Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[C:9](=[O:16])[C:10]1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.C(OC(C)(C)C)(=O)C.CO[C:35](=[O:44])[C:36]1[C:37](=[CH:39][CH:40]=[CH:41][C:42]=1[F:43])[OH:38].[Cl-].[NH4+]>CCCCCCC.C1COCC1.C(OCC)(=O)C>[F:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:37]2[C:36]=1[C:35]([OH:44])=[CH:10][C:9](=[O:16])[O:38]2
Reactant: O=C(NCc1ccccc1)c1ccccc1
Reactant: COC(=O)c1c(O)cccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)(C)C
Product: O=c1cc(O)c2c(F)cccc2o1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A catalytic amount of N-benzyl-benzamide (Aldrich) and dry THF (Aldrich) (20 mL) were put into a three neck flask (inert atmosphere). To the cooled solution (−60° C.), 2.0 M solution of LDA (Aldrich) (10 mmole) in heptane (5 mL) was added. Subsequently, a solution of tert-butyl acetate (Aldrich) (1.3 mL, 10 mmole) dissolved in dry THF (4 mL) was slowly added to the reaction mixture drop by drop and the stirring was continued for 50 minutes at the temperature of −60° C., whereat the colour of solution changed from red-brown to yellow. A solution obtained by dissolving methyl-6-fluorosalicylate (474 mg; 2.4 mmole) in dry THF (10 mL) was added slowly to the carbanion solution and the stirring was continued overnight, whereat the temperature of the reaction mixture reached room temperature. Ethyl acetate (50 mL) and a saturated solution of ammonium chloride (50 mL) were added to the mixture, the layers were separated and then the organic layer was washed with a saturated sodium chloride solution (2×50 mL) and dried with sodium sulfate. The solvent was removed by evaporation under reduced pressure. The remaining brown oily product was mixed with trifluoroacetic acid (3 mL) and the obtained mixture was stirred for 4 hours at room temperature and diluted by a hexane:ether (2:1) solvent mixture (30 mL). A light brown precipitate was precipitated, which by purification on a silica gel column (12 g) using the solvent system chloroform:methanol:acetic acid (60:10:1) yielded 54 mg (12.5%) of light brown amorphous 5-fluoro-4-hydroxycoumarin.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+].O>CO>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCCCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(C2CCCCC2)c1Cl
Temperature: 82.5 °C
Yield: 95.6 %

Procedure:
5-Chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.969 g, 7.67 mmol) was dissolved in methanol (11.5 mL). Lithium hydroxide (0.250 g; 10.44 mmol) and water (11.5 mL) were added. The mixture was heated at 80-85° C. for 1.5 hours, cooled to room temperature and concentrated in vacuo to remove the methanol. The residue was diluted with tetrahydrofuran and concentrated again to ensure complete removal of the methanol. This residue was then diluted with water and acidified with 6N HCl (1.80 mL) to pH 2-2.5. The solid which precipitated out of solution was collected by filtration, washed with water and dried under reduced pressure at 100° C. to give 5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (1.676 g, 96%) which was used without further purification. Mass spectrum: m/z: 229.0 (M+H)
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:15])=[CH:5][N:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2)=[CH2:2].[F:16][C@@H:17]1[CH2:21][NH:20][CH2:19][C@H:18]1[CH2:22][NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCO>[C:27]1([CH2:26][O:25][C:24](=[O:33])[NH:23][CH2:22][C@H:18]2[C@H:17]([F:16])[CH2:21][N:20]([CH2:2][CH2:1][C:3]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[N:11]=4)[N:6]=[CH:5][C:4]=3[F:15])[CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NC[C@@H]1CNC[C@H]1F)OCc1ccccc1
Reactant: C=Cc1c(F)cnc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2ncc(F)c(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@H](F)C3)c2n1
Yield: 92.1 %

