Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: COc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1F

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (15 mg, 0.075 mmol) in THF (1 mL) at −78° C. was added 0.5 M 3-fluoro-4-methoxyphenylmagnesium bromide in THF (0.3 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3-fluoro-4-methoxy-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH:33]=O>>[CH:20]1[C:28]2[C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[O:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:33][N:1]1[CH:2]([C:10]2[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1=[O:8]
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 416.86 g/mol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:19]=[CH:18][C:13]([O:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:11]=2)=[C:4]([O:20][C:21]([F:24])([F:23])[F:22])[CH:3]=1.[C:25]([C:27]1[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:29][CH:28]=1)#[CH:26]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[OH:17][CH2:16][CH2:15][O:14][C:13]1[CH:18]=[CH:19][C:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([C:26]#[C:25][C:27]3[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:29][CH:28]=3)=[CH:3][C:4]=2[O:20][C:21]([F:24])([F:23])[F:22])=[CH:11][CH:12]=1
Reactant: C#Cc1ccc(OCCCCCO)cc1
Reactant: OCCOc1ccc(C#Cc2ccc(Br)cc2OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCCCCOc1ccc(C#Cc2ccc(C#Cc3ccc(OCCO)cc3)c(OC(F)(F)F)c2)cc1
Yield: 82 %

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 2.99 g (7.44 mmol) of 2-(4-{2-[4-bromo-2-(trifluoromethoxy)phenyl]ethynyl}phenoxy)ethanol and 16 ml of triethylamine under a nitrogen atmosphere. Then 1.52 g (7.44 mmol) of 5-(4-ethynylphenoxy)pentanol, 11.2 mg (0.059 mmol) of copper (I) iodide, 51.5 mg (0.20 mmol) of triphenylphosphine, and 11.2 mg (0.016 mmol) of dichlorobis(triphenylphosphine)palladium were added at room temperature, and stirred under reflux for 6.5 hours. After the insolubles were filtered off and the solvent was distilled off, ethyl acetate was added to the resulting distillate, and the pH was adjusted to an acidity with 1N hydrochloric acid to effect ethyl acetate extraction. The resulting extract was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated to thereby obtain 4.27 g of a crude product in the form of a yellowish brown solid. The crude product was then purified by silica gel column chromatography using hexane/ethyl acetate as an eluting solvent to obtain 3.2 g of 5-{4-[2-(4-{2-[4-(2-hydroxyethoxy)phenyl]ethynyl}-3-(trifluoromethoxy)phenyl)ethynyl]phenoxy}pentane-1-ol in the form of a light yellow solid in a 82% yield.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].CS(Cl)(=O)=O.Cl.[CH2:38]([O:40][C:41](=[O:44])[CH2:42][NH2:43])[CH3:39].C(=O)([O-])O.[Na+]>C1COCC1.ClCCl.C(O)C.C(OCC)(=O)C>[CH2:38]([O:40][C:41](=[O:44])[CH:42]([CH2:7][C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][C:5]=1[N+:12]([O-:14])=[O:13])[NH2:43])[CH3:39]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCOC(=O)CN
Agent: CCOC(=O)Cl
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
5.0 g (21 mmol) of 4-trifluoromethyl-2-nitrobenzoic acid was dissolved in a mixture of 200 ml of THF and 4.4 ml (31.5 mmol) of triethylamine. 2.6 ml (28 mmol) of ethyl chloroformate was added to the obtained solution under cooling with ice, and they were stirred for 15 minutes. Precipitates thus formed were removed by the suction filtration. A piece of ice was added to the obtained filtrate, and then 1.6 g (42 mmol) of sodium borohydride was added thereto under cooling with ice. The temperature was elevated to room temperature, and the obtained mixture was stirred overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 100 ml of dichloromethane. 1.96 ml (25.2 mmol) of methanesulfonyl chloride and 4.4 ml (31.5 mmol) of triethylamine were added to the obtained solution, and they were stirred under cooling with ice for 2 hours. After the treatment with dichloromethane as the extracting solvent, the obtained crude product was dissolved in 100 ml of ethanol. 5.9 g (42 mmol) of glycine ethyl ester hydrochloride and 5.3 g (16.1 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70□ for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[F-:12].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.O>[CH3:11][O:10][C:8]([C:6]1[N:7]=[C:3]([CH2:2][F:12])[O:4][CH:5]=1)=[O:9]
