Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13]([C:16]4([C:22]#N)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C[Mg]Br.[Cl-].[NH4+].Cl>O1CCCC1.ClCCl.CCOCC>[CH3:1][C:2]1[C:25]([CH3:26])=[CH:24][C:5]2[N:6]([C:10]3[CH2:11][CH2:12][N:13]([C:16]4([CH3:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH2:14][CH:15]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(=O)n(C3=CCN(C4(C#N)CCOCC4)CC3)c2cc1C
Agent: C[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc2[nH]c(=O)n(C3=CCN(C4(C)CCOCC4)CC3)c2cc1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 4-[4-(5,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-3,6-dihydro-1(2H)-pyridinyl]tetrahydro-2H-pyran-4-carbonitrile (D101) (0.32 mmol, 113 mg) in tetrahydrofuran (10 mL) was treated at room temperature under argon with methyl magnesium bromide (0.96 mmol, 0.32 mL of 3M solution in tetrahydrofuran, 3 eq) dropwise over 2 min. The mixture became a solution and was stirred for 45 min. Then 6 more equivalents of methyl magnesium bromide were added and stirred for 3 h. The mixture was cooled down to 0° C. and 1M aqueous ammonium chloride solution was added until everything was solubilised. Tetrahydrofuran was removed under reduced pressure and the mixture was diluted with water and extracted 3 times with ethyl acetate. The organics were combined, dried and concentrated to give a white solid (0.26 mmol, 89 mg, 81% crude yield). This solid was dissolved in 3 mL of dichloromethane and treated with 1 mL 1M ethereal hydrogen chloride. A yellow gum crashed out of the mixture. More ether was added and the gum turned into crystals upon trituration. The crystals were filtered off and dried to give the title compound as its hydrochloride salt (0.2 mmol, 75 mg, 62% yield) still containing hydrogenated compound (no double C═C bond in the piperidine core). M+H 342.1, 344.1, M−H 340.3.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:11]2[S:10][C:9]3[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Product: COc1ccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)cc1
Yield: 91 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and 4-methoxybenzoyl chloride were converted to the title compound by the procedure of Example 1 in 91% yield, after crystallization from methanol.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:17](=[O:27])(=[O:26])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:12][CH:13]=2)[CH2:8]1)C.[OH-].[Na+]>C(O)C>[Cl:25][C:21]1[CH:20]=[C:19]([NH:18][S:17]([C:11]2[CH:10]=[C:9]3[C:14]([CH2:15][CH2:16][N:7]([CH2:6][CH2:5][C:4]([OH:28])=[O:3])[CH2:8]3)=[CH:13][CH:12]=2)(=[O:26])=[O:27])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl-3-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]propionate (4.08 g) and 10% sodium hydroxide solution (10 ml) in ethanol (10 ml) was stirred at room temperature for one hour. Ethanol was removed in vacuo, water (15 ml) added and the pH was adjusted to 6-7 with 2N HCl. This was extracted with ethylacetate:methanol 4:1 (3×50 ml) and dried (MgSO4). Concentration and crystallization from ethanol-methanol gave 3-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]propionic acid. 1.2H2O, 0.8NaCl (1.61 g, 59%); mpt. 137°-40° C.
Reaction SMILES: [H-].[Na+].F[P-](F)(F)(F)(F)F.Cl[C:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)=[CH:12][C:13](=[N+](C)C)[CH3:14].[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:29][SH:30]>C(O)C>[CH3:14][C:13]1[CH:12]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[S:30][C:29]=1[C:28]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CS
Reactant: CC(C=C(Cl)c1ccc(C(F)(F)F)cc1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 110 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.528 g) was added to dry ethanol (20 ml), N-{3-chloro-1-methyl-3-[4-(trifluoromethyl)phenyl]prop-2-enylidene}-N-methylmethanaminium hexafluorophosphate (intermediate 34, 2.8 g) was added followed by ethyl thioglycolate (0.79 g) and the mixture heated at 110° C. for 2 hours under nitrogen. The cooled mixture was concentrated in vacuo and the residue partitioned between water and diethyl ether. The organic layer was collected, dried over magnesium sulphate and concentrated to give the title compound as a brown solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](OCC)=[O:7].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][OH:7]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCBr)c1ccccc1
Yield: 98.2 %

Procedure:
