Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:28])=[N:26][OH:27])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:42](=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[N:28]=[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[O:27][N:26]=1)=[CH:14][CH:13]=2)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=NO)ccc2c1=O
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)no1
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a mixture of tert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.23 g, 0.50 mmol) and pyridine (0.043 mL, 0.53 mmol) in toluene (20 mL), was added ethyl chlorooxoacetate (0.059 mL, 0.53 mmol), and the mixture was stirred at room temperature for 1 h and at 80° C. for 1 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1–1:3 (v/v)) and recrystallized from diisopropyl ether-ethyl acetate (20:1, v/v, 5 mL) to give ethyl 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,2,4-oxadiazole-5-carboxylate (0.13 g, 48%) as colorless crystals.
Reaction SMILES: [C:1]([CH:4]([CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:5]([NH:7][CH:8]([C:10]1[C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[N:14][N:15]=1)[CH3:9])=O)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O>>[C:1]([CH:4]([C:5]1[N:15]2[C:10]([C:11](=[O:27])[NH:12][C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1)[CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(Cc2nnc(C(C)NC(=O)C(CCCC3CCCCC3)C(C)=O)c(=O)[nH]2)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Cc2nn3c(C(CCCC4CCCCC4)C(C)=O)nc(C)c3c(=O)[nH]2)cc1OC

Procedure:
Analogously to Example 1, 240 mg (0.47 mmol) of 2-acetyl-5-cyclohexyl-N-{1-[3-(3,4-dimethoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}pentanamide and 350 mg (2.30 mmol) of phosphorus oxychloride are reacted to give 7-(1-acetyl-4-cyclohexylbutyl)-2-(3,4-dimethoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.Cl.Cl.[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:31][C@@H:29]([C:27]3[O:26][N:25]=[C:24]([CH3:23])[N:28]=3)[CH3:30])=[O:13])=[CH:8][CH:9]=2)[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: Cc1ccc(-n2nc(Br)c3ccc(C(=O)O)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(-n2nc(Br)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
3-Bromo-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (233.7 mg, 0.389 mmol, with 4 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (94.2 mg, 0.471 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (156.1 mg, 0.814 mmol), 1-hydroxy-7-azabenzotriazole (28.9 mg, 0.212 mmol), and N-methylmorpholine (0.171 mL, 1.554 mmol) were dissolved in N,N-dimethylformamide (3.800 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 0.5 mL) and trifluoroacetic acid (ca 0.5 mL). The reaction mixture purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid. The product fractions were concentrated under reduced pressure. The residue was taken up in ethyl acetate (15 mL), washed with sodium bicarbonate (2×20 mL) and saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give the title compound (153.9 mg, 0.350 mmol, 90% yield) as a tan solid. HRMS: [M+1]=440.0730.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]2[NH:11][C:12]3[C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[N:14][C:13]=3[C:8]2=[CH:7][CH:6]=1>O1CCCC1.CO>[CH3:3][O:4][C:5]1[N:10]=[C:9]2[NH:11][C:12]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[N:14][C:13]=3[C:8]2=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1nc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(=O)O)c3[nH]c4nc(OC)ccc4c3n2)cc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
Aqueous sodium hydroxide (1.0 N, 0.66 mL, 0.66 mmol) was added to a solution of methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylate (80 mg, 0.22 mmol) in a mixture of tetrahydrofuran (3 mL) and methanol (1 mL). After 1 hr, the organic solvents were removed on the rotary evaporator. The residue was diluted with water to bring most of the solid into solution and sufficient 1.0 N aqueous HCl was added to bring the pH of the mixture to about 3. After stirring for 0.5 hr, the precipitate was collected, washed with water, and dried under vacuum over solid sodium hydroxide to give 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[2′,3′:4,5]pyrrolo[2,3-b]pyridine-4-carboxylic acid (74 mg, 0.212 mmol, 96% yield) as an orange solid. MS (ESI) m/z 350.2 (M+H). 1H NMR (DMSO-d6) δ ppm 8.52 (1H, d, J=8.54 Hz), 8.17 (1H, s), 8.09 (2H, d, J=8.85 Hz), 7.07 (2H, d, J=8.85 Hz), 6.78 (1H, d, J=8.24 Hz), 4.02 (3H, s), 3.83 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH2:9][CH2:10][CH3:11])[C:6](Cl)=[O:7].[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH3:16][N:17]([C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1])[CH2:9][CH2:10][CH3:11])[O:18][CH3:19]
Reactant: CNOC
Reactant: CCCC(Oc1ccccc1Br)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Oc1ccccc1Br)C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
5.5 g (18.9 mmol) of 2-(2-bromophenoxy)pentanoic acid chloride, 2.03 g (20.8 mmol) of N-methyl-O-methylhydroxylamine and 190 ml of dichloromethane are placed in a 500 ml round-bottomed flask. The solution is cooled to 0° C. and 5.8 ml (41.6 mmol) of triethylamine are slowly added. The solution is stirred for 1 hour at room temperature and then concentrated under vacuum. 100 ml of a molar hydrochloric acid solution are added to the residue and extraction is carried out with 3×100 ml of ethyl ether. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum to give 6 g of N-methyl-O-methyl-2-(2-bromophenoxy)pentanohydroxamic acid in the form of a colourless oil; quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.O.[OH-].[Na+].Cl.[CH3:17][C:18]([CH3:20])=[O:19]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][C:18](=[O:19])[CH3:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CC(C)=O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC(C)=O)cc1OC
Yield: 17.75 %

