Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:22][CH:23]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[N:61]=1.C[Si](Cl)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([C:17]([C:18]4[CH:19]=[CH:20][C:21]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[C:3](/[CH:2]=[CH:59]/[C:60]4[CH:69]=[CH:68][C:67]5[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=5)[N:61]=4)[N:4]=3)[N:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(CO)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Reactant: Cc1ccc2ccccc2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(/C=C/c4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 21a (195 mg, 0.393 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added. Dess-Martin periodinane (184 mg, 0.433 mmol) was added and then the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCO3 solution (2×20 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in an 8 mL vial equipped with a stir bar and then dry DMF (4 mL) was added. 2-Methylquinoline (51.5 μL, 0.393 mmol) and TMSCl (150 μL, 1.18 mmol) were added sequentially and then the mixture was heated to 80° C. and stirred for 3 h. The reaction was cooled to rt and then poured into water (50 mL) and neutralized with saturated NaHCO3 solution (50 mL). The aqueous mixture was extracted with EtOAc (3×50 mL), and then the organic extracts were combined, washed with brine (2×50 mL), dried over Na2SO4, and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-80% EtOAc/DCM to afford compound 30a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.50 (d, J=2.0 Hz, 1H), 8.07 (dd, J=8.4, 4.3 Hz, 2H), 7.88-7.98 (m, 3H), 7.65-7.78 (m, 4H), 7.44-7.51 (m, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.05 (d, J=5.6 Hz, 1H), 4.02-4.10 (m, 4H), 3.92-4.01 (m, 4H), 3.63-3.71 (m, 4H), 3.57-3.63 (m, 4H), 1.51 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H38N8O3: 619.3 (M+H). Found: 619.3.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH2:15][O:16][N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[O:13][CH:14]=1)C1C=CC=CC=1.B(Br)(Br)Br>ClCCl>[OH:8][C:9]1[C:10](=[O:28])[CH:11]=[C:12]([CH2:15][O:16][N:17]2[C:18](=[O:27])[C:19]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]3[C:21]2=[O:22])[O:13][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1cc(=O)c(OCc2ccccc2)co1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1OCc1cc(=O)c(O)co1
Temperature: -70 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
N-[[5-(Benzyloxy)-4-oxo-4H-pyran-2-yl]methoxy]-phthalimide (1.77 g) (4.7 mmol) are suspended in 250 ml of dichloromethane and treated at -70° C. with 1.32 g (5.2 mmol) of boron tribromide (dissolved in 5 ml of dichloromethane). The mixture is stirred at -70° C. for 3 hours and at room temperature for 20 hours. The solvent is removed in a vacuum and the residue is treated at 0° C. with about 70 ml of water and 10 ml of ethanol. After stirring for 2 hours the product is filtered off and washed in succession with water, ethanol and diethyl ether. There are obtained 1.3 g of N-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methoxy]phthalimide as a white powder of m.p. 200°-203° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>COCCOC>[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc(-c2ccccc2SCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 54.3 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.430 ml, 0.86 mmoles) was treated with 3-methoxyphenylboronic acid (75 mg, 0.491 mmol) and Pd[PPh3]4 (29 mg, 0.025 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (58 mg, 55%). MS m/e 435.22 (M+H+)
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=C[C:31]2[N:36]([OH:37])N=[N:34][C:32]=2[CH:33]=1.O1C=C(N)C=N1>CN(C)C=O.O>[O:37]1[CH:33]=[C:32]([NH:34][C:11](=[O:12])[C:10]2[CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][C:9]=2[O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:31]=[N:36]1
Reactant: O=C(O)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: Nc1cnoc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cnoc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[(phenylmethyl)oxy]-5-(4-pyridinyl)benzoic acid (may be prepared as described in Description 79; 100 mg, 0.30 mmol), EDC (172 mg, 0.90 mmol) and HOBT (137 mg, 0.90 mmol) in dimethylformamide (3 ml) was stirred in air at room temperature for 1 h, then 4-isoxazolamine (may be prepared as described in Description 95; 100 mg, 1.189 mmol) was added in one charge. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 ml). The solid was filtered and dried in vacuo to obtain crude product, which was purified with Prep-HPLC (Waters, X-Bridge, 5 μm; 30×100 mm; A=0.05% NH3.H2O/water, B: MeCN; v=30 ml/min; 0-7 min, 42%-54%; 7-12 min, 95%; t=8.0 min.) to yield the title compound as a white solid. 34 mg.
