Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C1(C)C(C)=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 85 %

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 7.536 g (48 mmol) of bromobenzene, 6.769 g (40 mmol) of diphenylamine, 4.613 g (48 mmol) of sodium-tert-butoxide, 0.009 g (0.04 mmol) of palladium (II) acetate and 5 ml of xylene were weighed in the flask, followed by stirring. Further, 0.071 g (0.12 mmol) of di-tert-butyl-1-naphthylphosphonium tetraphenylborate obtained in Example B-11 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 125° C. for 4 hours. After the completion of the reaction, 45 ml of xylene and 50 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 8.341 g of triphenylamine (yield: 85 mol % based on diphenylamine). The melting point was 125-126° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[C:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[N:21]=[CH:20]3)=[CH:15][C:14]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O.C(OCC)(=O)C.[CH3:54][N:55](C)C(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[O:10][C:11]1[C:16]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[N:21]=[CH:20]3)=[CH:15][C:14]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:13]([C:54]#[N:55])[CH:12]=1
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC2Cc3ccccc3C2)cc1OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC2Cc3ccccc3C2)cc1C#N
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A solution of Intermediate 6 (30 mg) in N,N-dimethylacetamide (1 ml) was added with K4[Fe(CN)6]·3H2O (6.6 mg, Ald), sodium carbonate (5.5 mg), and palladium acetate (1.1 mg, WAKO), and stirred at 120° C. for 5 hours. The reaction mixture was added with water (3 ml), and ethyl acetate (3 ml×2) for extraction, and then successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (yield: 10 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH3:34][O:35][C:36](=[O:41])[C@@H:37]([CH2:39][OH:40])[NH2:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:41])[C@H:37]([NH:38][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:18]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:39][OH:40]
Reactant: COC(=O)[C@H](N)CO
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](CO)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (0.300 g, 0.703 mmol) of Example 5 Step E, D-serine methyl ester hydrochloride (0.131 g, 0.844 mmol), 1-hydroxy benzotriazole (0.104 g, 0.773 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.148 g, 0.773 mmol) were combined in amine-free N,N-dimethylformamide (2.8 mL), followed by the addition of N,N-diisopropylethylamine (0.307 mL, 1.76 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The combined aqueous washings were saturated with sodium chloride, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform, to afford 0.320 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:15](=[O:16])[CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Reactant: CNc1ccc(C(=O)OC)cc1
Product: CN(C(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Yield: 55.3 %

Procedure:
In a manner similar to Example 4(c), by reaction of 2.46 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 1.65 g (10 mmol) of methyl 4-methylaminobenzoate, 2.1 g (54%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:23]#[N:24].C(P(C(C)(C)C)C1(C)CC1(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:20]([NH:19][C:2]2[CH:3]=[C:4]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH:21]=1)#[N:24]
Reactant: COc1ccc(C#N)cc1N
Reactant: N#Cc1cnc2c(NCC(F)(F)F)cc(Cl)nn12
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(C#N)cc1Nc1cc(NCC(F)(F)F)c2ncc(C#N)n2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 5.4 %

Procedure:
A mixture of 9A (100 mg, 0.36 mmol), 3-amino-4-methoxybenzonitrile (108 mg, 0.73 mmol) and di-tert-butyl(1-methyl-2,2-diphenylcyclopropyl)phosphine (25.6 mg, 0.073 mmol) in toluene (1 mL) was purged with nitrogen. Allylpalladium (II) chloride dimer (13.3 mg, 0.036 mmol) and sodium tert-butoxide (41.8 mg, 0.435 mmol) were added, and the reaction mixture was purged with nitrogen and heated at 100° C. After 20 minutes, the reaction mixture was cooled to room temperature, diluted with DCM, and filtered through CELITE®. The filtrate was concentrated under reduced pressure, dissolved in DMSO/methanol, and purified by reverse phase HPLC (PHENOMENEX® Luna Axia 5 micron 30×250 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in (Solvent A=10% MeOH-90% H2O-0.1% TFA) in 15 min.) to obtain Example 9, (9.9 mg, 0.020 mmol, 5.4% yield) as a light yellow solid. HPLC: Rt=0.95 min. (BEH C18 2.1×50 mm, 1.7 u, 0 to 100 B in 1 min. with 0.5 min. hold time, flow rate=1 mL/min., detection at 254 nm, Solvent A: 100% water/0.1% TFA; Solvent B: 100% ACN1/0.1% TFA). MS (ES): m/z=388.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.76 (1H, d, J=1.94 Hz), 8.67 (1H, s), 8.23 (1H, s), 8.03-8.12 (1H, m), 7.41-7.55 (1H, m), 7.24 (1H, d, J=8.32 Hz), 6.75 (1H, s), 4.06-4.17 (2H, m), 4.00 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:28][C:27]1[C:18]([C:16]2[CH:17]=[C:4]3[N:3]=[C:2]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:7]=[C:6]([O:8][CH:9]4[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)[N:5]3[N:15]=2)=[N:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:26]=1
Reactant: C1CCNC1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(OC3CCOCC3)n2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cc2nc(N3CCCC3)cc(OC3CCOCC3)n2n1
Temperature: 100 °C

