Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1SC=CC=1.[Mg].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2(C#N)[CH2:19][CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[Cl:15].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH:27]=[N:28][Mg]Br>CCOCC>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([NH:28][CH2:27][C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:18][CH2:19]2)[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: Br[Mg]N=Cc1cccs1
Agent: Brc1cccs1
Agent: [Mg]
Solvent: CCOCC
Product: Cl
Product: Clc1ccc(C2(NCc3cccs3)CCC2)cc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-bromothiophene (32.9 g) in dry ether (50 ml) was added dropwise to a stirred mixture of magnesium turnings (4.85 g) and ether (50 ml) under nitrogen. When all the magnesium had dissolved a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbonitrile (30.6 g) in dry ether (200 ml) was added and the mixture stirred at 20° C. for one hour and then heated under reflux for one hour. A solid formed which is believed to be 1-(3,4-dichlorophenyl)cyclobutyl](thien-2-yl)methaniminylmagnesium bromide and was collected by filtration. The solid was dissolved in ethanol (200 ml) and a solution of sodium borohydride (10 g) in ethanol (500 ml) added and the mixture heated under reflux for four hours. The mixture was cooled and water (200 ml) and then 5N hydrochloric acid added. The ethanol was removed by evaporation and the aqueous solution basified by the addition of 5N sodium hydroxide solution. The aqueous layer was extracted with ether and the extract dried. Hydrogen chloride gas was passed into the ethereal solution to give [1-(3,4-dichlorophenyl)cyclobutyl](thien-2-yl)methylamine hydrochloride (m.p. 238°-242° C.).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C>CCO.Cl.O1CCOCC1>[ClH:23].[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][NH:8]1)[CH3:30]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(Cl)cc1C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.26 g, 5.23 mmol, 1.0 eq.) in EtOH (100 mL), 4M HCl in dioxane (25 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was triturated with cold methyl tert-butyl ether (50 mL), filtered, and rinsed with cold methyl tert-butyl ether (20 mL) to give the desired salt as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[C:25]2[NH:24][C:23]3[CH:26]4[CH2:32][CH2:31][N:29]([CH2:30][C:22]=3[C:21]=2[CH:20]=[CH:19][CH:18]=1)[CH2:28][CH2:27]4>C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:17]2[C:25]3[NH:24][C:23]4[CH:26]5[CH2:32][CH2:31][N:29]([CH2:30][C:22]=4[C:21]=3[CH:20]=[CH:19][CH:18]=2)[CH2:28][CH2:27]5)=[CH:6][CH:7]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C=Cc1ccc(C)nc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(/C=C/c2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Temperature: 105 °C

Procedure:
A mixture of bis(tri-t-butylphosphino)palladium (26.3 mg, 0.052 mmol; Aldrich), the product of Example 1C (123 mg, 0.52 mmol), sodium t-butoxide (124 mg, 1.29 mmol; Aldrich) and the product of Example 1B (150 mg, 0.52 mmol) was combined with 1,4-dioxane (3 mL). The mixture was purged with a stream of nitrogen for 2 minutes, then heated at 105° C. for 6 hours in a sealed tube. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in dimethyl sulfoxide (5 mL), filtered through a glass microfiber frit and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.05-2.15 (m, 4 H), 2.54 (s, 3 H), 3.02-3.12 (m, 2 H), 3.14 (pent, J=3.6 Hz, 1 H), 3.20-3.29 (m, 2 H), 4.23 (s, 2 H), 7.02 (t, J=7.6 Hz, 1 H), 7.23 (d, J=16.5 Hz, 1 H), 7.24-7.27 (m, 1 H), 7.31 (d, J=8.2 Hz, 1 H), 7.39 (d, J=7.3 Hz, 1 H), 7.68 (d, J=16.5 Hz, 1 H), 8.01 (dd, J=8.2, 2.4 Hz, 1 H), 8.61 (d, J=2.4 Hz, 1 H); MS (APCI) m/z=330 (M+H)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[C:15]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Brc1cncc(Br)c1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Br)cncc1Br
Reaction time: 0.75 h
Yield: 91.7 %

