Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([CH2:32][CH2:33][C:34](Cl)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(Oc2ccccc2)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(phenyloxy)phenyl)-1-propanol (550 mg, 1.63 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (360 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the title compound (152 mg, 20%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[F:12][CH:13]([CH2:15][C:16](Cl)=[S:17])[F:14]>ClCCl>[F:12][CH:13]([CH2:15][C:16]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[S:17])[F:14]
Reactant: FC(F)CC(=S)Cl
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=S)CC(F)F
Yield: 48.6 %

Procedure:
To a stirred and ice cooled solution of t-butanol (1.2 equivalents) and pyridine (1.3 equivalents) in dichloromethane (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride, and the mixture is stirred for 4 hours. The mixture is washed with water, dried and concentrated in vacuum. The residual liquid is distilled to give t-butyl difluoromethylthioacetate as an oil. Yield: 48.6%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:13]([O:18][CH2:19][CH:20]1[O:22][CH2:21]1)(=[O:17])[C:14]([CH3:16])=[CH2:15]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[C:13]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([O:11][CH3:12])[O:2][CH3:1])=[CH:5][CH:6]=1)(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COC(OC)c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COc1ccc(C(OC)OC)cc1
Temperature: 80 °C

Procedure:
In a 500 ml. 4-neck flask fitted with a mechanical stirrer, thermometer, condenser and a vented nitrogen bubbler were placed 84 g. 4-dimethoxymethyl phenol (0.5 mole), 71 g. glycidyl methacrylate (GMA) (0.5 mole), and 1.5 g. benzyl tributyl ammonium chloride (0.005 mole). The apparatus was flushed with air for 5 minutes and the solution was then heated to 80° C. for 5 hours. The progress of the reaction was followed from disappearance of the GMA. Gas chromatographic analysis of the reaction mixture indicated 95% reaction. The solution was cooled and dissolved in 250 ml. methylene chloride and washed three times with lN sodium hydroxide (100 ml.) and then with water until the washings were neutral. The organic layer was dried over magnesium sulfate and the solvent was removed at reduced pressure using a Rotovap. The oily residue was dried under high vacuum for 30 minutes. The yield was 133 g. (86%) product. H-1 NMR showed signals typical of GMA except the signal for the protons that were attached to the epoxide carbon at 2.8 and 3.3 ppm showed up as doublets and a quintet respectively. The spectrum also showed signals for the 4-dimethoxymethylphenyl group at ppms 7.8-6.9 and 3.4.
Reaction SMILES: [CH:1]([C:3](CC)=[O:4])=[CH2:2].[CH3:7][O:8][CH:9]=[CH:10][CH:11]=[CH2:12].Cl(O)(=O)(=O)=O.[CH2:18]([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)[C:19]1C=CC=CC=1>C(O)C>[CH3:7][O:8][C@H:9]1[CH:19]=[CH:18][CH2:12][CH2:11][C@H:10]1[C:3](=[O:4])[CH2:1][CH3:2]
Reactant: C=CC(=O)CC
Reactant: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Reactant: C=CC=COC
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CCC(=O)[C@@H]1CCC=C[C@@H]1OC
Yield: 88 %

