Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>CCOCC>[O:22]([CH2:5][CH:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: CC(C)N1CC(OCc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)NCC(COc1ccccc1)OCc1ccccc1
Temperature: 180 °C
Yield: 85 %

Procedure:
To a mixture of 6.2 parts of 1-(iso-propyl)-3-benzyloxyazetidine and 28 parts of phenol 1.5 parts of potassium hydroxide was added, and the mixture was heated at 180° C. for 6 hours. The reaction mixture was cooled and 100 parts of ether were added thereto. The excessive phenol was extracted with 2N-sodium hydroxide aqueous solution and removed. The remaining ether layer was washed in water and dried over anhydrous sodium sulfate. After distillation of ether, the residue was successively subjected to distillation to yield 7.6 parts of 1-phenoxy-2-benzyloxy-3-(iso-propylamino)-propane boiling at 158°-160° C. under 2 mm Hg. The yield was 85%. Results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@H:14]([OH:16])[CH3:15])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH2:24].C(Cl)CCl>ClCCl>[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH:24][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:14]([OH:16])[CH3:15]
Reactant: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)O
Reactant: NOC1CCCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@@H](O)[C@@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Yield: 100 %

Procedure:
To a solution of (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid (33.0 g, 148.7 mmol) in dichloromethane (300 mL) is added 2-tetrahydropyranyloxyamine (18.3 g, 156.1 mmol) and EDC (31.2 g, 163.5 mmol). The resulting solution is stirred at 23.degree. C. for 16 h. then diluted with dichloromethane (500 mL) and washed sequentially with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The reaction mixture is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(3-phenyl-1-propyl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (47.8 g, 100% yield).
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:16]=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)c(CCCCCC)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCCCCC)c1
Reaction time: 24 h
Yield: 81.4 %

Procedure:
A mixture of 11.64 g of 3-(2-hexyl-4-tetradecylphenoxy)-1,2-propanediol, 12.32 g of trityl chloride and 40 ml of pyridine was stirred for 24 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, water, dried and the solvents evaporated under reduced pressure. The residue was coevaporated with toluene, giving 14.6 g of the desired compound.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH:18]5[CH2:20][CH2:19]5)[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Reactant: Clc1ccc(-c2cc3nc(C4CCN(C5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(C5CC5)CC4)nn23)ccc1C(=O)C(F)(F)F
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-cyclopropylpiperidin-4-yl)-[1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 45A), 92 mg (0.71 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.125 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 59 mg (78% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:14])(=[O:13])=[O:12])[C:4]=2[S:3]1(=[O:16])=[O:15].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.CCOCC>[CH2:17]([NH:21][C:22]([NH:14][S:11]([C:10]1[C:4]2[S:3](=[O:16])(=[O:15])[N:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)(=[O:12])=[O:13])=[O:23])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=O
Reactant: CN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1cccc2c1S(=O)(=O)N(C)C2
Reaction time: 16 h