Procedure:
To a solution of LDA (2 M solution in THF/heptane/ethylbenzene) (2.26 g, 10.54 mL, 21.06 mmol) in anhydrous THF (20 mL) under nitrogen atmosphere cooled to −78° C. was added a solution of the 3,5-dibromopyridine (5.0 g, 21.10 mmol) in anhydrous THF (40 mL) at −78° C. The reaction mixture was allowed to stir at the same temperature for 45 minutes. Then, a solution of chloro(ethoxy)methanone (22.90 g, 211.02 mmol) was added slowly over 15 minutes. After stirring for 20 minutes, the reaction mixture was quenched with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified through CombiFlash using 0-10% ethyl acetate in hexane to provide ethyl 3,5-dibromopyridine-4-carboxylate as pale yellow oil (5.98 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ1.43 (t, 3H), 4.49 (q, 2H), 8.67 (s, 2H); M+ 307.9.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:42])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13].[C:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[CH:70]=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[C:68](Br)=[CH:67][C:66]=3[F:77])=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]>C1(C)C=CC=CC=1.O.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:43]([O:47][C:48]([N:50]1[CH2:55][C@@H:54]([CH3:56])[N:53]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:78])[NH:64][C:65]3[C:66]([F:77])=[CH:67][C:68]([C:30]4[CH:31]=[CH:32][C:27]([C:25]5[N:26]=[C:22]([C@@H:18]6[CH2:19][CH2:20][CH2:21][N:17]6[C:15](=[O:16])[C@@H:11]([NH:10][C:9]([O:8][CH3:7])=[O:42])[CH:12]([CH3:14])[CH3:13])[NH:23][CH:24]=5)=[CH:28][CH:29]=4)=[C:69]([O:71][C:72]([F:75])([F:74])[F:73])[CH:70]=3)=[CH:59][N:58]=2)[CH2:52][C@@H:51]1[CH3:79])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
Potassium carbonate (470 mg, 3.4 mmol) was added to a solution of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (340 mg, 0.68 mmol) and (2S,5R)-4-[5-(4-bromo-2-fluoro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 0.68 mmol; Preparation 49) dissolved in toluene (2.5 mL) and water (0.73 mL). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. for 4 h. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce (2S,5R)-4-[5-(5-fluoro-4′-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-2-trifluoromethoxy-biphenyl-4-ylcarbamoyl)-pyridin-2-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a red solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.CCN(CC)CC>CN1C(=O)CCC1>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:13]#[N:14])[N:3]=[C:2]2[NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(Cl)cc23)C1
Temperature: 160 °C
Yield: 79 %

Procedure:
To a solution of 1,7-dichloroisoquinoline-3-carbonitrile (500 mg, 2.24 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (460 mg, 2.46 mmol) and Et3N (453 mg, 4.48 mmol). The solution was heated to 160° C. for 30 minutes in a microwave reactor. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:10 to 1:5 gradient) to give the title compound (660 mg, 79%). ESI-MS m/z [M+H-tert-butyl]+ 317.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([I:19])=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)OC>[I:19][C:7]1[C:6](=[O:20])[C:5]2[CH:4]=[CH:3][C:2]3[N:1]=[CH:21][O:12][C:11]=3[C:10]=2[O:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1O
Solvent: COC(OC)OC
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccc1ncoc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 3494.8 %

Procedure:
To a solution of 7-amino-8-hydroxy-3-iodo-2-phenyl-chromen-4-one (151 mg, 0.4 mmol) in trimethylorthoformate (3 mL) was added p-toluenesulfonic acid (2 mg, 0.01 mmol). The reaction mixture was stirred at 100° C. for 2 hours, allowed to RT and the solvent removed. The resulting residue was subjected to flash chromatography (SiO2, gradient 20-100% ethyl acetate in cyclohexane) to give the title compound as a beige solid (136 mg, 87%). LCMS (Method G): RT=3.52 min, [M+H]+=389.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH:7]([OH:9])[CH2:6]1)=[O:4].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:8][C@H:7]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-trans mixture of 3-hydroxy-cyclobutanecarboxylic acid methyl ester (1.30 g, 10 mmol) in DMF 13 mL is added NaH (50% in oil, 720 mg, 15 mmol) at 0° C. After stirring at 0° C. for 15 minutes, benzyl bromide (1.43 ml, 12 mmol) is added at 0° C. The mixture is stirred at room temperature for 2 hours and quenched with H2O. The solution is extracted with EtOAc. The organic layer is washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; hexane/EtOAc) to give trans-3-benzyloxy-cyclobutanecarboxylic acid methyl ester (340 mg, 15.4%). TLC (hexane/EtOAc, 5:1) Rf 0.40.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].C1C(=O)N([Br:24])C(=O)C1.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[C:13]([F:15])([F:14])[F:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of ethyl 4-methyl-3-(trifluoromethyl)benzoate (for a preparation see Intermediate 19)(2.25 g, 9.69 mmol) in carbon tetrachloride (25 ml) was added NBS (1.90 g, 10.7 mmol, Aldrich) and then benzyl peroxide (0.030 g, 0.124 mmol, Acros). The suspension was heated overnight at 90° C. under nitrogen. The suspension was filtered through a hydrophobic frit and the residue washed with carbon tetrachloride (10 ml). The filtrate was concentrated in vacuo to leave a mobile colourless oil (3.1 g). The residue was loaded in dichloromethane and purified on silica (100 g×2) using 0-100% dichloromethane-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white crystalline solid (1.6 g). LCMS: (System 4) MH+=312, tRET=3.32 min
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:15].[CH3:16][CH:17](O)[CH:18]=[CH2:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:16]([CH:6]1[C:5](=[O:15])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[C:7]21[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:17]=[CH:18][CH3:19]
Reactant: C=CC(C)O
Reactant: Cc1ccc2c(c1)C(=O)CC21CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(C)ccc2C12CCCC2
Yield: 59 %