According to the procedure given for the synthesis of 206e, 205b (23.70 g, 79.21 mmol) was reduced with LiBH4 (3.45 g, 158.4 mmol) and methanol (5.24 g, 163.5 mmol) in anhydrous CH2Cl2 (150 mL) to give 206b (20.0 g, 98%) as an oil. 1H NMR (CDCl3): δ 7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, 2H, J=6.0), 1.96-1.44 (m, 5H), 1.32 (s, 3H). 13C NMR (CDCl3): δ 144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS (LSIMS, nba): Calcd for C12H16Br (MH+-H2O): 239.0435, found: 239.0444.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 67.3 %

Procedure:
A mechanical stirrer was used for this reaction. A solution of diisopropylamine (29.2 mL, 0.21 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL) was cooled to −78° C. and then treated with a 2.5 M solution of n-butyllithium in hexanes (83.4 mL, 0.21 mol). The yellow-orange reaction mixture was stirred at −78° C. for 35 min and then slowly treated with a solution of 4-(methanesulfonyl)phenyl acetic acid methyl ester (45.35 g, 0.20 mol) in dry tetrahydrofuran (186 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (62 mL). The reaction mixture turned dark in color. The reaction mixture was then stirred at −78° C. for 50 min, at which time, a solution of iodomethylcyclopentane (50.08 g, 0.24 mol) in a small amount of dry tetrahydrofuran was added slowly. The reaction mixture was then stirred at −78° C. for 50 min, and then allowed to warm to 25° C., where it was stirred for 36 h. The reaction mixture was quenched with water (100 mL), and the resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining residue was diluted with ethyl acetate (1.5 L). The organic phase was washed with a saturated aqueous sodium chloride solution (1×500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid methyl ester (41.79 g, 68%) as a yellow viscous oil: EI-HRMS m/e calcd for C16H22O4S (M+) 310.1239, found 310.1230.
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[C:10]([NH:44][CH:45]2[CH:51]3[CH2:52][CH2:53][CH:47]([CH2:48][CH2:49][CH2:50]3)[CH:46]2[C:54]([O:56][CH3:57])=[O:55])=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:16]=2)=[N:13][CH:14]=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:9]1[C:10]([NH:44][CH:45]2[CH:51]3[CH2:52][CH2:53][CH:47]([CH2:48][CH2:49][CH2:50]3)[CH:46]2[C:54]([O:56][CH3:57])=[O:55])=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=3)[NH:17][N:16]=2)=[N:13][CH:14]=1
Reactant: COC(=O)C1C2CCCC(CC2)C1Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1C2CCCC(CC2)C1Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylsilane (0.434 mL, 2.721 mmol) was added to a stirred solution of racemic methyl 7-(5-fluoro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-ylamino)bicyclo[3.2.2]nonane-6-carboxylate, 58, (0.365 g, 0.544 mmol) and trifluoroacetic acid (0.419 mL, 5.440 mmol) in dichloromethane (20 mL). The resulting yellow solution was stirred at room temperature for 2 hr and concentrated in vacuo. Water (10 mL) and aqueous saturated NaHCO3 (5 mL) were added and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phases were dried (MgSO4), filtered and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (10-90% MeOH/CH2Cl2 gradient) to afford 178 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 5.20 (s, 1H), 3.71 (s, 3H), 2.62 (m, 1H), 2.53 (m, 1H), 2.24 (m, 1H), 2.06 (m, 1H), 1.98-1.58 (m, 9H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.74 minutes (M+H) 329.86.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:17][S:14]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)[C:3]([OH:18])=[O:2])(=[O:16])=[O:15]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methanesulfonyl-5-trifluoromethyl-benzoic acid methyl ester (1.0 g, 3.54 mmol) in dioxane (15 mL) was added water (15 mL) and lithium hydroxide monohydrate (186 mg, 4.43 mmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 100 ml 1M aqueous hydrochloric acid and 100 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 100 mL ethyl acetate. The organic layers were washed with 100 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. Colorless solid (930 mg, 98%). MS (ESI−): m/z=266.995 ([M−H]−).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
To a solution of cis-3-(benzyloxymethyl)cyclobutanol (Albany Molecular, 1.0 g, 5.2 mmol) in CH2Cl2 (20 mL) was added imidazole (0.71 g, 10.4 mmol), DMAP (64 mg, 0.52 mmol) and tert-butyldimethylsilylchloride (TBSCl) (1.6 g, 10.4 mmol). This mixture was stirred at ambient temperature for 16 h, quenched with saturated, aqueous NH4Cl (5 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×5 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes/EtOAc) to give the title compound (1.15 g, 3.8 mmol, 72% yield). MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14].C([Li])CCC.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>O1CCCC1.[Cl-].[NH4+]>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH:25]([C:2]1[C:3]([CH3:16])=[N:4][N:5]([CH3:15])[C:6]=1[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])[OH:26]