Reaction SMILES: [CH3:1][C:2]([CH:14]([CH3:21])[CH2:15][CH:16]=[C:17]([CH3:20])[CH2:18][CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.ClCCl>[O:30]1[C:17]([CH3:20])([CH2:18][CH3:19])[CH:16]1[CH2:15][CH:14]([CH3:21])[C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH3:13])=[CH:10][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C)=CCC(C)C(C)=CCOc1ccc(CC)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(OCC=C(C)C(C)CC2OC2(C)CC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10 g. of p-ethylphenyl 3,4,7-trimethyl-2,6-nonadienyl ether are dissolved in 110 ml. of dichloromethane and treated portionwise at -10° C. with 7.8 g. of 80% m-chloroperbenzoic acid. After completion of the treatment, the mixture is stirred for a further 2 hours at 0° C., shaken out with 10% sodium sulfite solution, 1-N sodium hydroxide solution and water, dried over sodium sulfate and evaporated. There is obtained pure 6,7-epoxy-1-(p-ethylphenoxy)-3,4,7-trimethyl-2-nonene; NMR (CDCl3): 7.25-6.7 ppm (AB-quartet of the four aromatic protons); 5.5 ppm (a vinyl proton at C-2); 4.52 ppm doublet of the --O--CH2 group); 2.59 ppm (quartet of the aromatic-bound --CH2 group); 2.8-2.2 ppm (multiplet of the protons at C-4 and C-6); 1.65 ppm (wide singlet of the methyl group at C-3); 1.78-0.8 ppm (complicated multiplet of 19 protons).
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>C(Cl)Cl>[O:1]=[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCC#CC(O)c1ccccc1Cc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCC#CC(=O)c1ccccc1Cc1ccccc1
Reaction time: 2 h
Yield: 67 %

Procedure:
To a stirred mixture of 0.3 g (0.93 mmol) methyl 7-hydroxy-7-[2-(phenylmethyl)phenyl]-5-heptynoate in 20.0 ml methylene chloride at room temperature was added 0.5 g (2.32 mmol) of pyridinium chlorochromate (PCC). The mixture was stirred for 2 hours and 80.0 ml of diethylether was added to the reaction mixture. The reaction mixture was filtered through Florisil® brand magnesium silicate evaporated to an oil and purified by flash chromatography to give the title compound in 67% yield (200 mg; 0.625 mmol). NMR (CDCl3, 200 MHz) δ: 2.0 (m, 2H), 2.5 (m, 4H), 3.67 (s, 3H), 4.40 (s, 2H), 7.12-8.25 (m, 9H). Mass spectrum: m/z=320 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH2:16][CH3:17])[N:9]=2)[N:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([C@@H:20]1[CH2:15][C@H:14]1[C:12]1[CH:13]=[C:8]([N:4]2[C:5]([CH3:7])=[N:6][C:2]([CH3:1])=[N:3]2)[N:9]=[C:10]([CH2:16][CH3:17])[N:11]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(CC)n1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(CC)n1

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-ethyl-6-vinylpyrimidine (19-3, 860 mg, 3.75 mmol, 1.0 eq.) in toluene (20 mL) at 120° C. was added ethyl diazoacetate (0.79 mL, 7.50 mmol, 2.0 eq.) dropwise and the resulting mixture was refluxed for 4 hours. Toluene was removed by roto-evaporation and the resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to afford ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-ethylpyrimidin-4-yl)cyclopropanecarboxylate (19-4) as a light yellow solid which was carried forward for next step without further purification. LRMS m/z (M+H) 316 found, 316 required.