Procedure:
To a stirred solution of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (0.44 g, 2.14 mmole) in EtOH (5 mL) was added (±)-phenylmethyl {[trans-4-fluoro-3-pyrrolidinyl]methyl}carbamate (0.54 g, 2.14 mmole). After 24 h at 80° C. the reaction contents were purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) affording the title compound (0.90 g, 92%) as a light yellow foam: LC-MS (ES) m/e 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.CO.C1COCC1.[Li+].[OH-]>O>[Cl:1][C:2]1[S:6][C:5]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(Cl)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(Cl)s1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of ethyl 5-chloro-2-thienyloxyacetate (0.39 g, 1.77 mmol) in 9 mL of a 1:1:1 mixture of CH3OH:THF:water is added LiOH (0.38 g, 9.0 mmol). The solution is stirred for 16 hours. After this time, the solution is concentrated to ⅓ its volume. The resulting solution is acidified to pH=3 with 1N HCl. The aqueous solution is extracted with CH2Cl2. The organic layer is dried over MgSO4, filtered and concentrated under vacuum. The title compound (0.32 g, 1.66 mmol) is obtained as a white solid. 1H NMR (CDCl3, 300 MHz) δ6.50 (d, 1H), 6.07 (d, 1H), 4.66 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10].[CH2:11]([Mg]Br)[CH2:12][CH3:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:10])[CH2:11][CH2:12][CH3:13]
Reactant: O=CCc1ccccc1Br
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(2-bromophenyl)acetaldehyde (16 g, 80.8 mmol) in THF (100 ml) was added propyl magnesium bromide (48 ml (2.0 M) in THF), 97 mmol) at 0° C. then stirred at room temperature for 5 h. The reaction mixture was quenched with ammonium chloride then the title compound was purified by separation methods A, E and H. (Yield 740 mg). The enantiomer-2 showed up at tr=5.70 min with Chiralcel OD-H (4.6×250 mm) 5μ, hexane:2-PrOH:TFA (90:5:0.1), 1 ml/min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[CH2:24]([C@H:31]1[CH2:33][O:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:32][C@@H:31]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:33][N:14]1[CH2:15][CH2:16][C:11]2([O:10][C:9]3[C:19]4[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=3[S:18][CH2:17]2)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[CH2:12][CH2:13]1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: c1ccc(C[C@H]2CO2)cc1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@@H](O)Cc3ccccc3)CC2)CS1

Procedure:
Compound 203 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=146-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.28-7.12 (m, 4H), 4.43 (d, J=4.7 Hz, 1H), 3.84 (s, 3H), 3.03 (s, 2H), 2.80-2.68 (m, 2H), 2.58 (dd, J=7.4, 14.0 Hz, 1H), 2.47-2.26 (m, 3H), 1.99-1.90 (m, 2H), 1.87-1.72 (m, 2H). LCMS: 466 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1ccncc1
Reactant: CN(C(=O)OCc1ccccc1)C1CCCNC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OCc1ccccc1)C1CCCN(c2ccncc2)C1
Yield: 77 %

Procedure:
A mixture of benzyl methyl(piperidin-3-yl)carbamate (6.32 mmol, 1.0 eq.), 4-brompyridine HCl (2.5 g, 12.64 mmol, 2.0 eq.) and DIPEA (5.7 ml, 31.6 mmol, 5.0 eq.) in n-butanol (40 ml) was refluxed for 24 hours. The reaction mixture was concentrated and the residue was taken up in DCM (200 ml) and washed with sat. NaHCO3 solution (3×100 ml), water (100 ml) and sat. NaCl solution (100 ml). The org. phase was then dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 5% MeOH in DCM). Yield: 77% (1.6 g, 4.92 mmol)
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([Cl:18])=[CH:13][C:12]=1[NH:19][CH:20]1[CH2:22][CH2:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(Cl)=[O:25]>O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][N:9]1[C:10](=[O:23])[C:11]2[C:12](=[CH:13][C:14]([Cl:18])=[C:15]([F:17])[CH:16]=2)[N:19]([CH:20]2[CH2:21][CH2:22]2)[C:24]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)cc1NC1CC1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Yield: 46.4 %