Procedure:
A suspension of 13.0 g of 2-methyl-2,3-dihydro-1,2-benzisothiazole-7-sulfonamide-1,1-dioxide, 11.2 ml of butyl isocyanate and 13.8 g of potassium carbonate in 200 ml of dry methyl ethyl ketone was heated at reflux for 2 hours. 13.8 g of potassium carbonate was added and heating was continued for an additional 16 hours. The mixture was cooled, the solvent was decanted from the solids, concentrated in vacuo, the residue dissolved in ethyl acetate and washed with saturated aq. NaHCO3. The aqueous wash was added to the original solids diluted with water and acidified to pH 3 with dilute HCl. The mixture was extracted with methylene chloride, the extract was washed with water and brine, dried and concentrated in vacuo leaving a solid which was slurried in ether and filtered to give 13.24 g of the title compound as a white powder, m.p. 162°-164° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:11][N:12]2[CH:17]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)C1C=CC=CC=1.Br>CC(O)=O>[OH:8][C:9]1[C:10]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:11][N:12]2[CH:17]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12
Reactant: CCOC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2c1nc(C)cs1
Agent: Br
Solvent: CC(=O)O
Product: CCOC(=O)c1nn2c(c1O)C(=O)N(C)CC2c1nc(C)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 3-benzyloxy-5-methyl-7-(4-methyl-1,3-thiazol-2-yl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (76 mg, 0.178 mmol) was treated with a 5% solution of HBr in AcOH, and the reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue azeotroped twice with MeOH to afford the title product as a bright orange solid. ES MS (M+H)=337.
Reaction SMILES: [I:1]I.I([O-])(=O)(=O)=O.[Na+].[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH3:10]>OS(O)(=O)=O>[CH2:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[I:1])[CH3:10]
Reactant: CCc1ccc(C=O)cc1
Reactant: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CCc1ccc(C=O)cc1I
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
Iodine (0.245 mL, 4.73 mmol) and sodium metaperiodate (0.340 g, 1.59 mmol) were added slowly portionwise successively to stirred 95% H2SO4 (30.0 mL) at 25° C. and the mixture was stirred for 30 min to afford a dark brown iodinating solution. The iodinating solution was added dropwise to a stirred suspension of 4-ethylbenzaldehyde (1.34 g, 10 mmol) in 95% H2SO4 (10.0 mL) over 45 min while maintaining the temperature at 25-30° C. Stirring was continued for a further 15 min and the reaction was quenched by slowly pouring into stirred ice-water (300 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to afford 4-ethyl-3-iodobenzaldehyde, as a colorless solid. 1H NMR (600 MHz, CDCl3): δ 9.87 (s, 1H); 8.28 (d, J=1.7 Hz, 1H); 7.77 (dd, J=7.8, 1.6 Hz, 1H); 7.36 (d, J=7.8 Hz, 1H); 2.78 (q, J=7.6 Hz, 2H); 1.23 (t, J=7.6 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].S(=O)(=O)(O)O.[CH3:37]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[NH:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24][CH3:37])=[O:23])[CH:17]=3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=C(Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Yield: 90 %

Procedure:
4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinic acid (0.5 g, 1.11 mmol) was suspended in methanol (10 mL). Concentrated sulfuric acid (2 mL) was added at room temperature, and the resulted mixture was refluxed for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=10:1) to give methyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)picolinate A11 (0.46 g, purity 95%, yield 90%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:13]>C(O)(C)C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[C:5]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]([CH3:13])=[CH:11][C:6]=2[C:7](=[O:9])[CH:8]=1
Reactant: COC1=CC(=O)C=CC1=O
Reactant: C=C(C)c1ccccc1
Solvent: CC(C)O
Product: COC1=CC(=O)c2cc(C)c3ccccc3c2C1=O
Yield: 2.5 %

Procedure:
2-Methoxy-1,4-benzoquinone (30.0 g, 72 mM) and α-Methylstyrene (236 g, 2.0 M) were dissolved in 290 ml of isopropanol and refluxed for 30 hours. The reaction solution was subjected to vacuum distillation to recover isopropanol and α-Methylstyrene, and the reaction solution was concentrated. The resulting product was purified by chromatography to give to 1.38 g (5.47 mM) of 3-Methoxy-9-methyl-1,4-phenanthrenequinone.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.Cl[C:15]([O:17][CH3:18])=[O:16].O>CCOC(C)=O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: Fc1cccc(Cl)c1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An oven-dried round bottom flask successively evacuated and purged with N2 gas was charged with drisolv THF (84 ml) and placed in a −78° C. dry ice/acetone bath. To this was added n-butyllithium (2.5 M in hexanes) (18 ml, 46 mmol) and the mixture was stirred for 10 min before adding neat 1-chloro-3-fluorobenzene (5.48 g, 42.0 mmol). The solution was stirred for 2 hrs before adding neat methyl chloroformate (4.0 ml, 50 mmol). The resultant solution was stirred at −78° C. for 3 hrs and then allowed to warm to RT. Water was added to the mixture followed by EtOAc. The layers were separated and the aqueous layer was extracted 3× EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a clear liquid.
Reaction SMILES: C[Si](C)(C)[N:3]=[C:4]([C:22]1[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=1[F:32])[C:5]([C:11]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=1[F:21])=[N:6][Si](C)(C)C.[C:35](Cl)(Cl)=[O:36]>>[F:28][C:27]1[C:22]([C:4]2[C:5]([C:11]3[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[C:13]([F:20])[C:12]=3[F:21])=[N:6][C:35](=[O:36])[N:3]=2)=[C:23]([F:32])[C:24]([F:31])=[C:25]([F:30])[C:26]=1[F:29]
Reactant: C[Si](C)(C)N=C(C(=N[Si](C)(C)C)c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(Cl)Cl
Product: O=C1N=C(c2c(F)c(F)c(F)c(F)c2F)C(c2c(F)c(F)c(F)c(F)c2F)=N1
Yield: 82 %

