Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][B:3](OC)OC.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([B:3]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[O:2][CH3:1])=[CH:11][CH:10]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COB(OC)OC
Solvent: C1CCOC1
Product: COB(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
Trimethylborate (2.2 ml, 1.92×10−2 mol) is added dropwise to a freshly prepared solution of p-chlorophenyl magnesium bromide (40.4 ml, 1 M, 4.04×10−2 mol) in tetrahydrofuran (60 ml) under argon at −78° C. The mixture is warmed to room temperature and stirred overnight. The solution is cooled to −78° C. and excess grignard reagent is destroyed by the dropwise addition of methanol until no more effervescence is observed. The solvents are removed in vacuo and the residue dissolved in diethyl ether and washed with water. The organic layer is dried (MgSO4), filtered and the solvents removed in vacuo to give methyl di(p-chlorophenyl)borinate (4.60 g, 92%) as a solid which was used without further purification.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2[CH:7]=O)[CH2:3][CH2:2]1.[CH3:16][NH2:17].[BH4-].[Na+]>CO>[CH:1]1([S:4][C:5]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=2[CH2:7][NH:17][CH3:16])[CH2:3][CH2:2]1
Reactant: CN
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a stirred solution of 2-(cyclopropylthio)-5-nitrobenzaldehyde (5 g, 22.40 mmol, see WO 2008/079759 for preparation) in MeOH (50 mL) was added methylamine (6.32 g, 67.2 mmol) dropwise and stirred for 1 h at 25° C. The reaction mixture was cooled to 0° C. and sodium borohydride (1.695 g, 44.8 mmol) was added portionwise with stirring. The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (250 mL), washed with water (2×100 mL), brine (1×100 mL) and dried (Na2SO4). Solvent was removed under reduced pressure to give Intermediate 6A (5 g, 20.98 mmol, 94% yield) as a orange oil. It was utilized in the subsequent step without any further purification. 1H NMR (400 MHz, chloroform-d) δ 8.11 (d, J=2.6 Hz, 1H), 8.04 (dd, J=8.8, 2.6 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 3.69 (s, 2H), 2.40 (s, 3H), 2.13-2.09 (m, 1H), 1.18-1.12 (m, 2H), 0.73-0.67 (m, 2H); MS (ESI) m/z: 239.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1)#[N:28]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(-c2cc(-c3ccccc3C#N)nc(N3CCOC[C@@H]3C)n2)cc1
Yield: 41.4 %

Procedure:
(S)-1-(4-(6-chloro-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)-3-ethylurea (Intermediate 2) (90 mg, 0.24 mmol), 2-cyanobenzeneboronic acid (43 mg, 0.29 mmol), cesium carbonate (235 mg, 0.72 mmol) and bis(diphenylphosphino)-ferrocenedichloropalladium(II)-DCM-complex (10 mg, 0.01 mmol) in dioxane/water (1:3, 1 mL) were irradiated in a Biotage microwave for 40 min at 110° C. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMSO, filtered and purified by prep HPLC (low pH) to afford a green solid (44 mg, 41%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[C@@H:24]([CH2:25][CH3:26])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].Cl.O1CCOCC1>ClCCl>[CH2:25]([C@H:24]1[CH2:23][NH:22][CH2:21][C@H:20]1[NH:19][C:5]1[C:6]2[N:7]([CH:10]=[C:11]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[CH:12]=2)[N:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3])[CH3:26]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (62 mg, 0.136 mmol) in dichloromethane (1 mL) was added 4N HCl in 1,4-dioxane (0.512 mL, 2.046 mmol). After stirring at room temperature overnight, the deprotection was complete. The volatile were removed in vacuo to afford the hydrochloride salt of the title compound (52 mg, 98% yield) as an off-white solid. MS (ES+) m/z: 355.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32]>ClCCl.O1CCCC1>[C:31](=[O:32])([O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:28])=[CH:21][CH:22]=1)[NH2:33]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(COC(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
Compound of Example 206 (0.868 g, 1.93 mmol) was suspended in dichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 M in toluene, 2.12 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours then diluted with tetrahydrofuran (50 mL) and Al2O3 (5.0 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite® washing with methonal. The filtrate was then concentrated and the residue was redissolved in tetrahydrofuran (30 mL). Al2O3 (5.0 g) was added and the mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the reaction was filtered through a pad of Celite ® washing with methanol. The filtrate was concentrated and the resulting solid was washed with diethyl ether to give an off-white solid (0.831 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.54 (app q, J=7.7 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.25 (app dt, J=2.0, 8.3 Hz, 1H), 6.86-6.30 (m, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s, 2H), 4.81 (br s, 2H), 2.25 (s, 3H). ES-HRMS m/z 493.0580 (M+H calcd for C22H20BrF2N2O4 requires 493.0569).
Reaction SMILES: [Cl-].C([Al+]CC)C.CCCCCC.[Cl-].[Al+3].[Cl-].[Cl-].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:31]1[O:34][CH:32]1[CH3:33]>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:31][C@@H:32]([OH:34])[CH3:33])=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC1CO1
Agent: CC[Al+]CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Product: C[C@H](O)COc1ccc(Oc2ccccc2)cc1
Yield: 72 %

