Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:23]=[N:22][C:21]([N:24]2[CH:28]=[C:27]([CH2:29][OH:30])[N:26]=[CH:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:23]=[N:22][C:21]([N:24]4[CH:28]=[C:27]([CH2:29][OH:30])[N:26]=[CH:25]4)=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: OCc1cn(-c2ccc(Cl)nn2)cn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OCc1cn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1
Temperature: 180 °C

Procedure:
To a mixture of 6-fluoro-1-(piperidin-4-yl)indoline (100 mg, 0.4 mmol) and (1-(6-chloropyridazin-3-yl)-1H-imidazol-4-yl)methanol, prepared as in STEP 1 above (63 mg, 0.3 mmol) in DMSO (1.5 mL) was added DIPEA (0.16 mL, 0.9 mmol). The resulting mixture was sealed and heated at 180° C. for 1.5 h under microwave irradiation. The resulting mixture was then poured into H2O (30 mL) and the aqueous layer was extracted with 10% CH2Cl2/Et2O (80 mL×4). The combined organic layer was dried (Na2SO4) and filtered. The solvent was removed and the resulting residue was purified by column using EtOAc then 3-5% MeOH/EtOAc as the eluent to yield (1-(6-(4-(6-fluoroindolin-1-yl)piperidin-1-yl)pyridazin-3-yl)-1H-imidazol-4-yl)methanol.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:11][O:10]C(C)(C)[O:8]1)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]>CC(O)=O>[CH2:11]([OH:10])[C@H:7]([OH:8])[CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH3:6]
Reactant: CC/C=C\CC[C@@H]1COC(C)(C)O1
Solvent: CC(=O)O
Product: CC/C=C\CC[C@@H](O)CO

Procedure:
(R,Z)-4-(hex-3-enyl)-2,2-dimethyl-1,3-dioxolane (5.95 g, 32.3 mmol) was stirred in 80% aq. AcOH (50 mL) for 20 h. The mixture was concentrated in vacuo and purified by silica gel chromatography (40% EtOAc in hexanes gradient to 70% EtOAc in hexanes) to give (R,Z)-oct-5-ene-1,2-diol as a clear oil. 1H NMR (406 MHz, CDCl3): δ 5.45 (1H, m), 5.36 (1H, m), 3.75 (1H, m), 3.67 (1H, dd, J=10.8, 2.8 Hz), 3.45 (1H, dd, J=11.2, 7.6 Hz), 2.16 (2H, m), 2.04 (2H, m), 1.50 (2H, m), 0.96 (3H, t, J=7.6 Hz).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:14]12[O:9][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
A solution of m-CPBA (7.53 g, 32.7 mmol) in DCM (10 mL) was added to a solution of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 27.3 mmol) in DCM (20 mL) at 0° C. The reaction was stirred at 0° C. for 15 minutes and then at room temperature for 3 hours. Saturated sodium sulfite solution (20 mL) and saturated sodium bicarbonate solution (30 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.36 g, 99%) as oil.
Reaction SMILES: CCN(CC)CC.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.O.C(C1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1)(C)(C)C>ClCCCl>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccc(CO)cc1
Agent: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Solvent: O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 98 %

Procedure:
Complex 8 (8.8 mg, 0.021 mmol) and NEt3 (14 μL, 0.10 mmol) were dissolved in 1,2-dichloroethane (2 mL). The solution was added to a flask containing 4-methoxybenzyl alcohol (140 mg, 1.01 mmol), H2O (91 μL, 5.05 mmol), and a 1,3,5-tri-tert-butylbenzene internal standard (19.2 mg, 0.078 mmol). The flask was equipped with an air condenser and a stir bar and heated at 60° C. for 24 h with stirring (˜700 rpm). The reaction mixture was cooled to room temperature, the solvent removed under vacuum, and the extent of conversion determined by integration of the 1H NMR spectrum against the internal standard. 4-Methoxybenzaldehyde was formed in >98% yield (based on the average of two runs of this type).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[CH:29](OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:29]=[N:28][C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine in ethanol (100 mL) was added triethyl orthoformate (4.45 g, 30.03 mmol) and p-toluenesulfonic acid monohydrate (0.075 g, 0.39 mmol). As the resulting mixture was warmed to reflux, the solids gradually dissolved to provide an orange solution. After 45 min, the reaction mixture was allowed to cool to room temperature, resulting in the formation of a precipitate. Water (250 mL) was added to the mixture, and the solids were isolated by filtration. The moist solids were dissolved in ethyl acetate (250 mL), and this solution was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 5.99 g (91%) of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1C(=O)N([Br:23])C(=O)C1>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:23][CH2:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2ccccc2c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1cc2ccccc2c2ccccc12
Temperature: 0 °C
Yield: 89.7 %

