Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9].[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O=P(Cl)(Cl)Cl>[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17]2[NH:9][C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1N
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc3ccc(F)cc3[nH]2)cc1

Procedure:
2-(4-Nitrophenyl)-5-fluoro benzimidazole was synthesized as follows: 1,2-diamino-4-fluorobenzene (1.26 g, 10.0 mmole) was mixed with 4-nitrobenzoic acid (1.67 g, 9.8 mmole) and dissolved in POCl3 (10 ml) and heated to reflux for 2.5 hours. The reaction mixture was cooled and cautiously poured onto ice. The resulting solid was filtered, washed with NaHCO3 and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][C@@H:33]([OH:36])[C:34]#[CH:35].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][C@@H:33]([OH:36])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#C[C@@H](C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[C@H](O)C#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added (R)-(+)-3-butyn-2-ol (0.047 mL, 0.599 mmol). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 90.7 mg (34%) of the desired product as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:3][CH2:2]1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:42])([CH3:41])[CH3:43])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:5][CH2:6]1)[CH3:50]
Reactant: CCOC(=O)CBr
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCNCC1
Product: CCOC(=O)CN1CCC(NC(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 146, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (example 206) was reacted with ethyl bromoacetate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3074.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:22]=[CH:23][N:24]=3)[CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:32]1[CH:33]=[C:34]([C:38]2[N:39]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[CH:41][N:42]=2)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1>[C:7]1([N:13]([C:36]2[CH:37]=[CH:32][CH:33]=[C:34]([C:38]3[N:39]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH:40]=[CH:41][N:42]=3)[CH:35]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:22]=[CH:23][N:24]=3)[CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccc(-c2nccn2-c2ccccc2)c1
Reactant: c1ccc(Nc2cccc(-c3nccn3-c3ccccc3)c2)cc1
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2cccc(-c3nccn3-c3ccccc3)c2)c2cccc(-c3nccn3-c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
Sodium tert-butoxide (1.082 g, 11.27 mmol), N-phenyl-3-(1-phenyl-1H-imidazol-2-yl)aniline (2.45 g, 7.87 mmol), 2-(3-bromophenyl)-1-phenyl-1H-imidazole (2.1 g, 7.04 mmol), tris(dibenzylideneacetone)palladium(0) (Pd2dba3) (0.161 g, 0.176 mmol) and 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (0.289 g, 0.704 mmol) were charged into the reaction vessel with 100 mL of toluene. This mixture was degassed with nitrogen then was heated to reflux for 24 h. The reaction mixture was cooled to room temperature then was partitioned with 100 mL of water. The toluene layer was separated and the aqueous was extracted with another 100 mL of toluene. The toluene extracts were combined, dried over magnesium sulfate then were filtered and stripped under vacuum. The crude residue was passed through a silica gel column (15-30% acetone/DCM) and was purified if necessary using neutral alumina chromatography (7-10% ethyl acetate/DCM) yielding N-phenyl-3-(1-phenyl-1H-imidazol-2-yl)-N-(3-(1-phenyl-1H-imidazol-2-yl)phenyl)aniline (1.35 g, 2.55 mmol, 36.2%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:10]=1[CH2:11][CH2:12][NH:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:5])C.[OH-].[K+]>CCO>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:10]([CH2:11][CH2:12][NH:13][CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2Cl)c1CCNC1CCCC1
Temperature: 85 °C

Procedure:
To a solution of 2-(4-chloro-phenyl)-1-(2-chloro-phenyl)-5-(2-cyclopentylamino-ethyl)-1H-imidazole-4-carboxylic acid ethyl ester I-5i (22 mg, 0.46 mmol) in absolute EtOH (2 ml) was added 1N KOH (500 μl). The reaction mixture was heated to 85° C. for 4 hours and then was concentrated to a quarter fraction of the original volume. The pH of the solution was adjusted to approximately 3.5 using 10% HCl. The aqueous ethanolic solution was concentrated to dryness to give the I-5j as a solid (20 mg): +APCI MS (M+1) 444.4.
Reaction SMILES: CC([O:5][C:6](=[O:50])[C@H:7]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([NH:27][C@H:28]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:10])(C)C>ClCCl.FC(F)(F)C(O)=O>[C:11]1([C:9]([NH:8][C@H:7]([C:6]([OH:50])=[O:5])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC(=N)N)NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)C(=O)O
Yield: 59.8 %

Procedure:
This compound was prepared according to the general method of Example 122 using N,N'-[Dithiobis (2,1-phenylenecarbonyl)bis-L-arginine-bis(1,1-dimethylethyl) ester, (1.31 g, 2.0 mmol) from Example 127 in 15 mL of dichloromethane and 15 mL of trifluoroacetic acid. The residue was triturated with ethanol and 1N HCl to yield 0.74 g of the title compound, mp 208°-211° C.;
Reaction SMILES: [C:1](OC)(OC)(OC)[CH3:2].[NH2:9][C:10]1[C:11]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:12][C:13]([CH3:31])=[C:14]([CH3:30])[C:15]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:15]2[C:14]([CH3:30])=[C:13]([CH3:31])[N:12]=[C:11]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:10]=2[N:9]=1
Reactant: COC(C)(OC)OC
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCNC(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCNC(=O)OC(C)(C)C)c2c1C
Yield: 83.1 %

