Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:29]2[N:30]=[C:31]([O:39][C@@H:40]([C@H:42]3[CH2:46][NH:45][C:44](=[O:47])[CH2:43]3)[CH3:41])[C:32]3[N:33]([N:35]=[CH:36][C:37]=3[CH3:38])[CH:34]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[C:1]([N:26]1[CH2:25][CH2:24][N:23]([C:22]2[CH:21]=[CH:20][C:19]([C:29]3[N:30]=[C:31]([O:39][C@@H:40]([C@H:42]4[CH2:46][NH:45][C:44](=[O:47])[CH2:43]4)[CH3:41])[C:32]4[N:33]([N:35]=[CH:36][C:37]=4[CH3:38])[CH:34]=3)=[CH:18][C:17]=2[O:16][CH3:15])[CH2:28][CH2:27]1)(=[O:3])[CH3:2]
Reactant: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(C)=O)CC1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
Acetic Anhydride (4 μl, 0.04 mmol) was added to a solution of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.60 (18.1 mg, 0.03 mmol) and triethylamine (0.04 ml, 0.28 mmol) in dichloromethane (2 mL) at room temperature. After 90 min, reaction mixture was directly loaded onto silica gel and purified (0-8% methanol/dichloromethane) to yield (R)-4-((R)-1-((6-(4-(4-acetylpiperazin-1-yl)-3-methoxyphenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.61 (13.6 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[O:22][C:21]([SH:23])=[N:20][N:19]=3)=[CH:17][C:12]=2[O:11][CH2:10]1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[O:22][C:21]([S:23][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:20][N:19]=3)=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: BrCc1ccccc1
Reactant: Sc1nnc(-c2ccc3c(c2)OCO3)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccc4c(c3)OCO4)o2)cc1
Reaction time: 2 h

Procedure:
Benzylbromide (20.2 g, 118.1 mmol) was added over 5 minutes time-period to a mixture of 5-benzo[1,3]dioxol-5-yl-[1,3,4]oxadiazole-2-thiol (25 g, 112.5 mmol), trietylamine (22.8 g, 225 mmol) and ethanol (200 ml, 99%). The reaction mixture was stirred at room-temperature for 2 hours. Aqueous sodium hydroxide (150 ml, 1 M) and water (100 ml) was added followed by filtration. The product was isolated as a solid. Yield 31.0 g (94%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:17][CH:16]([NH:18]C(=O)OC(C)(C)C)[CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[ClH:26]>CO>[ClH:26].[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][CH:14]3[CH2:17][CH:16]([NH2:18])[CH2:15]3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CC(Oc2ncccc2C2CCOCC2)C1
Agent: Cl
Solvent: CO
Product: NC1CC(Oc2ncccc2C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To tert-butyl (3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutyl)carbamate (348 mg, 1 mmol) was added 4 M HCl in MeOH (100 mL). The solution was stirred at RT for 2 hours. The solvent was removed under reduced pressure to give 3-((3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)oxy)cyclobutanamine hydrochloride (248 mg, 0.95 mmol, yield 95%). ESI-MS (M+1): 249 calc. for C19H28N2O4 248.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]=1)[CH:7]=[C:6]2[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[Br:31][C:32]1[C:40]2[C:35](=[N:36][CH:37]=[N:38][C:39]=2Cl)[NH:34][N:33]=1>>[Br:31][C:32]1[C:40]2[C:35](=[N:36][CH:37]=[N:38][C:39]=2[N:28]2[CH2:27][CH2:26][N:25]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[C:8]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[N:14]=4)[CH:7]=3)[CH2:30][CH2:29]2)[NH:34][N:33]=1
Reactant: COCCCNc1nccc(-c2cc(N3CCNCC3)c3cc(OC)ccc3c2)n1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Product: COCCCNc1nccc(-c2cc(N3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c3cc(OC)ccc3c2)n1