Procedure:
A mixture of 9-methylphenanthrene (14.2 g, 74 mmol), benzoyl peroxide (40 mg, 0.16 mmol) and NBS (13.3 g, 74.6 mmol) in 210 mL of benzene was refluxed for 5 h. The reaction mixture was cooled to 0° C. and the succinimide precipitated was removed by filtration. The filtrate was washed by 15% NaOH, dried over MgSO4 and concentrated to yield 18 g of product which was used for the next step without further purification.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:21][CH:20]=1>C1COCC1.CO>[ClH:10].[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:14]([NH:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[NH:17])=[CH:23][CH:24]=1
Reactant: NCCCCCc1ccc(O)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: C1CCOC1
Solvent: CO
Product: Cl
Product: N=C(NCCCCCc1ccc(O)cc1)NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 0 °C
Yield: 131.5 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl-2-methyl-pseudothiourea hydroiodide (0.25 g, 0.65 mmol) was added to a solution of 21 (0.6 g, 3.4 mmol) in THF (50 mL). The reaction mixture was stirred at reflux for 2 h, then the solvent was removed under reduced pressure and the resulting oil was washed with ether (2×50 mL) and treated with ethyl acetate until a yellow powder was formed. The yellow solid was dissolved in methanol (70 mL) and the volume was slowly reduced until precipitation began (approximately 25 mL). The solution was cooled to 0° C. and the precipitate was collected by centrifugation. Diluted HCl (20 mL of a 10% solution) was added and the mixture was vigorously stirred for 20 min, then the precipitate was filtered off, washed with cold water, and dried to give 22 (183 mg, 39%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.32 (br s, 2H), 1.55 (m, 4H), 2.45 (m, 2H), 3.29 (m, 2H), 6.68 (d, 2H), 6.97 (d, 2H), 7.46 (s, 1H), 8.00 (br s, 1H), 8.83 (br s, 1H), 8.97 (br s, 1H), 9.46 (d, 2H), 10.55 (s, 1H). APCI MS m/z=392[C17H22ClN7O2+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7](=[N:10][OH:11])[C:8]#[N:9].[CH3:12][N:13]=[C:14]=[O:15]>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1[C:7](=[N:10][O:11][C:14]([NH:13][CH3:12])=[O:15])[C:8]#[N:9]
Reactant: CN1CCN=C1C(C#N)=NO
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C#N)C1=NCCN1C

Procedure:
15.2 g (0.1 mol) of α-[1-methyl-imidazolin-2-yl]-α-oximino-acetonitrile and 6.4 g (0.11 mol) of methyl isocyanate are stirred in 200 ml of ethyl acetate with a few drops of triethylamine for 16 hours. 16 g (76.5% of theory) of end product are filtered off and this is washed with a little ethyl acetate; melting point 186°-190° C. (decomposition).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1.[C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)#[N:17].C1C(O)=CC=CC=1C>>[CH3:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[NH:17])[CH:14]=[CH:13][CH:12]=1
Reactant: N#CN1CCCCC1
Reactant: Cc1cccc(-c2ccccc2N)c1
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(-c2ccccc2NC(=N)N2CCCCC2)c1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-3'-methylbiphenyl hydrochloride (1.09 g), N-cyanopiperidine (0.6 g) and m-cresol (0.5 ml) was heated at 100° C. for 3 hours to give N-(3'-methyl-2-biphenylyl)piperidine-1-carboxamidine (m.p. 131° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.FC(F)(F)S(O[C:16]1[C:17]2[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=2[N:19]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:25][CH:24]=2)[N:21]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[CH3:1][N:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:16]1[C:17]2[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=2[N:19]=[C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:27][CH:28]=2)[N:21]=1
Reactant: CNCc1ccccn1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(C)Cc3ccccn3)c2C1
Yield: 12 %