Procedure:
A solution of N-benzyloxy-4-chloro-2-cyclopropylamino-5-fluoro-benzamide (Example D-3, 3.00 g, 8.96 mmol) in 1,4-dioxane (50 mL) was reacted with a 20% solution of phosgene (7.00 mL, 9.86 mmol) in toluene in a sealed tube. The mixture was heated to reflux for 24 hours, then cooled and quenched with H2O. The mixture was extracted three times with ethyl acetate, the organic layers combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 1.5 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([Cl:47])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][CH2:38][O:39][CH3:40])=[CH:27][C:26]=2[CH3:41])[CH2:16][NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:9]=1.Cl.O1CCOCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([Cl:47])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH2:37][CH2:38][O:39][CH3:40])=[CH:27][C:26]=2[CH3:41])[CH2:16][NH2:17])=[CH:10][CH:9]=1
Reactant: COCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCc1ccccc1-c1ccc(C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2′-(2-methoxyethyl)-3-methylbiphenyl-4-yl]propyl}carbamate from step 4 (1 eq.) in CH2Cl2 (0.06M) at room temperature was added HCl 4M in dioxane (30 eq.). The reaction mixture was stirred for 3 h at room temperature and then concentrated to dryness. Purification by column chromatography on silica gel, eluting with CH2Cl2/MeOH(NH3 2M) 4%, afforded the title compound as a colorless oil. 1H NMR (400 MHz, acetone-d6): δ 7.46-7.20 (m, 6H); 7.22-7.12 (m, 2H); 7.07-6.97 (m, 3H); 6.81 (d, 2H); 4.39-4.32 (m, 4H); 3.60 (s, 3H); 3.55-3.45 (m, 2 H); 3.31-3.19 (m, 1H); 3.0-2.75 (m, 6H); 2.45 (t, 2H); 2.32 (s, 3H); 2.20 (s, 3H).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH2:13]([O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH3:28])[CH3:14]>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:13]([O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[CH:28]=[O:2])[CH3:14]
Reactant: CCOC(=O)CCCOc1cccc(C)c1C
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCCOc1cccc(C)c1C=O
Temperature: 64 °C
Yield: 205.6 %

Procedure:
A mixture of copper(II) sulfate pentahydrate (21.98 g, 88.06 mmol) and potassium persulfate (71.42 g, 264 mmol) in water (396 mL) was heated to 63-65° C. to obtain a blue colored solution. Then, a solution of 4-(2,3-dimethyl-phenoxy)-butyric acid ethyl ester (20.81 g, 88.06 mmol) in acetonitrile (220 mL) was added at the above temperature. The resulting light green solution was refluxed for 40 minutes. Then, the reaction mixture was cooled to ˜5° C. in order to precipitate most of the inorganic solids. The resulting solids were collected by filtration and the solid cake was washed with dichloromethane (1.0 L). The two layers of filtrate were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a brown oil. The crude mixture was purified by using a Biotage™ (40 L) column chromatography eluting with 5-10% ethyl acetate in hexanes to obtain 4-(2-formyl-3-methyl-phenoxy)-butyric acid ethyl ester (45.32 g, 94%) as a colorless oil: EI(+)-HRMS m/e calculated for C14H18O4 (M+)+ 250.1205, found 250.1202.
Reaction SMILES: [CH3:1][OH:2].CC(C)(C)CCN[C:8]([C:10]1[C:19]2[CH2:18][CH2:17][CH:16](CCN3CCC(C4C=CC=CC=4)CC3)[C:15](=[O:34])[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:8]([C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][C:15](=[O:34])[C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: CO
Reactant: CC(C)(C)CCNC(=O)c1cccc2c1CCC(CCN1CCC(c3ccccc3)CC1)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1CCCC2=O
Temperature: 80 °C
Yield: 90 %

