Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([O:17]CC)=[O:16])=[C:11]([F:22])[CH:10]=1)=[O:7].[OH-].[Na+].Cl>C(O)C>[CH3:29][Si:26]([CH3:27])([CH3:28])[C:24]1[CH:23]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:31])([CH3:30])[CH3:1])[CH:25]=1)[C:6]([NH:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[C:11]([F:22])[CH:10]=1)=[O:7]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)c1cc(C(=O)Nc2ccc(C=CC(=O)O)c(F)c2)cc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
Compound 2b (80 mg) was dissolved in ethanol (2.6 ml), and a 2N sodium hydroxide aqueous solution (1.7 ml) was added to the obtained solution in a nitrogen atmosphere. The mixture was stirred overnight at room temperature. A 2N hydrochloric acid aqueous solution (3.4 ml) was added thereto. The resulting white precipitate was filtered off and dissolved in ethyl acetate. The reaction mixture was separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvent was distilled off and n-hexane was added to the obtained residue, the mixture was pulverized with ultrasonic waves. The solid was filtered off, and the obtained powder was dissolved in butyl acetate (0.5 ml) by heating. The reaction mixture was allowed to cool and then filtered. Thus, Compound 2 (39 mg, 55%) was obtained as an opalescent solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].Br[CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15].C(N(CC)CC)C.O>CN(C)C=O>[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1OCCC1Br
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC1CCOC1=O)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
Dissolved in 30 ml of dimethylformamide were 2.54 g of L-alanine t-butyl ester hydrochloride and 2.38 g of 2-bromo-γ-butyrolactone. After a dropwise addition of 2.83 g of triethylamine, the resultant mixture was heated and stirred at 70° C. for 5 hours. The reaction mixture was poured into chilled water, followed by extraction with ethyl acetate. The extract was washed successivley with water, a 2% aqueous solution of sodium hydrogencarbonate, and water. After drying the extract over anhydrous sodium sulfate, it was distilled under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (toluene:ethyl acetate=20:1), thereby obtaining 1.86 g of N-(2-oxo-3-tetrahydrofuranyl)-L-alanine t-butyl ester as a colorless oily substance.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[C:10]([S:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[OH:23])([CH3:5])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]([C:37]1[N:38]([CH3:46])[C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:40][CH:41]=1)=[O:36]>C1COCC1.C(OCC)(=O)C>[CH3:33][O:34][C:35]([C:37]1[N:38]([CH3:46])[C:39]([S:42]([N:16]2[CH2:17][CH2:18][CH:13]([S:12][C:10]3[CH:9]=[C:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([OH:23])=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:11]=3)[CH2:14][CH2:15]2)(=[O:44])=[O:43])=[CH:40][CH:41]=1)=[O:36]
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To a solution of 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol hydrochloride (Ex. 3c, 5.4 g) in 44 mL of THF at room temperature was added N,N-diisopropylethylamine (8.8 mL), followed by 5-chlorosulfonyl-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (4 g). The mixture was stirred at room temperature for 18 h and then diluted with ethyl acetate and washed twice with 1 N HCl (aq), and once with brine. After concentration of the organic extracts, the crude solid was triturated with 15% ethyl acetate in hexanes to give 4.5 g of 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as an off-white solid, mp 181-183° C. 1H-NMR (300 MHz, CDCl3): δ 7.23 (s, 2H), 7.17 (d, 1H, J=1.5 Hz), 7.09 (d, 1H, J=1.2 Hz), 5.30 (s, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.60-3.54 (m, 2H), 2.80-2.74 (m, 1H), 2.54-2.45 (m, 2H), 2.03-1.97 (m, 2H), 1.73-1.67 (m, 2H), 1.41 (s, 18H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].[CH:24]1([CH2:30]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C)C=O>CCCCCC.C(OCC)(=O)C>[CH:24]1([CH2:30][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]3[CH:18]=[CH:19][C:20]([CH3:21])=[C:2]([CH3:1])[CH:3]=3)=[CH:8]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCC1CCCCC1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(CC3CCCCC3)c3ccccc3c2=O)cc1C
Yield: 58.2 %

