Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][C:6]=2[CH2:5][CH2:4]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:8]1[C:7]2[O:3][CH2:4][CH2:5][C:6]=2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=1
Reactant: BrBr
Reactant: CCOC(=O)CCc1ccc2c(c1)CCO2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Bromine (10.5 g, 65.8 mmols) was dropwise added to an acetic acid (150 ml) solution containing ethyl 3-(2,3-dihydrobenzofuran-5-yl)propionate (14.5 g, 65.8 mmols) and sodium acetate (5.94 g, 72.4 mmols), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to obtain 19.2 g (yield: 97%) of the target compound. This was oily.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:26])[C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([CH3:24])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH:1]1([N:4]2[C:14]3[C:13](=[C:18]([N+:19]([O-:21])=[O:20])[C:17]([F:22])=[C:16]([F:23])[C:15]=3[CH3:24])[C:12](=[O:26])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 90.5 %

Procedure:
To a solution of 10.0 g of ethyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate and 0.1 g of 18-crown-6-ether in 100 ml of tetrahydrofuran, 8.04 g of potassium carbonate was added, and then the mixture was stirred at room temperature for 23 hours. The deposited crystals were collected by filtration and washed with tetrahydrofuran, water and acetone to give 8.56 g of the desired compound. Recrystallization from N,N-dimethylformamide gave colorless needles, which were identified as the compound of Example 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2.COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC.Cl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2
Reactant: O=C(O)C1CCc2cc(F)ccc21
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCc2cc(F)ccc21
Yield: 10.5 %

Procedure:
The combined mother liquors from the resolution of Intermediate T3 were concentrated under reduced pressure until no acetone remained and acidified to pH 3 with 0° C. 5N HCl. This solution was extracted 3 times with Et2O (200 ml portions) and the combined Et2O portions were washed successively with 1N HCl, H2O and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow solid (71 g). This residue was recrystallized from hexane to give pure 5-fluoro-indan-1-carboxylic acid (Intermediate 2a, 58.6 g, 325.5 mmol) which was enriched in the R enantiomer. To Intermediate 2a in refluxing acetone (1 L) was added pulverized brucine (128.4 g, 325.5 mmol). After most solids had dissolved the solution was hot filtered and reheated to reflux as H2O (1 L) was added gradually. Excess acetone was boiled off until the solution became hazy. The solution was allowed to stand in a recrystallization dish for 1 month before solids appeared. The resultant solids were broken up, filtered off and recrystallized four more times in similar manner from acetone and H2O to give a buff colored solid which was taken up in 0° C. 1N HCl (150 ml). This solution was extracted 3 times with Et2O (75 ml portions) and the combined Et2O portions were washed successively with 1N HCl, H2O and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 6.13 g of (R)-5-fluoro-indan-1-carboxylic acid (Intermediate T4) as a pale solid which rotates sodium light at 20° C. with [α]20D+31.8 (c=4.49, benzene).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@H:21]2[O:23][C@@H:22]2[C:24]([O:26]C2C=CC3C(=CC=CC=3)C=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:37]>CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C@H:21]2[O:23][C@@H:22]2[C:24]([NH2:37])=[O:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Oc1ccc2ccccc2c1)[C@H]1O[C@@H]1c1ccccc1CCCCCCCCc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1O[C@@H]1c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 5 h
Yield: 76 %

Procedure:
The ester of Example 6b, (2S-trans)-2-naphthalenyl 3-[2-(8-phenyloctyl)phenyl]oxiranecarboxylate (2.03 g, 4.2 mmol), in methanol (21 mL) was cooled to 5° C. and a solution of ammonia saturated methanol (20 mL) was added dropwise. After stirring for 5 h at 10°-15° C., the solution was evaporated. The residue was dissolved in toluene and evaporated to a solid. The solid was dissolved in toluene and washed with water, NaOH (10%), water, and finally brine. After drying (MgSO4) and evaporation, the residue was dissolved in boiling hexane CH2Cl2 (8:2), filtered and allowed to stand at 20° C. for 4 h. The solid was collected and dried (0.1 mm Hg, 25° C.) to yield the titled oxiranecarboxamide 1.11 g (76%): mp 80°-82° C.; [α]D -8.3° (c 1, CH2Cl2); HPLC RT 5.48 min (2S-enantiomer); 9.99 min (2R-enantiomer) (Bakerbond Chiracel OC; 25 cm×4.6 mm; hexane:isopropanol, 1:1; 1.0 mL/min; UV detection at 211 nm); HPLC showed the product at >99% e.e. Anal. Calcd for C23H29O2N: C, 78.59; H, 8.32; N, 3.99. Found: C, 78.35; H, 8.34; N, 3.90.
Reaction SMILES: C(O[C@@H:5]1[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.ClCCCl.[C:42]([Si](C)(C)C)#[N:43].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C@H:5]1[C:42]#[N:43])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: N#C[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 0.03 h