Procedure:
Prepared according to general procedure B from ethyl vinyl ketone (59 μL, 0.59 mmol), 1-methoxy-butadiene (75 μL, 0.74 mmol) added via syringe pump over 12 hours, 70% aqueous perchloric acid (10.2 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32 mg, 0.12 mmol) in ethanol (590 μL) for 3.5 days at −30° C. Purification by silica gel chromatography (9:1 pentane:ether) provided the title compound as a single diastereomer (as judged by GLC analysis) in 88% yield (88 mg, 0.52 mmol) and 92% ee. IR (film) 3027, 2975, 2937, 2879, 2821, 1715, 1452, 1432, 1375, 1211, 1191, 1129, 1108, 1084, 917.8, 889.2 cm−1; 1H NMR (300 MHz, CDCl3) δ 5.95 (m, 2H, CH═CH), 4.06 (m, 1H, CHOCH3), 3.30 (s, 1H, OCH3), 2.53 (m, 3H, CH2CO and CHCO), 2.20 (m, 1H, one of CH2CH═CH), 1.85 (m, 3H, CH2CHCOEt and one of C(H)HCH═CH), 1.05 (dd, J=7.2, 7.2 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 211.5, 133.2, 124.5, 73.0, 56.7, 51.8, 33.8, 25.6, 18.7, 8.1; HRMS (CI) exact mass calc'd for [M—CH3OH]+(C9H12O) requires m/z 136.0888, found m/z 136.0889. [α]D=+16.7 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (100° C., 23 psi); (1R, 2S) endo isomer tr=29.6 min, and (1S, 2R) endo isomer tr=32.6 min, exo isomers tr=19.1, 19.4 min.
Reaction SMILES: [NH2:1][CH:2]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[CH2:3][N:4]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[O:35][CH3:36])[C:5](=[O:14])OCC1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH:2]2[CH2:3][N:4]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=3[C:26]3[CH:31]=[C:30]([CH:32]([CH3:33])[CH3:34])[CH:29]=[CH:28][C:27]=3[O:35][CH3:36])[C:5](=[O:14])[NH:1]2)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(N)c1ccc(Cl)cc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1CC(c2ccc(Cl)cc2)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl [2-amino-2-(4-chlorophenyl)ethyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (30 mg, 0.05 mmol) in THF (2 mL) was added potassium bis(trimethylsilyl)amide (295 μL of a 0.5M solution in toluene, 0.147 mmol) The reaction was stirred at room temperature for 30 minutes and then quenched with saturated NH4Cl (15 mL). The resultant mixture was extracted with EtOAc (25 mL) and the organic layer was washed with H2O (15 mL) and brine (15 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 5% to 60% EtOAc/hexanes afforded 4-(4-chlorophenyl)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}imidazolidin-2-one. Rf=0.46 (5% MeOH/CH2Cl2). LCMS=503.1 (M+1)+. 1H NMR (C6D6, 600 MHz, atropisomers observed; doubling of peaks.) δ 7.90-7.03 (m, 6H), 6.89-6.20 (m, 4H), 4.69-3.88 (m, 3H), 3.16 (s, 3H), 2.88-2.30 (m, 3H), 1.18-1.13 (m, 6H).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][N:35]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([O-:31])=[O:30])=[C:19]([CH2:22][N+:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][N:35]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([O-:31])=[O:30])=[C:19]([CH2:22][N+:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nccc(N)n1
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 44 %

Procedure:
A mixture of 7-[2-t-butoxycarbonylmethoxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.31 g) and anisole (2.5 ml) in trifluoroacetic acid (7.5 ml) was stirred for 50 minutes under cooling in an ice-bath and for 70 minutes at room temperature. The mixture was poured into cold diisopropyl ether (60 ml) and the resulting precipitates were collected by filtration. The powder was dissolved in water (30 ml) and the mixture was adjusted to pH 4 to 5 with aqueous sodium bicarbonate and subjected to column chromatography on a non ionic adsorption resin "Diaion HP 20" (60 ml). After the column was washed with water, the elution was carried out with 30% aqueous methanol. The eluate was evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-carboxymethoxyimino-2-[4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.52 g).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=O.[Na+].[Na+].[C:15]1(B(O)O)[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.CO.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>[CH:7]([C:5]1[O:6][C:2]([C:15]2[CH:20]=[CH:19][C:18]([C:5]3[O:6][C:2]([CH:9]=[O:12])=[CH:3][CH:4]=3)=[CH:17][CH:16]=2)=[CH:3][CH:4]=1)=[O:8]
Reactant: OB(O)c1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)o1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)o3)cc2)o1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a stirred solution of 5-bromofuran-2-carboxaldehyde (10 mmol), and tetrakis(triphenylphosphine)palladium (400 mg) in toluene (20 mL) under a nitrogen atmosphere was added 10 mL of a 2 M aqueous solution of Na2CO3 followed by 1,4-phenylenebisboronic acid (5 mmol) in 6 mL of methanol. The vigorously stirred mixture was warmed to 80° C. for 12 h. The solvent was evaporated, the precipitate was partitioned between methylene chloride (300 mL) and 2 M aqueous Na2CO3 (15 mL) containing 5 mL of concentrated ammonia. The organic layer was dried (Na2SO4), and then concentrated to dryness under reduced pressure to afford 11 in 93% yield; mp 233-234° C. (EtOH). 1H NMR (DMSO-d6); δ 9.64 (s, 2H), 8.01 (s, 4H), 7.70 (d, J=3.6 Hz, 2H), 7.43 (d, J=3.6 Hz, 2H). MS (ESI) m/e (rel. int.): 266 (M+, 100), 238 (5), 209 (25). Anal. Calc. for C16H10O4: C %, 72.16; H %, 3.78; Found. C %, 72.41; H %, 3.93.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C:26]2=[N:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1>[CH2:14]([O:21][CH2:22][C@@H:23]1[O:31][CH2:30][C@:26]2([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[F:8])[NH:27][O:28][CH2:29][C@@H:25]2[CH2:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccccc1[C@]12CO[C@@H](COCc3ccccc3)C[C@H]1CON2
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
Toluene (100 ml) and THF (10 ml) were added to 2-bromofluorobenzene (3.11 g). The reaction solution was cooled to −78° C., and n-butyllithium (2.63 M, 6.15 ml) was added dropwise. After stirring at the same temperature for one hour, a mixed solution of (3aR,5R)-5-benzyloxymethyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole (2.00 g) in toluene (20 ml) and THF (2 ml) and a boron trifluoride-diethyl ether complex (2.03 ml) were added dropwise at the same time. After stirring at the same temperature for two hours, an ammonium chloride solution was added to the reaction solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.29 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:23])[C:11]([Cl:22])=[C:12]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:8]1=[O:24])(=[O:3])[CH3:2].N12CCCC1=CCCN2.[CH:34]([C:36]([CH3:38])=[O:37])=[CH2:35].C(O)(=O)C>O1CCCC1.N12CCCC1=CCCN2.C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1([CH2:35][CH2:34][C:36](=[O:37])[CH3:38])[CH2:15][C:14]2[C:9](=[C:10]([Cl:23])[C:11]([Cl:22])=[C:12]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=2)[C:8]1=[O:24])(=[O:3])[CH3:2]
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Reactant: C=CC(C)=O
Agent: C1=C2CCCN2NCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)(CCC(C)=O)C2
Temperature: 40 °C
Reaction time: 2.33 h

