Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14].C(Cl)Cl.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=2)[C:30]([F:33])([F:32])[F:31])=[N:26][CH:27]=1>C1(C)C=CC=CC=1.C(=O)=O.CCCCCCC>[Cl:41][C:36]1[CH:35]=[C:34]([CH:29]([O:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:13]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[O:14])=[CH:27][N:26]=2)[C:30]([F:33])([F:31])[F:32])[CH:39]=[CH:38][C:37]=1[Cl:40]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(OC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)nc1
Agent: O=C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(OC(c2ccc(Cl)c(Cl)c2)C(F)(F)F)nc1
Temperature: 25 °C

Procedure:
A stirred mixture of 2,6-difluorobenzamide (0.56 g, 0.0036 mole), oxalyl chloride (0.45 g, 0.0036 mole), and methylene chloride (10 ml) in toluene (70 ml) was heated at reflux for three hours. Approximately 10 ml of solvent was removed by distillation under reduced pressure. A solution of 5-amino-2-[1-(3,4-dichlorophenyl)-2,2,2-trifluoroethoxy]pyridine (1.2 g, 0.0036 mole) in toluene (35 ml) was added to the reaction mixture. The resultant solution was stirred at room temperarture for approximately 18 hours. Most of the solvent was evaporated under reduced pressure, leaving a liquid residue. About 150 ml of n-heptane was added to the residue, and the mixture was stirred at room temperature, slowly forming a precipitate. The mixture was cooled in dry ice before collecting the precipitate by filtration. A total of 1.65 g of N-[[[2-[-1-(3,4-dichlorophenyl)2,2,2-trifluoroethoxy]pyridin-5-yl]amino]carbonyl]2,6-difluorobenzamide was collected (mp 171°-172° C.). The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].[Cl:14][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])(=O)C.[Na+]>C(Cl)Cl.CC(O)=O.S(=O)(=O)(O)O.CC(O)=O.O.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]=[N:10][CH:17]([C:16](=[O:23])[CH2:15][Cl:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1Br
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(N=Nc1ccc(F)cc1Br)C(=O)CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-4-fluoroaniline (10 g, 52.6 mmol, 1.0 eq.) in DCM/HOAc (1/1, 160 mL, 0.3M) at 0° C. was added dropwise a precooled solution of sodium nitrite (4.1 g, 57.9 mmol, 1.1 eq.) in conc. sulfuric acid (20 mL). After stirring for 30 min at 0° C. a mixture of ethyl 4-chloroacetoacetate (14.6 mL, 17.8 g, 108 mmol, 1.2 eq.) in HOAc (40 mL) and H2O (80 mL) was added within 5 min. After further 15 min at 0° C. a solution of sodium acetate (72 g, 0.878 mol, 16.7 eq.) in H2O (140 mL) was added slowly. The mixture stirred for 30 min at 0° C. and than 12 h at RT. DCM (200 mL) was added and the organic phase was separated. The aq. phase was extracted with DCM (3×100 mL). The combined organic phase was washed with water, phosphate buffer and subsequent with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the product ethyl 2-(2-bromo-4-fluoro-phenyl)azo-4-chloro-3-oxo-butanoate as a red solid. MS (ES) C12H11BrClFN2O3 requires: 365. Found: 365/367 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH2:21]([N:28]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)N3CCC(=NCc4ccccc4)CC3)ccc2N1

Procedure:
0.8 Gram of 6-(4-oxo-1-piperidyl)carbonyl-3,4-dihydrocarbostyril, 1.6 ml of benzylamine and 1 g of Molecular Sieve 3A (a trademark for synthetic feldspar manufactured by Linde Co., U.S.A.) were dispersed in 15 ml of chloroform and refluxed by heating for 6 hours. Molecular Sieve 3A was removed by filtration, the filtrate was concentrated, then the residue obtained was washed several times with diethyl ether, next, purified by means of a silica gel column chromatography to obtain 6-(4-benzylimino-1-piperidyl)carbonyl-3,4-dihydrocarbostyril.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:19])[O:11][C:10](=[O:12])[NH:9][C@H:8]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([CH2:26][O:27][C@@H:28]([CH3:32])[C:29](Cl)=[O:30])=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O>O1CCCC1>[C:20]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:25]=[CH:24][C:23]([CH2:26][O:27][C@@H:28]([CH3:32])[C:29]([N:9]2[C@@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]([CH3:19])([CH3:6])[O:11][C:10]2=[O:12])=[O:30])=[CH:22][CH:21]=1
