30 minutes and the pH reduced to 7 with dilute HCl. The solvent was evaporated and the residue triturated under water. The product was filtered and dried under vacuum to give a white solid (346 mg); MS (APCI−) m/z 195 ([M−H]−, 50%), 165(100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C@H:16]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[N:21]3[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:17])[C:10]=1[C:36]#[N:37].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[C:10]([C:36]#[N:37])=[C:11]([NH:15][C@H:16]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:27])[N:21]3[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:17])[N:12]=[CH:13][N:14]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)n2c1-c1ccccc1
Reactant: CN1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)N3CCN(C)CC3)n2c1-c1ccccc1

Procedure:
A solution of N-methylpiperazine (0.040 mL, 0.356 mmol), (S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylic acid (0.071 g, 0.178 mmol), PyBOP (0.185 g, 0.356 mmol) and DIEA (0.062 mL, 0.356 mmol) in DMF (1.78 mL) was stirred at rt for 1 h. The solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford an off-white solid that was repurified by MPLC (eluted with a gradient of 0-80% (1:10:90 NH4OH:MeOH:DCM) solution in DCM) to afford 4-amino-6-(((1S)-1-(5-((4-methyl-1-piperazinyl)carbonyl)-3-phenylimidazo[1,2-a]pyridin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (dd, J=14.18, 6.75 Hz, 3H) 1.88-2.01 (m, 1H) 2.03-2.10 (m, 1H) 2.12-2.44 (m, 6H) 3.00-3.14 (m, 1H) 3.22 (m, J=9.19 Hz, 1H) 3.40 (d, J=4.30 Hz, 1H) 5.13-5.34 (m, 1H) 6.75-6.98 (m, 2H) 7.16-7.53 (m, 8H) 7.75 (m, J=9.00, 5.09 Hz, 1H) 7.94 (d, J=6.85 Hz, 1H). LC-MS (ESI) m/z 482.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:10][C:11]=2[CH2:12][OH:13])=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1(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)C=CC=CC=1>[C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:10][C:11]=2[CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of [4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol (0.33 g, 0.78 mmoles, 1 eq) in dry 1,2-dimethoxyethane (5 ml, 0.16M) was added tetrakis(triphenylphosphino) palladium I (0.45 g, 0.39 mmoles, 0.5 eq) and stirred for 5 minutes at room temperature. Phenylboronic acid (0.143 g, 1.2 mmoles, 1.5 eq) was then added followed by the addition of sodium carbonate (2M aqueous solution, 2.3 ml, 4.68 mmoles, 6 eq). The reaction mixture was heated at 100 degrees centigrade for 13 hours at which point, after cooling to room temperature, the reaction was partitioned between EtOAc and water. After separation of the phases the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to yield after purification by silica gel chromatography (CH2Cl2 to 2% MeOH/CH2Cl2) 268 mg (80%) of product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1>>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:19]2[N:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:22]3[S:23][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:31])=[O:7])[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:18]=2)=[CH:41][N:42]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine via General Procedure A. Purification on silica yielded 155. NMR (CDCl3): 2.57-2.60 (m, 4H, 2×CH2), 2.92 (s, 3H, CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.57 (m, 4H, 2×CH2), 3.86 (s, 2H, CH2), 3.89-3.92 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 5.28 (sbr, 2H, NH2), 7.29 (s, H, ArH), 7.33 (s, H, ArH), 9.29 (s, 2H, 2×ArH). MS: (ESI+): MH+ 528.44
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[OH:18])=[O:10])=[CH:4][CH:3]=1.[C:19]([Cu])#[N:20].O.CCOC(C)=O>CN(C=O)C>[OH:18][C:12]1[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=1[C:9](=[O:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:19]#[N:20])=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccc(Br)cc1)c1ccc(O)cc1O
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(=O)c2ccc(O)cc2O)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 36.3 %

