Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@@H:2]1[C:11]([OH:13])=[O:12].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C(O)(=O)C.O.[Cl-].[Zn+2].[Cl-]>[I:14][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[O:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4]2
Reactant: O=I(=O)Cl
Reactant: O=C(O)[C@H]1CCc2ccccc2O1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)[C@H]1CCc2cc(I)ccc2O1

Procedure:
(2R)-3,4-Dihydro-2H-chromene-2-carboxylic acid (WO 99/32476) (26.7 g, 150 mmol), benzyltrimethyl-ammonium dichloroiodate (50.1 g, 144 mmol) and zinc chloride (25.3 g, 186 mmol) were stirred in glacial acetic acid (500 mL) under argon at room temperature for 18 hours. The solid was removed by vacuum filtration and then washed with acetic acid (100 mL). The filtrate was concentrated in vacuo to obtain a solid which was slurried in water (300 mL). The crude product was obtained as a pink solid after vacuum filtration and dried (38.3 g, 84%): 1H NMR (DMSO-d6) δ1.95-2.10 (m, 1H), 2.60 (m, 1H), 2.70-2.80 (m, 1H), 4.79 (dd, J=6.0, 3.9 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H). CI-MS m/z 305 (M+H+). The crude was used for next step directly.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Reactant: BrCC1CCCCC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CCCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexylmethyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(cyclohexylmethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 100 °C
Yield: 90 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine](295 mg, 1 mmol), trimethylsilylacetylene (0.355 mL, 2.5 mmol), tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol), triethylamine (2 mL) and anhydrous acetonitrile (2 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100° C. for 4 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated ether/methanol, 9:1) afforded the title compound (280 mg, 0.90 mmol, 90%): chemical ionization MS (m/z, relative intensity) 313 ([MH]+, 30).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1nnc(Br)s1
Reactant: NCCCOc1cccc(CN2CCOCC2)c1
Product: Nc1nnc(NCCCOc2cccc(CN3CCOCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-(4-morpholinylmethyl)phenoxy]1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([O:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:31]=2)[CH:27]=[CH:28]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 90 °C
Yield: 50.7 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (200 mg, 0.6 mmol), (prepared as described for the starting material in Example 50), and 6hydroxyindole (97 mg, 0.73 mmol) in DMF (3 ml) containing potassium carbonate (125 mg, 0.91 mmol) was heated at 90° C. for 2.5 hours. After cooling, water was added. The precipitate was filtered, washed with water and dried under vacuum. The residue was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(indol-6-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (130 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH2:35][OH:36])[N:34]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(Cl)Cl.CCOC(C)=O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH:35]=[O:36])[N:34]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(CO)cs1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 132) (40.9 mg, 0.070 mmol) in CH2Cl2 (5 mL) was added DMP (59.4 mg, 0.140 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. Next the reaction was diluted with EtOAc (40 mL) and washed with 1N NaOH (2×15 mL) and brine (2×15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (50% EtOAc/hexanes) afforded 2-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-1,3-thiazole-4-carbaldehyde. Rf=0.24 (40% EtOAc/hexanes). LCMS=583.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 10.09 (s, 1H), 8.33 (s, 1H), 7.87 (s, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.79 (s, 2H), 7.72, (d, J=8.1 Hz, 1H), 5.70 (d, J=8.0 Hz, 1H), 5.13 (d, J=16.0 Hz, 1H), 4.83 (d, J=16.0 Hz, 1H), 4.23 (m, 1H), 0.75 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[CH:38][C:37]([CH3:40])=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[CH:38][C:37]([CH3:40])=[N:36]1)=[O:11]
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)O)c1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)benzoic acid. MS (ESI) 327 (M+H).
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:7]([OH:9])=O>C(OCC)C>[Br:3][C:4]1[CH:5]=[C:6]([C:7](=[O:9])[CH3:1])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: [Li]C
Reactant: O=C(O)c1cc(F)cc(Br)c1
Solvent: CCOCC
Product: CC(=O)c1cc(F)cc(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Methyllithium (1.3 M in diethyl ether, 35 mL) was added dropwise to 3-bromo-5-fluorobenzoic acid (5 g) in diethyl ether at −78° C. keeping the temperature below −60° C. The reaction was then left to warm to −10° C. and was stirred for 1 h before being carefully quenched with saturated ammonium chloride (100 mL) until pH=3. The product was extracted with diethyl ether (2×100 mL), dried over sodium sulfate and the solvent removed by evaporation to yield 1-(3-bromo-5-fluorophenyl)ethanone as an off-white solid (4.67 g, 94%). 1H NMR (CDCl3): 2.59 (3H, s, ArCOCH3), 7.44 (1H, dd, Ar), 7.59 (1H, dd, Ar), 7.87 (1H, s, Ar).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Cl[CH2:15][C:16]([CH3:18])=[CH2:17]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:17][C:16]([CH3:18])=[CH2:15])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: C=C(C)Cn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as a pale yellow oil in 86.2% yeild in a similar procedure to that described in Referential Example 9 by using but using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-chloro-2-methyl-1-propene.
Reaction SMILES: [Mg].II.F[C:5]1C=C(Br)C=CC=1OC(F)(F)F.[CH3:17][O:18][C:19](=[O:27])[CH:20]([N:22]1[N:26]=[N:25][CH:24]=[N:23]1)[CH3:21].Cl>O1CCCC1.O>[CH2:17]([O:18][C:19](=[O:27])[CH:20]([N:22]1[N:26]=[N:25][CH:24]=[N:23]1)[CH3:21])[CH3:5]
Reactant: COC(=O)C(C)n1ncnn1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)n1ncnn1
Yield: 43.5 %