Reactant: C[C@H](OCc1ccc(-c2ccccc2)cc1)C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@H]1c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](OCc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC(C)(C)[C@@H]1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A butyllithium solution (9.7 M in hexanes, 7.64 mL, 74 mmol) was added drop-wise to a solution of C3 (13.5 g, 70.6 mmol) in tetrahydrofuran (800 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C. A solution of C6 (21.3 g, 78 mmol) in tetrahydrofuran (50 mL) was then added slowly, and the reaction was stirred at −78° C. for 30 minutes and then at 25° C. for about 3 hours. The reaction mixture was then poured into phosphate buffer (pH 7) and extracted with ethyl acetate (2×). The organic extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a minimal volume. The resultant residue was then precipitated by addition of 1 liter of hexanes. The solid white product was collected by filtration, and the filtrate was concentrated. The resultant residue was purified by silica gel chromatography (gradient: 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate), to provide C7 as a white solid. Yield: 22.8 g, 75 LCMS m/z 430.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 0.85 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.57 (3H, s), 4.36 (2H, apparent s, actual AB quartet, J=12.3 Hz), 5.21 (1H, s), 5.21 (1H, q, J=6.6 Hz), 7.23 (2H, m), 7.36 (8H, m), 7.61 (4H, m).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[S:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH3:18]I>[OH-].[Na+].CO>[CH3:18][S:16][C:14]1[S:15][C:11](=[CH:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[C:12](=[O:17])[N:13]=1
Reactant: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one (8 g, 30.6 mmol) in 12.6% aq. NaOH (12 mL) and methanol (80 mL), methyl iodide (2.25 mL, 36 mmol) was added and the reaction mixture stirred at RT for 4 h. Most of the solvent was distilled off and the precipitate was filtered and washed first with water, then with diethylether. The washings were concentrated and extracted with dichloromethane, dried over sodium sulphate and joined to the first solid crop. The whole crop was suspended in methanol, stirred 30′, filtered and dried to yield 2-(methylthio)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-1,3-thiazol-4(5H)-one as a yellow solid (8.15 g, 29.5 mmol, 96%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][OH:40])=O)(C)(C)C.[H-].[Na+].[Cl-:43].[NH4+]>CN(C=O)C>[ClH:43].[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([NH:13][C:14](=[O:25])[C:15]3[CH:20]=[C:19]([O:40][CH2:39][C@H:35]4[CH2:36][CH2:37][CH2:38][NH:34]4)[CH:18]=[CH:17][C:16]=3[N+:22]([O-:24])=[O:23])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: [Cl-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC[C@H]2CCCN2)ccc1[N+](=O)[O-]
Product: Cl
Temperature: 25 °C
Reaction time: 43 h

Procedure:
To a solution of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide (3.0 g) and (R)-(+)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol (2.54 g) in DMF (45 ml) was added sodium hydride (1.54 g of a 60% dispersion in oil) portion-wise (ice bath cooling). The reaction was stirred for 43 hours at room temperature under an atmosphere of argon. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (200 ml) and the resulting precipitate was collected by filtration, dissolved in methanol (10 ml) and 4N HCl in dioxane (5 ml) added. The reaction mixture was stirred at room temperature for 16 hours, concentrated and re-precipitated from methanol/ethyl acetate to yield N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-[(2R)-pyrrolidin-2-ylmethoxy]benzamide hydrochloride salt (3.32 g) as a yellow solid; NMR Spectrum: (DMSOd6) 0.64 (m, 2H), 0.75 (m, 2H), 1.83 (m, 1H), 1.95-2.12 (m, 2H), 2.21 (m, 1H), 2.37 s, 3H), 2.91 (m, 1H), 3.30 (m, 2H), 4.02 (m, 1M), 4.45 (m, 1H), 4.55 (m, 1H), 7.37 (m, 3H), 0.70 (d, 1H), 8.02 (s, 1H), 8.29 (d, 1M), 8.49 (d, 1H), 9.50 (s, 1H), 10.22 (s, 1H); Mass Spectrum: M+H+ 439.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:12][C:13]([OH:15])=[O:14].[CH2:16](O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)CBr
