Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1C[O:39]CC1>>[Si:11]([O:18][C@@H:19]1[CH2:20][CH2:21][C@H:22]([CH:25]([OH:39])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:23][CH2:24]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](CC(=O)OCc2ccccc2)CC1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(O)C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A 1.0 M sodium bistrimethylsilylamide solution in THF (3.3 ml, 3.25 mmol) was added to anhydrous THF (5.0 ml), and the mixture was cooled to −78° C. A solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)acetate (1.0 g, 2.76 mmol) in anhydrous THF (10 ml) was added dropwise to the mixture over 20 min. The mixture was stirred at −78° C. for 30 min, and a solution of n-benzyl-benzenesulfonyloxaziridine (860 mg, 3.25 mmol) in anhydrous THF (7 ml) was added dropwise over 30 min. The mixture was stirred at −78° C. for one hr, was quenched with a saturated aqueous ammonium chloride solution, and was extracted with ether. The organic layer was washed with water and saturated brine, was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=93:7) to give the title compound as a yellow oil (650 mg, yield 63%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]([OH:9])[CH3:8])[N:4]([CH3:10])[N:3]=1.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[N:6]=[C:5]([C:7](=[O:9])[CH3:8])[N:4]([CH3:10])[N:3]=1
Reactant: CC(O)c1nc(Br)nn1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1nc(Br)nn1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
A solution of 1-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)ethanol (1.639 g, 7.95 mmol, Eq: 1.00) and pyridine (944 mg, 965 μl, 11.9 mmol, Eq: 1.5) in dichloromethane (237 ml) was cooled to 0° C. then Dess-Martin periodinane (15% in dichloromethane, 24.7 g, 8.75 mmol, Eq: 1.1) was added. The resulting mixture was stirred for 4 hours at 0° C. under nitrogen atmosphere. The mixture was diluted with dichloromethane and washed with sat. sodium hydrogen carbonate. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using dichloromethane/methanol 0-3% & 5% NH3 as eluent affording 1-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (948 mg, 58.4%) as a white solid. MS: m/z=203 (EI)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:30].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[Br:30][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:17]=1
Reactant: COc1ccc(S(=O)(=O)NCC#CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(Br)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 86.3 %

Procedure:
To a stirred solution of 3-(p-methoxyphenylsulfonylamino)-1-propinyl 3,4,5-trimethoxy-phenyl ketone (2.02 g, 2.78 mmol, Example 94c) in CH2Cl2 (10 ml) a solution of HBr (732 μl, 1.5 equiv., 33% in acetic acid) is added at 4° C. The reaction mixture is stirred for 45 min at 4° C., and poured onto ice, saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried (MgSO4), the solvents are evaporated and the residue chromatographed on SiO2 with ethyl acetate/hexane (1:3) to yield the title compound (2.0 g, 86.3%) as a pink solid. 1H-NMR (300 MHz, DMSO-d6): 7.65 (d, J=1.9, 1H); 7.38 (d, J=9.0, 2H); 7.02 (d, J=9.0, 2H); 6.40 (m, 3H); 3.82 (s, MeO); 3.72 (s, MeO); 3.69 (s, 2MeO).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:30])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:29][O:28][C:26]([CH2:25][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH:16]([NH:1][CH2:2][CH:3]([C:5]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=2)[OH:4])[CH3:30])=[CH:24][CH:23]=1)=[O:27]
Reactant: NCC(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2ccc3ccccc3c2)cc1
Yield: 51.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 3 g of 2-amino-1-(2-naphthyl)ethanol (prepared as described in Preparation 9), 3.87 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 60 ml of benzene, 50 ml of absolute methanol and 2.49 g of sodium cyanoborohydride, 3.23 g of the title compound were obtained having an Rf=0.15 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:8]1[O:15][CH2:14][CH2:13]N(CCCC)CC[O:9]1.[Li][CH2:21]CCC.CC(C)=O.Cl>C1COCC1>[CH3:21][C:14]1([CH3:13])[O:15][B:8]([OH:9])[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: CCCCN1CCOB(c2ccccc2Br)OCC1
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.7 %