Procedure:
1-(4-(Methyl(pyridin-2-ylmethyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (8.8 mg 12%) was prepared from N-methyl-1-(pyridin-2-yl)methanamine and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.O1CCOCC1.[H][H]>[Ni].O>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(OC(F)F)ccc1O
Agent: [Ni]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(OC(F)F)ccc1O
Yield: 57.9 %

Procedure:
A mixture of 4-(difluoromethoxy)-2-nitrophenol (D94, 450 mg, 1.974 mmol), Raney-nickel (est. 200 mg), 1,4-dioxane (10 mL) and water (5 mL) was stirred at room temperature in a hydrogen atmosphere for 20 h. The reaction mixture was filtered through kieselguhr under an argon atmosphere and evaporated to dryness. The unreacted starting material was sufficiently volatile that most of it was removed by using a rotary evaporator. The residue was purified by flash column chromatography on a pre-packed silica cartridge (column size 50 g), eluting with 0-30% ethyl acetate in hexane, followed by 10-50% 2 M ammonia in methanol in DCM. The residue was further purified on an IST SCX-2 cartridge 20 g, washing with methanol (125 mL) and eluting with 2 M ammonia in methanol (125 mL). The basic eluent was evaporated to dryness to afford the desired product (D95) as a brown solid (200 mg). (M+H)+=176.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([NH:16][CH3:17])(=[O:15])=[O:14])=[CH:8][CH:7]=1.[ClH:18]>O>[ClH:18].[NH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([NH:16][CH3:17])(=[O:15])=[O:14])=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(NN)cc1
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (13.72 g) in water (160 ml) was added slowly to a cooled stirred mixture of 4-Amino-N-methylbenzene methanesulphonamide (39.3 g), water (240 ml) and conc. hydrochloric acid (400 ml) such that the temperature did not exceed 0°. After stirring for 15 min this mixture was added slowly to a cold solution of stannous chloride dihydrate (221.1 g) in conc. hydrochloric acid (400 ml) again keeping the temperature below 0°. Once the addition was complete the mixture was allowed to warm to room temperature (1 h). The solid was collected by filtration, washed well with diethyl ether (4×250 ml) and dried at 45° to give the title compound as a white powder (31.6 g). An assay by periodate titration showed this to be 91.3% pure.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>C(#N)C>[N+:28]([C:16]1[CH:17]=[C:18]([S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:11][CH:8]([CH2:9][O:10][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]([F:26])([F:27])[F:25])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29])[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:30])=[O:29]
Reactant: OCC(O)CN1CCOCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1OCC(CN1CCOCC1)Oc1ccc(S(=O)(=O)C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Using the same procedure as for Example 54, a mixture of 3-morpholin-4-yl-propane-1,2-diol (40 mg, 0.25 mmol), sodium hydride (60%, 30 mg) and 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (174 mg, 0.6 mmol) in acetonitrile (1 mL) was heated to reflux, worked-up and purified on silica gel to give the title compound. 1H NMR (360 MHz, DMSO-d6) δ 8.59 (d, J=2.3 Hz, 2H), 8.35 (dd, J=2.3 & 9.2 Hz, 1H), 8.30 (dd, J=2.3 & 9.2 Hz, 1H), 7.97 (d, J=9.2 Hz, 1H), 7.79 (d, J=9.2 Hz, 1H), 5.49 (m, 1H), 4.79 (m, 1H), 4.66 (m, 1H), 3.41 (m, 4H), 2.74 (d, J=6.1 Hz, 2H), 2.4-2.5 (m, 4H). MS+ve APCI 668 [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[O-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>C1(O)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: [O-]c1ccccc1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: O
Product: Brc1ccc2nccc(Oc3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A mixture of 6-bromo-4-chloro-quinoline (1.5 g, 6.18 mmol) and sodium phenoxide (2.32 g, 24.74 mmol) in phenol (8.65 g) was heated to 150° C. in a sealed tube and stirred for 15 h. Then, the suspension was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with 1.0N sodium hydroxide (3×50 mL), brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.33 g (71.6% yield) of 6-bromo-4-phenoxy-quinoline as a light brown solid: EI-HRMS m/e calcd for C15H10BrNO (M+) 298.9946, found 298.9946.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C[O:10][CH:11](O)[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[N:7]=[C:6]([CH:11]([OH:10])[C:12]([F:15])([F:14])[F:13])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: COC(O)C(F)(F)F
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(O)c(C(O)C(F)(F)F)n1
Temperature: 180 °C
Yield: 66.1 %