Procedure:
To a solution of 3, 4-dimethoxybenzaldehyde (8.31 g, 50 mmol) in acetone (25 ml) and 95% ethanol (25 ml) was added water (200 ml) under stirring. During this time white precipitated solid was formed, and 10% sodium hydroxide aqueous solution (40 ml) was added dropwise under stirring below 10° C. Then the reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0, the prepicitated yellow solid was collected by filtration and washed with ethanol, dried , then recrystallized from 95% ethanol to give 4.16 g of a pale yellow crystal, mp: 78-80° C., yield: 17.75%.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:34]=1)[CH:32]=O.CC#N.O>CC#N>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:35])=[C:31]([CH:32]=[CH:6][CH2:5][CH2:4][O:3][CH3:2])[CH:34]=1
Reactant: Cc1ccc(Br)cc1C=O
Reactant: COCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COCCC=Cc1cc(Br)ccc1C

Procedure:
The title compound is prepared analogously as described for the title B compound in Example 45 using (3-methoxy-propyl)-triphenyl-phosphonium bromide and 5-bromo-2-methyl-benzaldehyde (prepared in Example 48; containing 20% of 3-bromo-2-methyl-benzaldehyde): Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.60 min.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC1CC=CCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimethylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2CI2 under N2 at 25° C. was added tert-butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][C:3]=1[O:19][CH3:20].[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C.Cl>C1COCC1>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([C:10]([CH3:18])([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:17])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[B:26]([OH:29])[OH:27]
Reactant: CCCCCCC(C)(C)c1cc(OC)c(Br)c(OC)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1cc(OC)c(B(O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a stirred solution of 37.1 (2.78 g, 8.0 mmol) in anhydrous THF (20 ml) under an argon atmosphere at −78° C. was added n-BuLi (5.5 ml, 8.8 mmol using 1.6 M solution in hexane) over a 30 min period. Stirring was continued at −78° C. for 15 min and then trimethyl borate (2.7 ml, 24 mmol) was added. Following addition, the reaction mixture was allowed to warm to room temperature over 12 hours period. The pH was adjusted to 6.5 by addition of 5% aqueous HCl solution at 0° C., and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (12% acetone in hexane) to give 38.1 as colorless oil, in 83% yield (2.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cnc(N2CCOCC2)cc1N
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1cnc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.1 %