Procedure:
To a solution of 2-(2′-bromophenyl)-6-butyl[1,3,6,2]dioxazaborocan (93.1 g, 277.1 mmol) in THF (2.3 L) at −78° C. was added n-BuLi (133.0 mL, 2.5M in hexane, 332.5 mmol, 1.2 equiv.) dropwise via a syringe over a period of 10 min while maintaining reaction temperature at −78° C. After the addition the reaction solution was stirred for 20 min at −78° C. before acetone (23.2 mL, 387.9 mmol, 1.4 equiv.) was added dropwise via a syringe over a period of 10 min while maintaining the reaction temperature at −78° C. The resulting mixture was allowed to stir for 20 min at −78° C. then warm to room temperature gradually. Once the reaction vessel reached room temperature, 6N HCl solution (1 L) was added and the mixture was stirred for an additional 30 min. The mixture was extracted with EtOAc (3×). The EtOAc extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The light yellow oil was then subjected to flash chromatography (Isco Companion, 80 g SiO2 cartridge, solid loaded SiO2, neat heptanes to 20:80 EtOAc gradient at 60 ml/min for 90 min). The title compound was recovered as clear colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (s, 6 H) 7.31 (d, J=1.1 Hz, 1 H) 7.38-7.47 (m, 2 H) 7.66 (d, J=7.2 Hz, 1 H) 8.99 (s, 1 H). Amount obtained: 16.9 g (37.7% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH:16]=[C:17]([C:23]([O:25]CC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([NH:8][C:9]1[N:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]2=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=CNc1ccc(NCc2ccccc2)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(NCc3ccccc3)nc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
Diethyl (2-benzylamino-5-pyridylaminomethylene)malonate (2.23 g) was added to diphenyl ether (10 mL) preheated to 230° C. Heating was continued for 0.5 h, the reaction flask removed from the oil bath, and the mixture allowed to cool to ambient temperature. The product was triturated with 1:1 ether:hexanes, collected, rinsed with ether, and dried to give 1.47 g of ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate as a brown solid.
Reaction SMILES: Cl.[NH2:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C(OCC)(=O)C>O1CCOCC1>[C:20]([NH:2][O:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([O:22][CH2:23][CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21]
Reactant: NOCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NOCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of 4-aminooxymethyl-benzoic acid, hydrochloride 111 (2.0 g, 0.010 mol) in dioxane (20 mL) and half saturated Na2CO3 solution (20 mL) was added Fmoc-Cl (2.8 g, 0.011 mol) and the mixture was stirred for 2 h. Ethyl acetate (100 mL) was added and the pH of the aqueous phase was adjusted to 1-3 by careful addition of HCl(conc.). The mixture was poured in to a separating funnel and the organic phase was isolated, washed once with water (100 mL), dried over Na2SO4 and the solvent was removed on a rotavap to give an oil that solidified upon standing. The crude product was purified by flash column chromatography (petroleum ether, ethyl acetate, AcOH 60:40:1). Yield: 3.5 g (92%) 1H-NMR (250 MHz, DMSO-d6) =4.05 (1H, t, J=6.3 Hz), 4.27 (2H, d, J=6.3 Hz), 4.51 (2H, s), 7.08-7.22 (6H, m), 7.46 (2H, d, J=7.4 Hz), 7.66 (2H, d, J=7.1 Hz), 7.72 (2H, d, J=8.4 Hz), 10.29 (1H, br. s), 12.78 (1H, br. s). 13C-NMR (63 MHz, DMSO-d6) =47.04, 66.03, 76.91, 120.51, 125.41, 127.45, 128.03, 128.89, 129.33, 129.63, 130.82, 141.19, 144.01, 157.12, 167.48. MS (ES) m/z=389 (MH+). 1The material was prepared as previously described: Deles, J. et al.; PJCHDQ; Pol. J. Chem.; EN; 53; 1979; 1025-1032
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[I:19]I>C(Cl)(Cl)Cl.C(#N)C.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:19]
Reactant: II
Reactant: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 106.8 %