Procedure:
Methyl {[2-(2-acetoxyethyl)-6,7-dichloro-2,3-dihydro-1-oxo-1H-inden-5-yl]oxy}acetate (3.2 gm, 0.00853 mole) was dissolved in tetrahydrofuran (30 ml), stirred and heated to 40° C. Then diazabicyclo[4.3.0]non-5-ene (50 microliters) was added followed by methyl vinyl ketone (1.2 gm, 0.0170 mole). The mixture was stirred and heated at 50°-52° C. for 100 minutes, then more diazabicyclo[4.3.0]non-5-ene (2 drops) and methyl vinyl ketone (0.6 ml) were added and stirring and heating continued for another 140 minutes. The mixture was cooled, diluted with ethyl acetate, poured into ice water (250 ml) containing acetic acid (1 ml). The layers were separated and the aqueous layer extracted first with methylene chloride then with ether. The combined organic extracts were washed with water and dried over MgSO4. Evaporation of the solvents in vacuo gave the product (3.6 gm.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][CH2:12][O:13][C:6]=2[CH:5]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:15]([O-:17])=[O:16])=[CH:8][C:7]2[O:10][CH2:11][CH2:12][O:13][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc2c(c1)OCCO2
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5.0 g. of 3,4-ethylenedioxybenzoic acid methyl ester in 5.0 mls. of glacial acetic acid is added dropwise 5.0 mls. of 70% nitric acid at 50°-60°C. After addition the reaction mixture is kept at 55°C. for one hour, then cooled and 50 mls. of ice water added. The resulting precipitate is recovered by filtering, water washed and dried to obtain 6-nitro-3,4-ethylenedioxybenzoic acid methyl ester, m.p. 115°-118°C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[CH:10]([C:11](O)=[O:12])[S:9][CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1.C(Cl)(=O)C(Cl)=O.[NH3:23].C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[CH:10]([C:11]([NH2:23])=[O:12])[S:9][CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1
Reactant: N
Reactant: Cc1cc2c(cc1C)C(C(=O)O)SCC2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(C(N)=O)SCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
In THF (10 ml) was dissolved 6,7-dimethyl3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (0.473 g) followed by addition of oxalyl chloride (0.305 g) and, then, DMF (1 drop). The mixture was stirred at room temperature for 2 hours. This reaction mixture was added to aqueous ammonia (20 ml)--ethyl acetate (40 ml) and the whole mixture was stirred at room temperature for 30 minutes. The ethyl acetate layer was then separated, washed with water, dried (MgSO4) and the solvent was distilled off to give 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0.38 g, 81%). Recrystallization from ethyl acetate gave colorless plates melting at 197°-198° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:30])[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][N:12]([CH2:25][CH2:26][C:27](O)=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[C:15]([Cl:24])[CH:14]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:30])[CH2:6][CH2:7][CH2:8][N:9]1[C:27](=[O:28])[CH2:26][CH2:25][N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[C:15]([Cl:24])[CH:14]=2)[CH2:11][CH2:10]1
Reactant: COC(=O)CCCNCCN(CCC(=O)O)c1ccc(OC(F)(F)F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN1CCN(c2ccc(OC(F)(F)F)c(Cl)c2)CCC1=O
Reaction time: 15 h