Reactant: Fc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Product: COC(=O)CSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluorothiophenol (10 g, 78 mmol) in ethanol(200 mL) was treated with powdered KOH (9.6 g), stirred for 30 min at rt, then treated with a solution of bromoacetic acid (10.84 g, 78 mmol) in ethanol (50 mL) and stirred at 80 C for 4 h. the reaction was cooled to rt, partitioned between 1N HCl and EtOAc and the organics were washed with water, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in MeoH (250 mL), cooled to 0 C, treated with SOCl2 (8.5 mL) and stirred at rt overnight. The reaction was quenced with water, concentrated then partitioned between EtOAc (3 times) and water. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated to give 14.6 g of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].ClC1C2C(=C(C(F)(F)F)C=CC=2)N=CC=1.NC1C(C)=CC=CC=1C(O)=O.S(Cl)(Cl)=O.[CH2:57]([N:60]([CH2:69][CH2:70][CH3:71])[CH2:61][CH2:62][CH2:63][CH2:64][NH:65][CH2:66][CH2:67][CH3:68])[CH2:58][CH3:59]>>[CH2:69]([N:60]([CH2:57][CH2:58][CH3:59])[CH2:61][CH2:62][CH2:63][CH2:64][N:65]([CH2:66][CH2:67][CH3:68])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH3:2])[C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[CH2:70][CH3:71]
Reactant: CCCNCCCCN(CCC)CCC
Reactant: Cc1cccc(C(=O)Cl)c1Nc1ccnc2c(C(F)(F)F)cccc12
Agent: Cc1cccc(C(=O)O)c1N
Agent: Cl
Agent: FC(F)(F)c1cccc2c(Cl)ccnc12
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)CCCCN(CCC)C(=O)c1cccc(C)c1Nc1ccnc2c(C(F)(F)F)cccc12

Procedure:
3-Methyl-2-(8-trifluoromethyl-4-quinolylamino)benzoyl chloride hydrochloride prepared by the reaction of 4-chloro-8-trifluoromethylquinoline with 2-amino-3-methylbenzoic acid and treatment of the reaction product with thionyl chloride, is reacted with 1-dipropylamino-4-propylaminobutane to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C@@H:27]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH2:26]2>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[CH2:28][C@@H:27]([NH:32][S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[CH2:26]3)[CH:7]=1)(=[O:5])=[O:4]
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(O)cc2C1
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)c1cccc(Oc2ccc3c(c2)C[C@H](NS(=O)(=O)C(C)C)C3)c1

Procedure:
To a mixture of the 3-(N-methylsulfamoyl)phenylboronic acid (0.274 mmol, 59 mg), copper (II)acetate (0.137 mmol, 25 mg), triethylamine (0.685 mmol, 96 μL) and 4 Å molecular sieves (100 mg) in DCM (1 mL) was added (R)-N-(5-hydroxy-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.137 mmol, 35 mg) and the resultant mixture stirred at room temperature overnight. The reaction mixture was diluted with DCM (1 mL) before water (0.5 mL) was added and the organic layers separated using hydrophobic frits. The aqueous was extracted with further DCM (1 mL), and the combined organics concentrated using to dryness. The residue was taken up in DMSO and purified by preparative HPLC to give the title compound as a clear film (5.9 mg, 10.1%). MS (ESI): m/z [M−H]− 423.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[F:12][C:13]([F:17])([F:16])[CH2:14][O-:15].[Na+].C(O)C(F)(F)F.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[O:15][CH2:14][C:13]([F:17])([F:16])[F:12]
Reactant: [O-]CC(F)(F)F
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: C1CCOC1
Product: Fc1nc(F)c(Cl)c(OCC(F)(F)F)c1F
Temperature: -78 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
3-Chloro-2,4,5,6-tetrafluoropyridine (18.0 g, 97.0 mmol) was dissolved in anhydrous THF (100 mL) under an N2 atmosphere and the resulting solution cooled to −78° C. To the cold solution was slowly added a solution of sodium 2,2,2-trifluoroethoxide (97 mmol), prepared from trifluoroethanol (7.1 mL, 97.0 mmol) and NaH (3.88 g, 97.0 mmol, 60% dispersion in mineral oil), in anhydrous THF (100 mL). The resulting mixture was slowly warmed to ambient temperature. After 18 h at ambient temperature a GC analysis indicates all the starting material was consumed. The volatiles were evaporated and the residue dissolved in CH2Cl2 (200 mL). The organics were washed with H2O (3×100 mL), dried (MgSO4), filtered and concentrated to give the crude product as a yellow oil. The yellow oil was distilled at reduced pressure to afford 3-chloro-2,5,6-trifluoro-4-(2,2,2-trifluoroethoxy)pyridine as a clear oil (16.3 g, 63% yield): by 48° C. (ca 0.2 mm Hg); 1H NMR (CDCl3) δ 4.81-4.78 (dq, J=1.6, 7.7 Hz); GC-MS (EI, 70 eV) m/z (% relative intensity) 267 (33), 265 (100), 248 (5), 246 (16), 198 (22), 196 (60).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[C:9]1(/[CH:15]=[CH:16]/B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CN(C=O)C>[CH:16](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:15]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: O=Cc1cc(Br)co1
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CN(C)C=O
Product: O=Cc1cc(/C=C/c2ccccc2)co1