Procedure:
The titled compound was prepared following the procedure described in Step 3 of Example 1. 63 mg (0.23 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one 3a, 12 mg (0.30 mmol) of 60% sodium hydride and 52 mg (0.30 mmol) of cyclohexylmethyl bromide and 0.9 mL N,N-dimethylformamide were combined at 90° C. for 5 h. Flash chromatography using 10-75% ethyl acetate in hexane yielded 50 mg of the product 4b as white solid: LC-MSD, m/z for C25H27NO2 [M+H]+=374.6; HPLC retention time: 2.8 min; 1H NMR (400 MHz, CDCl3): δ 1.0-1.3 (m, 6H), 1.7-1.85 (m, 4H), 1.9-2.0 (m, 1H), 2.3 (s, 3H), 2.35 (s, 3H), 4.0-4.05 (m, 2H), 7.15-7.2 (m, 1H), 7.4-7.5 (m, 2H), 7.5-7.6 (m, 1H), 7.6 (s, 1H), 7.65-7.75 (m, 1H), 8.05 (s, 1H), 8.45-8.5 (m, 1H).
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19]>O1CCCC1>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[CH:4]([C:1](=[O:3])[CH2:2][C:17](=[O:23])[C:18]([OH:20])=[O:19])[CH2:5]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C1COc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)C1COc2ccccc2C1=O

Procedure:
Solid 3-acetyl-4-chromanone (0.570 g, 3 mmoles, described in Example 5) is added in portions at room temperature to a suspension of 57% sodium hydride (0.379 g, 9 mmoles) in dry tetrahydrofuran (10 ml). The mixture is heated within 15 min to 60° C and diethyl oxalate (0.438 g, 3 mmoles) in tetrahydrofuran (10 ml) is added. After heating at reflux temperature under an atmosphere of nitrogen for 17 hr., the solvent is removed under reduced pressure, the residue is dissolved in ice-water and extracted with ether. The aqueous phase is acidified with 6N hydrochloric acid and extracted with chloroform. The organic phase is dried, evaporated, and the residue crystallized from methanol-chloroform to give 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid (Vl; R1, R2, R3, Rl4 and R5 = H, and X = O), νmaxnujol 1705, 1615 and 1560 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](C#C[Si](C)(C)C)[C:7]([NH:16][C:17](=O)[CH3:18])=[CH:6][C:5]=1[Cl:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:20][C:5]1[CH:6]=[C:7]2[C:8]([CH:18]=[CH:17][NH:16]2)=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:21]
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(NC(C)=O)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc[nH]c2cc1Cl
Yield: 79.2 %

Procedure:
A solution of methyl-2-chloro-4-acetamido-5-(2-trimethylsilylethynyl)-benzoate (1.9 g, 5.9 mmol) in THF (15.0 mL) containing tetrabutyl ammonium fluoride (1.9 g, 6.0 mmol) was heated to reflux for 6 h under nitrogen. The reaction mixture was concentrated to dryness and the residue partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with water, dried (MgSO4) and concentrated to dryness. The residue was purified by silica gel flash chromatography using 25% ethyl acetate in heptane to afford the title compound as a light brown powder (0.98 g, 86%), m/z 210 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:13])=[O:12])[C@@H:7]([C:25]([OH:27])=O)[CH2:6]1)=[O:4].C(N(CC)CC)C.Cl.[CH2:36]([O:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:13])=[O:12])[C@@H:7]([C:25](=[O:27])[NH:44][O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:6]1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)CCCOc2ccc(F)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Reaction time: 16 h
Yield: 66.4 %

Procedure:
To a stirred solution of (2R,4R)-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-piperidine-2,4-dicarboxylic acid 4-methyl ester (970 mg, 2.4 mmol) in 5 mL of methylene chloride was added triethylamine (1.0 mL, 7.2 mmol) and O-benzylhydroxylamine hydrochloride (410 mg, 2.64 mmol) at ambient temperature (22° C.) To the resulting solution was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.17 g, 2.64 mmol) and the mixture was stirred for 16 hours under a nitrogen atmosphere. The mixture was diluted with 25 mL of 1 N hydrochloric acid and 25 mL of ethyl acetate. The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium carbonate (1×) and brine (1×). The organic layer was dried (sodium sulfate), filtered, and the filtrate was concentrated in vacuo. Purification of the viscous yellow residue by flash chromatography (eluting with 1:1 ethyl acetate/hexanes) gave 810 mg of (2R,4R)-2-benzyloxycarbamoyl-1-[3-(4-fluorophenoxy)-propane-1-sulfonyl]-piperidine-4-carboxylic acid methyl ester as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.C([O-])([O-])=O.[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:14]1([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=[CH:10][C:6]=2[C:7]([OH:9])=[O:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: Clc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: O=C(O)c1cccc([N+](=O)[O-])c1-c1ccccc1
Yield: 65 %