Procedure:
A mixture of 2-[5-chloro-7-(tetrahydro-2H-pyran-4-yloxy)pyrazolo[1,5-a]pyrimidin-2-yl]-3-methylquinoxaline (90 mg, 0.227 mmol), pyrrolidine (49 mg, 0.682 mmol), sodium tert-butoxide (33 mg, 0.341 mmol), palladium(II) acetate (52 mg, 0.227 mmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (179 mg, 0.454 mmol) in 1,4-dioxane (4.0 mL) was heated at 100° C. for 40 min. After being cooled to ambient temperature, the reaction mixture was poured into water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to 1:9) to give 2-methyl-3-[5-pyrrolidin-1-yl-7-(tetrahydro-2H-pyran-4-yloxy)pyrazolo[1,5-a]pyrimidin-2-yl]quinoxaline. MS (APCI): m/z 431 (M+H).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([O:11][C:12]([C@@H:14]([NH:23][C@@H:24]([CH3:35])[C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH3:10]>[Pd]>[CH2:9]([O:11][C:12]([C@@H:14]([NH:23][C@@H:24]([CH3:35])[C:25]([OH:27])=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:13])[CH3:10]
Reactant: CCCCCCCC[C@H](N[C@@H](C)C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Product: CCCCCCCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Yield: 75.9 %

Procedure:
16.8 g of benzyl (2S)-2-[N-((1S)-1-ethoxycarbonyl-n-nonyl)amino]propionate maleate and 200 mg of palladium black are treated in the same manner as described in Preparation 6-(2). The residue is crystallized with a mixture of ether and n-hexane. 7.42 g of (2S)-2-[N-((1S)-1-ethoxycarbonyl-n-nonyl)amino]propionic acid are obtained as colorless crystals. Yield: 75.9%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH3:17])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:22]>C(O)C>[NH2:22][C:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:16][CH3:17])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: [NH4+]
Reactant: COc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: COc1ccc(Cl)cc1C1CC(=O)C=C(N)C1