Reactant: Cc1nn(C)c(-c2c(F)cccc2F)c1Br
Reactant: O=Cc1ccc(F)cc1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(-c2c(F)cccc2F)c1C(O)c1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 4-bromo-5-(2,6-difluorophenyl)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (500 mg, 1.7 mmol) in tetrahydrofuran (15 mL) at −78° C. was added dropwise n-butyllithium (2.0 M in hexanes, 0.76 mL, 1.9 mmol). The reaction mixture was stirred at −78° C. for about 20 minutes, and then a solution of 2,4-difluorobenzaldehyde (1534, 1.4 mmol) in tetrahydrofuran (1 mL) was added dropwise. After the addition was complete, the reaction mixture was stirred at about −78° C. for about 15 minutes, and then diluted with saturated aqueous ammonium chloride solution (1 mL) and allowed to warm to room temperature. The resulting mixture was poured onto a solid phase extraction tube (Varian Chem Elute®, prepacked with diatomaceous earth) eluting with ethyl acetate (50 mL). The ethyl acetate eluant was concentrated under reduced pressure and the resulting material was purified by MPLC (20 to 50% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (560 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(F)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(F)c1
Temperature: -30 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g, 7.94 mmol) in dichloromethane (100 mL) was added BBr3 (1.5 mL, 16 mmol) dropwise at −78° C. under N2. After addition, the mixture was warmed to −30° C. and it was stirred at this temperature for 5 h. The reaction mixture was poured into ice water. The precipitated solid was collected by filtration and washed with dichloromethane to afford 3-fluoro-4,5-dihydroxy-benzaldehyde (1.1 g, 89%), which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[OH-].[Na+].[Br:11][CH:12](Br)[CH3:13].S([O-])(O)(=O)=O.C([NH3+])(C)(C)C>>[Br:11][CH2:12][CH2:13][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1O
Reactant: CC(Br)Br
Agent: CC(C)(C)[NH3+]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: Cc1ccccc1OCCBr
Reaction time: 72 h

Procedure:
2-Methyl-phenol (1 g, 9.25 mmol) in NaOH (aq) (3.24 mL, 12.96 mmol, 4M soln.) was treated with dibromoethane (2.74 mL, 31.7 mmol) and t-butylammoniumhydrogen sulfate (catalytic), and then placed in a Robbins™ oven at 99° C. for 72 hours. The pH was then adjusted to ˜8 with NaOH (4M aq. soln.) and the product extracted with CH2Cl2 (x3). The combined organic layer was washed with H2O (x2) and brine, dried over MgSO4. The resulting oil taken up in 4:1 hexane/EtOAc and passed through a plug of silica gel. The plug was then washed with 4:1 hexane/EtOAc and the filtrate concentrated to provide crude 2-bromo-1-(2-methylphenoxy)ethane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([O:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2].COC(=O)C(OC)CC1C=CC=C(O)C=1>>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([O:21][CH2:22][CH2:23][CH3:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Agent: COC(=O)C(Cc1cccc(O)c1)OC
Product: CCCO[C@@H](Cc1ccc(O)cc1)C(=O)OCC

Procedure:
The title compound was prepared from (2S)-3-(4-be yloxy-phenyl)-2-propoxy-propionic acid ethyl ester (Example 377, Step 3) via the same procedure used for the preparation of 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) to produce a yellow oil. MS (ES) for C14H20O4 [M+H]+: 253.1.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:16]1([S:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[C:16]1([S:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:30][CH:31]=2)(=[O:23])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in dimethylacetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution was stirred at -10° C. for approximately 30 mins. 4-(Phenylsulfonyl) aniline (0.58 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, sodium bicarbonate solution added to give a pH of 7 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (Na2SO4), decolorized (charcoal), and evaporated. The crude solid was dissolved in ether, clarified by filtration, and evaporated. Crystallization from methanol/water gave the title compound (0.56 g, 57%) as white, silky needles; mp 105°-108° C. 1H-NMR (300 H B z, d6 -DMSO) 6.44 (t, J=53.94 Hz, 2H, HCF2), 7.58-7.68(m, 3H, ArH), 7.92-8.01 (m, 7H, ArH, OH), 10.51 (s, 1H, NH). MS(CI,CH4): 392 (M+1, 100%).