Procedure:
Analogous to Example 13, 5.33 g (10 mmol) of N,N'-bis(trimethylsilyl)-1,2-di(pentafluorophenyl)-ethanediimine, which was made in Example 2, was reacted with 10 mmol (1.0 g) of phosgene to yield 3.4 g (8.2 mmol, 82%) of 4,5-di(pentafluorophenyl)-2H-imidazol-2-one as a dark red solid. This product is also referred to as decafluorobenzilimidazolone. 3C[1H]NMR (δ; CDCl3) 177.6 ppm (>C=O--; s), 156.2 ppm (>C=N--; t, J3 =13.4 Hz), 112.6 ppm (i, t, J2 =23.6 Hz), 138.1 ppm (dt, J1 =254 Hz), 142.7 (dm, J1 =254 Hz), 144.5 ppm (dd, J1 =249 Hz). Elemental analysis was carried out: calcd (found) for C15F10N2O: C, 43.50% (43.57%), F, 45.87% (45.82%), N, 6.76% (6.71%), O, 3.86% (3.78%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[C:22]([F:25])=[N:23][CH:24]=1.C([O-])(=O)C.[K+].O>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:22]([F:25])=[N:23][CH:24]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc(Cl)cnc1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Cl)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
6-Chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.979 mmol) and 5-chloro-2-fluoropyridin-3-ylboronic acid (1.388 g, 7.91 mmol) (Combi-Blocks, Inc., San Diego, Calif.) in THF (25 ml) were added to a 100 mL round-bottomed flask. Potassium acetate (0.583 g, 5.94 mmol) was added to the mixture, followed by water (1 mL). The mixture was evacuated, then backfilled with Nitrogen gas. Then bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.050 g) (Aldrich, St. Louis, Mo.) was added into the mixture. The mixture was evacuated, then backfilled with nitrogen gas. The flask was fitted with a reflux condenser, then placed into a pre-heated (90° C.) oil bath and allowed to stir under inert atmosphere for 2 h. The progress of the reaction was monitored by LCMS, which showed mostly desired product. The reaction mixture was allowed to cool to room temperature, diluted with water (10 mL) and extracted with CH2Cl2 (3×25 mL). The organic extracts were washed with satd aqueous Na2CO3 (1×20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a tan oil. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep RediSep®, Teledyne ISCO, Lincoln, Nebr., pre-packed silica gel column (120 g), eluting with a gradient of 1% to 40% EtOAc in CH2Cl2, to give 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.502 g, 1.443 mmol, 73.0% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.37-8.45 (m, 1H); 8.27-8.33 (m, 2H); 5.79-5.92 (m, 1H); 4.14-4.26 (m, 1H); 3.74-3.91 (m, 1H); 2.89 (s, 3H); 1.96-2.25 (m, 3H); 1.63-1.91 (m, 3H). m/z (ESI, +ve) 348 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[N:13]=[C:12](Cl)[N:11]([CH2:16][C:17]#[C:18][CH3:19])[C:10]=2[C:9](=[O:20])[N:8]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]1=[O:29])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:12]2[N:11]([CH2:16][C:17]#[C:18][CH3:19])[C:10]3[C:9](=[O:20])[N:8]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:7](=[O:29])[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[C:14]=3[N:13]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC#CCn1c(Cl)nc2c1c(=O)n(CCc1ccccc1)c(=O)n2CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCc1ccccc1)c(=O)n2CC(=O)OCC
Temperature: 150 °C
Yield: 86.9 %

Procedure:
A mixture of [7-(2-butynyl)-8-chloro-1-(2-phenylethyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]acetic acid ethyl ester (273 mg) and piperazine-1-carboxylic acid tert-butyl ester (360 mg) was heated in an oil bath of 150° C. for 30 minutes. The reaction mixture was purified by silica gel column chromatography using 20–30% ethyl acetate/hexane to give 320 mg of the title compound.
Reaction SMILES: CO.[N+](C1C=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([O-])=O.[C:13]([O:21]CC)([O:18][CH2:19][CH3:20])(OCC)[CH3:14].C(O)C>C(OCC)(=O)C>[O:12]1[CH:7]=[CH:8][CH:9]=[C:10]1[CH2:14][C:13]([O:18][CH2:19][CH3:20])=[O:21]
Reactant: CCOC(C)(OCC)OCC
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CO
Product: CCOC(=O)Cc1ccco1
Yield: 377.8 %

