Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:18](COCC[Si](C)(C)C)[C:17]([CH3:27])=[N:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:6][CH:5]1[CH3:36])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:18]=[C:17]([CH3:27])[NH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:6][CH:5]1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cnc(C)n3COCC[Si](C)(C)C)cc2C(Nc2ccc(Cl)cc2)CC1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1c2ccc(-c3c[nH]c(C)n3)cc2C(Nc2ccc(Cl)cc2)CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[Step 2] 12 mg (cis:trans=3:1) of 1-acetyl-6-{2-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1 H-imidazol-5-yl}-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 1 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added to the solution. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, trifluoroacetic acid and dichloromethane were distilled off under reduced pressure. The resulting residue was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then was extracted three times with chloroform. The extraction product was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (methanol:chloroform=1:10), and thus 9 mg (cis:trans=3:1, 100%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14](O)=[O:15])[S:13][C:6]=12.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([Cl:27])=[O:15])[S:13][C:6]=12
Reactant: O=C(O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reaction time: 2 h
Yield: 104.3 %

Procedure:
To a solution of 39 (2.0 g, 5.98 mmol) in anhydrous CH2Cl2 (30 ml) under an atmosphere of nitrogen, was added oxalyl chloride (2.6 ml, 29.8 mmol). After stirring for 2 hours the solvent was evaporated, anhydrous toluene (10 mL) was added and the resultant mixture was evaporated (procedure of addition of toluene followed by evaporation was performed twice) to afford title compound 40 (2.2 g, 94% yield) as a white solid. The product was used without further purification and characterization and was assumed to be the mono-HCl salt.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.CON(C)[C:12]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]>O1CCCC1>[O:17]1[CH2:16][CH2:15][CH:14]([C:12](=[O:13])[CH3:4])[CH2:19][CH2:18]1
Reactant: CON(C)C(=O)C1CCOCC1
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)C1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Add 3 M methyl magnesium bromide in diethyl ether (1.14 L, 2.0 eq) to a solution of N-methoxy-N-methyl-tetrahydropyran-4-carboxamide (296 g, 1.71 mol) in tetrahydrofuran (2.96 L) over one hour at 0° C. Stir for an additional two hours, then pour the contents into a mixture of ice/water. Extract with methyl tert-butyl ether. Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give 1-(tetrahydro-pyran-4-yl)-ethanone (105 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][C:15]#[C:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.C[N:33](C=O)C.N>CCO>[F:31][C:2]([F:1])([F:30])[CH2:3][N:4]=[C:5]([NH2:33])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH2:14][C:15]#[C:16][CH2:17][NH2:18])[N:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCSc1nccc(NC(=S)NCC(F)(F)F)n1
Reactant: CN(C)C=O
Agent: N
Solvent: CCO
Product: NCC#CCSc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(4-phthalimidobut-2-ynylthio)pyrimidine (0.37 g.), DMF (10 ml.), saturated ethanolic ammonia (1 ml.), EtOH (10 ml.) and yellow mercuric oxide (0.32 g.) was stirred at room temperature for 2 hours and then filtered and the filtrate evaporated to dryness. The residue was treated with EtOH (20 ml.) and 98% hydrazine hydrate (1 ml.) and the mixture heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N aqueous HCl and then filtered, The filtrate was basified with 10 N aqueous NaOH and the mixture extracted four times with ether. The combined extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(4-aminobut-2 -ynylthio)pyrimidine (0.17 g.) characterised as the bis hydrogen maleate, m.p. 153°-155° (decomp.)
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([F:24])[C:14]=1[C:15](Cl)=[O:16]>CN(C=O)C>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[C:18]([F:24])[C:14]=1[C:15]([N:9]([C:15](=[O:16])[C:14]1[C:18]([F:24])=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]=1[Cl:12])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:16]