Procedure:
In Example 2, 0.1 mL of a diethyl aluminum chloride/hexane solution was used in place of anhydrous aluminum chloride, and the color of the catalyst solution changed from brown to dark green by the addition of a diethyl aluminum chloride/hexane solution. Then 4-phenoxyphenol and propylene oxide were added to the dark green catalyst solution to achieve the reaction in the same manner as described in Example 2. Thus (S)-(+)-1-(4-phenoxyphenoxy)-2-propanol was obtained in 72% yield and the optical purity was 87% e.e.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].N1C=CC=CC=1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=[N:26][OH:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(-n2nc(CCC=O)cc2-c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(CCC=NO)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of the aldehyde 11 (1.00 g, 2.93 mM) in EtOH (30 ml) was added hydroxylamine hydrochloride (0.31 g, 4.40 mM) and pyridine (0.47 g, 5.87 mM). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The remaining residue was taken up in CH2Cl2, washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Crystallization from Et2O:hexane afforded 26, (0.67 g, 64%) as a white crystalline solid, mp=134°-135° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH3:52])=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=5)[CH:41]=4)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:24]=2[O:23][CH2:22]1.CCN(C(C)C)C(C)C>O1CCOCC1>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]3([C:33]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([CH3:52])=[C:40]([C:42]5[CH:47]=[CH:46][C:45]([S:48]([N:1]6[CH2:8][CH2:7][CH2:6][C@H:2]6[C:3]([OH:5])=[O:4])(=[O:49])=[O:50])=[CH:44][CH:43]=5)[CH:41]=4)=[O:34])[CH2:32][CH2:31]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reaction time: 1 h

Procedure:
L-Proline (57 mg, 0.50 mmol) was treated with N,O-bis(trimethylsilyl)acetamide (250 μl, 1.0 mmol) in 1 mL dioxane overnight at 50° C. To this mixture was added 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-4-sulfonyl chloride (˜35 μmol, 400 μl solution in chloroform) followed by DIEA (100 μL). The reaction mixture was kept at room temperature for 1 h, evaporated, and diluted with DMSO (400 μl). The resulting solution was subjected to preparative HPLC purification. Fractions containing the desired material were combined and concentrated in vacuum centrifuge at 40° C. to provide the trifluoroacetic salt of (S)-1-{5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methyl-biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylic acid. ESI-MS m/z calc. 548.1, found 549.1 (M+1), retention time 3.40 min; 1H NMR (250 MHz, DMSO-d6) δ 1.04 (m. 2H), δ 1.38 (m, 2H), δ 1.60 (m, 1H), δ 1.80-1.97 (m, 3H) δ 2.16 (s, 3H), δ 3.21 (m, 1H), 3.39 (m, 1H), 4.15 (dd, 1H, J=4.1 Hz, J=7.8 Hz), δ 6.01 (s, 2H), δ 6.89 (s, 2H), δ 6.98 (s, 1H), δ 7.21 (d, 1H, J=8.3 Hz), δ 7.45 (d, 1H, J=2 Hz), δ 7.52 (dd, 1H, J=2 Hz, J=8.3 Hz), δ 7.55 (d, 2H, J=8.3 Hz), δ 7.88 (d, 2H, J=8.3 Hz), δ 8.80 (s, 1H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[S:11]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:2]([N:13]1[CH:14]([C:16]([OH:18])=[O:17])[CH2:15][S:11][CH2:12]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(O)C1CSCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(O)C1CSCN1C(=O)c1cccnc1
Temperature: 64 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
Nicotinoyl chloride hydrochloride (534 g) is added over 1 hour at a temperature of between 30° and 52° C. to a solution of thiazolidine-4-carboxylic acid (400 g) and triethylamine (613 g) in chloroform (4,500 cc). The solution obtained is heated at a temperature of about 64° C. for 4 hours. After stirring at a temperature of about 20° C. for 16 hours, the crystals which have appeared are separated off by filtration, washed 3 times with chloroform (1,500 cc in total), then 3 times with diethyl ether (1,500 cc in total) and are dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. in the presence of potassium hydroxide pellets. N-nicotinoylthiazolidine-4-carboxylic acid (403 g) is thus obtained in the form of white crystals melting at 190° C.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S@:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:8])=[CH:3][CH:2]=1.C([Mg]Br)(C)(C)C.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][C@H:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH:33]=[O:34].Cl>CCOCC.C1COCC1>[OH:34][CH:33]([CH2:32][CH:31]([O:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@H:9]([S@@:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)=[O:8])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CCCCCCCCCCC[C@H](CC=O)OC1CCCCO1
Reactant: Cc1ccc([S@@](=O)CC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(CC(O)[C@H](C(=O)OC(C)(C)C)[S@](=O)c1ccc(C)cc1)OC1CCCCO1
Temperature: -78 °C
Yield: 61.3 %