Procedure:
Trimethyl orthoacetate (3.55 mL, 28.27 mmol), tert-butyl 2-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate (11.21 g, 26.92 mmol), pyridine hydrochloride (1.12 g) and toluene (120 mL) were combined and heated at reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (3×100 mL) and brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 9.85 g of tert-butyl 2-[2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](O)=[O:10]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)cc1
Product: O=CNc1ccc(Cl)cc1
Yield: 96.7 %

Procedure:
4-Chloroaniline (15 g, 117 mmol) and formic acid (25 mL, 663 mmol) were heated to reflux for 2 hours. The mixture was concentrated in vacuo. Saturated aqueous sodium hydrogen carbonate was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to give N-(4-chloro-phenyl)-formamide (17.6 g, 97%) as a grey crystalline compound.
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-:3])=[O:2].C1(C)C(S([C:21]2([CH3:31])[CH:30]=[CH:29][C:24]([S:25](Cl)(=[O:27])=[O:26])=[CH:23][CH2:22]2)(=O)=O)=CC=CC=1.C(N([CH2:38][CH3:39])CC)C.Cl>C1COCC1>[S:25]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][S:25]([C:24]2[CH:23]=[CH:22][C:21]([CH3:31])=[CH:30][CH:29]=2)(=[O:26])=[O:27])[C:4]=1[N+:1]([O-:3])=[O:2])([C:39]1[CH:38]=[CH:30][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:27])=[O:26]
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1S(=O)(=O)C1(C)C=CC(S(=O)(=O)Cl)=CC1
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cccc(OS(=O)(=O)c3ccc(C)cc3)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 2-nitroresorcinol (31.0 g, 0.2 mole) and p-toluenesulfonyl(tosyl) chloride (83.9 g, 0.44 mole) in THF (500 ml) at ≤15° C. was added triethylamine (84 ml, 0.6 mole) at such a rate that the temperature did not exceed 15° C. The mixture was stirred two additional hours at ambient temperature. The reaction was then poured into ice water (5 liters) and hydrochloric acid (100 ml) with stirring. The resulting precipitate was collected, air dried, and recrystallized from acetonitrile (250 ml) to yield 85.6 g (92.3 percent) of a white crystalline product. Thin layer chromatography (TLC) showed the product to be pure.
Reaction SMILES: [C:1]([C@@:9]1([OH:37])[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:16]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:15]([CH2:35][OH:36])[O:14][C@H:10]1[S:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[C:44]([O:36][CH2:35][C@H:15]1[O:14][C@@H:10]([S:11][CH2:12][CH3:13])[C@:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:37])[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCS[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl 2,3-O-dibenzoyl-4-O-benzyl-1-thio-β-D-glucohexopyranoside (200 mg, 0.38 mmol) was dissolved in an ice-cooled mixture of pyridine and acetic anhydride (1:1, 6 Å). The mixture was stirred and attained at room temperature overnight. The mixture was diluted with dichloromethane, washed with satd. aq. sodium hydrogen carbonate and water and dried over sodium sulphate. The solvents were removed under reduced pressure and the residue was subjected to flash chromatography on silica gel (toluene-acetonitrile 6:1) to yield 204 mg, 93% of ethyl 6-O-acetyl-2,3-O-dibenzoyl-4-O-benzyl-1-thio-β-D-glucohexopyranoside.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]1[CH:27]([C:28]([OH:30])=O)[CH2:26][S:25][CH:24]1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH3:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[CH3:37][CH:38]1[CH2:43][CH2:42][N:41]([C:28]([CH:27]2[CH2:26][S:25][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:23]2[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[O:30])[CH2:40][CH2:39]1
Reactant: CC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CCN(C(=O)C2CSC(c3cccnc3)N2C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A solution of 540 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 810 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid, 260 mg of 4-methylpiperidine, 530 mg of 1-hydroxybenzotriazole and 10 ml of tetrahydrofuran with ice cooling, and the mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-methyl-1-[3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperidine. Trifluoroacetic acid (5 ml) was added to the thus-obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluent: ethyl acetate) to give 4-methyl-1-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperidine. This compound was dissolved in ethyl acetate, and 3 ml of 2N hydrogen chloride solution in dioxane was added The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 530 mg of 4-methyl-1-(3-pyridyl)thiazolidin-3-ylcarbonyl]piperidine dihydrochloride. Melting point 130° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:21])([F:22])[F:23])=[CH:12][C:11]=1[O:24][CH3:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NCc1ccccc1