Reactant: N#Cc1cc(F)c(C(=O)Cl)c(Cl)c1
Reactant: Nc1ccnc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(C(=O)N(C(=O)c2c(F)cc(C#N)cc2Cl)c2ccnc(Cl)c2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To a solution of 2-chloro-3-fluoropyridin-4-ylamine (1.05 g, 7.1 mmol) in DMF (25 mL) at 0° C. was added sodium hydride (0.343 g, 14.3 mmol). The resulting violet mixture stirred for 20 minutes before a solution of 2-chloro-4-cyano-6-fluoro-benzoyl chloride (1.87 g, 8.6 mmol) in DMF (10 mL) was added. The mixture was warmed to room temperature stirred for 16 hours, then quenched with water and 1M HCl. The mixture was filtered through Celite®, washing with EtOAc. The organic filtrate was dried over Na2SO4 and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography eluting with DCM to give the desired compound as an off-white foam (0.869 g, 25% yield). 1H NMR (300 MHz, CDCl3): δ 8.24 (d, J=5.1 Hz, 1H), 7.55 (s, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.32-7.23 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:53])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=5)=[N:24][N:25](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[CH:9][CH:8]=1.O1CCCC1.Cl>CO>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:53])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=5)=[N:24][NH:25][CH:26]=4)[CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: NCCCNC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCCNC(=O)c1ccc(-c2cnc3ccc(-c4c[nH]nc4-c4ccc(F)cc4)cn23)cc1
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of 50 mg N1-(3-aminopropyl)-4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}benzamide obtained in Example 43 in a solvent mixture of 1.5 mL tetrahydrofuran, 1.5 mL methanol and 1.5 mL of 5 N hydrochloric acid was left at room temperature for 1 hour. The mixture was washed with ethyl acetate, and the aqueous layer was basified with 5N aqueous sodium hydroxide. Water was added thereto, and the formed solid was collected and recrystallized from ethanol/diethyl ether to give 15 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[CH2:7][C:8](=[O:13])[NH:9][C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>ClCCl.O>[CH3:1][O:2][C:3]1[C:15]([O:16][CH3:17])=[CH:14][C:6]2[CH2:7][C:8](=[O:13])[N:9]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)NC(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3cc(OC)c(OC)cc3CC2=O)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
3 g of 7,8-dimethoxy-1H-3-benzazepine-2,4(3H,5H)-dione (12.8 mmol), 2 g of 4-methoxy-benzyl chloride (12.8 mmol, 1 eq), 2.64 g of K2CO3 (19.1 mmol, 1.5 eq), 1.06 g of KI (6.4 mmol, 0.5 eq) and 30 mL of acetonitrile are introduced into a 100-mL three-necked flask. The reaction mixture is heated at 80° C. for 3 hours 30 minutes. 1 g of 4-methoxybenzyl chloride is introduced three times and the reaction mixture is held at 80° C. for 24 hours. After returning to ambient temperature, 30 mL of water and 30 mL of dichloromethane are introduced. After extraction and drying of the organic phase, the dark red oil obtained is purified by flash chromatography on a silica column (eluant: dichloromethane/methanol 99/1) to obtain the title product.
Reaction SMILES: CC1C=CC=CC=1CC(=O)C.C1(CC(=O)C)C=CC=CC=1.CC1C=CC=CC=1C(CCCC(OCC1C=CC=CC=1)CCCCC)C(=O)C.[C:50]([C:53]([C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=1[CH3:88])([CH2:65][CH2:66][CH2:67][CH:68]([O:74]CC1C=CC=CC=1)[CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([O:62]CC)=[O:61])(=[O:52])[CH3:51].C(C(C1C=CC=CC=1C)(CCCC(OCC1C=CC=CC=1)CCCCC)CCCCCCC(O)=O)(=O)C.C(C(CCCC(O)CCCCC)CCCCCC(C1C=CC=CC=1C)C(O)=O)(=O)C>>[C:50]([C:53]([C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=1[CH3:88])([CH2:65][CH2:66][CH2:67][CH:68]([OH:74])[CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])(=[O:52])[CH3:51]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1C)OCc1ccccc1
Agent: CC(=O)Cc1ccccc1
Agent: CC(=O)Cc1ccccc1C
Agent: CCCCCC(CCCC(C(C)=O)c1ccccc1C)OCc1ccccc1
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1C