Reaction SMILES: C([NH:8][C@@:9]1([CH3:27])[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH2:15]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)(C)C>[CH3:27][C@:9]1([NH2:8])[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH2:15]2)[CH2:11][CH2:10]1
Reactant: [H][H]
Reactant: C[C@@]1(NCc2ccccc2)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Solvent: CC(C)O
Product: C[C@@]1(N)CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21

Procedure:
(3aR,4R,6aS)—N-Benzyl-4-methyl-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-amine (30 mg, 0.080 mmol) from Example 21 and isopropanol (14 mL) were added to 20% Pd(OH)2—C, wet (6.0 mg, 0.043 mmol) in a 50 mL pressure bottle and stirred for 90 minutes under 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane as eluent to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.54-7.46 (m, 1H), 6.97 (d, J=7.2, 1H), 6.52 (d, J=8.6, 1H), 3.75 (dd, J=11.3, 5.2, 1H), 3.56 (dd, J=10.3, 8.4, 1H), 3.52-3.43 (m, 1H), 3.36 (dd, J=10.5, 3.9, 1H), 2.72-2.62 (m, 1H), 2.31 (td, J=8.7, 5.3, 1H), 1.92-1.81 (m, 1H), 1.77-1.68 (m, 1H), 1.60-1.35 (br m, 2H), 1.54-1.42 (m, 2H), 1.16 (s, 3H); MS (ESI+) m/z 286 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)C.[OH-].[Li+].Cl>C1COCC1.O>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([OH:17])[CH:14]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1OB(O)c2cc(O)cc(F)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (127 mg, 0.50 mmol) in THF (2 mL) was added dropwise a solution of lithium hydroxide (102 mg, 2.5 mmol) in water (3 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h and after cooling to 0° C., acidified to pH=2 by addition of diluted hydrochloride acid, extracted with ethyl acetate (2×15 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by HPLC to give the title compound as a white solid (52 mg, Yield: 46%). 1H NMR (400 MHz, DMSO-d) δ 12.12 (s, 1H), 9.91 (s, 1H), 9.37 (s, 1H), 6.94-6.94 (d, J=1.6 Hz, 1H), 6.65-6.68 (m, 1H), 5.46-5.49 (m, 1H), 2.88-2.93 (m, 1H), 2.23-2.29 (m, 1H). MS (ESI) m/z=455 [2M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:16]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:16][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][NH:6][C:2]=1[CH3:1]
Reactant: Cc1cc(C(F)(F)F)n[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1[nH]nc(C(F)(F)F)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Dissolve 5-methyl-3-(trifluoromethyl)pyrazole (1.00 g, 6.66 mmol) in 60% aqueous acetic acid (13 mL). Add sodium acetate (0.819 g, 9.99 mmol) and cool to 0° C. Add bromine (1.17 g, 7.33 mmol) dropwise over 10 min. Stir at 0° C. for 3 hr, then at room temperature for 18 hr. Add ethyl acetate and saturated aqueous sodium sulfite solution. Separate organics and wash one time with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give 4-bromo-5-methyl-3-trifluoromethyl-1H-pyrazole (1.50 g, 100%). GC-MS: m/z=229 [M+].
Reaction SMILES: [H-].[Na+].C1COCC1.[OH:8][CH:9]([CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[C:13]=1F.C1(C)C=CC=CC=1>CN(C=O)C>[F:18][C:15]1[C:14]([F:19])=[C:13]2[C:12]([CH2:11][CH2:10][CH:9]([CH2:21][CH2:22][CH3:23])[O:8]2)=[CH:17][CH:16]=1
Reactant: CCCC(O)CCc1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1CCc2ccc(F)c(F)c2O1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Sodium hydride (60% in oil) was suspended in DMF under nitrogen replacement. Then, the THF solution containing 1-(3-hydroxy-1-hexyl)-2,3,4-trifluorobenzene was added dropwise for 30 minutes, and stirred for 3 hours at 50° C. After toluene was added and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by column chromatography (silica gel, hexane) to obtain 7,8-difluoro-2-propylchroman.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].[NH3:22]>>[NH2:22][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CC(CO)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [K+]
Agent: [OH-]
Product: CC(CO)Cn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C

Procedure:
R 3-(4-Chloro-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol (1.0 g, 3.6 mmol) and methanolic ammonia (30 mL of ˜15%) were combined and then heated in a steel bomb at 150° C. The container was allowed to cool to ambient temperature. Excess methanolic potassium hydroxide was added to the reaction mixture which was then concentrated under reduced pressure to decrease the volume. Water was added and then concentration was continued until a solid formed. The solid was isolated by filtration, washed with water and then dried to provide a near white solid. This material was recrystallized from methanol/dichloromethane to provide R 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-1-ol as colorless solid, m.p. 258-261° C. Analysis: Calculated for C14H16N4O: % C, 65.61, % H, 6.29; % N, 21.86. Found: % C, 65.50, % H, 6.3, % N, 21.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][C:11](=[CH:14][O:15]C)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC=C1CCC(c2cccc(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C[C@H]1CC[C@H](c2cccc(F)c2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
The compound (36) (45.0 g), formic acid (87%; 54.0 g), and toluene (250 ml) were mixed, and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled to 30° C., and then water (200 ml) and toluene (200 ml) were added and mixed thereto. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and light yellow solids. The residue was dissolved in toluene (50 ml). The solution was added to a mixture of 5.0 g of 95% sodium hydroxide and 200 ml of Solmix A-11 cooled to 7° C., and the solution obtained was stirred at 10° C. for 2 hours. Then, an aqueous 2N-sodium hydroxide solution (100 ml) was added thereto, and the mixture was stirred at 5° C. for 2 hours. The reaction mixture obtained was poured into a mixture of water (200 ml) and toluene (200 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue obtained was concentrated and purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder and dried, giving 39.8 g of 1-(3-fluorophenyl)-trans-4-cyclohexanecarboaldehyde (37). The yield based on the compound (36) was 94.5%.