Procedure:
A solution of 60.8 g (0.4 mole) of the carbinol obtained according to letter (a) above, 11.1 g (0.08 mole) of o-nitro-phenol and 194.4 g (1.2 mole) of triethyl ortho-acetate were slowly heated during 8-10 h to 145°-150° under nitrogen atmosphere while stirring. Meanwhile, ethanol and ethyl acetate formed in the course of the reaction were gradually distilled off whereas the excess of triethyl ortho-acetate was recovered by vacuum distillation. The thus obtained residue was dissolved in petrol ether (b.p. 30°-50°) and the resulting solution was washed with 5% aqueous NaOH, dried over Na2SO4 and finally evaporated. 46.6 g (yield 52.5%) of the title ethyl furyl-acetate were obtained by fractional distillation. Purity ca. 35%; b.p. 65°-70°/0.2 Torr.
Reaction SMILES: I[C:2]([F:16])([F:15])[CH2:3][C:4]([F:14])([F:13])[CH2:5][C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].[Cl-].[Li+]>CN(C)C=O>[F:15][C:2]([F:16])=[CH:3][C:4]([F:13])([F:14])[CH2:5][C:6]([F:11])([F:12])[C:7]([F:8])([F:10])[F:9]
Reactant: FC(F)(I)CC(F)(F)CC(F)(F)C(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: FC(F)=CC(F)(F)CC(F)(F)C(F)(F)F
Temperature: 125 °C

Procedure:
A round-bottomed flask was charged with a mixture of 1-iodo-1,1,3,3,5,5,6,6,6-nonafluorohexane [C2F5—CH2CF2—CH2CF2—I] (97 g, 0.26 mol) and lithium chloride (16 g, 0.376 mol) in anhydrous N,N-dimethylformamide (DMF, 120 ml) solvent. The mixture was vigorously stirred throughout the reaction. A vacuum was applied (210-220 mm Hg) and the mixture was then slowly heated up to 125° C. over a period of 1-2 hours. The volatile component which was distilled off during this heating period was collected in a cold trap. Re-distillation afforded the 1,1,3,3,5,5,6,6,6-nonafluoro-1-hexene [C2F5—CH2CF2—CH═CF2] product as a clear colorless liquid having a boiling point 72-74° C. (at a pressure of 760 mm Hg) and a yield of 36 grams (56%).
Reaction SMILES: C[O:2][C:3]([C:5]12[O:11][CH2:10][C:9]1([CH3:12])[CH2:8][CH2:7][CH:6]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:6]2[C:5]3([CH2:3][OH:2])[C:9]([CH3:12])([CH2:10][O:11]3)[CH2:8][CH2:7]2)=[CH:19][CH:18]=1
Reactant: COC(=O)C12OCC1(C)CCC2Cc1ccc(Cl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: CC12CCC(Cc3ccc(Cl)cc3)C1(CO)OC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
In 20 ml of ethanol, 970.6 mg of Compound 7a-1 synthesized in Production Example 18 was dissolved. Thereafter, the solution thus obtained was cooled to 0° C. To the solution thus cooled, 249 mg of sodium borohydride and 365 mg of calcium chloride (powder) were added. The resulting mixture was stirred at 0° C. for 2 hours. After the reaction, the reaction was stopped with an aqueous solution of 1 mol/l citric acid. Then, extraction with ethyl acetate was carried out. The organic layer thus extracted was washed with an aqueous solution of sodium hydrogen carbonate and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 845.3 mg of Compound 8a-1.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]>CC(O)=O>[NH2:3][C:4]1[N:13]=[CH:12][C:11]([Br:1])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccnc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
Bromine (0.7 mL, 14 mmole) was added dropwise to a stirred solution of methyl 2-aminonicotinate (2.0 g, 13 mmole) in HOAc (50 mL). A suspension formed within 30 min. The reaction was allowed to stir at room temperature for 2 h, then was concentrated under vacuum. The residue was triturated with 1.0 N Na2CO3 (50 mL) and the solid was collected by suction filtration. The solid was washed with H2O (50 mL) and dried under vacuum to give the title compound (2.95 g, 98%) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=2.5 Hz, 1 H), 8.23 (d, J=2.5 Hz, 1 H), 6.40 (br s, 2 H), 3.90 (s, 3 H).