Procedure:
By following the procedures described in Example 3, but substituting (2-methyphenyl) acetone for the phenylacetone employed in Step C, there are obtained successively from that point: 3-(2-methylphenyl)-7-benzyloxy-2-dodecanone (Step C); ethyl 8-acetyl-8-(2-methylphenyl)-12-benzyloxyheptadecanoate (Step D); 8-acetyl-8-(2-methylphenyl)-12-benzyloxyheptadecanoic acid (Step E); and 8-acetyl-(2-methylphenyl)-12-hydroxyheptadecanoic acid (Step F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[CH2:15][CH2:14]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]3)=[CH:24][N:23]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Clc1cc(Br)c2nccn2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Cl)cn4ccnc34)nc2)CC1
Temperature: 100 °C
Yield: 43.8 %

Procedure:
A mixture of 101a (2.3 g, 10 mmol), 5-(4-methylpiperazin-1-yl)pyridin-2-amine (1.9 g, 10 mmol), XantPhos (576 mg, 1.0 mmol), Pd2(dba)3 (915 mg, 1.0 mmol) and Cs2CO3 (6.5 g, 20 mmol) in dioxane (50 mL) was heated at 100° C. for 12 h under nitrogen. It was then filtered and evaporated in vacuo. The residue was purified by silica-gel column eluting with 1:1 ethyl acetate/petroleum ether to afford 101b as a green solid (1.5 g, 44%). MS: (M+H)+ 343.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.[CH2:23]([NH:30][CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(OCC)C>[CH2:23]([N:30]([CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:42])([CH3:43])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCc3ccccc3)ccc2O1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)Cc3ccccc3)ccc2O1
Temperature: 25 °C
Yield: 113.1 %

Procedure:
A stirred mixture of 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide (11.1 g), (1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (9 g) and diisopropyl ethylamine (8.9 ml) in acetonitrile (28 ml) was heated at reflux for 18 h. The resulting mixture was cooled to room temperature, diluted with diethyl ether (250 ml) and washed with water (2×100 ml) and brine (100 ml) before being dried over anhydrous Na2SO4. The suspension was filtered and concentrated under reduced pressure to give the title compound (20 g) as an oil. LC RT=4.68 min, δ (CDCl3) 7.70 (2H, m), 7.38 (2H, m), 7.29 (5H, m), 7.02 (1H, d, J 8.3 Hz), 6.91 (1H, s), 6.73 (1H, d, J 8.3 Hz), 4.79 (2H, s), 4.53 (1H, m), 3.87 (1H, m), 3.40 (5H, m), 2.69 (2H, t, J 7.2 Hz), 2.54 (2H, m), 2.43 (2H, m), 1.70 (2H, m), 1.60 (2H, m), 1.51 (10H, m), 1.25 (4H, m)
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>CN(C=O)C>[NH2:24][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[CH:23]=[CH:18][N:19]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CC(C)(O)c1n[nH]c2cc(I)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (1.00 g, 3.31 mmol) in dry DMF (30 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (212 mg of a 60% dispersion in mineral oil, 5.3 mmol). After 20 minutes at this temperature, 4-chloropyrimidin-2-amine (858 mg, 6.62 mmol) was added and the solution warmed to RT for 10 minutes, then to 65° C. for 23 hr. The reaction mixture was cooled to RT, quenched carefully with water (20 mL) and extracted with EtOAc (2×20 mL extractions). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAc gradient) furnished the title compound as an off-white solid: 1H NMR (250 MHz, CDCl3) delta 1.73-1.83 (6H, m), 2.77 (1H, s), 5.16 (2H, s), 7.23-7.33 (1H, m), 7.55-7.64 (1H, m), 7.68-7.78 (1H, m), 8.30 (1H, d, J=5.79 Hz), 9.15-9.28 (1 H, m); LC-MS: m/z=+395.90 (M+H)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[CH2:12][C:13](=[NH:17])[O:14]CC>ClC1C=CC=CC=1Cl>[C:13]([CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])([OH:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)(=[O:14])[NH2:17]
Reactant: CCOC(=N)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: NC(=O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: 178 °C
Reaction time: 0.17 h

Procedure:
3-(2,4-Dichlorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butyrimidic acid, ethyl ester dihydrochloride (3.42 g) was suspended in 1,2-dichlorobenzene (35 ml) and the mixture was heated to the reflux temperature of the solvent [178° C.). After refluxing for five minutes, a solution was obtained. Refluxing was then continued for an additional 10 minutes. The reaction mixture was cooled, evaporated, and the resulting gum was triturated with hexane and heated with acetone. On cooling a cream-colored granular solid was formed which was filtered to yield the title compound as a solvate (1.26 g). On standing overnight in a refrigerator some further solvated product precipitated (0.62 g). After drying at 80° C. for 6 hours to remove the solvent the pure (unsolvated) title compound was obtained, yield 1.5 g, m.p. 144°-145° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:11]([C:10](=[O:15])[CH3:9])[C:12](=[O:14])[CH3:13])[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: CC(=O)CC(C)=O
Product: CC(=O)C(=Cc1cccnc1)C(C)=O