Procedure:
Magnesium turnings (1.22 g) and iodine (1 crystal) were added to dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. A solution of 3-fluoro-4-trifluoromethoxybromobenzene (12.95 g) in dry tetrahydrofuran (30 ml) was placed in a dropping funnel. About 10% of this was added to the mixture, and the Grignard reaction began immediately. The rest of the mixture was added dropwise with stirring, and the temperature rose until the solvent was at reflux. After the addition was complete the mixture was allowed to cool, then a solution of methyl-2-(2H-tetrazol-2-yl)propionate (3.9 g) in dry tetrahydrofuran (10 ml) was added with stirring. An exotherm was noted, and the reaction was allowed to stir at room temperature for 30 minutes. The mixture was then poured into water (100 ml). The mixture was acidified by adding 3M hydrochloric acid (100 ml) and then extracted with diethyl ether (3×100 ml). The combined ethereal extracts were dried over anhydrous sodium sulphate and evaporated to a brown oil (10 g). This was chromatographed on silica gel eluting with 4:1 hexane/ethylacetate to give an oil (1.85 g).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH2:2][O:10]1
Reactant: CC(=O)c1ccncn1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC1(c2ccncn2)CO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
Trimethylsulfonium iodide (3.34 g, 16.3 mmol) was dissolved in DMF (20 mL) and stirred at RT for 5 min. Sodium hydride (600 mg, 25 mmol) was added portionwise at the same temperature and stirred for 15 min. 4-Acetyl pyrimidine (1 g, 8.1 mmol) in 0.5 mL DMSO was added dropwise and the reaction mixture stirred for 1 h. After completion of reaction, the mixture was poured into ice-cold water and extracted with Ether (3×). The combined organic layer was washed with water several times followed by brine, and dried over sodium sulfate, then evaporated to provide 600 mg of 4-(2-Methyl-oxiranyl)-pyrimidine. 1H NMR (CDCl3, freebase) δ (ppm): 9.15 (s, 1H), 8.7 (d, 1H), 7.35 (d, 1H), 2.95 (d, 1H), 2.88 (d, 1H), 1.8 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: FC(F)(F)Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A reaction mixture comprising 3.0 g of 4-benzyloxy-4′-(trifluoromethoxy)biphenyl, 0.1 g of palladium hydroxide and 30 ml of ethyl acetate was filled with hydrogen gas, and stirred at room temperature for 8 hours. The reaction mixture was filtered, and the solvent of the filtrate was evaporated away. The resulting residue was recrystallized from heptane, and 1.5 g of 4-hydroxy-4′-(trifluoromethoxy)biphenyl was obtained. m.p.: 140-140.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[CH:19]=[CH:18][C:17]=1[F:36])[C:11](=[O:37])[NH:10]2)=[O:5])[CH3:2].N1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46].Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]3[C:29]([O:30][CH2:31][CH2:32][O:33][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[CH:19]=[CH:18][C:17]=1[F:36])[C:11](=[O:37])[NH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1scc2[nH]c(=O)n(-c3cc(OCc4c(OCCO)ccc(F)c4F)ccc3F)c(=O)c12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCOc1ccc(F)c(F)c1COc1ccc(F)c(-n2c(=O)[nH]c3csc(C(=O)OCC)c3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-ethoxycarbonyl-3-{2-fluoro-5-[2,3-difluoro-6-(2-hydroxyethoxy)benzyloxy]phenyl}thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (80 mg) in ethyl acetate (2 mL) were added pyridine (0.036 mL) and ethyl chloroformate (0.021 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2) to give the title compound (38 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[O:22]([CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]Cl)[CH2:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:38][CH2:37][CH2:36][N:33]1[CH2:32][CH2:31][CH:30]([CH2:29][O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:35][CH2:34]1
Reactant: ClCCCN1CCC(COc2ccccc2)CC1
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2c1ncn2CCCN1CCC(COc2ccccc2)CC1
Temperature: 40 °C
Yield: 42 %