Procedure:
To a stirred solution of 27.5 g (132 mmol) 5-methoxy-2-morpholin-4-yl-pyridin-4-ylamine in 400 ml acetone was added dropwise 19.5 ml (145 mmol) benzoyl isothiocyanate at room temperature. The reaction mixture then heated at reflux for 90 min before being cooled to room temperature and poured onto 400 ml hexane and stirred for 5 min. The resulting crystals were collected by filtration, washed with hexane and dried to afford 32.5 g (66%) 1-benzoyl-3-(5-methoxy-2-morpholin-4-yl-pyridin-4-yl)-thiourea as a brown crystalline solid. ES-MS m/e (%): 373 (M+H+, 100).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([NH:12][C:13]3([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:11])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+]>C(O)C.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]([NH:12][C:13]3([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:11])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1(NC(=O)c2ccc3c(c2)OCO3)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccc2c(c1)OCO2
Yield: 66.9 %

Procedure:
Subsequently, 5.21 g of ethyl 1-[N-(3,4-methylenedioxyphenylcarbonyl) amino]cyclohexanecarboxylate synthesized in the above was dissolved in ethanol, and then, 16 ml of aqueous solution of 1N-sodium hydroxide was added dropwise thereto. After making heat reflux for 18 hours, the reaction solution was concentrated under reduced pressure. The residue thus obtained was dissolved in water and was washed with ether. After the resulting water layer was made acid (pH=2) by addition of 4-hydrochloric acid thereto, said layer was extracted with ethylacetate and was washed with 1N-hydrochloric acid and saturated brine. The resultant organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, whereby 3.18 g of the captioned 1-[N-(3,4-methylenedioxyphenylcarbonyl)amino]cyclohexanecarboxylic acid was obtained in a yield of 68%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([NH2:17])[CH:11]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[S-:18][C:19]#[N:20].[Na+].C(O)(=O)C.BrBr>O>[NH2:17][C:12]1[C:13]([F:16])=[CH:14][C:15]([S:18][C:19]#[N:20])=[C:10]([C:8](=[O:9])[C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:11]=1
Reactant: Cc1cccnc1C(=O)c1ccc(F)c(N)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccnc1C(=O)c1cc(N)c(F)cc1SC#N
Yield: 36.6 %

Procedure:
To a mixture of 3-amino-4-fluorophenyl 3-methyl-2-pyridyl ketone(4.20 g, 0.171 mol), sodium thiocyanate (4.19 g, 0.0517 mol) and glacial acetic acid is added a solution of bromine in acetic acid (2M, 12 ml, 0.0240 mol) over a one hour period. The resultant mixture is stirred one hour at room temperature and poured into cold water. The precipitate is filtered and dried to afford the title compound as a green solid (5.43 g, >100%) which is identified by NMR and mass spectral analysis.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[CH:14][N:13]=[C:12]2[N:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]4[O:29][N:28]=[C:27]([CH:30]([CH3:32])[CH3:31])[N:26]=4)[CH2:21][CH2:20]3)[N:17]=[CH:18][C:11]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:30]([C:27]1[N:26]=[C:25]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[C:12]4=[N:13][CH:14]=[N:15][C:10]([O:1][C:2]5[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=5)=[C:11]4[CH:18]=[N:17]3)[CH2:20][CH2:21]2)[O:29][N:28]=1)([CH3:32])[CH3:31]
Reactant: Cc1ncccc1O
Reactant: CC(C)c1noc(N2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(c2nc(C(C)C)no2)CC1
Temperature: 160 °C
Yield: 38.9 %

Procedure:
A mixture of 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA; 1.25 mg, 0.011 mmol), 4-chloro-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 22; 4 mg, 0.012 mmol) and potassium carbonate (3 mg, 0.022 mmol) in DMF (0.5 mL) was heated in a microwave at 160° C. for 10 min, but TLC showed no reaction. Potassium carbonate (3 mg, 0.022 mmol) and DMF (0.1 mL) were added and the reaction mixture was heated in a microwave at 180° C. for 15 min. The solvent was evaporated and water was added. The mixture was extracted with ethyl acetate and the extracts were dried, held under high vacuum, and purified by HPLC to give 1-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-4-(2-methyl-pyridin-3-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (1.8 mg, 39%).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])C.[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13]C#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13][C:5]#[C:3][CH2:2][CH3:1])[CH3:11]
Reactant: C#CCOC(C)(C)OC
Reactant: C=CC(=C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: CCBr
Solvent: CCCCCC
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 105.6 %