Procedure:
A mixture of commercially available 6-methylpyridin-3-ol (500 mg), trifluoroacetaldehyde methylhemiacetal (715 mg) and potassium carbonate (69 mg) was heated in a microwave reactor at 180° C. for 3 min. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography using 1:1 hexane:ethyl acetate and recrystallized from ethyl acetate and hexane to give 627 mg of 6-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-3-ol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:22][CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])=[O:6]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 178.7 %

Procedure:
Preparation I7, Step 1: A solution of 2-fluoro-5-trifluoromethylbenzoic acid (5.80 g) in N,N-dimethylformamide (190 mL) was treated sequentially with glycine t-butyl ester (5.50 g), BOP reagent (18.50 g), and N-methylmorpholine (9.20 mL). The mixture was stirred at rt for 12 h, then was diluted with ethyl acetate. The organic layer was washed with 1 M HCl, saturated aqueous NaHCO3, 5% aqueous LiCl, and brine, then was dried over Na2SO4 and concentrated under vacuum to provide tert-butyl 2-(2-fluoro-5-(trifluoromethyl)benzamido)acetate (16 g) as a white solid. MS found: (M+H)+=322.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][NH:27][CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.[CH2:32](N(CC)CC)[CH3:33].C(I)C>CN(C)C=O.Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2
Reactant: O=C(N[C@@H]1CCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (500 mg) obtained in Example 23 was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (576 μl) and ethyl iodide (329 μl) were added, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to collect insoluble matter by filtration. This product was purified by silica gel column chromatography (methylene chloride:methanol=100:3) to give a pale brown foamy substance. This substance was suspended in 1N hydrochloric acid (2 mL), and the suspension was concentrated under reduced pressure to give the title compound (180 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[C:24]([C:26](Cl)=[O:27])=[N:23][C:22]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH3:30])=[CH:21]2>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[C:24]([C:26]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:27])=[N:23][C:22]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[CH3:30])=[CH:21]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)Cl)n4)ncnc32)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)N5CCOCC5)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of morpholine (34 mg, 0.392 mmol, 1.3 eq) and triethylamine (100 mg, 0.981 mol, 3 eq) in DCM (20 mL), (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonyl chloride 11 was added at RT. The resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl) (morpholino)methanone 12.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4].C(N([CH2:29][CH3:30])CC)C>C(O)C1C=CC=CC=1>[CH2:1]([O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=[O:4])[C:30]1[CH:29]=[CH:7][CH:6]=[CH:5][CH:3]=1
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCN(CC)CC
Solvent: OCc1ccccc1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)OCc2ccccc2)[C@@H](O)[C@H]1O
Temperature: 100 °C

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are suspended in 200 ml of benzyl alcohol, with the addition of 7 g of triethylamine, and the reaction mixture heated to 100° C. for 5 hours, the methyl ester thereby going into solution. After termination of the reaction, the base and excess alcohol are stripped off in a vacuum, the residue is triturated with ether for the removal of traces of amine and solvent and, after filtering off with suction, the product is recrystallized from water. There are thus obtained 3.3 g (53% of theory) of adenosine-5'-carboxylic acid benzyl ester, which has a melting point of 144°-145° C.