Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13]C(OCC[Si](C)(C)C)=O)[CH:10]([C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>CCOCC>[NH2:13][CH:11]1[CH:10]([C:23](=[O:32])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCC[Si](C)(C)C)C(C(=O)Nc2cccc(F)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(N)C(C(=O)Nc2cccc(F)c2)C1
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To 3-(3-Fluoro-phenylcarbamoyl)-4-(2-trimethylsilanyl-ethoxycarbonylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (1700.00 mg; 3.64 mmol; 1.00 eq.) was added of TBAF (2851.67 mg; 10.91 mmol; 3.00 eq.) (1.0M in THF 11 ml). The resulting mixture was stirred overnight. The reaction mixture was poured into water, washed with brine, then 5% NaHCO3, brine, dried and concentrated to give the crude, which was added of ether (5 ml). The precipitated white solid was filtered to afford the title compound (710 mg, 60.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31](=[O:42])[CH:32]=[C:33]([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C1(C2C=C[N+]([O-:55])=CC=2)C=CC=CC=1.[O-]Cl.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:30][C:31]([CH:32]2[C:33]([C:38]([F:39])([F:41])[F:40])([C:34]([F:35])([F:36])[F:37])[O:55]2)=[O:42])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:27])([F:28])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: O=C(C=C(C(F)(F)F)C(F)(F)F)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC#N
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)C1OC1(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
At 0° C., to a solution of (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-(trifluoromethyl)but-2-enamide (260 mg, 0.41 mmol) and 4-phenyl pyridine N-oxide (56 mg, 0.33 mmol) in acetonitrile (16 mL) was added NaOCl solution (363 uL, chlorine wt % 10-3%, 1.23 mmol). The reaction mixture was stirred at 0° C. for 10 min, then at room temperature for 1 h. After removal of the solvents in vacuo the residue was diluted with EtOAc (30 mL) and the solution washed with saturated Na2SO3 (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (40 g column, flow rate 20 mL/min) using hexanes/EtOAc (0-10% over 30 min) to give N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3,3-bis(trifluoromethyl)oxirane-2-carboxamide as a diastereomer mixture at a retention time of 27-35 min (243.9 mg, 92% yield). The diastereomeric mixture was separated by Chiral preparative HPLC chiralpak AD 20μ column, 5×50 cm, eluting with 10% IPA/Heptane with flow rate 50 mL/min.
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:9][S:10]([O:8][CH2:7][C:5]1[N:6]=[C:2]([Cl:1])[O:3][CH:4]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1coc(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1coc(Cl)n1
Reaction time: 1 h

Procedure:
A solution of (2-chloro-1,3-oxazol-4-yl)methanol (5 g, 37.44 mmol, 1 eq, prepared according to the method described in Tetrahedron Lett. (2004), 45, 3797-3802) in dichloromethane (250 ml) is reacted with methanesulfonyl chloride (3.19 ml, 41.19 mmol, 1.1 eq) in the presence of triethylamine (5.79 ml, 41.19 mmol, 1.1 eq) at 0° C. After 1 h 30, the mixture is poured into a saturated solution of ammonium chloride and extracted twice with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to afford 7.9 g of (2-chloro-1,3-oxazol-4-yl)methyl methanesulfonate i59. This product is used in the next step without further purification or analysis.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[C:9]([O:13][C:14](=[O:42])[C@H:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1)[NH:16][C:17](=[O:33])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[C:49]1(B(O)O)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:9]([O:13][C:14](=[O:42])[C@H:15]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:39][CH:40]=1)[NH:16][C:17](=[O:33])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24])([CH3:10])([CH3:12])[CH3:11]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared from the corresponding triflate (which was prepared from (N-(Toluene-4-sulfonyl)-L-prolyl-L-tyrosine tert-butyl ester as taught by Tilley and coworkers, J. Org. Chem., 55, 906, 1990). The dipeptide (505 mg, 0.8 mmol.), a catalytic amount of tetrakis(triphenylhosphine)palladium(0), potassium carbonate (201 mg, 1.5 eq.), phenylboronic acid (199 mg, 2.0 eq.), and 15 mL of toluene were refluxed for 10 hours with stirring. Ethyl acetate was added and the organic layer was washed with water, 1N NaOH, brine and dried over magnesium sulfate. Upon filtration, the solvent was evaporated under reduced pressure. The crude material was purified on a preparative plate (1:1 ethyl acetate:hexanes). The silica gel was washed several times with acetonitrile and ethyl acetate. The combined fractions were evaporated and the residue was dried under reduced pressure.
Reaction SMILES: [CH2:1]([C:4]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8](O)=[O:9])[CH:2]=[CH2:3].S(Cl)([Cl:21])=O>>[CH2:1]([C:4]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][C:8]([Cl:21])=[O:9])[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCc1c(OCC(=O)O)cccc1C(F)(F)F
Product: C=CCc1c(OCC(=O)Cl)cccc1C(F)(F)F

