Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1C=C(O)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:12]([O:14][C:15](=[O:31])[C:16]([C:29]#[N:30])=[CH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([Br:28])[CH:19]=1)[CH3:13]>C1(C)C=CC=CC=1>[C:29]([C:16]1[C:15](=[O:31])[O:14][C:12]2[C:6]([C:17]=1[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([Br:28])[CH:19]=1)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:13]=2)#[N:30]
Reactant: COc1cccc(O)c1
Reactant: CCOC(=O)C(C#N)=Cc1cc(Br)c(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(-c3cc(Br)c(OC)c(OC)c3)c(C#N)c(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.7 %

Procedure:
To a solution of 5-bromoveratraldehyde (1.0 g, 4.1 mmol) and ethyl cyanoacetate (0.45 mL, 4.1 mmol) in ethanol (4 mL) was added piperidine (0.4 mL, 4.1 mmol). The mixture was stirred at room temperature for 0.5 h and precipitate was collected by filtration to yield the product (1.16 g) 3-(3-bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid ethyl ester as a solid. To a solution of 3-methoxyphenol (0.11 mL, 1 mmol) in toluene (10 mL) was added sodium hydride (60 mg, 1.5 mmol, 60%) and the mixture was stirred at room temperature for 0.5 h. To the mixture was added 3-(3-bromo-4,5-dimethoxy-phenyl)-2-cyano-acrylic acid ethyl ester (340 mg, 1 mmol) as a solid, then the mixture was refluxed for 2 h. The solvent was evaporated and the residue was purified by chromatography on silica gel with ethyl acetate and hexane (1:2) as eluant, yielding 7 mg (1.7%) of the title compound. 1H NMR (CDCl3): 7.34 (d, J=9.6, 1H), 7.21 (d, J=1.8, 1H), 6.98 (d, J=1.8, 1H), 6.91-6.90 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:34][C:20](=[O:22])[C@H:11]([CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-L-aspartic acid 4-benzyl ester was coupled with 3-phenyl-L-alanine benzyl ester to give N-[3-[(benzyloxy)carbonyl]-N-(t-butoxycarbonyl)-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 93°-94° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:36]=[CH:37][C:38]([N+:42]([O-:44])=[O:43])=[C:39]([NH2:41])[CH:40]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:17]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:19]=[C:20]([O:22][C:35]3[CH:36]=[CH:37][C:38]([N+:42]([O-:44])=[O:43])=[C:39]([NH2:41])[CH:40]=3)[CH:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc([N+](=O)[O-])c(N)c3)c2)CC1

Procedure:
Using {trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.5 g, 5.29 mmol) and 5-fluoro-2-nitro-phenylamine (0.91 g, 5.82 mmol) following the procedure of Example 42(b) afforded 1.6 g of the required product 1H NMR (DMSO-d6): δ 1.45 (9H, s), 1.8 (4H, m), 2.5 (4H, m), 3.2 (1H, m), 6.48 (2H, m), 6.75 (1H, d), 7.24 (2H, m), 7.51 (4H, m), 7.78 (2H, d), 8.05 (1H, d), 8.38 (1H, d).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[N:7][C:8]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:10]=1[Sn](C)(C)C.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:10]1[CH:9]=[C:8]([C:15]([F:18])([F:17])[F:16])[N:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: COc1cnc(C(F)(F)F)cc1[Sn](C)(C)C
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1cnc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (0.52 ml, 10 mmol) was added via syringe to a stirred solution of 3-methoxy-6-trifluoromethyl-4-trimethylstannylpyridine (1.7 g, 5 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 30 min at room temperature and treated with saturated aqueous Na2SO3 (15 ml). The phases were separated. The aqueous layer was extracted with dichloromethane (2×15 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (hexane:ethyl acetate 0-15%) to afford 4-bromo-3-methoxy-6-trifluoromethylpyridine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:23])=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=[C:10]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[C:7]([OH:23])=[C:8]([C:19]([CH3:21])([CH3:20])[CH3:22])[CH:9]=[C:10]([C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[O:4][CH:3]=1
Reactant: Cc1c(C(=O)O)oc2c(C(=O)c3ccccc3)cc(C(C)(C)C)c(O)c12
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: Cc1coc2c(C(=O)c3ccccc3)cc(C(C)(C)C)c(O)c12
Temperature: 195 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-5-t-butyl-7-benzoylbenzofuran-2-carboxylic acid (0.334 g, 0.98 mmol), quinoline (1 mL), and copper powder (0.062 g, 0.98 mmol) was warmed to 195° C. until gas evolution had ceased (about 10 minutes). The reaction mixture was allowed to cool and poured into 2N HCl (40 mL). Ethyl acetate (25 mL) was added and the biphasic mixture was filtered through a pad of celite. The layers were separated and the aqueous layer extracted with ethyl acetate (25 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Flash chromatography using 10% ethyl acetate in hexane as eluant afforded 3-methyl-4-hydroxy-5-tert-butyl-7-benzoylbenzofuran, compound 16 as a white solid after trituration from hexane. 1H NMR d 1.49 (9H, s), 2.51 (3H, d, J=2 Hz), 5.78 (1H, s), 7.31 (1H, s), 7.54 (3H, m), 7.66 (1H, s), 7.85 (2H, m).