Procedure:
A 450-mL Parr bomb was charged with methanol (81 mL), DMF (160 mL), compound 2 (24.0 g, 81.6 mmol), palladium acetate (549 mg, 2.45 mmol), 1,3-bis(diphenylphosphino)-propane (1.01 g, 2.45 mmol), and triethylamine (23 mL, 163 mmol). The bomb was purged with carbon monoxide using 2 fill/vent cycles. The bomb was repressurized to 150 psi and was heated to 80° C. for 3 hours. During this time additional CO was admitted to maintain the pressure at 150 psi. The bomb was cooled to room temperature and vented. A second identical run was made. The combined reactions were diluted with methylene chloride (2 L), washed with water (4×800 mL), dried (MgSO4) and concentrated in vacuo to a black solid. Chromatography (flash, silica, 120 mm dia×20 cm, 2% ethyl acetate/methylene chloride) provided semi-pure product. Recrystallization of this material from hot hexanes in 2 crops followed by chromatography of the final mothor liquors (silica gel, methylene chloride (700 mL) then 2% ethyl acetate/methylene chloride) provided a total of 30.3 g (90%) of the title compound.
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](O)=[O:14])([O-:5])=[O:4].B(F)(F)F.CCOCC>>[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][CH2:13][OH:14])([O-:5])=[O:4]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccccc1CCO
Temperature: 0 °C
Reaction time: 12 h
Yield: 73.3 %

Procedure:
A 22-liter, 4-necked glass reaction vessel equipped as described in Example 1 was charged with 624 grams (15.8 moles plus 5% excess) of sodium borohydride and 3620 grams (20 moles) of o-nitrophenylacetic acid and flushed for 0.5 hour with dry nitrogen. The reaction vessel was cooled to 0°C using an external dry ice/isopropyl alcohol bath as 10 liters of tetrahydrofuran was added dropwise over a 2 hour period. Boron trifluoride diethyl etherate (2.58 liters, 21 moles) was then added dropwise over a 4 hour period while maintaining a reaction temperature of 0°-10°C. The reaction mixture was then stirred for 12 hours at 20°-25°C. Isolation of the product as described in Example 1 gave 2450 grams (73% yield) of o-nitrophenethyl alcohol as a clear, light-orange liquid, bp 112°C/0.15 mm, n20D 1.5644.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][C:15]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[CH:17][N+:16]=1[O-].CO>ClCCl>[OH:4][CH2:14][C:15]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[CH:17][N:16]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(F)c(Cl)cc[n+]1[O-]
Solvent: ClCCl
Solvent: CO
Product: OCc1nccc(Cl)c1F
Reaction time: 72 h