Procedure:
A solution of 17.0 g of 5'-methyl-2',3'-dihydro-spiro[cyclo-pentane-1,1'-[1H]indene]-3'-one, 17.5 ml of 3-buten-2-ol and 170 mg of p-toluenesulfonic acid in 170 ml of 2,2-dimethoxy-propane was boiled under reflux for 71 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). In addition to 4.0 g of educt, there were obtained 12.7 g (59%) of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH:12]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:13]2[CH2:18][CH2:17][CH2:16][N:15](S(CC[Si](C)(C)C)(=O)=O)[CH2:14]2)[CH2:3][CH2:2]1.[F-].C([N+](CC)(CC)CC)C>C(#N)C>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][O:28][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]#[C:4][CH:1]1[CH2:2][CH2:3]1)[CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: COCCCOC(c1ccccc1C#CC1CC1)C1CCCN(S(=O)(=O)CC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: COCCCOC(c1ccccc1C#CC1CC1)C1CCCNC1
Temperature: 65 °C
Yield: 95.4 %

Procedure:
A 50-mL round bottom flask was charged with 3-((2-(cyclopropylethynyl)phenyl)(3-methoxypropoxy)methyl)-1-(2-(trimethylsilyl)ethylsulfonyl)piperidine (63 mg, 0.128 mmol, 1.0 equiv), tetraethylammonium fluoride (63 mg, 0.422 mmol, 3.4 equiv) and acetonitrile (5 mL). The mixture was heated to 65° C. for 17 h. Analysis of the yellow reaction mixture by LC-MS showed consumption of the protected piperidine and formation of a new signal containing the mass of the desired product. The acetonitrile was removed under reduced pressure and the residue was partitioned between CH2Cl2 and water. The layers were separated and the aqueous layer was extracted twice with additional CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated, yielding 3-((3-methoxypropoxy)(2-(2-cyclopropylethynyl)phenyl)methyl)piperidine (40 mg, 95%). No additional purification was attempted. MS ESI+ve m/z 328 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH3:20].C(Br)CCC.[Mg].[O:29]1CCCC1>>[CH:1]1([CH2:7][C:8]([OH:29])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C(CCC1CCCCC1)Cn1ccnc1
Reactant: CCCC[Mg]Br
Agent: [Mg]
Solvent: CCCCBr
Product: CCCCC(O)(CCn1ccnc1)CC1CCCCC1
Reaction time: 1 h