Procedure:
G)a) 16.5 g of t-butyl [(S)-p-tolylsulfinyl]acetate were dissolved in a mixture of 600 ml of ether and 60 ml of THF and cooled to -78° C. 43 ml of t-butylmagnesium bromide were then added dropwise in such a manner that the temperature remained below -70° C. After stirring at -78° C. for 1 hour 13.4 g of (R)-3-[(tetrahydro-2H-pyran-2yl)oxy]-tetradecanal in 100 ml of THF were added dropwise. After 2 hours at -78° C. the reaction mixture was hydrolyzed with 2N hydrochloric acid and the solvent was evaporated off. The reaction mixture remaining behind was extracted with ether and the ethereal phase was dried and evaporated. After chromatography on silica gel there were obtained 14.9 g of t-butyl 3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl) oxy]-2-[(S)-p-tolylsulfinyl]-hexadecanoate (67% yield). m.p. 97°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:12]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:12]([O:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(Br)c1
Reactant: COc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(C(=O)OCc3ccccc3)ccc2OCc2ccccc2)cc1
Yield: 5.6 %

Procedure:
To a degassed solution of 4-methoxybenzeneboronic acid (5.0 g, 32.9 mmol), benzyl 4-benzyloxy-3-bromobenzoate (12.1 g, 30.5 mmol), and potassium carbonate (10.4 g, 76.2 mmol) in toluene/ethanol 2/1, (140 mL), Pd(PPh3)4 (400 mg, 1 mol %) was added and the mixture is degassed for further 5 minutes. The mixture is then refluxed for 12 hours. The mixture was partitioned between ethyl acetate and water and extracted. The organic solvent was dried over sodium sulphate, removed under reduced pressure, and the residue purified by column chromatography (9/1 DCM/hexane) to afford 0.73 g of pure title compound, 9.74 g of a 4:6 mixture of title compound and the corresponding ethyl ester, and 0.71 g of the ethyl ester derivative.
Reaction SMILES: Cl.CN[O:4][CH3:5].C[Al](C)C.C([C@H:17]1COC(=O)[N:18]1[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:26]1)=[O:24])C1C=CC=CC=1>C(Cl)Cl>[CH3:5][O:4][N:18]([CH3:17])[C:23]([C@@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)[CH2:28][N:27]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:26]1)=[O:24]
Reactant: CNOC
Reactant: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a suspension of N,O-dimethylhydroxylamine hydrochloride (7.82 g, 80.6 mmol) in DCM (130 mL) at RT was added trimethylaluminium (2.0M solution in heptane, 40.3 ml, 80.6 mmol) dropwise and stirring was continued for one hour. To this mixture was added a solution of (S)-4-benzyl-3-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carbonyl]-oxazolidin-2-one (19.2 g, 40.3 mmol) in DCM (100 mL) over 10 minutes. Stirring was continued for three hours. The reaction was quenched by an addition of aq. Potassium sodium tartarate solution and extracted with ethyl acetate. The separated organic layer was washed with brine and dried on Na2SO4 and concentrated under vacuo. Its purification by column chromatography (SiO2, EtOAc/H, 15:85) yielded 13 g (90%) of the title compound as a light yellow oil. ES-MS m/e: 361.2 (M+H+).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[CH:15]1([CH2:27][CH2:28][N:29]=[C:30]=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:15]1([CH2:27][CH2:28][NH:29][C:30]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1COC(=O)C1