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and trans-phenylvinyl-boronic acid (1.4 g, 9.4 mmol, 1.5 equiv) using the conditions used to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that the reaction was run in DMF (25 mL). The resulting residue was purified via ISCO Companion (0-30% EtOAc/heptane) and preparative HPLC using the Chromeleon purification system (0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 min)) afforded a clean product, retention time of product: 3.4-3.6 min. Amount of (E)-4-styrylfuran-2-carbaldehyde isolated: 89.1 mg (7% yield). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.62 (d, J=0.59 Hz, 1 H), 7.91 (s, 1 H), 7.63 (d, J=0.63 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.35-7.42 (m, 2 H), 7.26-7.32 (m, 1 H), 7.08 (s, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:21]=[CH:20][C:12]3[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=3[CH:10]=2)[CH:5]=[CH:6][CH:7]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1=Cc2cc(Sc3cccc(O)c3)ccc2OC1(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1=Cc2cc(Sc3cccc(O[Si](C)(C)C(C)(C)C)c3)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
6-(3-Hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.2 g) (see Preparation 9) was dissolved in dry dimethylformamide (4 ml) and imidazole (1.1 g) and tert-butyidimethylsilyl chloride (1.2 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture was stirred at 40° C. for one hour. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution (×2), dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product chromatographed on silica using (4:1 hexane: dichloromethane as the eluent to yield 6-(3-tert-butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.84 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:22]=[N:21][C:14]3[O:15][CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:13]=3[CH:12]=2)([OH:10])[C:26]([F:28])([F:27])[F:25])=[C:4]([Cl:24])[CH:3]=1
Reactant: CC(C(=O)c1cnc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1cnc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 7-[2-(4-bromo-2-chloro-phenyl)-propionyl]-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=477.0 [M−H+].
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][C@H:19]([CH3:21])[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17][C@H:16]1[CH3:30])=[O:14].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.CCOC(C)=O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:18]2[C@@H:19]([CH3:21])[CH2:20][N:15]([C:13](=[O:14])[CH2:12][O:1][C:2]3[C:3]([CH:9]=[O:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=3)[C@H:16]([CH3:30])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(O)c(C=O)n1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(C=O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
To a solution of 3-hydroxy-6-methyl-pyridine-2-carbaldehyde (0.27 g, 1.95 mmol) in dimethylformamide (4 mL) was added 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.53 g, 1.77 mmol), potassium carbonate (0.49 g, 3.5 mmol) and potassium iodide (0.29 g, 1.8 mmol). The resulting mixture was stirred at 60° C. overnight, then diluted with EtOAc, washed with brine and the organic layer was dried over magnesium sulfate. Filtration followed by concentration in vacuo gave the title compound (0.85 g)
Reaction SMILES: [Li][CH3:2].C[Si](Cl)(C)C.[CH3:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12](/[C:19](/[CH3:26])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[CH:14][CH:15]=2)[N:10]=1>CCOCC.C(Cl)Cl>[CH3:26][C:19]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[C:9]([CH3:8])[CH:18]=[CH:17]2)([CH3:2])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: [Li]C
Reactant: CCOC(=O)/C=C(/C)c1cccc2ccc(C)nc12
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC(C)(C)c1cccc2ccc(C)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a mixture of Cu(I)I (2.42 g, 12.7 mmol) in ether (5 mL) was added a solution of 1.6 M MeLi (15.9 ml, 25.4 mmol) in ether at 0° C. and the mixture was stirred at 0° C. for 10 minutes. The solvent was removed under reduced pressure and cold DCM (10 mL) was added. The solvent was removed under reduced pressure. Cold DCM (40 mL) was added and the mixture was cooled to −78° C. TMSCl (1.54 mL, 12.7 mmol) was added, followed by a solution of (Z)-ethyl 3-(2-methylquinolin-8-yl)but-2-enoate (0.81 g, 3.17 mmol) in DCM (10 mL). The reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution. The organic layers was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (7:1 hexane/ethyl acetate) to give ethyl 3-methyl-3-(2-methylquinolin-8-yl)butanoate (0.66 g, 76.8%) as an oil.