Procedure:
A mixture of 15.4 g (0.1 mole) of 6-chloropurine, 75 ml of N,N-dimethyl formamide, 13.8 g (0.1 mole) of potassium carbonate and 26.8 g (0.1 mole) of 3-(4-phenoxymethylpiperidino)-propyl chloride is heated to 40° C for 6 hours, while stirring. The reaction mixture is then mixed with water extracted with ethyl acetate and the extract is dried and evaporated. The residue obtained is recrystallized from ethyl acetate/ligroin. There are obtained 16.2 g (42% of theory) of 6-chloro-9-[3-(4-phenoxymethylpiperidino)-propyl]-purine; m.p. 95° - 96° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][C@H:9]([C:11]2[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH:9]([C:11]2[CH:12]=[C:13]([C:17]([NH:35][CH3:34])=[O:18])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33]
Reactant: C[C@H](Sc1nc(N)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N)c1cccc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(C(C)Sc2nc(N)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
33 mg (0.072 mmol) of rac-3-[(1S)-1-({6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-pyridin-2yl}sulfanyl)ethyl]benzenecarboxylic acid (Example 16) were initially charged in 0.66 ml of DMF. At 0° C., 54.5 mg (0.143 mmol) of HATU were added, and the reaction solution was stirred at 0° C. for 20 min. After addition of 6.7 mg (0.215 mmol) of methylamine (2N in tetrahydrofuran) and 18.5 mg (0.143 mmol) of N,N-diisopropylethylamine, the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (Chromasil, water/acetonitrile).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:38]([OH:40])=[O:39])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]3[C:30]4[C:29](=[O:31])[CH2:28][C:27]([CH3:33])([CH3:32])[CH2:26][C:25]=4[O:24][C:23]4[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]3=4)[C:10]=2[CH3:37])=[CH:7][CH:8]=1)#[CH:2].[H][H].ClCCl>CO.[C].[Pd]>[CH2:1]([C:3]1[C:4]([C:38]([OH:40])=[O:39])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]3[C:30]4[C:29](=[O:31])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][C:25]=4[O:24][C:23]4[CH2:22][C:21]([CH3:34])([CH3:35])[CH2:20][C:19](=[O:36])[C:18]3=4)[C:10]=2[CH3:37])=[CH:7][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: C#Cc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)nc1C(=O)O
Yield: 36.1 %

Procedure:
A suspension of the 3-ethynyl-6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid produced in Example 12-3 (100 mg, 0.19 mmol) and 10% palladium carbon (wet) (100 mg) in methanol (2 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at the same temperature as above under a hydrogen atmosphere for 2.5 hours. Thereafter, a solid was removed from the reaction solution by filtration, and the solvent was then distilled away from the filtrate thus obtained under reduced pressure. The residue thus obtained was purified by silica gel thin-layer chromatography (methanol:dichloromethane=1:10, v/v) to obtain the title compound (37.3 mg, yield: 37%).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH3:5])[CH2:2]1.[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>C(#N)C>[N:6]1([CH2:2][CH:3]([OH:1])[CH2:4][CH3:5])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: c1c[nH]cn1
Reactant: CCC1CO1
Solvent: CC#N
Product: CCC(O)Cn1ccnc1
Yield: 48.7 %

Procedure:
A solution of 1,2-epoxybutane (2.0 mL, 23 mmol) and imidazole (2.37 g, 35 mmol) in acetonitrile (20 mL) was stirred at reflux for 24 h. The mixture was concentrated, taken up in water (30 mL) and extracted with ethyl acetate (9×10 mL). The combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, CH2Cl2-methanol-ammonium hydroxide 80:20:1) to give 1-(1H-imidazol-1-yl)-2-butanol (1.57 g, 48%) as a colorless oil. NMR spectrum was consistent with structure. MS EI: M+• 140.0948 (M+• 140.0950).
Reaction SMILES: [CH2:1]([S:5]([N-:8][Si](C)(C)C)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([NH:20][C@H:21]([C:26](F)=[O:27])[C@H:22]([CH2:24][CH3:25])[CH3:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C1C=CC=CN=1)C>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([S:5]([NH:8][C:26](=[O:27])[C@H:21]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: CCCCS(=O)(=O)[N-][Si](C)(C)C
Agent: CN(C)c1ccccn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-butanesulfonyl-N-trimethylsilylamide (prepared according to the procedure described in Example 8) (0.64 g, 3.06 mmol), t-butoxycarbonylisoleucine fluoride (0.475 g, 2.04 mmol), and dimethylaminopyridine (110 mg, 0.9 mmol) in tetrahydrofuran (7 ml) is stirred at room temperature for 2 hours. The mixture is diluted with 10% citric acid and extracted with ethyl acetate. The organic layer is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The crude material is chromatographed on silica gel with ethyl acetate/hexane (4:1) to give N-butanesulfonyl-(t-butoxycarbonyl)isoleucineamide.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[O:17][CH2:18][C:19]([N:21]1[CH2:26][C@H:25]([CH3:27])[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:23][C@H:22]1[CH3:36])=[O:20])(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:18][C:19]([N:21]2[CH2:26][C@H:25]([CH3:27])[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:23][C@H:22]2[CH3:36])=[O:20])=[C:10]([CH:15]=1)[CH2:9][O:8][CH2:7][C:6]([OH:37])=[O:5]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1COCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyloxy)-acetic acid tert-butyl ester (0.14 g, 0.25 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at ambient temperature overnight, diluted with dichloromethane and treated with excess hydrogen chloride gas. The mixture was concentrated in vacuo to give the title compound as its hydrochloride salt (0.14 g).