Reactant: COC(=O)c1coc(CCl)n1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1coc(CF)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-(chloromethyl)oxazole-4-carboxylate (CAS208465-72-9) (150 mg, 0.85 mmol) in acetonitrile (4.27 ml) was treated with tetra-n-butylammonium fluoride (2.56 ml, 2.56 mmol). The blue solution turned to orange and was left under stirring at room temperature overnight. For the workup, the reaction mixture was poured in water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated at reduced pressure. The crude material was purified by chromatography on a flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 50/50 as the eluent. The 2-fluoromethyl-oxazole-4-carboxylic acid methyl ester was obtained as a white solid (64 mg, 47% of theory). MS (ISP): m/z=160.1 [M+H]+. b) 2-Fluoromethyl-oxazole-4-carboxylic acid
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:20][O:19][C:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][C:12]=1[N+:21]([O-:23])=[O:22])=[O:18]
Reactant: COC(=O)Cc1ccc(OC(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(O)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred suspension of 4-methoxycarbonylmethyl-3-nitrophenyl benzoate (26.2 g, 79 mmol) in methanol (600 mL) at 20° C. was added, dropwise over 0.3 h, a solution of sodium methoxide (4.7 g, 87 mmol) in methanol (300 mL). The resulting mixture was stirred at 20° C. for 2 h then at 50° C. for 1 h. The solution was concentrated to 200 mL in vacuo, then poured into water (1 L) and extracted with ether-hexane (1:5, 500 mL). The aqueous phase was neutralised with 2 M hydrochloric acid, then extracted with dichloromethane (6×300 mL). The combined dichloromethane extracts were dried (Na2SO4) and evaporated in vacuo to give a semi-solid, which was triturated with ether-hexane (1:3, 2×100 mL) to give the title compound (15.3 g, 85%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C(Br)c1cccc(Br)c1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To a solution of 3-bromophenylacetic acid (25.0 g, 116 mmol) in carbon tetrachloride (200 ml) was added N-bromosuccinimide (22.8 g, 128 mmol) at room temperature. The mixture was refluxed for 3 hours and cooled to room temperature. The resulting precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=4/1) to afford bromo-(3-bromo-phenyl)-acetic acid as yellow liquid (27.8 g, 81%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:29])[NH:13][C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:23](=[O:26])[CH2:24]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:10])([CH3:9])[CH3:8].O>CN(C)C=O>[C:7]([O:11][C:12]([N:13]1[CH2:24][C:23](=[O:26])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:14]1([CH3:28])[CH3:27])=[O:29])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2)CC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
11.19 g of cesium carbonate (34.4 mmol) was added to a solution of 4.41 g of {2-[(2-bromoacetyl)phenylamino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in the above reaction (11.5 mmol) in N,N-dimethylformamide (58 ml) under ice-cooling, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=10/1-5/1-2/1) to obtain 1.83 g of 2,2-dimethyl-5-oxo-4-phenylpiperazine-1-carboxylic acid t-butyl ester (yield: 53%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]1.[Cl-].[NH4+].Cl>C(OCC)C.C1COCC1>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13]1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Temperature: -50 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
3.9 ml (11.7 mmol) of a 3M solution of phenylmagnesium bromide in diethyl ether are added dropwise to a solution, immersed in a bath at −50° C., containing 500 mg (2.92 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium is stirred for 1 hour at −50° C. and hydrolysed by adding a saturated solution of ammonium chloride. After a return to ambient temperature, a 1N solution of hydrochloric acid is added, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 253 mg in the form of a white powder are obtained with a yield of 35%.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3].CC(C)CCN.[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]([C:29]3[S:33][C:32]([C:34]([O-])=[O:35])=[CH:31][CH:30]=3)=[O:28])=[CH:21][C:20]=12.[Li+].[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>>[N:16]1[CH:17]=[CH:18][N:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]([C:29]3[S:33][C:32]([C:34]([N:6]4[CH2:7][CH2:8][CH2:9][CH:5]4[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:35])=[CH:31][CH:30]=3)=[O:28])=[CH:21][C:20]=12