Reaction SMILES: [C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23](OC)=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Li+].[BH4-].[Na+].C(O)C>C1COCC1>[OH:24][CH2:23][CH:19]1[O:20][CH2:21][CH2:22][N:17]([C:15]([O:14][C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:16])[CH2:18]1
Reactant: COC(=O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(Oc1cccc2c1Cc1ccccc1-2)N1CCOC(CO)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.56 g of methyl 4-fluorenyloxycarbonyl-morpholine-2-carboxylate in 25 mL of THF was added 0.58 g of lithium chloride, 0.52 g of sodium borohydride, and 25 mL of ethanol. The mixture was stirred overnight at room temperature, concentrated, and redissolved in 200 mL of CH2Cl2. This CH2Cl2 solution was washed with 2×100 mL of water and 100 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 1:1 hexanes-EtOAc, to yield 2.34 of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3): δ7.77 (d, J=7.6 Hz, 2H), 7.56 (d, J=7.3 Hz, 2H), 7.40 (t, J=7.6 Hz, 2H), 7.32 (t, J=7.3 Hz, 2H), 4.49 (br s, 2H), 4.24 (t, J=6.4 Hz, 1H), 3.24-4.03 (m, 7H), 2.97 (br s, 1H), 2.80 (br t, J=11.7 Hz, 1H).
Reaction SMILES: [CH:1](=[O:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)C>[OH:7][CH:1]([C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccco1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccco1
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A solution of furfuraldehyde (288 g.) in diethyl ether (400 ml.) was added over 30 minutes to a stirred solution of phenyl magnesium bromide [prepared from bromobenzene (314 g.) and magnesium (48 g.)] in diethyl ether (1400 ml.) at -25° C. The cooling bath was removed and the mixture was allowed to attain 10° C. over 30 minutes. The mixture was recooled to 0° C. and saturated aqueous ammonium chloride solution was added at that temperature. The mixture was diluted with water (2 liters) and the organic phase was separated. The aqueous phase was filtered and extracted with diethyl ether (3 × 200 ml.) and the combined etheral solutions were dried over sodium sulphate, filtered and evaporated to dryness. The resulting pale red oil was distilled to give (±) 2-(α-hydroxybenzyl)furan (240 g.), b.p. 110°-130° C./0.05 mm.Hg.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]([O:34]CC2C=CC=CC=2)=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:24]([OH:34])=[CH:23][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(F)cc2)c(OCc2ccccc2)cc1OCCCOc1ccccc1CCc1nnn[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc(-c2ccc(F)cc2)c(O)cc1OCCCOc1ccccc1CCc1nnn[nH]1
Reaction time: 1 h

Procedure:
5-(2-(2-(3-(2-Ethyl-4-(4-fluorophenyl)-5-benzyloxyphenoxy)propoxy)phenyl)ethyl)-1H-tetrazole (90 mg, 0.16 mmol) was dissolved in ethanol and 10% palladium on carbon catalyst was added under an atmosphere of carbon dioxide. The mixture was then hydrogenated at 30 psi at room temperature for 1 hour. The catalyst was filtered off and the solution evaporated to dryness to give an oil. This oil was then purified by reverse phase HPLC on a C18 column eluting with methanol/water (90:10) containing 0.01% acetic acid. The title compound was isolated as an oil (yield 41 mg, 55%) containing 0.3 equivalents of acetic acid. NMR, MS.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH3:9][O:10][C:11]1[S:15][C:14]([N:16]=[C:17]=[O:18])=[CH:13][CH:12]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:9][O:10][C:11]1[S:15][C:14]([NH:16][C:17]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:18])=[CH:13][CH:12]=1
Reactant: CN1CC(=O)N=C1N
Reactant: COc1ccc(N=C=O)s1
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)N=C2NC(=O)CN2C)s1
Temperature: 65 °C