Procedure:
A solution of 5-(5-chloro-2-methoxyphenyl)cyclohexane-1,3-dione (5.0 g) and ammonium acetate (4.6 g) in ethanol (100 ml) was refluxed for 20 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-amino-5-(5-chloro-2-methoxyphenyl)cyclohexen-3-one, which was dissolved in ethanol (120 ml) and toluene (210 ml). To the solution were added 3-oxobutylaldehydedimethylacetal (6.5 g) and powdery potassium hydroxide (0.92 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (0.19 g), 30 minutes later; were added powdery potassium hydroxide (0.19 g) and 3-oxobutylaldehydedimethylacetal (0.52 g), 1 hour later; and was added powdery potassium hydroxide (0.19 g), 1.5 hours later, and the mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column (ethyl acetate-hexane) to give 7-(5-chloro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (2.2 g) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3](OC(=O)CBr)=[O:4].[NH2:10][C:11]1[CH:12]=[C:13]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]2[OH:26].C(N(CC)CC)C>CN(C=O)C>[N:28]1([CH2:27][C:13]2[CH:14]=[C:15]3[C:16](=[O:26])[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:19]4[CH2:2][C:3](=[O:4])[NH:10][C:11]([CH:12]=2)=[C:20]34)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Reactant: O=C(CBr)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)NC(=O)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Bromoacetic anhydride (280 mg) is added to ethyl 8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 2, 330 mg) in DMF (4.0 mL). Triethylamine (400 mg) is added and the reaction is heated for 10 min at 60° C. After 1 h, the DMF is removed and the product is chromatographed on silica gel with 10% methanol as the eluant to give 310 mg of the title compound as a mixture with triethylamine hydrobromide. Physical characteristics: 1H NMR (DMSO-d6) δ1.40, 2.45, 3.56, 3.69, 4.39, 4.88, 7.49, 7.97, 8.34.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[CH2:17][C:18]1[C:19]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:27][C:26]1[C:19]2[C:18]([CH2:17][C:16]3[N:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]4=[N:9][C:8]=3[S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:22][S:21][C:20]=2[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2cccc(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2scc(Cc3c(SCCCC(=O)O)nc4ccccn34)c12
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.24 mmol) of 4-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-ylsulfanyl]-butyric acid methyl ester in 2 mL of THF is treated with a solution of 20 mg (0.48 mmol) of lithium hydroxide monohydrate in 1 mL of water at room temperature. The resulting mixture is heated to 40° C., and stirred at this temperature for 3 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is diluted with water and neutralized with 1N HCl solution. The product is extracted with ethyl acetate, and the organic layer is separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 3˜10% methanol in dichloromethane solution to give the title compound. LCMS (ESMS): m/z 397 (M+H+)
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[CH3:23][O:24][C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27](OC)=O.[H-].[Na+]>CN(C=O)C>[OH:15][CH2:14][C@H:9]1[C@H:8]([C:7]2[C:6]([O:16][CH3:17])=[CH:5][C:4]([O:18][CH3:19])=[C:3]3[C:2]=2[O:1][C:27]([C:26]2[CH:31]=[CH:32][CH:33]=[CH:34][C:25]=2[O:24][CH3:23])=[CH:21][C:20]3=[O:22])[CH2:12][CH2:11][N:10]1[CH3:13]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1ccccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(=O)c2c(OC)cc(OC)c([C@@H]3CCN(C)[C@H]3CO)c2o1

Procedure:
Compound of example 6 (0.7 g, 2.2 mmol) in dry DMF (10 mL) was reacted with methyl 2-methoxybenzoate (1.13 g, 6.8 mmol) in the presence of NaH (50%, 0.544 g, 11.3 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[N:8][N:7]4[C:2]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20]1
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CC3)n2)cc1
Reactant: COCCN
Product: COCCNc1cccc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(OC)cc3)nn12
Temperature: 140 °C
Yield: 95 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine (75 mg, 0.19 mmol) and 2-methoxyethylamine (5 mL, 58 mmol) was heated in a sealed tube at 140° C. for 24 hours. After cooling to room temperature, the mixture was concentrated. Flash chromatography (1:1 to 1:3 hexanes-ethyl acetate) provided 3-[2-(cyclopropylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (77.7 mg, 95%) as a yellow solid. 1H NMR (CDCl3): δ 8.03 (d, 1 H), 7.96 (d, 1 H), 7.60 (d, 2 H), 7.31 (t, 1 H), 7.00 (d, 2 H), 6.41 (d, 1 H), 6.31 (t, 1 H), 6.04 (d, 1 H), 5.40 (broad, 1 H), 3.89 (s, 3 H), 3.72 (t, 2 H), 3.57 (q, 2 H), 3.43 (s, 3 H), 2.88 (m, 1 H), 0.88 (m, 2 H), 0.64 (m, 2 H); MS m/z 431 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[NH2:13][CH2:14][CH2:15][OH:16]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:13][CH2:14][CH2:15][OH:16])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)nc1C(=O)NCCO
Yield: 15 %