Procedure:
Acetic acid (5R)-3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (15.2 g, 60 mM) was dissolved in a mixture of chloroform (100 ml) and acetonitrile (100 ml) under nitrogen, and silver trifluoroacetate (16.96 g, 77 mM) added. Iodine (18.07 g, 71 mM) was added in portions over 30 minutes to the vigorously stirred solution, and stirring continued at ambient temperature for 18 hours. As reaction was not complete, a further portion of silver trifluoroacetate (2.64 g, 12 mM) was added and stirring continued for 18 hours. After filtration, the mixture was added to sodium thiosulfate solution (3%, 200 ml) and dichloromethane (200 ml), and the organic phase separated, washed with sodium thiosulfate (200 ml), saturated aqueous sodium bicarbonate (200 ml), brine (200 ml), dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 ml), and sufficient diethyl ether added to dissolve out the brown impurity while stirring for 1 hour. Filtration gave the desired product (24.3 g) as a cream solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([CH3:24])([CH3:23])[CH3:22])=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[C:25]([F:28])([F:27])[F:26].C([Sn](CCCC)(CCCC)[C:34]([O:36][CH2:37][CH3:38])=[CH2:35])CCC>O1CCOCC1.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>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:9]1[C:8]([NH:7][C:5]2[S:6][C:2]([C:34]([O:36][CH2:37][CH3:38])=[CH2:35])=[C:3]([C:25]([F:28])([F:27])[F:26])[N:4]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(OCC)c1sc(Nc2cccnc2Oc2ccccc2C(C)(C)C)nc1C(F)(F)F
Temperature: 100 °C

Procedure:
A solution of N-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 323a, 1.3 g, 2.75 mmol) in dioxane (30 mL) was added tributyl(1-ethoxyvinyl)tin (1.1 mL, 3.3 mmol) was degassed and Pd(PPh3)4 (160 mg, 0.14 mmol) was added. The mixture was degassed and heated at 100° C. overnight. The mixture was concentrated on vacuum, dissolved in EtOAc and treated with saturated KF solution. The solid was removed by filtering through a pad of Celite®. The filtrate was extracted with EtOAc. The organic layers were combined, washed with bring, dried over magnesium sulfate and concentrated to give crude Example A154a (1.12 g) as a brown oil.
Reaction SMILES: C(O[C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH3:13])CCC.Cl.[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:23][C:6]1[C:7](=[O:17])[C:8](=[O:16])[C:9]=1[NH:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH3:13]
Reactant: Cc1cccc(CN)c1C
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)Nc1c(NCc2cccc(C)c2C)c(=O)c1=O

Procedure:
Tetrahydrofuran (15 mL), 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1,20 g, 5 mmol), 2,3-dimethylbenzylamine hydrochloride (0.858 g, 5 mmol, prepared according to the procedure of R. Fuller et al., J. Med. Chem., 16 (2), 101 (1973)) and triethylamine (0.506 g, 5 mmol) were refluxed 22.5 hours and then processed in a manner similar to that of Example 4, Step 3, to provide 1.337 g of crude product. Recrystallization (twice) of this material from methanol afforded 0.777 g of the title compound as a white solid: mp 196°-198° C. MS (m/z) 300 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][CH:9]=[CH:8][C:7]=1I)[CH3:2].[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[C:7]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)Nc1c(I)cccc1OC(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(C#C[Si](C)(C)C)cccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 108.6 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol) and copper(I) iodide (0.3 g, 1.6 mmol) were added to triethylamine (600 mL) and heated with stirring for 20 min. The mixture was cooled to room temperature and (2-iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester (60.2 g, 160 mmol) was added. After stirring for 30 min at room temperature trimethylsilylacetylene (21.1 g, 152 mmol) was added and the mixture was stirred for another 2 h at room temperature. Triethylamine was removed in vacuo and the residue was partitioned between water and diethyl ether. The organic phases were washed with 1N HCl, brine, pooled and dried with MgSO4. Evaporation of the solvent yielded 57 g of brownish solid, which was purified by chromatography on silica gel with hexane/ethyl acetate (9:1). This yielded the title compound, (52.8 g, 95%) as a beige amorphous solid. (EI-MS: m/e=345.0 (M+))
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[O:6]
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)ccc1Br)N1CCOCC1
Reaction time: 0.17 h

Procedure:
2-Bromo-5-(trifluoromethyl)benzoic acid (200 mg, 0.74 mmol) was dissolved in DMF (4.65 mL) and HATU (424 mg, 1.12 mmol) added to the resultant mixture at rt. The solution was stirred for 10 min then treated with N,N-diisopropylethylamine (0.51 mL, 3.0 mmol) and morpholine (0.096 mL, 1.1 mmol). The reaction was stirred for 15 hours then quenched by the addition of saturated NH4Cl (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL) and the combined organic extracts washed with brine, dried over Na2SO4 and concentrated to dryness. The crude product was purified by FCC to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.55-7.49 (m, 2H), 3.92-3.86 (m, 1H), 3.83-3.69 (m, 4H), 3.66-3.58 (m, 1H), 3.32-3.24 (m, 1H), 3.25-3.17 (m, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:10]=[C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=3[O:19][C:18]2=[O:34])[CH:12]=[C:13]([CH3:16])[C:14]=1[OH:15]>C1(C)C(C)=CC=CC=1.CS(O)(=O)=O>[C:1]([O:15][C:14]1[C:13]([CH3:16])=[CH:12][C:11]([CH:17]2[C:21]3[CH:22]=[C:23]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[C:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]=3[O:19][C:18]2=[O:34])=[CH:10][C:9]=1[CH3:8])(=[O:3])[CH3:2]
Reactant: Cc1cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1c(C)cc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 105 °C
Yield: 96.7 %