Procedure:
7 g of the product of Step D in 50 ml of thionyl chloride was refluxed for 2 hours and after concentrating, the residue was taken up in toluene. The solvents were eliminated under reduced pressure and the crude product obtained was used as is for Step F.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(Cl)Cl>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][S:31][C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:26][CH:25]=1
Reactant: Fc1ccc(CS)cc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(-n2cnc(SCc3ccc(F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A of procedure 11 (20 mg, 0.06 mmol), (4-fluorophenyl)methanethiol (26 mg, 0.18 mmol), and potassium carbonate (25.5 mg, 0.185 mmol) in THF (0.5 mL) was stirred at 70° C. overnight. The reaction was diluted with CH2Cl2, filtered, and concentrated. The crude product was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 6-(4-fluorobenzylthio)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one H-3 (17.25 mg, 0.038 mmol, 61.8% yield) as off-white solid. LC/MS 431 (M+H)+, tR 0.91 min (method 5). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 (1H, s), 7.35-7.45 (2H, m), 6.95-7.09 (3H, m), 6.80-6.90 (2H, m), 6.49 (1H, s), 4.28 (2H, s), 3.88 (5H, s), 1.39 (6H, s)
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:5](=[O:15])[C:4]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN1CCOCC1.[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32]>C(OCC)(=O)C>[CH3:32][C:31]([NH:35][C:36]([N:16]([C:4]1[C:5](=[O:15])[O:6][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:3]=1[OH:2])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:37])([CH3:34])[CH3:33]
Reactant: CC(C)(C)N=C=O
Reactant: O=c1oc(-c2ccccc2)cc(O)c1NCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)NC(=O)N(Cc1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Reaction time: 2.5 h

Procedure:
To a suspension of 4-hydroxy-6-phenyl-3-(phenylmethyl)amino-2H-pyran-2-one, monohydrochloride (0.153 mmol) in ethyl acetate (10 ml) was added N-methylmorpholine (2.0 ml) and tert-butyl isocyanate (2.0 ml). The reaction was allowed to stir for 2.5 hrs and then quenched by dilution with ethyl acetate. The organic layer was washed with 5% citric acid and saturated sodium chloride and was dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 5% methanol in dichloromethane as eluents.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].ON1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C.[CH2:24]([CH2:26][NH2:27])[OH:25]>C(Cl)Cl>[OH:25][CH2:24][CH2:26][NH:27][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: NCCO
Reactant: CCOC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)NCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl chloroformate (4 g, 0.037 mol.) and N-hydroxysuccinimide (6.3 g, 0.055 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added N,N-Diisopropylethylamine (9.5 g, 0.055 mol) in 10 mL of DCM. The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 3 hrs at room temperature, the reaction mixture was filtered and the precipitate was washed with 2×10 mL of dichloromethane. The combined filtrate was evaporated and dissolved in 20 mL of acetonitrile, cooled in an ice-bath and then added dropwise a solution of Ethanolamine 23 (3.3 mL, 2.5 eq). The resulting mixture was stirred at ice-bath temperature for 1 h and then overnight at room temperature. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was filtered, and the precipitate was washed with 2×10 mL DCM and dried over sodium sulfate. After removing the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give ethyl (2-hydroxyethyl)carbamate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[O:12].Cl>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]([OH:12])([CH3:13])[C:10]([OH:15])=[O:14])=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(=O)C(=O)O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A Grignard reagent was prepared from a solution of 1-bromo-4-fluorobenzene (50 g.) in diethyl ether (100 ml.) and a stirred suspension of magnesium (6.8 g.) in diethyl ether (20 ml.), and was heated under reflux for 1 hour and then cooled to 0° C. A solution of pyruvic acid (10.8 g.) in diethyl ether (50 ml.) was added dropwise and the mixture was stirred at laboratory temperature for 17 hours, cooled to 0° C., acidified with dilute aqueous hydrochloric acid and extracted three times with diethyl ether. The combined ethereal extracts were washed with water and extracted with saturated aqueous sodium bicarbonate solution, and the bicarbonate extract was acidified with concentrated aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. There was thus obtained as residue 2-p-fluorophenyl-2-hydroxypropionic acid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.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>[CH3:15][Si:16]([C:19]#[C:20][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:14])([CH3:1])[CH2:3][CH2:4][C:5]2=[O:13])=[CH:10][CH:9]=1)([CH3:18])[CH3:17]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2cc(C#C[Si](C)(C)C)ccc21
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 7 g (27.6 mmol) of 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound B) in 150 ml of triethylamine was added 0.97 g (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.26 g (1.3 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 39 ml (36.6 mmol) of (trimethylsilyl)acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 7-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 0.6 g (4.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O, washed with water, 10% HCl and brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3): δ1.39 (6H, s), 2.02 (2H, t, J=7.0 Hz), 2.73 (2H, t, J=7.0 Hz), 3.08 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.61 (1H, dd, J=1.8 , 8.2 Hz), 8.14 (1H, d, J=9 1.8 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]([C:16]3[S:20][C:19]([CH:21]=[O:22])=[C:18]([CH3:23])[CH:17]=3)=[N:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[OH:9])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C)C.Cl>C(#N)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]([C:16]3[S:20][C:19]([CH:21]=[O:22])=[C:18]([CH3:23])[CH:17]=3)=[N:13][N:12]=2)[CH:6]=[C:7]([CH3:10])[C:8]=1[O:9][CH2:31][CH2:32][OH:33])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)s2)cc(C)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(-c2nnc(-c3cc(C)c(C=O)s3)s2)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.1 %