Reactant: O=C([O-])c1ccc(C(=O)NCc2ccn3ccnc3c2)s1
Reactant: CC(C)CC1CCCN1
Agent: CC(C)CCN
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Product: CC(C)CC1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 1A, substituting), 2-isobutylpyrrolidine for 3-methylbutan-1-amine and lithium 5-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)thiophene-2-carboxylate for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) ppm 9.23 (t, J=6.0 Hz, 1H), 8.49 (dd, J=6.9, 0.9 Hz, 1H), 7.90-7.88 (m, 1H), 7.79 (d, J=4.0 Hz, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.52 (d, J=1.2 Hz, 1H), 7.42-7.39 (m, 1H), 6.85 (dd, J=7.0, 1.7 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 4.35-4.23 (m, 1H), 3.78-3.65 (m, 2H), 3.26 (s, 3H), 2.02-1.81 (m, 4H); MS (ESI(+)) m/e 411 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10](O)(=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCNCC1
Reactant: C#CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCCCC(=O)N1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
1-Isopropylpiperazine (228 mg, 1.78 mmol) was added over a mixture of hex-5-ynoic acid (200 mg, 1.78 mmol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (393 mg, 2.05 mmol) and N,N-dimethylpyridin-4-amine (10 mg, 0.05 mmol) in dichloromethane (10 ml) at 0° C. and the resulting mixture was stirred at room temperature overnight. 100 ml of dichloromethane were added and washed with sodium bicarbonate 4%. Then a solution of hydrogen chloride 0.5 N was added to the organic phase. The aquose phase was separated and neutralised with a solution of NaOH 2N and treated with ethyl acetate. The ethyl acetate phase was washed with water and brine, dried over magnesium sulphate and the solvent removed to give 152 mg (34% yield) of the title compound. Purity 90%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[O:16][CH3:17])=O)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>O.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][CH2:7][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1ccc(Br)cc1OC
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc(Br)cc1OC
Temperature: 55 °C
Yield: 52.5 %

Procedure:
A solution of 4-(4-bromo-2-methoxy-phenyl)-4-oxo-butyric acid ethyl ester (Intermediate 60, 14.73 g, 46.8 mmol) in trifluoroacetic acid (72 mL, 935 mmol) was treated with triethylsilane (30 mL, 187 mmol) and the resulting reaction mixture was heated at 55° C. for 4 h. The reaction mixture was then cooled to ambient temperature, neutralized with solid sodium bicarbonate, diluted with water and extracted with diethyl ether. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 8% ethyl acetate in hexane as the eluent to afford the title compound (7.4 g, 53%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:4][CH:3]=1.[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CCN(CC)CC>[CH3:33][CH2:32][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])=[CH:7][CH:6]=2)[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:14]=2[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:30])[CH3:31])[CH:23]=2)[NH:19]3)=[CH:11]1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(N)cc2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a stirred solution of 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (0.34 mmol) in tetrahydrofuran (5 mL) was added phenyl isocyanate (0.41 mmol) and two drops of Et3N. The reaction was stirred at room temperature for 1 h and concentrated to dryness under vacuum. The remaining solid was triturated with (1:1) diethyl ether:petroleum ether, filtered, and dried under vacuum. Purification by Gilson reverse phase HPLC gave the title compound as an off-white solid (44%). ESMS (M+H)+: 556.4