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([N+]1C=CC=CC=1Br)CC.N1(C2C=CN=CC=2)CCCC1.CCN(C(C)C)C(C)C.[CH:39]1([CH2:45][CH2:46][C:47](=O)[CH:48]([CH2:66][CH:67]2[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[C:49]([N:51]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)[CH:52]([CH3:56])[C:53]([OH:55])=[O:54])=[O:50])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CCOCC>[CH:39]1([CH2:45][CH2:46][C:47]23[O:54][C:53](=[O:55])[C:52]2([CH3:56])[N:51]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)[C:49](=[O:50])[CH:48]3[CH2:66][CH:67]2[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1ccc(CN(C(=O)C(CC2CCCCC2)C(=O)CCC2CCCCC2)C(C)C(=O)O)cc1
Agent: CCC[n+]1ccccc1Br
Agent: O=S(=O)([O-])C(F)(F)F
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2C(=O)C(CC3CCCCC3)C3(CCC4CCCCC4)OC(=O)C23C)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of N-propyl-2-bromo pyridinium triflate (285 mg, 0.824 mmol) and 4-pyrrolidinopyridine (183 mg, 1.24 mmol) in CH2Cl2 (11.5 mL) was added Hünig's base (72 μL, 0.41 mmol) at 0° C. After stirring for 10 min, a solution of keto-acid 60 (200 mg, 0.412 mmol) in CH2Cl2 (5 mL) was added via syringe pump over 1 h at 0° C. The resulting suspension was stirred for 3 h at 0° C., at which point the volatiles were removed up to one-third under reduced pressure. The crude reaction mixture was diluted with Et2O (100 mL) and washed with aqueous NH4Cl solution and brine (each 30 mL). The organic layer were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (1:10 EtOAc/hexanes) to give a mixture of two beta-lactones (60 mg, 31%, dr 1:1.6) as a colorless oil. (±)-61 (major): Rf=0.56 (20% EtOAc/hexanes); IR (neat) 1829,1701 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J=8.5 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.76 (d, J=15.5 Hz, 1H), 4.28 (d, J=15.0 Hz, 1H), 3.80 (s, 3H), 2.75 (t, J=7.0 Hz, 1H), 1.65-2.03 (m, 15H), 1.39 (s, 3H), 0.85-1.34 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 175.0, 169.2, 159.3, 129.6, 129.4, 114.2, 86.8, 76.4, 55.4, 44.4, 42.2, 38.1, 35.0, 33.6, 33.5 (2), 33.3, 33.2, 31.7, 30.8, 26.7, 26.6, 26.3 (3), 13.0; LRMS (ESI) Calcd. for C29H41NO4 [M+H] 468, found 468. (±)-61b (minor): Rf=0.63 (20% EtOAc/hexanes); IR (neat) 1829, 1702 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.87 (d, J=15.5 Hz, 1H), 4.17 (d, J=15.5 Hz, 1H), 3.79 (s, 3H), 2.87 (dd, J=3.5, 11.0 Hz, 1H), 2.06 (br d, J=12.5 Hz, 1H), 1.46-1.87 (m, 12H), 1.14-1.42 (m, 12H), 0.79-1.10 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 174.3, 169.3, 159.0, 129.6, 128.9, 114.0, 87.2, 76.8, 55.2, 44.2, 43.8, 37.9, 37.4, 34.7, 34.5, 33.2, 33.0, 32.1, 30.4, 27.3, 26.5, 26.4, 26.2, 25.8, 12.3.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20]C1(CC(C)(C)C(C2C=CC=CC=2)=O)OCCO1.Cl>>[CH3:19][O:20][C:9]1[CH:8]=[C:7]([C:2](=[O:6])[CH3:1])[CH:12]=[CH:11][C:10]=1[C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: COC1(CC(C)(C)C(=O)c2ccccc2)OCCO1
Reactant: CC(C)(C)C(=O)c1ccc(C2(C)OCCO2)cc1
Agent: Cl
Product: COc1cc(C(C)=O)ccc1C(=O)C(C)(C)C

Procedure:
Again following the above procedure and using in place of 4'-(2-methyl-2-dioxolanyl)pivalophenone an equivalent amount of (2-methoxy-2-dioxolanyl)pivalophenone in the presence of a dilute hydrochloric acid in place of concentrated hydrochloric acid, there is obtained 2'-methoxy-4'acetylpivalophenone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH-].[K+].[I-].[K+].[CH:16]1(Br)[CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(C=O)cc1O
Reactant: BrC1CCCC1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
To a solution of 54.9 g (0.36 mol) of 3-hydroxy-4-methoxybenzaldehyde in 400 mL of absolute ethanol was added 40.4 g (0.72 mol) of potassium hydroxide, 1.0 g (0.01 mol) of potassium iodide, and 77.0 mL (0.72 mol) of cyclopentyl bromide. The mixture was warmed to reflux for 48 hours at the end of which time the completed reaction was cooled to room temperature and concentrated to a syrup. The resulting residue was dissolved in 500 ml of ethyl acetate, washed with one, 100-mL portion of water, with one, 50-mL portion of dilute hydrochloric acid, with one, 100-mL portion of saturated sodium bicarbonate, and with one, 50-mL portion of saturated sodium chloride. The organic fraction was dried over sodium sulfate and concentrated to dryness. The amber syrup was liquid chromatographed over 500 g of silica gel using 20% ethyl ether in hexane as an eluent to provide the analytically pure oil upon drying in vacuo.