Procedure:
53.6 g (0.53 mol) of acetic anhydride are added dropwise over a period of about 10 minutes to a suspension of 183.3 g (0.50 mol) of 3-(3,5-dimethyl-4-hydroxyphenyl)-5,7-di-tert-butylbenzofuran-2-one (compound (107), Table 1, Example 2) in 250 ml of xylene and 0.5 ml (7.7 mmol) of methanesulfonic acid which is stirred at 105° C. under a nitrogen atmosphere. The clear, colourless reaction mixture is concentrated at about 170° C. under a slight vacuum. 500 ml of 1-butanol are carefully added to the residue and the mixture is cooled with ice/water. The precipitated product is filtered and washed with 100 ml of 1-butanol. Drying gives 197.6 g (97%) of 3-(4-acetoxy-3,5-dimethylphenyl)-5,7-di-tert-butylbenzofuran-2-one, melting point 165°-166° C. (compound (109), Table 1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C([C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[S:20]([N:23]([CH2:40][CH2:41]Br)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])(=[O:22])=[O:21])C>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]([CH2:40][CH2:41][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[S:20]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[CH:10]=2)(=[O:22])=[O:21])=[C:25]([CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[CH:26]=1
Reactant: CCc1c(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2Cc2c(F)cccc2F)ccc(OC)c1OC
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N(CCn2ccnc2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 18 h
Yield: 22 %

Procedure:
To 2 ml of dimethylformamide are added, at room temperature, 51 mg of sodium hydride at 50% in oil, followed by 72 mg of imidazole. After 30 minutes at this temperature, 0.4 g of ethyl N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-chlorophenyl]-3,4-dimethoxybenzenesulfonamide dissolved in 5 ml of dimethylformamide is introduced. The reaction medium is left for 18 hours at room temperature and then taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 97/3 (v/v) toluene/ethyl acetate mixture to give 0.082 g of the expected product.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[NH2:38][CH2:39][CH2:40][OH:41]>CO>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@@:8]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)([CH2:7][CH2:6][NH:38][CH2:39][CH2:40][OH:41])[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: NCCO
Solvent: CO
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNCCO)(c2ccc(F)cc2)OC1=O
Yield: 3.6 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobi-phenyl-4-yl)ethyl)-6-(4-fluorophenyl)2-oxo 1,3-oxazinan-6-yl)ethyl methanesulfonate (58 mg, 0.11 mmol) in anhydrous MeOH was added 2-amino-ethanol (54 mg, 0.88 mmol). Then the reaction mixture was refluxed overnight. When the reaction was over, solvent was removed in vacuo. The residue was purified by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(2-hydroxyethylamino)ethyl)-1,3-oxazinan-2-one (2 mg, 3%). 1H NMR (CDCl3): 1.53 (m, 3H), 2.25-2.36 (m, 4H), 2.51 (m, 1H), 2.87-3.24 (m, 5H), 3.75-4.02 (m, 2H), 5.60 (m, 1H), 6.85-6.96 (m, 2H), 6.96-7.10 (m, 4H), 7.22 (m, 2H), 7.38 (m, 4H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1>CN(C=O)C.O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][CH2:12][CH2:11][O:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccnc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cncc(OCCOC2CCCCO2)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Sodium hydride (1.02 g of a 50% suspension in mineral oil, 42 mmol) was added to a solution of 3-hydroxypyridine (2.01 g, 21 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(2-Bromoethoxy)tetrahydropyran (4.0 g, 19 mmol), (J. Am. Chem. Soc. 1948, 70, 4187), was added and the mixture heated at 100° C. for 3 hours and then stirred at ambient temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 97/3) to give 3-(2-(tetrahydropyran-2-yloxy)ethoxy)pyridine (2.28 g, 48%).