Procedure:
The procedure described in Example 3 was repeated by using 3.21 g of pyridine-3-carboxaldehyde and 3.3 g of 2,4-pentanedione. Yield 2.95 g, mp 52°-57° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[N-:23]=[N+:24]=[N-:25].[Na+].O.[OH-].[Na+]>CN(C)C=O>[N:23]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12)=[N+:24]=[N-:25]
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.0 g, 3.2 mmol) and sodium azide (0.23 g, 3.5 mmol) in N,N-dimethylformamide (5 mL) was heated and stirred at 100° C. for 30 minutes. The solution was cooled to room temperature, and poured into water, and the resulting solution was made basic by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. To a solution of the ethyl 4-azido-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in ethanol (150 mL) was added 10% palladium-carbon (1.2 g, 50% hydrate), and the mixture was stirred at room temperature for 1 hour under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (basic silica gel, ethyl acetate:methanol=93:7) gave the title compound (900 mg, 96% yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].CCN(CC)CC>CN(C1C=CN=CC=1)C>[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])=[O:15]
Reactant: OCCCCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Yield: 81 %

Procedure:
This compound was synthesized as a colorless oil from 6-phenylhexan-1-ol (137.0 mg, 0.77 mmol), TsCl (190.7 mg, 1.00 mmol), Et3N (155.0 mg, 1.54 mmol), and DMAP (93.8 mg, 0.77 mmol) in 81% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.87-7.77 (m, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.33-7.24 (m, 2H), 7.23-7.13 (m, 3H), 4.03 (t, J=6.5 Hz, 2H), 2.65-2.53 (m, 2H), 2.45 (s, 3H), 1.75-1.50 (m, 4H), 1.45-1.19 (m, 4H); 13C NMR (100 MHz, CDCl3, 144.93, 142.73, 133.40, 130.08, 128.60, 128.52, 128.11, 125.92, 70.89, 35.99, 31.44, 28.98, 28.78, 25.47, 21.88. ESI-MS: 333.1 (M+H+), 355.1 (M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-])=O)=[C:12]2[C:24]([C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO.C(OCC)(=O)C.[Fe]>[NH2:21][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[C:24]([C:26]1[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=1)=[O:25])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[C:18]([O:19][CH3:20])[CH:17]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2ncc(N)c(C(=O)c3ccc(C#N)cc3)c2cc1OCc1ccccc1
Temperature: 66 °C
Yield: 70.9 %

Procedure:
4-(6-Benzyloxy-7-methoxy-3-nitroquinoline-4-carbonyl)benzonitrile (8.82 g, 20.07 mmol), iron powder (11.21 g, 200.7 mmol) and 2.0 M hydrochloric acid (22.76 ml) are suspended in methanol (455 ml) (stirrer motor) and heated at 66° C. for 18 h. When the reaction is complete (TLC (HPTLC) monitoring), the solid material is filtered off through kieselguhr with suction and rinsed with tetrahydrofuran (500 ml). The filtrate is evaporated to half its volume in vacuo. Semi-saturated NaCl solution (300 ml) is subsequently added, and the mixture is extracted twice with ethyl acetate (300 ml each time). The combined organic phases are dried over sodium sulfate, filtered with suction and evaporated to dryness in vacuo. The residue obtained is dissolved in ethyl acetate and filtered through a little flash silica gel. The filtrate is evaporated in vacuo, the residue is suspended in ethyl acetate (70 ml) and ethanol (20 ml), subsequently filtered off with suction and dried in a high vacuum, giving 4-(3-amino-6-benzyloxy-7-methoxyquinoline-4-carbonyl)benzonitrile (5.83 g, 14.23 mmol) as a solid having a melting point of 192.6° C. MS: 410.1 (M+H+), TLC (HPTLC): Rf=0.36 (ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Br[CH2:10][C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:22]3[N:23]=[C:24]([NH2:33])[N:25]=[C:26]([C:27]4[O:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:21]=3[N:20]=[N:19]2)[CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:10][C:11]1[N:16]=[C:15]([CH2:17][N:18]2[C:22]3[N:23]=[C:24]([NH2:33])[N:25]=[C:26]([C:27]4[O:28][C:29]([CH3:32])=[CH:30][CH:31]=4)[C:21]=3[N:20]=[N:19]2)[CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOCCO
Reactant: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCOCc1cccc(Cn2nnc3c(-c4ccc(C)o4)nc(N)nc32)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A solution of 2-ethoxyethanol (242 μl, 2.5 mmol) in anhydrous THF (15 mL) was cooled to 0° C. and treated with NaH (100 mg, 2.5 mmol). The reaction was stirred at 0° C. for 10 mins, then treated with 3-(6-bromomethylpyridin-2-ylmethyl)-7-(5-methyl-2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine (100 mg, 0.25 mmol), stirred at room temperature for 30 mins. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The resulting solid was suspended in MeOH (10 mL) and treated with 4M HCl in dioxane (2 mL), the reaction mixture was then diluted with diethyl ether (40 mL) and the resulting solid isolated by filtration to give the product (34 mg, 31%) as a yellow solid.