Procedure:
A stirred solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (50.3 g, 80 mmol), 1,2-dichloroethane (100 ml), and cyanotrimethylsilane (15.84 g, 160 mmol) was treated in one portion via a syringe with anhydrous stannic chloride (20.8 g, 9.33 ml, 80 mmol). The darkening solution was stirred for two minutes then poured into saturated sodium hydrogen carbonate (800 ml), and stirred five minutes (pH 7). Chloroform (1 liter) was added and the emulsion was filtered through Celite®. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure (15 torr, 40° ) to a light orange syrup which was crystallized from ethanol (charcoal to afford 2 (30 g from two crops, 80%) as long white needles; mp 77°-78° after drying at 0.05 torr, 60° for two hours; [α]D25 +24.4° (0.5 CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37]>CN(C=O)C>[CH:39]([O:38][C:36]([N:25]1[CH2:24][CH2:23][CH:22]([O:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:27][CH2:26]1)=[O:37])([CH3:41])[CH3:40]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottom flask was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (80 mg, 0.2 mmol) and triethylamine (200 μl). DMF (3 mL) was added to completely dissolve the solid material. The reaction flask was immersed in an ice-bath. Isopropyl chloroformate (1.0M in toluene, 0.22 mL) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by preparative HPLC to give 4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound A129). 1H NMR (CDCl3, 400MHz) δ 1.27 (d, 6H), 1.9 (m, 2H), 2.12 (m, 2H), 3.13 (s, 3H), 3.40 (m, 2H), 3.91 (m, 2H), 4.97 (m, 1H), 5.63 (m, 1H), 7.95 (m, 3H), 8.34 (s, 1H), 8.63 (s, 1H). Exact mass calculated for C21H24FN5O5S: 477.15, found 478.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[O:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:3][C:4]=2[N+:14]([O-:16])=[O:15])[CH2:9][CH2:10]1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(N2CCOCC2)cnc1N1CCOCC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(5-chloro-3-nitropyridin-2-yl)morpholine (2.48 g, 10 mmol; described herein) in toluene (190 mL) were sequentially added morpholine (1.8 mL, 20 mmol), tris(dibenzylideneacetone)dipalladium(o) (0.65 g, 0.71 mmol), 2-(dicyclohexylphosphino)-2,4,6,-tri-i-propyl-1,1-biphenyl (0.73 g, 1.5 mmol), and sodium tert-butoxide (2.0 g, 20 mmol). The reaction was heated to reflux overnight, cooled to rt, and concentrated. The resulting residue was taken up in EtOAc, washed with satd aq. sodium bicarbonate solution and brine, and the organic layer dried (magnesium sulfate) and concentrated. Column chromatography afforded 4-(6-morpholino-5-nitropyridin-3-yl)morpholine as a red oil. Mass Spectrum (ESI) m/e=295.1 (M+1).
Reaction SMILES: [O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[OH-].[Li+]>C1COCC1.O>[O:1]=[C:2]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=1)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cc1ccc(OCc2ccccc2C(=O)O)cc1)NCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Methyl 2-{[4-(2-oxo-2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]methyl}-benzoate (71 mg, 0.155 mmol) in THF (1.5 ml) was cooled in an ice-bath. Lithium hydroxide (7.5 mg, 0.310 mmol) in water (1.5 ml) was dropped in. The cooling-bath was then removed and the mixture was stirred overnight. HPLC showed that the reaction was not complete. More lithium hydroxide (0.2M, 0.5 ml) was added. The reaction mixture was stirred for 4 days more. It was then evaporated in vacuum to remove THF. The residue was acidified with 1% hydrochloric acid, pH=3-4, and then extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, MeOH/DCM (0.5:99.5, then 1:99, and then 2:98) as eluant gave 39 mg white solid product, yield 57%.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:33][OH:34])[CH:18]=[C:19]([F:32])[C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.[H-].[Na+].Cl>CN(C)C=O>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([F:32])[C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:33][O:34][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1cc(F)c(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol. An exemplary process is shown below: To a solution of 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-c]pyrimidin-6(2H)-one, trifluoroacetic acid salt (43 mg, 0.137 mmol) and (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (46.0 mg, 0.151 mmol) in N,N-dimethylformamide (DMF) (1.5 mL) were added NaH (16.45 mg, 0.411 mmol). The mixture was stirred at room temperature for 30 mins. Sufficient aqueous HCl solution (1 M) was added to adjust the solution to pH to ˜7. The resulted mixture was purified by Mass Directed AutoPrep (basic mobile phase) to afford the title compound (18 mg, 0.038 mmol, 28.0% yield) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH2:29][CH2:28][CH2:27][C:26]2=[O:30])[C:20]=1[CH3:31])(=[O:18])=[O:17])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:8].[OH-].[Na+].Cl>C1COCC1.C(OCC)C>[Cl:14][C:11]1[S:10][C:9]([C:7]([NH:6][CH2:5][C@H:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])[C:20]=2[CH3:31])(=[O:18])=[O:17])[C:3]([OH:32])=[O:2])=[O:8])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NS(=O)(=O)c1cccc(N2CCCC2=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(N2CCCC2=O)cccc1S(=O)(=O)N[C@@H](CNC(=O)c1ccc(Cl)s1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 86 was dissolved in 20 ml THF and sodium hydroxide (1N water solution) (38.16 ml, 38.16 mmol) was added. After 2 h stirring at RT the reaction mixture was extracted with diethyl ether and 1 N HCl (38.16 ml, 38.16 mmol) was added to the aqueous layer. The aqueous layer was extracted with n-butanol. The organic layer was dried with Na2SO4, filtered and evaporated to dryness. 8.28 g of crude product were obtained and used without further purification in step 24.6.
Reaction SMILES: [C:1]1([C:11](=O)[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])=O.[NH4+:24]>O>[C:1]1([CH:11]([NH2:24])[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(CCC1CCNCC1)c1nccc2ccccc12
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: O
Product: NC(CCC1CCNCC1)c1nccc2ccccc12
Temperature: 160 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
A mixture of 1-(1-isoquinolyl)-3-(4-piperidyl)-1-propanone (2.5 g) and ammonium formate (7.5 g) is heated to 160° C. for 5 hours. The mixture is cooled, water (100 ml) is added, and the insoluble material is extracted with ethyl acetate (3×50 ml). After the solvent has been evaporated, the residue is taken up in 6N hydrochloric acid (35 ml) and boiled for 1 hour. The mixture is diluted with water (100 ml), the pH of the aqueous mixture is adjusted to 7, and the solution is extracted with ethyl acetate. The aqueous phase is made alkaline to pH 11, and extracted again with chloroform (3×100 ml). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure. 1-(1-Isoquinolyl)-3-(4-piperidyl)-1-propanamine (0.13 g) is obtained, the proton NMR spectrum of which is deuterated chloroform has the following characteristics: ##STR8##
Reaction SMILES: Cl.[CH:2]1([O:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O:12][C@@H:13]1[C@H:17]([O:18]C(=O)C)[C@@H:16]([CH2:22][O:23]C(=O)C)[O:15][C@H:14]1[N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30]([CH3:37])=[N:31][C:32]=2Cl)(=O)C.C(N(CC)CC)C>O1CCOCC1>[CH:2]1([O:7][NH:8][C:32]2[C:33]3[N:34]=[CH:35][N:27]([C:28]=3[N:29]=[C:30]([CH3:37])[N:31]=2)[C@@H:14]2[O:15][C@H:16]([CH2:22][OH:23])[C@@H:17]([OH:18])[C@H:13]2[OH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NOC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1nc(NOC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 100 °C