Procedure:
259 mg (37 mmol) of granulated lithium were added within 5 minutes to 47.7 g (1.9 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 4.0 ml (40 mmol) of isoprene were added portion wise within 10 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 2.9 g (20 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (88.9% GC) were added with a dropping funnel to the reaction mixture at −40° C. within 20 minutes. The reaction mixture was held at −40° C. for about 1 hour. 8.9 g (80 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 10 minutes. The reaction mixture was subsequently stirred for 1 hour. 20 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 5 hours. 20 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and dried over 2 g of anhydrous magnesium sulfate. The solution was concentrated under reduced pressure (40° C., 40 mbar) and the crude product was analyzed by GC. 3.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 75.6% (yield 80.0% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=O>CN(C)C=O>[F:37][C:36]1[C:31]([O:18][C:17]([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:19])=[C:32]([F:41])[C:33]([F:40])=[C:34]([F:39])[C:35]=1[F:38]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 39.7 %

Procedure:
Stir under N2 a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (0.2 g, 0.78 mmol) in dimethylformamide, add pyridine (0.13 mL, 1.6 mmol) and then add dropwise pentafluorophenyl trifluoroacetate (0.31 g, 1.13 mmol). Stir the reaction overnight at ambient temperature and quench into water. Extract the aqueous mixture with ethyl acetate, wash with 5% aqueous potassium carbonate, brine and dry over MgSO4. Concentrate under vacuum to afford a crude solid, which is triturated with ether to obtain 0.13 g (41%) of the title compound: MS 420(M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:14]=1>>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)[N:14]=[C:13]2[O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(Oc3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 10 was used, starting from N-(4-hydroxy-phenyl)-acetamide and (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give N-{4-[5-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yloxy]-phenyl}-acetamide. LC-MS m/e 404(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[CH:10]=1.[Br:16]N1C(=O)CCC1=O>CN(C)C=O.S(=O)(O)[O-].[Na+]>[Br:16][C:10]1[C:11]([CH3:15])=[N:12][N:13]([CH3:14])[C:9]=1[C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: Cc1cc(-c2c(F)cccc2F)n(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step B) (1.53 g, 7.3 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added portionwise N-bromosuccinimide (1.37 g, 7.7 mmol). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was diluted with ice water (20 mL) and saturated aqueous sodium bisulfite solution (15 mL), briefly stirred, and then partitioned between water (75 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (10 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a solid (1.84 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[N:27]([O-])=O.[Na+].O>C(O)(=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[N:11]=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[N:13]=[CH:14][C:15]=4[N:16]=[N:27]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ncc(N)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](Nc1ncc2nnn(-c3cc(C4CC4)[nH]n3)c2n1)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 41.2 %

Procedure:
To a solution of (S)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-[1-(4-fluorophenyl)ethyl]pyrimidine-2,4,5-triamine (Method 8; 0.04 g, 0.1 mmol) in aqueous acetic acid (5%, 3 ml) was slowly added an aqueous NaNO2 solution (0.008 g, 0.1 mmol, 1 ml H2O). The reaction was allowed to stir for an additional 5 minutes, treated with water (10 ml), and extracted with DCM (3×25 ml). The combined organic layer was washed with saturated NaHCO3 solution (50 ml), dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=15:1) to give the title compound (0.015 g, 40%). NMR (400 MHz, CD3OD) 9.05 (s, 1H), 7.44-7.41 (m, 2H), 7.03-6.99 (m, 2H), 6.23 (s, 1H), 5.16-5.07 (m, 1H), 2.03-2.00 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.11-1.09 (m, 2H), 0.85-0.80 (m, 2H). MS: Calcd.: 364; Found: [M+H]+ 365.