Procedure:
The title compound, colorless gum, MS: m/e=475.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and benzaldehyde.
Reaction SMILES: C([Li])CCC.Cl[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH2:21]([Sn:16]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:17][CH2:18][CH2:19][CH3:20])[C:7]#[C:8][CH:9]1[CH2:11][CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#CCCCCl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](C#CC1CC1)(CCCC)CCCC
Reaction time: 3 h

Procedure:
To n-butyllithium (7.28 mL of a 2.5 M solution in hexane, 18.2 mmol) at −5° C. was added dry THF (80 mL) dropwise, maintaining the temperature below 5° C. 5-Chloro-1-pentyne (7.75 mL , 73.1 mmol) was added at 5° C., and the solution was stirred for 3 hours. The reaction was quenched by the addition of tri-n-butyltin chloride (21.0 mL, 77.4 mmol), and was allowed to stir for an additional 10 min. The solution was poured into saturated aqueous NaHCO3 (500 mL) and hexane (500 mL). The hexane layer was washed with H2O (200 mL), then brine (200 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled product as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:7]=1
Reactant: c1cn[nH]c1
Reactant: COc1cc(C)nc(Cl)n1
Solvent: C1CCOC1
Product: COc1cc(C)nc(-n2cccn2)n1
Yield: 54.2 %

Procedure:
In anhydrous tetrahydrofuran, 159 mg of 2-chloro-4-methoxy-6-methylpyrimidine was substituted with 68 mg of pyrazole. The reaction mixture was treated according to the procedure of Example 5 to yield 103 mg of 4-methoxy-6-methyl-2-(1-pyrazolyl)pyrimidine, and recrystallized from n-hexane to give a compound having a melting point of 52.5°-53° C.
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@H:11]1[N:34]1[CH:39]=[CH:38][C:37](=[O:40])[N:36]=[CH:35]1)(=O)C1C=CC=CC=1.C[O-].[Na+].CO>N1C=CC=CC=1>[C@@H:11]1([N:34]2[CH:39]=[CH:38][C:37](=[O:40])[N:36]=[CH:35]2)[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@H:10]1[OH:9]
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(=O)nc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cn1

Procedure:
Referring to FIG. 9, 1-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-1,4-dihydropyrimidine-4-one (3) was synthesized in accordance with Niedballa et al., J. Org. Chem 1974, 39, 3668-3671. 1-(β-D-Ribofuranosyl)-1,4-dihydropyrimidine-4-one (5) was prepared by standard NaOMe/MeOH deprotection of derivative 3 with nearly quantitative yield. 1-(5-O-Dimethoxytrityl-β-D-Ribofuranosyl)-1,4-dihydropyrimidine-4-one (6) was prepared by standard dimethoxytritylation of 5 in pyridine (rt., overnight) resulting in a yield of 83%. 1-(5-O-Dimethoxytrityl-2-O-tert-butyldimethylsilyl-β-D-Ribofuranosyl)-1,4-dihydropyrimidine-4-one was prepared using standard silylation procedure (Hakimelahi et al., Can. J. Chem. 1982, 60, 1106-1113). 1-[5-O-Dimethoxytrityl-2-O-tert-butyidimethylsilyl-3-O-2cyanoethyl-N,N-diisopropylaminophosphoramidite-β-D-Ribofuranosyl]-1,4-dihydro-pyrimidine-4-one (7) was prepared by phosphitylation using standard phosphitylation procedure (Tuschl et al., Biochemistry 1993, 32, 11658-11668).
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:18][C:8]([N:5]1[C:4](=[O:19])[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:2]([CH3:1])[O:7][CH2:6]1)([CH3:17])[C:9](=[O:16])[C:10](=[CH:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reactant: O=Cc1cccs1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccs1)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 31.4 %

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.50 g), 2-thiophenecarboxaldehyde(0.34 g), piperidine(0.43 g) and molecular sieve 4A in toluene was stirred at 80° C. for 7 hrs. The reaction solution was filtered (celite), evaporated and recrystallised (ethanol) to give ethyl 4-methyl-4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo-4H-1,3-oxazin-3-yl)-2-(2-thienylmethylidene)-3-oxo-pentanoate (Compound 206, 0.20 g), NMR 1.23(t,3H) 1.58(s,6H) 1.94(s,3H) 4.29(q,2H) 5.19(s,2H) 7.05(7.20-7.37(6H) 7.48(1H) 8.05(s,1H). By proceeding in a similar manner the following compounds were also obtained:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)(=O)=O.[C:16]1([CH2:22][SH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:22]([S:23][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:13])[CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 104.6 %

Procedure:
To a solution of 5-chloropyridin-3-yl trifluoromethanesulfonate (1.73 g) in toluene (15 mL) were added phenylmethanethiol (861 mg), N,N-diisopropylethylamine (1.88 g), tris(dibenzylideneacetone)dipalladium(0) (121 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (153 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=19:1) to give the title compound as a yellow oil (yield 1.63 g, quantitative).