Procedure:
Trifluoroacetic anhydride (16.18 ml) was added dropwise at 10°-15° to a solution of 2-methyl-3-fluoro-4-chloropyridine-N-oxide (6.17 g) in dichloromethane (50 ml). After three days at room temperature, methanol (30 ml) was added to the cooled solution. The excess solvent was removed and the residue dissolved in water. After basifying (NaOH), the solution was extracted with dichoromethane. The extracts were dried (K2CO3) and evaporated to dryness to give a solid which was purified by column chromatography (silica gel; 1% MeOH/CHCl3) to give 2-hydroxymethyl-3-fluoro-4-chloropyridine (3.8 g) m.p. indeterminate)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([NH:21][CH2:22][CH3:23])=[N:19][CH:20]=3)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1.O>[CH2:22]([NH:21][C:18]1[N:17]=[C:16]([O:24][CH3:25])[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:30]4[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=4)[CH:7]=3)=[CH:14][N:13]=2)=[CH:20][N:19]=1)[CH3:23]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)cn2)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)cn2)c(OC)n1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A mixture of 5-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-N-ethyl-4-methoxypyrimidin-2-amine (0.090 g, 0.25 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.060 g, 0.28 mmol), and K2CO3 (0.10 g, 0.76 mmol) in 5:1 dioxane/water (6 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.03 g, 0.025 mmol), sparged again with Ar and heated at 90° C. for 7 h. The mixture was cooled to RT, quenched with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain N-ethyl-4-methoxy-5-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (80 mg, 79%). MS (ESI) m/z: 404.2 (M+H+).
Reaction SMILES: C(N(CC)CC)C.C([O:11][CH2:12][C:13](Cl)=[O:14])(=O)C.[CH3:16][C@H:17]1[NH:22][C@@H:21]([CH3:23])[CH2:20][N:19]([C:24]2[N:25]([CH2:46][C:47]([F:50])([F:49])[F:48])[C:26]3[C:31]([N:32]=2)=[C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:29]=[C:28]([C:39]2[CH:40]=[N:41][C:42]([NH2:45])=[N:43][CH:44]=2)[N:27]=3)[CH2:18]1.C[O-].[Na+].CO>O1CCCC1.CO.C(Cl)Cl.CO.C(Cl)Cl>[NH2:45][C:42]1[N:43]=[CH:44][C:39]([C:28]2[N:27]=[C:26]3[C:31]([N:32]=[C:24]([N:19]4[CH2:18][C@@H:17]([CH3:16])[N:22]([C:12](=[O:11])[CH2:13][OH:14])[C@@H:21]([CH3:23])[CH2:20]4)[N:25]3[CH2:46][C:47]([F:50])([F:49])[F:48])=[C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:29]=2)=[CH:40][N:41]=1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Reactant: CC(=O)OCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1C(=O)CO
Temperature: 25 °C
Reaction time: 25 h
Yield: 79 %

Procedure:
Triethylamine (57.8 μl, 0.41 mmol) and acetoxyacetyl chloride (23.0 μl, 0.21 mmol) were added to a methylene chloride solution (3.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (92.9 mg, 0.19 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 25 hours followed by the addition of triethylamine (15.8 μl, 0.11 mmol) and acetoxyacetyl chloride (6.3 μl, 0.06 mmol) and the resulting mixture was stirred for 17 hours. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (86.3 μl, 0.38 mmol) was added to a methanol (9.0 ml) suspension of the resulting residue, and the resulting mixture was stirred at room temperature for 5.5 hours. Tetrahydrofuran (3.0 ml) was added, the resulting mixture was stirred at 40° C. for 16.5 hours, then methanol was concentrated to a half amount under reduced pressure, the resulting mixture was poured into methylene chloride, and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (82.6 mg, 80%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH2:23]([NH:27][C:28]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 46 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (3 ml) with heat, n-butyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 14 hours. The resulting residue was purified by chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 31 mg of the title compound (yield: 46%).
Reaction SMILES: C([SiH2]O[C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]1([OH:24])[CH2:20][CH2:19][CH2:18][N:17]2[CH:21]=[N:22][CH:23]=[C:16]12)(C)(C)C.C(=O)(O)[O-].[Na+]>Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[CH2:7][O:24][C:15]3([CH2:20][CH2:19][CH2:18][N:17]4[CH:21]=[N:22][CH:23]=[C:16]34)[C:9]=2[CH:10]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(Cl)cc1C1(O)CCCn2cncc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc2c(c1)C1(CCCn3cncc31)OC2
Temperature: 95 °C
Reaction time: 40 h

Procedure:
A suspension of 2.672 mmol of 8-[2-(tert-butyl-dimethyl-silanyloxymethyl)-5-chloro-phenyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-8-ol in 40 ml of 1N aqueous HCl is stirred at 95° C. for 40 hours, then cooled to room temperature. The mixture is basified to pH 12 by dropwise addition of aqueous saturated sodium bicarbonate solution, and then extracted with dichloromethane (3×140 ml). The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a beige solid. Rf=0.14 (EtOAc-methanol 10:1); Rt=3.04 (gradient I).