Procedure:
4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-(3-methoxypropyl)pyrimidin-2-amine was synthesized according to General Procedure E except 4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)-N-(3-methoxypropyl)pyrimidin-2-amine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. 4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-(3-methoxypropyl)pyrimidin-2-amine (177) was isolated as a yellow solid. M.p.=225-227° C. LCMS (m/z): 605 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])=[CH:4][CH:3]=1.[Cl:12]Cl>Cl>[Cl:12][C:7]1[CH:6]=[C:5]([C:8]([Cl:9])([Cl:10])[Cl:11])[CH:4]=[CH:3][C:2]=1[Cl:1]
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: ClCl
Agent: Cl
Product: Clc1ccc(C(Cl)(Cl)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
In this apparatus, a mixture of 1,725 g (7.5 moles) of 4-chlorobenzotrichloride and 12 g (0.075 mole) of FeCl3 was heated to 70° C. and circulated. The introduction of 585 g (8.25 moles) of chlorine gas was then started. (chlorine gas was fed in at a rate such that no chlorine was detectable in the exit gas.) The reaction was complete after 5 hours. 2 liters of dilute hydrochloric acid were added to the reaction mixture and the organic phase was separated off, washed twice with 2 liters of water and dried over CaCl2. Subsequent fractional distillation gave 1,824 g of 3,4-dichlorobenzotrichloride (92% of theory) (98% purity according to a gas chromatogram), of boiling point 138°-140° C. at 12 mbar.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21]Br)=[CH:19][C:14]=2[S:13](=[O:23])[CH2:12]1>O1CCOCC1>[CH3:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][CH2:21][N:2]([CH3:1])[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:19][C:14]=2[S:13](=[O:23])[CH2:12]1
Reactant: CNCc1ccccc1
Reactant: CN1CS(=O)c2cc(CCBr)ccc21
Solvent: C1COCCO1
Product: CN(CCc1ccc2c(c1)S(=O)CN2C)Cc1ccccc1

Procedure:
0.04 mol of N-methyl-N-benzylamine and 0.02 mol of 3-methyl-6-(2-bromoethyl)benzothiazolinone, the latter being dissolved beforehand in 120 cm3 of dioxane, are introduced into a 100-cm3 ground-necked flask fitted with a reflux condenser. The mixture is heated to reflux for 96 hours with magnetic stirring. After cooling, the reaction mixture is filtered and the filtrate is then evaporated on a water bath under vacuum. The residue is taken up with 50 cm3 and alkalinized with 10 cm3 of normal sodium hydroxide solution.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1)=[O:13])[CH3:10]>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][Br:1])[N:15]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(CBr)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
Finely ground N-bromo-succinimide (29.4 g, 165.2 mmol) was added in several portions to a solution of 6-methyl-pyridine-2-carboxylic acid ethyl ester (24.7 g, 150.0 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.) in carbon tetrachloride (500 mL), and then benzoyl peroxide (100 mg, 0.4 mmol) was added. The mixture was heated at 84 degrees under nitrogen for approximately 40 h. Further portions of N-bromo-succinimide (14.8 g, 83.2 mmol) and then benzoyl peroxide (100 mg, 0.4 mmol) were added and heating was continued overnight. The reaction mixture was cooled to room temperature, filtered, evaporated, and purified by chromatography on silica gel using a Biotage system, eluting with 1:1 dichloromethane/hexane and dichloromethane to give 6-bromomethyl-pyridine-2-carboxylic acid ethyl ester (11.8 g, 32%) as a pale yellow oil. MS (MH+): 244/246. From HPLC, the purity was estimated at 85-90% and the material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.Cl>C(Cl)Cl>[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:2]([Cl:1])=[O:4]
Reactant: C[C@H]1CCCCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCCN1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 184.4 %

Procedure:
To a pale yellow solution of triphosgene (742 mg, 2.50 mmol) and pyridine (0.404 mL, 5.00 mmol) in dry DCM (10 mL) at 10° C. under N2 was added (S)-2-methyl piperidine (Aldrich, 0.603 mL, 5.00 mmol) cautiously over 2 min. The vivid orange solution was stirred at RT for 18 h, then pyridine (0.404 mL, 5.00 mmol) and triphosgene (742 mg, 2.50 mmol) were added sequentially (CARE: exotherm on addition of triphosgene) and the orange solution stirred at RT for 4 h. Aqueous HCl solution (1M, 10 mL) was added and the mixture stirred vigorously until gas evolution ceased (30 min). The aqueous layer was extracted with DCM (10 mL), then the combined organics passed through a hydrophobic fit and concentrated in vacuo to leave the title compound as a dark red oil (745 mg, 92%). 1H NMR (300 MHz, CDCl3): 1.25 (3H, d, J 7.0), 1.42-1.77 (6H, m), 3.07 (1H, br s), 4.17 (1H, dd, J 13.8, 4.0), 4.62 (1H, apparent quin, J 6.3).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:19])[C:10]1=[O:20])=O)(C)(C)C.[ClH:21]>O1CCOCC1>[ClH:21].[NH2:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:19])[C:10]1=[O:20]
Reactant: CN1C(=O)[C@H](NC(=O)OC(C)(C)C)Cc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)[C@H](N)Cc2ccccc21