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][N:17]1[Si:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][Si:18]1([CH3:25])[CH3:24]>CN(C)C=O>[CH3:22][Si:21]1([CH3:23])[CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[N:17]1[CH2:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si]1(C)CC[Si](C)(C)N1CCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: C[Si]1(C)CC[Si](C)(C)N1CCCN1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
About 3.36 g of potassium phthalimide, 4.89 g of 1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane, and 12 mL of N,N-dimethylformamide were mixed in a flask. The mixture was stirred for 5 hour while the flask was kept in an oil bath maintained at 75° C. The N,N-dimethylformamide was removed under vacuum. The residue was extracted with 90 mL of toluene and filtered. The filtrate was evaporated under vacuum. The residue was triturated with 80 mL of hexane, cooled with dry ice, and then filtered to give N-[3-(2,2,5,5-tetramethyl-1-aza-2,5-disila-1-cyclopentyl)-1-propyl]phthalimide (TMADSCPPI) as a white solid (4.3 g, 68% yield). 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product: δ 7.41 (multiplet, 2H, aromatic protons), 6.81 (multiplet, 2H, aromatic protons), 3.55 (multiplet, 2H, CH2 protons), 2.79 (multiplet, 2H, CH2 protons), 1.77 (multiplet, 2 H, CH2 protons), 0.70 (singlet, 4H, CH2—Si protons), 0.06 (singlet, 12H, Si—CH3 protons).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.Cl.[OH:28][C:29]1[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(CC)CC)C>C(O)CC>[OH:28][C:29]1[C:36]([OH:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: NCc1cccc(O)c1O
Agent: Cl
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCCO2)c1O
Yield: 60 %

Procedure:
A mixture of 10 mmol (2387 mg) 6-chloro-9-(tetrahydropyran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (2100 mg) 2,3dihydroxybenzylamine hydrochloride, and 7 mL of triethylamine was refluxed in n-propanol for 3 hrs. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate solvent was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 60%, white solid. TLC (CHCl3:methanol) (4:1) (v:v): single spot; HPLC: purity >98%. 1H-NMR (300 MHz, DMSO): 1.57m (2H); 1.71m (1H); 1.95m (2H); 2.27qq (1H, Ja=12 Hz, Jb=4.0 Hz); 3.67m (1H); 4.00d (1H, J=11.7 Hz); 4.58bs (2H); 5.63dd (1H, Ja=11.2 Hz, Jb=1.9 Hz); 6.55tt (1H, Ja=7.7 Hz, Jb=1.5 Hz); 6.63dd (1H, Ja=7.7 Hz, Jb=1.8 Hz); 6.66dd (1H, Ja=7.7 Hz, Jb=1.8 Hz); 8.24s (1H); 8.27bs (1H); 8.37s (1H), 8.96bs (1H), 9.53bs (1H). MS (ES): [M+H]+=342 (100).
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.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=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>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[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]=2)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: OB(O)c1ccc(OCc2ccccc2)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: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(OCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 85 °C
Yield: 76.6 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.41 g, 7.74 mmol) in ethylene glycol dimethyl ether (50 mL) was treated with 4-(benzyloxy)phenylboronic acid (1.94 g, 8.51 mmol), tetrakis(triphenylphosphine)palladium (0.537 g, 0.464 mmol), and a solution of sodium carbonate (1.97 g, 18.58 mmol) in water (25 mL). The reaction mixture was stirred over night at 85° C. under a nitrogen atmosphere. The organic solvent was removed under reduced pressure. Ethyl acetate (300 mL) was added to the aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were washed with water and brine (1 L each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. Ethyl acetate was added to the solid. A significant amount of the solid was not soluble in ethyl acetate, and was subsequently filtered to give 2.95 g (77%) of cis-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.217 (s, 1H), 7.592-7.570 (m, 2H), 7.504-7.483 (m, 2H), 7.440-7.369 (m, 3H), 7.206-7.184 (m, 2H), 5.186 (s, 2H), 4.802-4.755 (m, 1H), 2.497-2.354 (m, 7H), 2.256-2.228 (m, 4H), 2.151 (s, 3H), 2.076-1.989 (m, 2H), 1.694-1.673 (m, 2H), 1.607-1.545 (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 5.128 min (100%).