Procedure:
Palladium acetate (5.6 mg, 0.025 mmol), 3-nitrobenzoic acid (84 mg, 0.5 mmol) and 4-chlorobenzene (283 mg, 2.5 mmol), butyldi-1-adamantylphosphine (19.2 mg, 0.05 mmol, Cs2CO3 (358 mg, 1.1 mmol), molecular sieves 3 Å (155 mg) and anhydrous DMF (2.5 mL). After flash chromatography and preparative HPLC 79 mg (65%) of a white solid was obtained. Analytical data are consistent with that of previously reported data.3 1H NMR (300 MHz, CDCl3) δ 7.32-7.37 (m, 2H), 7.42-7.46 (m, 3H), 7.57 (d, J-8.4 Hz, 1H), 8.40 (dd, J-8.4 Hz, 2.1 Hz, 1H), 8.80 (d, J-2.1 Hz, 1H). Carboxylate proton signal was not observed. The 1H NMR spectrum is shown in FIG. 37.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:34].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:34])=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(F)c(C(F)(F)F)c1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(F)c(C(F)(F)F)c1

Procedure:
According to the general procedure (GP12), chlorination of 3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-1-iodo-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (844 mg; 1.482 mmol), and purification by FC (DCM/MeOH=60/1) gave the expected product 1-chloro-3-ethyl-8-(4-fluoro-3-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange solid (186 mg; 26%). LC-MS: tR=1.04 min.; [M+H]+=478.39 g/mol.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)=[O:4].[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=4)=[O:20])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl {4-[(trifluoroacetyl)amino]phenyl}carbamate (200 mg, 0.527 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (130 mg, 0.527 mmol), diisopropylethylamine (0.184 ml, 1.05 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 12-hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 43.0 mg (17.1%) of the desired product as a solid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[N+:9]([O-])([OH:11])=[O:10]>CCOCC>[N+:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[C:3]=1[OH:4])([O-:11])=[O:10]
Reactant: Oc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(O)c1O
Temperature: 25 °C

Procedure:
To a solution containing 2.5 g of catechol in 125 ml of ether 1.0 ml of conc. nitric acid (d=1.52) was gradually added. The solution was stirred over night at room temperature and washed with water. The solvent was evaporated and the residue was treated with boiling petroleum ether (b.p. 60°-80° C.). The insoluble 4-nitrocatechol was filtered and the filtrate concentrated in vacuo. After cooling the 3-nitrocatechol was filtered. Yield 0.85 g (24%), m.p. 82°-85° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>C1(C)C=CC=CC=1>[C:14]1([O:13][C:11](=[O:12])[NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[F:1])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(F)cc1F)Oc1ccccc1
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
To a solution of 1.94 g of 2,4-difluoroaniline in 20 ml of toluene was added dropwise 1.29 g of phenyl chloroformate. The mixture was stirred for 15 minutes, washed with three 10 ml portions of water, dried over anhydrous sodium sulfate, and filtered through a pad of diatomaceous earth. The filtrate was evaporated in vacuo to give an oil which solidified on cooling. The solid was crystallized from hexane to give 1.73 g of the desired product as pale tan crystals in 93% yield, mp 82°-84° C.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.C([OH:32])C>>[OH:32][C:3](=[CH:9][CH:10]=[C:11]([S:26][CH3:27])[C:12](=[O:25])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=CC=C(SC)C(=O)c1ccc(N2CCCCC2)cc1)N(C)C
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SC)C(=O)c1ccc(N2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The procedure is as in Example 4, starting with ethyl 2-dimethylamino-5-methylthio-6-oxo-6-(4-piperidinophenyl)-2,4-hexadienoate (23.5 g) and 1N hydrochloric acid (139 cc) in ethanol (139 cc). The mixture is stirred for 16 hours at a temperature in the region of 20° C. After purification by chromatography on a silica column with dichloromethane as eluent and a second chromatography on a second silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluents; the corresponding eluate is concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized in boiling isopropyl ether (100 cc). Ethyl 2-hydroxy-5-methylthio-6-oxo-6-(4-piperidinophenyl)-2,4-hexadienoate (3 g), m.p. 65° C., is thereby obtained.
Reaction SMILES: I[Si](C)(C)C.[CH3:6][C:7]1[O:11][N:10]=[C:9]([NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18]CC)[O:15]CC)[CH:8]=1>C(Cl)(Cl)(Cl)Cl>[CH3:6][C:7]1[O:11][N:10]=[C:9]([NH:12][CH:13]([P:22](=[O:23])([OH:29])[OH:26])[P:14](=[O:15])([OH:18])[OH:21])[CH:8]=1
Reactant: CCOP(=O)(OCC)C(Nc1cc(C)on1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(NC(P(=O)(O)O)P(=O)(O)O)no1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Iodotrimethylsilane (7.1 ml) was added dropwise to an ice-cold solution of 4.8 g of tetraethyl [(5-methyl-3-isoxazolyl)amino]methylene-bis(phosphonate) in 90 ml of carbon tetrachloride. Then the temperature was allowed to rise to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated, methanol was then added, and the mixture was again concentrated. The solid thus obtained was washed with a hot acetone to give 2.9 g of [(5-methyl-3-isoxazolyl)amino]methylene-bis(phosphonic acid) as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([NH:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16]C2)[N:3]=1.C(N(CC)CC)C.C1(NC2N=CN=C(C(OC)=O)C=2)CCCC1.C1(NC2N=CN=C(C(OCC)=O)C=2)CCCC1.[OH-].[Li+]>[Pd].CCO.C1COCC1.CCO.O.O>[CH:13]1([NH:12][C:4]2[N:3]=[CH:2][N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=2)[CH2:14][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc(NCC2CCCC2)nc(Cl)n1
Agent: [Pd]
Agent: CCOC(=O)c1cc(NC2CCCC2)ncn1
Agent: COC(=O)c1cc(NC2CCCC2)ncn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(NC2CCCC2)ncn1
Reaction time: 2 h