Procedure:
A solution of 3-amino-6-bromo-2-carbomethoxypyrazine (100 mg, 0.4 mmol ) and 2-aminoethanol (500 mg, 8.2 mmol ) in THF (5 mL) was heated at reflux for 2 days. The reaction mixture was cooled, diluted with ethyl acetate (20 mL), washed with water then brine, dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-N-(2-hydroxyethyl)-6-bromo-pyrazine-2-carboxamide, a pale yellow oil, (108 mg, 96% yield) MS (EI) for C7H9BrN4O2: 262 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(#N)C>[CH:11]([O:10][CH2:9][C:4]1[CH:5]=[C:6]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)[N:7]=[C:2]([NH2:1])[N:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)OCc1cc(=O)[nH]c(N)n1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)OCc1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14 %

Procedure:
To a solution of 2-amino-6-isopropoxymethyl-3H-pyrimidin-4-one (0.050 g, 0.27 mmol) in acetonitrile (2.37 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.157 g, 0.355 mmol), DBU (0.82 mL, 0.55 mmol), and 1-methyl-piperazine (0.091 ml, 0.82 mmol). The reaction mixture was stirred at rt for 12 h, then at 60° C. for 3 h. The mixture was concentrated and the resultant residue was purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (10 mg, 14%). MS (ESI): mass calcd. for C13H23N5O, 265.4; m/z found, 266.3 [M+H]+. 1H NMR (MeOD): 6.55 (s, 1H), 4.49 (s, 2H), 3.78 (quintet, J=6.1, 1H), 3.70-3.00 (m, 8H), 2.95 (s, 3H), 1.25 (d, J=6.1, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([NH2:17])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:8][C:7]1[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]([F:18])([F:31])[F:30])=[CH:3][C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([NH2:17])=[O:16])=[N:10]2)=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: Cc1cc(C(N)=O)nn1-c1ccc(F)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C(N)=O)nn1-c1ccc(F)c(-c2ccccc2OC(F)(F)F)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of the carboxamide (from step 2) (0.063 g, 0.2 mmol) and 2-trifluromethoxyphenyl boronic acid (0.076 g, 0.37 mmol) in dioxane (1 mL) were added NiCl2(dppf)2 (0.002 g, 1 mole %) and potassium phosphate (0.158 g, 0.74 mmol) and the mixture was stirred at 95° C. for 16 hours. After cooling, the reaction was partitioned between EtOAc and water. The organic phase was washed with saturated sodium bicarbonate, brine and then dried over sodium sulfate. The crude product, obtained upon concentration of the organic phase, was purified by reverse phase HPLC (acetonitrile/water system) (gradient: 10% to 90% acetonitrile over 10 minutes) to yield the titled product (0.009 g, 9.5%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[NH:10][N:9]=1)=[O:7])[CH3:4].[F:23][C:24]([F:35])([F:34])[CH2:25]OS(C(F)(F)F)(=O)=O.ClCCl>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:25][C:24]([F:35])([F:34])[F:23])[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 56.8 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 203 mg, 5 mmol) was added to an ice cooled solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (1 g, 4 mmol; PCT Int. Appl. (2003), WO 2004000785 A2) in DMF (60 ml) under an argon atmosphere. The solution was stirred for 10 min at 0° C. and for 40 min at ambient temperature. Trifluoroethyltriflate (1.07 g, 5 mmol) was added and the mixture was stirred for 3 h at ambient temperature. The solution was cooled to 0° C., 1 N HCl/ice water 1/2 and dichloromethane were added. The aqueous layer was extracted two times with dichloromethane, the combined extracts were washed with brine/ice water 1/1 and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave yellow crystals which were purified by column chromatography (silica gel, n-heptane/AcOEt) to yield 833 mg (2.27 mmol, 65%) of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(O)C>[C:1]1([B:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[B:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[O:8][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)c1ccccc1Oc1ccccc1B(O)c1ccccc1
Reactant: OCc1ccccn1
Solvent: CCO
Product: c1ccc(B(OCc2ccccn2)c2ccccc2Oc2ccccc2B(OCc2ccccn2)c2ccccc2)cc1

Procedure:
The entitled compound (38 mg) was obtained by allowing 42 mg of bis(4,4′-(phenylhydroxyboryl)phenyl) ether and 20 mg of 2-hydroxymethylpyridine to act in 0.25 mL of ethanol.