Procedure:
O-Cyclopentylhydroxylamine hydrochloride (0.52 g, 3.75 mmol) was reacted with 9-(2,3,5-triO-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine (1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of Organic Chemistry, 1967, 32, 3258-3260) by standard acylation and chlorination steps] in dioxan (40 ml) in the presence of triethylamine (0.63 g, 6.25 mmol). The reaction mixture was heated at 100° C. for 70 h, before being filtered and evaporated. The product (after purification by chromatography), followed by debenzoylation using methanolic ammonia to provide the title N-cyclopentoxy-2-methyladenosine (after column chromatography) as a foam 1H NMR (DMSO-d6)γ 1.47-1.93 (8H, m,--CH2CH2CH2CH2 --), 2.32 (3H, s,--CH3), 4.59 (1H, br m,--O--CH--), 5.88 (1H, d, H-1').
Reaction SMILES: [K+].[Br-].O1[CH2:7][CH2:6][CH2:5][CH2:4]1>>[CH2:4]([C:5]1[CH:4]=[CH:4][C:5]([CH:6]=[CH:7][C:5]2[CH:4]=[CH:4][C:5]([C:6]3[CH:7]=[CH:6][C:5]([CH:4]=[CH:5][C:6]4[CH:7]=[CH:6][C:5]([CH2:4][CH2:5][CH:6]=[CH2:7])=[CH:4][CH:7]=4)=[CH:4][CH:7]=3)=[CH:7][CH:6]=2)=[CH:7][CH:6]=1)[CH2:5][CH:6]=[CH2:7]
Reactant: C1CCOC1
Agent: [Br-]
Agent: [K+]
Product: C=CCCc1ccc(C=Cc2ccc(-c3ccc(C=Cc4ccc(CCC=C)cc4)cc3)cc2)cc1