Procedure:
(R)-3-t-butyloxycarbonylamino-1-methyl-3,4-dihydrocarbostyril (20 mg) was dissolved in 4 M hydrogen chloride in 1,4-dioxane solution (5 mL) at room temperature. After 1 h the solvent was evaporated under vacuum, and the residue was twice taken up in toluene (5 mL) and evaporated under vacuum to provide (R)-3-amino-1-methyl-3,4-dihydrocarbostyril hydrochloride (25 mg).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].I[CH2:20][CH2:21][C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:30][C:22]([F:31])([C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(F)CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.6 g of 1-iodo-3,3,4,4,5,5,5-heptafluoropentane were dissolved in 5 ml of ethylene glycol dimethyl ether, 0.83 g of potassium carbonate was added, and the mixture was stirred at room temperature for 8 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.75 g of 2-(3,3,4,4,5,5,5-heptafluoropentyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (71)).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=1[Cl:28])[CH2:10][C:9]2([CH3:30])[CH3:29])=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[CH:11]1[CH2:10][C:9]([CH3:29])([CH3:30])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12]1
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(N3CCOCC3)ccc1Cl)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)CC(c2cc(N3CCOCC3)ccc2Cl)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
To a stirred mixture solution of 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.8 g, 6.5 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (100 mL×2), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2.4 g, 92%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=401.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].C([Li])(CC)C.I[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[C:34]([O:35][CH2:36][O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=[C:31]([O:41][CH2:42][O:43][CH3:44])[C:30]=1[O:45][CH3:46].C(OCC)C>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:8]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[C:34]([O:35][CH2:36][O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=[C:31]([O:41][CH2:42][O:43][CH3:44])[C:30]=1[O:45][CH3:46]
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCI)c1OC
Agent: [Li]C(C)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1cc(OC)c(OCOC)c(CCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
280 Milligrams (1.08 mmoles) of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in a mixed solvent of 5 ml of tetrahydrofuran with 1 ml of hexamethylphosphoric triamide, then this solution was cooled to -78° C. in a dry ice-acetone bath. To this cooled solution was added 1.08 ml (1.21 mmoles) of secbutyllithium (1.21 M, cyclohexane solution) and the mixture was stirred for 30 minutes, then 2 ml of tetrahydrofuran solution containing 440 mg (1.0 mmole) of 1-(4-iodobutyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was added thereto and stirred for 12 hours. The reaction mixture was concentrated, to the residue obtained was added 60 ml of diethyl ether, and washed twice with water, then washed twice with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The dried diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a silica gel column chromatography (diameter 2 cm×length 20 cm, eluent: 20% ethyl acetate-benzene) to obtain 467 mg of 2,2'-tetramethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene]. Colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.Cl.[NH2:21][OH:22]>CCO>[OH:22][NH:21][C:4](=[NH:5])[C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: NO
Reactant: N#Cc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N=C(NO)c1ccc(F)cc1F
Temperature: 70 °C