Procedure:
A mixture of methyl 2-chloro-6-[(cyclopentylmethyl)amino]pyrimidine-4-carboxylate (Intermediate 2, 2.00 g; 7.82 mmol; 1.00 eq.), palladium on charcoal (750 mg) and triethylamine (3.27 mL; 23.5 mmol) in EtOH (200 mL) was stirred under an atmosphere of hydrogen for 2 hours. After 2 hours the reaction mixture was filtered on celite and evaporated to give a mixture of methyl 6-(cyclopentylamino)pyrimidine-4-carboxylate and ethyl 6-(cyclopentylamino)pyrimidine-4-carboxylate. The crude mixture was dissolved in a mixture of THF/EtOH/H2O (3/2/1, 120 mL) and treated with an aqueous solution of lithium hydroxide (1N, 23.5 mL, 23.5 mmol). The reaction mixture was stirred at RT for 60 minutes. Water was added (50 mL) and the aqueous layer was washed with DCM (30 mL). The aqueous layer was acidified to pH 5 by addition of an HCl solution (1N). The aqueous layer was evaporated in vacuo to reduce the volume by 30-50%. The resulting white solid was filtered to afford the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])[CH2:23][S:22][C:21]1=[S:26])[CH3:16].N1CCCCC1>ClCCl>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])/[C:23](=[CH:13]/[C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)=[CH:9][CH:10]=2)/[S:22][C:21]1=[S:26])[CH3:16]
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCOC(=O)CN1C(=O)/C(=C/c2ccc(-c3cccc(I)c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) and ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (22 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) for 3 hours. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give the target compound 1 in a yield of 38 mg (yield 76.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.[Li]CCCC.[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[CH:10][CH:11]=1)[OH:24])[CH3:21]
Reactant: COc1ccc(Cn2cccn2)cc1
Reactant: CCC(C=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1Cc1ccc(OC)cc1
Reaction time: 1.25 h
Yield: 44.8 %

Procedure:
To 1-(4-methoxybenzyl)-1H-pyrazole (Synthetic Comm. 25(5), 761-774 (1995)) (2.43 g, 12.9 mmol) in THF (100 mL) at −78° C. was added a solution of n-BuLi (2 M in cyclohexane, 7.1 mL, 14.2 mmol) dropwise. After 75 min, 2-ethylbutyraldehyde (1.3 mL, 10.6 mmol) was added. After 45 min the reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL), extracted with EtOAc (3×100 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexanes, 1:4) provided 1.37 g (37%) of 2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butan-1-ol as an oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(OCC)C.C(OCC)(=O)C.CCCCCC>N1C=CC=CC=1.C(Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C=C[C@H](O[Si](C)(C)C(C)(C)C)C1
Yield: 98 %

Procedure:
Dissolve (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (1 9, 4.67 mmol, prepared in example 10) in pyridine (20 mL) and treat with acetic anhydride (2 mL). Stir the reaction overnight. Dilute the reaction with diethyl ether (100 mL), wash with 3M hydrochloric acid (3×100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide the title compound (1 g, 98% yield), Rf =0.5 (5% ethyl acetate/hexane), [α]20D =+1.3°, (c=1.00, chloroform), 1H NMR (CDCl3) δ 5.9 (m, 1 H), 5.5 (m, 1 H), 4.7 (m, 1 H), 2.8 (m, 1 H), 2.05 (s, 3 H), 1.6 (m, 1 H), 0.91 (s, 9 H), 0.09 (s, 6 H); 13C NMR (CDCl3) δ 170.8, 138.8, 131.1, 76.9, 74.8, 41.1, 25.8, 21.1, 18.1, -4.7, -4.6; IR (neat) νmax 2955, 2932, 2859, 1739, 1369, 1240, 1105, 1062, 1049 cm-1 ; CIMS m/e (% relative intensity) 256 (M+H+, 7), 197 (M+H+ --AcOH, 100).