Yield: 3.2 %

Procedure:
To a stirred suspension of 3.0 g (26 mM) of creatinine in 25 ml of anhydrous DMF was added a solution of 4.1 g (26 mM) of 5-methoxy-2-thienyl isocyanate in 20 ml of toluene. The resulting mixture was heated at 65° C. for 4.5 hrs., cooled, and poured into 200 ml of water. The mixture was extracted with ethyl acetate, and the combined extracts dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate and then ethanol. Final purification was accomplished by chromatography over silica gel (ethyl acetate as eluant), decolorizing the product with charcoal, concentration and recrystallization from acetone-hexane to give 0.23 g of the above urea as a light brown solid, m.p. 180°-182° C. (dec.).
Reaction SMILES: [C:1]([C:6]1[N:7]=[C:8]([CH2:50][CH2:51][CH3:52])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+]>>[OH:5][CH:1]([C:6]1[N:7]=[C:8]([CH2:50][CH2:51][CH3:52])[N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:10]=1[C:11]#[N:12])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 93.5 %

Procedure:
Following a procedure similar to that described in Example 74(b), but using 1.60 g of 4-isobutyryl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (a) above] and 0.13 g of sodium borohydride, 1.50 g of the title compound was obtained as crystals, melting at 154°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([S:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].[OH-].[Na+].O.Cl>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([S:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCCC(Sc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)OCC)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(Sc1nc(-c2ccccc2)cs1)c1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4-{1-[(4-phenyl-1,3-thiazol-2-yl)thio]butyl}benzyl)oxy]phenyl}propanoate (0.130 g, 0.236 mmol) in a mixture of ethanol (0.5 mL) and tetrahydrofuran (1 mL) was added 2N aqueous sodium hydroxide solution (0.25 mL) and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-70:30) to give the title compound (0.119 g, yield 97%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:10]=1.B(Cl)(Cl)Cl.CO.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[F:17][C:14]([F:15])([F:16])[C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[O:13][N:12]=1
Reactant: COc1ccccc1-c1cc(C(F)(F)F)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Oc1ccccc1-c1cc(C(F)(F)F)no1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
To a mixture of 5-(2-methoxyphenyl)-3-(trifluoromethyl)-1,2-oxazole (C10) (502 mg, 2.06 mmol) and tetra-n-butylammonium iodide (915 mg, 2.48 mmol) in dichloromethane (20 mL) cooled to −78° C. was added boron trichloride (1 M in dichloromethane, 4.95 mL, 4.95 mmol). The reaction was allowed to stir at room temperature for 24 hours, and then cooled to −78° C., whereupon methanol (3 mL) was slowly added followed by water (30 mL). The mixture was extracted with dichloromethane (2×10 mL), and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% tert-butyl methyl ether in heptanes) afforded the title compound as a white solid. Yield: 283 mg, 1.23 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 5.94 (s, 1H), 6.96 (br d, J=8.2 Hz, 1H), 7.02 (s, 1H), 7.09 (br dd, J=8, 8 Hz, 1H), 7.39 (ddd, J=8, 8, 1.6 Hz, 1H), 7.89 (dd, J=7.9, 1.7 Hz, 1H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[N:33]([CH3:44])[C:34](=[O:43])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:33]([CH3:44])[C:34](=[O:43])[CH2:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:27]([O:26][CH3:25])[CH:28]=3)[C:10]=12
Reactant: COc1cc(B(O)O)ccc1N(C)C(=O)CCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N(C)C(=O)CCc1ccccc1