Procedure:
A mixture of 2-(4-bromophenyl)-1-(2,4-dihydroxyphenyl)ethanone (5 g, 16.3 mmol) and CuCN (5.8 g, 65.4 mmol) in DMF (50 ml) was stirred at 150° C. for 6 h under nitrogen. Water (100 ml) and EtOAc (100 ml) was added to the mixture. The precipitate was filtered off and the filtrate was washed with brine (100 ml), dried over Na2SO4 and concentrated to give black oil, which was purified by Combiflash (PE/EtOAc=3/1) to afford product as a yellow powder (1.5 g, 36.6%). MS (ESI): m/z 254.1 [M+1]+.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>O.C(O)C.[Cu]>[N+:21]([C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O-:23])=[O:22]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6.5 g of potassium hydroxide in 80 ml of water is treated under a nitrogen atmosphere at 50° C with 10.3 ml of thiophenol and the mixture is then stirred for 30 minutes. After the addition of 0.5 g of copper powder and 22.5 g of 4-chloro-3-nitro-benzotrifluoride in 100 ml of ethanol, the mixture is heated under reflux for 48 hours. After filtration, the mixture is poured into water and extracted with ether. The ethereal phase is washed successively with aqueous sodium carbonate solution, water, aqueous sodium chloride solution, 2-N aqueous hydrochloric acid and water, dried, filtered and evaporated. There is obtained 3-nitro-4-(phenylthio)-benzotrifluoride as a red oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:31](=[O:50])(=[O:49])[N:32](CC2C=CC(OC)=CC=2OC)[C:33]2[S:37][N:36]=[CH:35][N:34]=2)=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH3:12])[C:6]=2[CH:30]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[Br:1][C:2]1[C:3]([S:31]([NH:32][C:33]2[S:37][N:36]=[CH:35][N:34]=2)(=[O:50])=[O:49])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:22]=3[CH2:21][NH:20][CH2:19][CH2:18]4)[CH3:12])[C:6]=2[CH:30]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4cccc5c4CN(C(=O)OC(C)(C)C)CC5)c3cc2Br)c(OC)c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1cccc2c1CNCC2)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Br)cc21
Reaction time: 1.5 h

Procedure:
Added 35-4 (120 mg, 0.153 mmol) to DCM (610 μl) and TFA (306 μl). After 90 min, diluted with 1 mL MeOH, filtered through Celite, washed with MeOH. Concentrated filtrate in vacuo and dissolved in 2 mL DMSO. Purified by reverse-phase HPLC (C18 column, 2-60% 0.1% TFA/CH3CN:0.1% TFA/H2O) to give 35-5 as a white solid
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](=[O:26])[NH:22][CH2:23][C:24]#[CH:25])=[CH:11][CH:12]=2)[N:7](C2CCCCO2)[N:6]=1)=[O:4].C(Cl)Cl.OC(C(F)(F)F)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21](=[O:26])[NH:22][CH2:23][C:24]#[CH:25])=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[O:4]
Reactant: C#CCNC(=O)c1ccccc1Nc1ccc2c(C(=O)NC)nn(C3CCCCO3)c2c1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(C(=O)NC)n[nH]c2c1
Yield: 49.7 %

Procedure:
Dissolved 6-(2-Prop-2-ynylcarbamoyl-phenylamino)-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxylic acid methylamide (30 mg) in 1.5 mL of a 90:10:1 mixture of CH2Cl2:Trifluoroacetate TFA:triethyl silane and heat to reflux for 2 hours. Diluted the solution with toluene (40 mL) and concentrate by rotary evaporation to an oil. Dissolved the oil in DMF (1 mL), and filter using a 0.2-micron syringe filter. Used prep-HPLC to isolate the desired compound (12 mg, 50%). 1H NMR (CDCl3-d) δ 9.96 (1H, s), 9.49 (1H, s), 8.28 (1H, d, J=8.85 Hz), 7.47 (1H, m), 7.34 (1H, m), 7.22 (1H, m), 7.15 (1H, dd, J1=8.76 Hz, J2=1.79 Hz), 6.99 (1H, m), 6.86 (1H, t, J=6.97 Hz), 6.31 (1H, m), 4.23 (2H, dd, J1=5.18 Hz, J2=2.54 Hz), 3.49 (3H, s), 2.29 (s,1H).