Procedure:
To a suspension of 5-[5-(3-ethyl-4-hydroxy-5-methyl-phenyl)-[1,3,4]thiadiazol-2-yl]-3-methyl-thiophene-2-carbaldehyde (54 mg, 157 μmol) and K2CO3 (65 mg, 470 μmol) in acetonitrile (10 mL), (2-bromoethoxy)-tert.-butyl-dimethyl silane (66 mg, 274 μmol) is added. The mixture is stirred at 70° C. for 2 h before another portion of (2-bromoethoxy)-tert.-butyl-dimethyl silane (66 mg, 274 μmol) is added. Stirring is continued at 60° C. for 16 h. The mixture is cooled to rt, acidified by adding 1 N aq. HCl (2 mL) and stirred at rt for 10 min. The reaction mixture is concentrated to a volume of about 1 mL, is diluted with DMF (1.5 mL) and is then separated by prep. HPLC (XBridge Rp C18, 30×75 mm, eluting with a gradient of acetonitrile in water containing 0.5% of aq. ammonia) to give 5-{5-[3-ethyl-4-(2-hydroxy-ethoxy)-5-methyl-phenyl]-[1,3,4]thiadiazol-2-yl}-3-methyl-thiophene-2-carbaldehyde (33 mg) as a pale yellow resin; LC-MS: tR=0.69 min; [M+1]+=429.06. b) The title compound (24 mg) is obtained as a colourless resin starting from the above 5-{5-[3-ethyl-4-(2-hydroxy-ethoxy)-5-methyl-phenyl]-[1,3,4]thiadiazol-2-yl}-3-methyl-thiophene-2-carbaldehyde (33 mg, 85 μmol) and dimethylamine (46 mg, 340 μmol); LC-MS*: tR=0.96 min; [M+1]+=418.01; 1H NMR (D6-DMSO): δ1.22 (t, J=7.5 Hz, 3H), 2.20 (s, 3H), 2.25 (s, 6H), 2.34 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 3.58 (s, 2H), 3.72-3.77 (m, 2H), 3.85 (t, J=4.5 Hz, 2H), 4.92 (t, J=5.5 Hz, 1H), 7.52 (s, 1H), 7.67 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: COc1ccc(O)c(C(=O)c2ccccc2)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(=O)c2ccccc2)c1
Temperature: 180 °C
Reaction time: 9 h
Yield: 8.1 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (93 mg) with 2-hydroxy-5-methoxybenzophenone (462 mg) was stirred at 180° C. for 9 hr. The reaction solution was cooled to room temperature and was purified by column chromatography on silica gel using acetone-hexane to give the title compound (14 mg, yield 8%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=N[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:37][CH:42]3[CH2:38][CH2:39][CH2:40][CH2:41]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1nc(-n2cc(C(=O)NCC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (0.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: [CH:1]1[C:6]([C@@H:7](O)[C@H:8]([NH:11]C(C(Cl)Cl)=O)[CH2:9][OH:10])=[CH:5][CH:4]=[C:3]([N+]([O-])=O)[CH:2]=1.CC(S[C@@H]1[O:30][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C>>[NH2:11][C@H:8]([C:9]([OH:10])=[O:30])[CH2:7][C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 12 h