Procedure:
A solution of 0.16 g (0.3 mmol) of 4-{2-[(2-carboxy-ethyl)-(3-chloro-4-trifluoromethoxy-phenyl)-amino]-ethylamino}-butyric acid methyl ester dihydrochloride in 2.5 ml CH2Cl2 was treated with 0.04 ml (0.3 mmol) of triethylamine and at 0° C. with 0.08 g (0.4 mmol) of EDCI. The cooling bath was allowed to come to RT and after 15 h the reaction was extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with 10% KHSO4, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 0.11 g (76%) of the title compound as a yellow oil. MS: 409.11 (MH+, Cl).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.C(O)(=O)C.O>CCO>[CH:24]1([NH:27][C:3]([C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:23])[N:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][C:13]=3[C:14]=2[OH:15])=[O:4])[CH2:26][CH2:25]1
Reactant: NC1CC1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(NC1CC1)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 46.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (35 mg, 0.11 mmol) and cyclopropylamine (0.080 mL, 1.1 mmol) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., acetic acid (0.1 mL) and water (3 mL) were added. The resulting suspension was filtered and the solid isolated was dried under high vacuum to afford 17 mg of the title compound. MS: (+) m/z 336.00 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:11]=1[C:12](O)=[O:13].S(Cl)([Cl:24])=O.CCCCCC>C(Cl)Cl.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:11]=1[C:12]([Cl:24])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COc1nc(Nc2ccc(F)cc2F)c(C(=O)O)cc1F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1nc(Nc2ccc(F)cc2F)c(C(=O)Cl)cc1F
Yield: 91.7 %

Procedure:
In 150 ml of methylene chloride was suspended 5.00 g of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinic acid, and 5.98 g of thionyl chloride and 3 drops of N,N-dimethylformamide was added thereto, after which the resulting mixture was subjected to reaction under reflux for 2 hours. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 10 ml of n-hexane, after which crystals were collected by filtration to obtain 4.87 g (yield 91.7%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl chloride having a melting point of 153°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[N:44]1([CH2:43][CH2:42][NH:41][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][S:22][C:11]2[NH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(-c2nc(SCCCCC(=O)O)[nH]c2-c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(SCCCCC(=O)NCCN3CCOCC3)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.33 h

Procedure:
A solution of 5-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]pentanoic acid (1.91 g, 4.63 mmol) and 1-hydroxy-1H-benzotriazole hydrate (890 rag, 6.59 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C., and treated with 2-aminoethylmorpholine (1.0 mL, 7.62 mmol). After 20 minutes, dicyclohexylcarbodiimide (1.42 g, 6.88 mmol) was added in small portions over 20 minutes. This mixture was allowed to stir an additional 48 hours, then poured into ethyl acetate (250 mL), filtered, and washed with water (200 mL). The phases were separated, and the aqueous phase was saturated with sodium chloride and reextracted with methylene chloride (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated. The mixture was separated by flash chromatography to afford the product, N-(2-morpholinyl-ethyl)-5-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-pentanamide, as an oil (1.77 g, 3.37 mmol, 73%). 1H NMR (CDCl3): 7.42 (4H, br d, J=9 Hz); 6.82 (4H, d, J=9 Hz); 6.22 (1H, br t, J=4 Hz); 3.80 (6H, s); 3.65-3.60 (4H, m); 3.15 (2H, q, J=6 Hz); 2.98 (2H, t, J=7 Hz); 2.38-2.24 (8H, m); 1.96-1.85 (2H, m); 1.70-1.60 (2H, m).
Reaction SMILES: C(N(CC)C(=S)S[CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1)C.[OH-:25].[K+].[N+:27]([CH3:30])([O-:29])=[O:28]>CO>[C:13]([C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])[CH2:6][C:30]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:10]([OH:25])=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH2:6][C:7]1[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]([OH:17])=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[N+:27]([O-:29])=[O:28])([CH3:14])([CH3:16])[CH3:15]
Reactant: C[N+](=O)[O-]
Reactant: [OH-]
Reactant: CCN(CC)C(=S)SCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(CC(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)[N+](=O)[O-])cc(C(C)(C)C)c1O

Procedure:
To a rapidly stirred solution of 11.0l g of 3,5-di-t-butyl-4-hydroxybenzyl N,N-diethyldithiocarbamate in 100 ml of hot methanol was added a freshly prepared solution of 1.68 g of potassium hydroxide and 0.61 g of nitromethane. The resulting stirred mixture was refluxed under nitrogen for 24 hours. Upon cooling, 3.0 g of the product precipitated as white crystals, mp 199°-201° C. An additional 2.07 g of pure product was obtained from the filtrate after recrystallization from acetonitrile and vacuum drying.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1B(O)O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1

Procedure:
was prepared under similar conditions as described in the preparation of Intermediate 1.4. using 2,4-dichloro-5-fluoropyrimidine (Aldrich Chemical Company Inc.) and [2-(benzyloxy)-4-fluorophenyl]boronic acid (ABCR GmbH & CO. KG). The batch was purified by column chromatography (hexane/ethyl acetate 1:1).