Reaction SMILES: OS([C:5]([F:8])(F)F)(=O)=O.[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][C@H:21]2[CH2:25][CH2:24]C([Sn](C)(C)C)=[C:22]2[C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1)=[O:12].C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl.[Al]>[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][CH2:20][C@H:21]2[CH2:25][CH2:24][C:5]([F:8])=[C:22]2[C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:34][CH:35]=2)=[CH:16][CH:17]=1)=[O:12]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C([Sn](C)(C)C)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: [Al]
Solvent: ClCCl
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(F)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reaction time: 0.5 h
Yield: 5 %

Procedure:
An analogous procedure to that described in Marcus A. Tius and Joel K. Kawakami Tetrahedron 1995, 51, 3997 was Used. A Solution of Triflic Acid (37 μL, 0.42 Mmol) in 0.37 mL CH2Cl2 was added to a mixture of Ag2CO3 (83 mg, 0.30 mmol) in 2.8 mL CH2Cl2 and the flask was covered in aluminum foil. After 30 min., a solution of 57 (ca. 0.38 mmol, directly from above) and 2,6-di-tert-butyl-4-methylpyridine (49 mg, 0.24 mmol) in 2.8 mL CH2Cl2 was added dropwise by cannula, rinsing with 1 mL CH2Cl2. At this time, a solution of XeF2 (82 mg, 0.48 mmol) in 5.5 mL CH2Cl2 was added by cannula. The reaction was stirred for 1 h and then was quenched by addition of 10 mL saturated NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (3×30 mL) and the combined solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography on a Teledyne Isco Combiflash unit (40 g silica gel column, 0%→100% ethyl acetate/hexanes) followed by HPLC (Phenomenex 50 mm×250 mm silica gel column, 5% ethyl acetate/hexanes) to give the title compound (12 mg, 5%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N.C[OH:28]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:28])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CO
Reactant: Nc1nc(Nc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Agent: Cl
Agent: N
Product: Nc1nc(Nc2ccccc2)nc2c1nc(O)n2Cc1ccccc1

Procedure:
6-Amino-2-anilino-9-benzyl-8-bromopurine (80 mg, 0.20 mmol) in concentrated hydrochloric acid (200 ml) and methanol (50 ml) were refluxed for 5 hours under heating. The reaction mixture was condensed in vacuo, 28% aqueous ammonia was added to the residue. The resulting solid was filtered, washed with water and dried to give the subject compound (67 mg yield: quantitatively).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8]([CH:15]=[CH2:16])=[CH:7]3.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:15]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]1=[N:13][C:12]=2[NH2:14])[CH3:16]
Reactant: [H][H]
Reactant: C=Cc1cnc2c(N)nc3cc(C)ccc3c2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cnc2c(N)nc3cc(C)ccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 8-methyl-2-vinylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite and washed with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethyl-8-methylbenzo[f][1,7]naphthyridin-5-amine as an off white solid. 1H NMR (CDCl3): δ 8.61 (d, 1H), 8.42 (d, 1H), 8.10 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 2.84 (q, 2H), 2.45 (s, 3H), 1.33 (t, 3H). LRMS [M+H]=238.1.