Procedure:
Both PAL and TAL activities were also investigated according to whole cell assays. Seed cultures consisting of 5 ml of LB broth containing 34 mg/L chloramphenicol were prepared of E. coli BL21(DE3) strains that were individually transformed with each of pSpalAv, pSpalNp, pSencPSm, pSpal1At, and pSpal2At. These cultures were grown for 12 hours at 30° C. while agitating at 250 rpm. 1 mL of each culture was then used to inoculate 3×250 mL cultures flasks containing 50 mL of LB supplemented with 34 mg/L chloramphenicol. All cultures were then grown at 30° C. while agitating at 250 rpm until an OD600 of 0.6 was reached, at which point the cultures were induced by IPTG addition to a final concentration of 0.2 mM. Cultures were then grown for an additional 6 h before the cells were then collected by centrifugation in 50 ml Falcon tubes for 5 min at 1400×g and washed once with pH7 PBS (phosphate buffered saline) buffer. The entire cell pellet was then resuspended in 10 ml pH7 PBS buffer before the appropriate substrate, L-phenylalanine or L-tyrosine, was added at a final concentration of 1 g/L. The results for L-phenylalanine addition are shown in FIG. 2. For all strains tested the addition of L-tyrosine did not result in the formation of p-coumaric acid, indicating that no TAL activity was displayed by these recombinant strains.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[OH-].[Na+]>>[O:7]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(Oc2ccncc2)cc1
Temperature: 150 °C
Yield: 64.3 %

Procedure:
Phenol (2.82 kg, 30.0 mol) was heated to 50° C. and 4-chloropyridine hydrochloride (1.5 kg, 10.0 mol) was added. The resulting solution was heated at 150° C. for 15 hours. The dark amber solution was cooled to 25° C. then poured into 3 M aqueous sodium hydroxide (16 L). The aqueous was extracted with dichloromethane (3×4 L). The combined organic was washed with 1 M sodium hydroxide (2×4 L), water (4 L), and brine (4 L) then dried over sodium sulfate and filtered. The solvent was removed under vacuum and the residual oil was dissolved in hexanes (6 L). The mixture was cooled to −60° C. with stirring and the resulting solid was collected by filtration and dried to give 1.1 kg of 4-phenoxypyridine (64% yield). mp 46-49° C. 1H NMR (300 MHz, CDCl3) δ 8.45 (dd, J=1.5, 8 Hz, 2H), 7.41 (dd, J=12, 12 Hz, 2H), 7.28 (dd, J=12, 1H), 7.06 (d, J=12 Hz, 2H), 6.84 (dd, J=1.5, 8 Hz, 2H).
Reaction SMILES: [OH-].[Na+].C([O-])(=O)C.[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Br:30])[CH:28]=4)[N:23]([CH3:31])[CH:22]=3)[C:17]([O:19]C)=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1.CO>O1CCOCC1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Br:30])[CH:28]=4)[N:23]([CH3:31])[CH:22]=3)[C:17]([OH:19])=[O:18])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2cc(Br)ccc21
Yield: 83.6 %

Procedure:
Aqueous sodium hydroxide (14.7 ml of 1M) was added to a solution of methyl 2-(1,3-benzodioxol-5-yl)-2-5-bromo-1-methyl-1H-3-indolyl) acetate from (b) (1.97 g, 4.9 mmol) in a 3:1 mixture of methanol and 1,4-dioxane at ambient temperature. The mixture was heated to reflux for 1 hour before recooling and removing the organic solvents in vacuo. The residue was redissolved in water and acidified with drops of concentrated hydrochloric acid. The resultant precipitate was extracted with diethylether, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was crystallised from diisopropylether to give the subtitle compound (1.59 g).