Temperature: 85 °C

Procedure:
A solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.293 g, 0.664 mmol) in ethylene glycol dimethyl ether (10 mL) was treated with 3-methoxy-4-[methyl(3-phenylpropanoyl)amino]phenylboronic acid (0.290 g, 0.730 mmol), tetrakis(triphenylphosphine)palladium (0.046 g, 0.040 mmol), and a solution of sodium carbonate (0.169 g, 1.59 mmol) in water (5 mL). The reaction mixture was stirred over night at 85° C. under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added to the aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 4% methanol in dichloromethane, 8% methanol in dichloromethane, and then 12% methanol in dichloromethane as eluent. A second column using a Supelco flash chromatography silica gel column using 30% methanol in dichloromethane afforded 0.037 g (10%) of cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide. 1H NMR (CDCl3, 400 MHz) δ 8.374 (s, 1H), 7.315-7.312 (m, 1H), 7.285-7.213 (m, 3H), 7.174-7.087 (m, 4H), 5.795 (br. s., 2H), 4.965-4.922 (m, 1H), 3.892 (s, 3H), 3.213 (s, 3H), 2.948-2.918 (m, 2H), 2.667 (m, 6H), 2.455-2.349 (m, 10H), 2.25-2.15 (m, 2H), 1.867-1.845 (m, 2H), 1.718-1.710 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.947 min (98%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:11][C:12](=[O:27])[CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1.[CH2:28]([O:30][C:31](=[O:34])[CH2:32]Br)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][NH:11][C:12](=[O:27])[CH2:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1)[CH3:29]
Reactant: O=C(CCC#Cc1ccc(C(F)(F)F)cc1)NCc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccc(CNC(=O)CCC#Cc3ccc(C(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 b], 5-(4-trifluoromethyl-phenyl)-pent-4-ynoic acid (1H-indol-6-ylmethyl)-amide was reacted with bromo-acetic acid ethyl ester in the presence of cesium carbonate and potassium iodide in acetonitrile under reflux conditions to give the title compound as off-white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[N:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: CC(C)(C)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,2-dimethylpropionyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (64% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 8.01, 6.98, 3.86-3.73, 3.57, 1.57-1.48, 0.79-0.70, 0.52-0.45, 0.16-0.12. MS (ES+) m/z 360.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[C:4]([CH3:13])[CH:3]=1>COCCOC.C([O-])([O-])=O.[K+].[K+].C(OCC)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>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH3:13])[CH:3]=[C:2]([CH:3]=[C:4]([CH3:13])[CH3:5])[N:7]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cc(C)cc(Cl)n1
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: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)cc(C=C(C)C)n1
Temperature: 80 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a solution of ethyl 6-chloro-4-methyl-pyridine-2-carboxylate (500 mg, 2.51 mmol) and 2,4,6-tris-(2-methyl-propenyl)-cyclotriboroxane pyridine complex (814 mg, 2.51 mmol) in DME (32 mL), 2 M aq. K2CO3 (12 mL) solution is added. The mixture is degassed and put under argon before Pd(PPh3)4 (52 mg, 0.045 mmol) is added. The mixture is stirred at 80° C. for 6 h before it is cooled to rt, diluted with diethyl ether (50 mL) and washed with sat. aq. NaHCO3 (2×30 mL) solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-methyl-6-(2-methyl-propenyl)-pyridine-2-carboxylic acid ethyl ester (176 mg) as a yellow oil; 1H NMR (CDCl3): δ 1.45 (t, J=7.0 Hz, 3H), 1.97 (s, 3H), 2.12 (s, 3H), 2.42 (s, 3H), 4.46 (q, J=7.0 Hz, 2H), 6.41 (s, 1H), 7.17 (s, 1H), 7.75 (s, 1H).