Procedure:
To a mixture of 2,4-difluorobenzonitrile (1.39 g, 10 mmol) and DIEA (5.13 ml, 30 mmol) in EtOH (15 ml) was added 2.12 g of hydroxylamine hydrochloride (30 mmol) and the reaction was heated at 70° C. for 48 h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100 ml) and water (30 ml). 2.5 ml of NaOH 1N was added until pH=9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organic layers were combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to afford N-hydroxy-2,4-difluoro-benzamidine which was used without further purification for the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Se](=O)=[O:17]>O1CCOCC1>[CH3:15][O:14][C:12](=[O:13])[C:11](=[O:17])[C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)C(=O)c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
To the solution of methyl 6-quinolineacetate (1.2 g, 6 mmol) in dioxane (30 mL) was added Selenium dioxide (1.65 g, 15 mmol). The mixture was heated to reflux for 3 days, cooled to room temperature, filtered through Celite and concentrated. The residue was purified by chromatography (methylene chloride to 5% ethyl acetate in chloride) to a white solid (0.75 g, 58%). 1H-NMR (CDCl3): δ 9.07-9.06 (1H, q, J=1.7, 2.5 Hz), 8.62-8.61 (1H, d, J=1.7 Hz), 8.32-8.31 (2H, m), 8.22-8.20 (1H, d, J=8.8 Hz), 7.54-7.51 (1H, q, J=8.8 Hz), 4.05 (3H, s).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=[CH:26][N:27]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=[CH:26][N:27]=1)[C@@H:15]1[O:23][C@H:20]([CH:21]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H]1O)c1ccccc1

Procedure:
Compounds 6 and 7 are prepared by treating N6 -benzoyl adenosine with tritylchloride in pyridine and refluxing for 2 hours. N6 -benzoyl-5'-trityladenosine is isolated by extraction with chloroform. The water from the chloroform phase is removed by drying with sodium sulfate N6 -benzoyl-2',5'-di-O-trityladenosine and N6 -benzoyl-3',5'-di-O-trityladenosine are isolated by preparative silica gel thin layer chromatography in chloroform/ethanol. Compounds 6 and 7 are prepared by treating the isolated compounds with n-pentylchloride and n-heptylchloride, respectively, under reflux in a suspension of sodium hydroxide in benzene. The solution is neutralized by refluxing in acetic acid followed by the addition of diethyl ether and water. The reaction products are extracted with chloroform followed by thin layer chromatography with chloroform:methanol (4:1) on silica gel plates. The trityl and benzoyl groups are removed by refluxing in acetic acid for one hour, cooling, extraction with diethyl ether, followed by concentration and cooling to yield crystalline compounds 6 and 7. This method of preparation is carried out according to Blank, H. U., Franne, D., Myles, A. and Pfleiderer, W., Justus Liebigs Ann. Chem. 742, 34 (1970), which is incorporated herein by reference.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([NH:21][C:18]2[C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:43])=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cccs3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cccs2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 44.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-2-yl)pyrazin-2-amine (7f) (600 mg, 1.59 mmol) and 4-(dimethylamino)pyridine (19.8 mg, 162 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethyl acetate) to give Compound 11f (446 mg, 706 μmol, 44.4%) as a colorless solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.97 (s, 9H), 3.65 (s, 2H), 0.678-6.86 (AA′BB′, 2H), 6.97-7.06 (m, 3H, includes AA′BB′), 7.19-7.27 (AA′BB′, 2H), 7.51 (dd, 1H, J=0.9, 3.7 Hz), 7.69 (dd, 1H, J=0.9, 5.0 Hz), 8.06-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.60 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.9, 119.6 (2C), 120.4 (2C), 127.8, 127.9, 128.0, 128.2 (2C), 128.4, 129.5, 130.5 (2C), 137.3, 140.5, 140.6, 142.5, 148.0, 153.9, 157.0, 170.3; IR (KBr, cm−1) 419, 519, 673, 704, 741, 781, 802, 839, 916, 1169, 1265, 1335, 1362, 1373, 1414, 1439, 1472, 1510, 1605, 1667, 2857, 2887, 2930, 2955, 3221; HRMS (ESI) m/z 654.2617 ([M+Na]+, C34H45N3NaO3Si2+ requires 654.2612).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[CH:8][CH:7]=1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
1,2-Dibromoethane (30 mL, 0.35 moles) was added to a mixture of 4-hydroxy-1-naphthaldehyde (6 g, 35 mmoles) and potassium carbonate (24 g, 175 mmoles) in DMF (110 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (0.5 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (300 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:1) to afford 8.5 g (88%) of 4-(2-bromoethoxy)-1-naphthaldehyde as a solid. M.p.: 83-84° C.