Procedure:
In the infra-red spectrum (KBr disc), significant bands are shown at 1512 (w), 1493 (w), 1415 (w), 1260 (s), 1095 (s), 1025 (s) and 800 (s) cm-1, and in the UV spectrum, in tetrahydrofuran as solvent, λmax (1 g ε)=350 nm (4.63).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Cc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-4-methylbenzene (Apollo, 35 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 2.40 (s, 3H), 7.41 (d, J=8.1 Hz, 2 H), 7.71 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 8.43 (dd, J=2.4, 1.7 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 271 (M+H)+, 273 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[N:19][N:20]([CH:23]4[CH2:28][CH2:27][CH2:26][O:25][CH2:24]4)[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.C(=O)(O)[O-].[Na+]>CN(C)C=O.[Cu]I>[N:29]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:12]4=[N:19][N:20]([CH:23]5[CH2:28][CH2:27][CH2:26][O:25][CH2:24]5)[C:21](=[O:22])[C:11]4=[N:10]3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: c1cn[nH]c1
Reactant: O=c1c2nn(Cc3ccc(I)cc3)c3ncccc3c-2nn1C1CCCOC1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=c1c2nn(Cc3ccc(-n4cccn4)cc3)c3ncccc3c-2nn1C1CCCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-5-[(4-Iodophenyl)methyl]-2-(tetrahydro-2H-pyran-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]pyrido[3,2-e]pyridazin-3-one (50 mg, 0.10 mmol), pyrazole (11 mg, 0.17 mmol, 1.7 equiv), potassium phosphate (71 mg, 0.41 mmol, 4 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (44 mg, 0.31 mmol, 3 equiv) and copper(I) iodide (20 mg, 0.10 mmol, 1 equiv) were combined in degassed N,N-dimethylformamide (2 mL) and placed into a preheated oil bath at 110° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium bicarbonate (25 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5 dichloromethane:methanol), providing the titled compound as a red solid: 1H-NMR (400 MHz, CDCl3) δ 8.74 (1H, dd, J=4.5, 1.7 Hz), 8.51 (1H, dd, J=8.0, 1.8 Hz), 8.78 (1H, d, J=2.5 Hz), 7.69 (1H, d, J=1.7 Hz), 7.64-7.62 (4H, m), 7.49 (1H, dd, J=8.0, 4.6 Hz), 6.44 (1H, dd, J=2.5, 1.6 Hz), 5.95 (2H, br s), 4.71-4.63 (1H, m), 4.01-3.95 (2H, m), 3.74 (1H, ap t, J=10.5 Hz), 3.47 (1H, td, J=11.1, 3.6 Hz), 2.22-2.06 (2H, m), 1.92-1.79 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 428.1837 [(M+H)+; calculated for C23H22N7O2:428.1829].
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10](C(C)(C)C)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[C:17](C1C=C(Br)C=CC=1)([CH3:20])([CH3:19])[CH3:18]>>[CH3:4][Si:2]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Reactant: CC(C)(C)c1cccc(Br)c1
Product: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1

Procedure:
Using the same general procedure as described for Compound 21, but using 3-tert-butyl-bromobenzene, (Compound 24) the title compound was synthesized as a colorless oil. PMR (CDCl3): & 0.36 (9H, s), 1.40 (9H, s), 7.32 (1H, m), 7.37 -7.47 (2H, m), 7.61 (1H, m).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])([CH3:21])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])C.C(OC(=O)CS(C1C=CC(OC)=CC=1)(=O)=O)C.C1(=O)N(CCCCBr)C(=O)C2=CC=CC=C12>>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:20])[N:10]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:23])=[O:24])([CH3:21])[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(C)(CCCCN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccc(OC)cc1
Agent: CCOC(=O)CS(=O)(=O)c1ccc(OC)cc1
Agent: O=C1c2ccccc2C(=O)N1CCCCBr
Product: COc1ccc(S(=O)(=O)C(C)(CCCCN2C(=O)c3ccccc3C2=O)C(=O)O)cc1
Yield: 88 %

Procedure:
Following the procedure as outlined in Example 9, 6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid ethyl ester was prepared, starting from (5.0 g, 20 mmol) of 2-(4-methoxy-benzenesulfonyl)-acetic acid ethyl ester and 4-phathalimido bromobutane (5.66 g, 20 mmol). Yield 8.4 g, 97%; Colorless oil; MS: 474 (M+H). Starting from 6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid ethyl ester (8.4 g, 17.7 mmol) 6;95 g (88%) of 6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-2-(4-methoxy-benzenesulfonyl)-2-methyl-hexanoic acid was isolated as colorless oil by following the procedure as outlined in Example 9. MS: 446 (M−H)−.