Procedure:
1-[4-Cyclohexyl-2-oxo-n-butyl]imidazole (2.2 g) in 15 ml of dry tetrahydrofuran was added dropwise to a stirred solution of butylmagnesium bromide [from butyl bromide (2.05 g) and magnesium (0.36 g)]in 20 ml of tetrahydrofuran at 0° C. under nitrogen. After one hour the mixture was allowed to come to room temperature and quenched with saturated ammonium chloride. Most of the tetrahydrofuran was removed under reduced pressure and the residue treated with aqueous potassium carbonate and extracted with ethyl acetate. The extracts were washed, dried (MgSO4) and evaporated to give 1-[3-(cyclohexylmethyl)-3-hydroxy-n-heptyl]imidazole. Purification could be effected if needed by chromatographpy on silica gel eluting with 5% methanol in methylene chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[CH3:30][C:29]([CH3:32])([CH3:31])[C:28](=[O:33])[CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)CN1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of benzyl piperidin-4-ylmethylcarbamate (Tetrahedron Lett. 1990, 31, 6903, 6.9 g, 27.8 mmol) in N,N-dimethylformamide (60 mL) were added triethylamine (9.7 mL, 69.5 mmol) and 1-bromo-3,3-dimethylbutan-2-one (7.9 g, 41.7 mmol) at room temperature. The mixture was stirred at room temperature for 2 h and quenched with water (60 mL) followed by extraction with ethyl acetate-toluene mixture (3×30 mL). Concentration and purification by column chromatography on silica gel eluting with ethyl acetate/hexane (2:1) gave the title compound (9.6 g, 100%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>ClCCl>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
10 mmol palmityl alcohol and 20 mmol pyridine are dissolved in 100 ml dry dichloromethane. 10 mmol toluene4-sulphonyl chloride is slowly added and the mixture is heated to 40° C. with stirring for 1 hour. The reaction is cooled to room temperature and 25 ml cold water is added to stop the reaction. The mixture is washed with 3×50 ml cold, 1% aqueous sulfuric acid to remove the pyridine followed by 3×25 ml cold water and evaporation to yield palmityl toluene-4-sulfonate.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16]O)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:40][C:41]([NH:43][S:44]([NH2:47])(=[O:46])=[O:45])=[O:42])[CH:38]=[CH2:39].C(OC(N=NC(OCC)=O)=O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][N:43]([S:44](=[O:45])(=[O:46])[NH2:47])[C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)NS(N)(=O)=O
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (8.02 g: ca. 30 mmole) in ethyl acetate (83 ml) under ice cooling, triphenylphosphine (9.44 g: 13.6 mmole), N-allyloxycarbonylsulfamide (3.12 g: 15.9 mmole), and azodicarboxylic acid diethylester (5.67 ml: 36 mmole) are successively added. The mixture is stirred under ice cooling for 55 minutes and at room temperature for 4 hours. The reaction mixture is dissolved in toluene (60 ml), concentrated, diluted with toluene (60 ml), filtered to remove separating crystals, and the filtrate is concentrated. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methylpyrrolidine (6.74 g). Yield: 55%. Colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([O:27]CC(F)(F)F)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[C:12]=1[N+:22]([O-:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C(N(CC)CC)C.O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[C:12]=1[N+:22]([O-:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(OC(F)(F)F)c1[N+](=O)[O-])C(=O)OCC(F)(F)F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(OC(F)(F)F)c1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2,2,2-Trifluoroethyl N-(tert-butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)-L-phenylalaninate (121) 2-Nitro-3-(trifluoromethoxy)-L-phenylalanine, hydrochloride salt (119) (250.6 mg, 0.758 mmol) was suspended in dioxane (3.5 mL)/water (3.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.368 mL, 2.65 mmol) was added, resulting in a solution. BOC2O (199 mg, 0.910 mmol) was added and the mixture was stirred at 0° C. for 15 min, then allowed to warm to RT. After 2 h at RT, most of the dioxane was removed by evaporation under reduced pressure, and saturated aqueous ammonium chloride solution was added until the pH was lowered to −3. The mixture was diluted with EtOAc (10 mL), and the aqueous layer was extracted with EtOAc (3×15 mL). The combined extracts were dried over sodium sulfate, filtered and evaporated in vacuo to give N-(tert-butoxycarbonyl)-2-nitro-3-(trifluoromethoxy)phenylalanine (120), which was dissolved in dichloromethane (7 mL). 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 0.195 mL, 0.874 mmol), N,N-dimethylpyridin-4-amine (97%, 45.7 mg, 0.363 mmol) and 2,2,2-trifluoroethanol (99%, 0.106 mL, 1.46 mmol) were added and the resulting mixture was stirred for 18 h at RT. The reaction mixture was washed with saturated aqueous sodium chloride solution, and the aqueous layer was extracted with dichloromethane (3×5 mL). The combined organic layers were dried, filtered and concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 30% EtOAc in heptane) provided the product as a white solid (170.3 mg, 47% over 2 steps). LCMS m/z 475.4 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 9H), 3.01-3.12 (m, 2H), 4.32-4.39 (m, 1H), 4.69-4.79 (m, 2H), 7.57-7.66 (m, 3H), 7.74 (dd, J=8.2, 8.2 Hz, 1H).