Reactant: O=C=NCCC1CCCCCCCCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NCCC1CCCCCCCCCCC1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry flask containing 40 mL of chloroform was added 1.87 g (18.7 mmol) of tetronic acid, 2.29 g (18.7 mmol) of 4-N,N-dimethylaminopyridine, 2.6 mL (18.7 mmol) of triethylamine followed by 4.4 g (18.7 mmol) of 2-cyclododecylethyl isocyanate. The reaction mixture was allowed to stir overnight at room temperature, after which time a small amount of starting materials was still evident by TLC. The reaction mixture was quenched with 1N HCl, the layers separated, the organic fraction dried over MgSO4, filtered, and stripped of solvent. The residue was flash chromatographed using acidic silica gel eluting with 25% EtOAc/hexane to give a yellow solid. M.P. 135°-137° C. Spectral data follow: 1H NMR (DMSO-d6) δ 8.05 (bs, 1H), 4.6 (s, 2H), 4.2 (bs, 10 H), 3.25 (t, 2H), 2.5 (s, 3H), 1.2-1.4 (bm,>20 H); IR (KBr) 3340, 2920, 2850 (C-H), 1750, 1650 cm-1 (C=O).
Reaction SMILES: [ClH:1].[Cl:2][CH:3]=[C:4]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][O:5]1>>[Cl:2][CH2:3][C:4](=[O:5])[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][Cl:1]
Reactant: CC1(C)CCOC1=CCl
Reactant: Cl
Product: CC(C)(CCCl)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A fast stream of hydrogen chloride gas is passed from a pressure cylinder into ice-cooled 476 g (3.25 mols) of 2-chloromethylene-3,3-dimethyltetrahydrofuran. All of the gas is absorbed, and the internal temperature rises to 30°. After the reaction mixture has been completely saturated with hydrogen chloride, it is stirred for 2 hours at room temperature. Excess hydrogen chloride is first distilled off under a water-jet vacuum, and then a distillation in a high vacuum is carried out. 531 g (2.93 mols, 90%) of 1,5-dichloro-3,3-dimethylpentan-2-one are obtained with a boiling point of 85°-90°/0.3.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]1[O:23][C:22]2[CH:21]=[CH:20][C:18]([O-:19])=[CH:17][C:16]=2[O:15]1.[Na+]>CS(C)=O.O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:2]([O:19][C:18]2[CH:20]=[CH:21][C:22]3[O:23][CH2:14][O:15][C:16]=3[CH:17]=2)[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [O-]c1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1c(F)cccc1F
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(F)cccc1Oc1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
Ethyl 2,6-difluorobenzoate (558 mg, 3.0 mmol) was added to dry sodium 3,4-methylenedioxyphenoxide (3.0 mmol, prepared as described in part A) in DMSO followed by addition of dry DMSO (2 ml). The reaction mixture was warmed to 50° C. forming a solution which turned from brown to green upon further heating. After 90 min., the reaction was cooled to 25° C., diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic extract was washed with water (2×7 ml) and brine (7 ml), dried (MgSO4) and concentrated to give a light yellow oil. The product was purified by flash chromatography on SiO2 (5-20% EtOAc/hexane) yielding 532 mg of ethyl 2-fluoro-6-[3,4-(methylenedioxy)phenoxy]benzoate as a colorless oil (58% yield).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.C(OCC)(=O)C>[CH2:1]([O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: OCc1ccccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCCOc1ccccc1CO

Procedure:
12.4 g (90.5 mmol) of butyl bromide, 11.2 g (90.5 mmol) of 2-hydroxybenzyl alcohol and 12.5 g (90.5 mmol) of potassium carbonate in 270 ml of 2-propanol are heated at reflux overnight. The suspension is cooled, taken up in ethyl acetate and washed with 1N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][O:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][O:19][S:61]([CH3:60])(=[O:63])=[O:62])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 2 h

Procedure:
To an ice-bath cooled solution of Intermediate 141b (132 mg, 0.19 mmol) in DCM (2.0 mL) was added DIPEA (135 μL, 0.78 mmol) followed by methanesulfonyl chloride (30 μL, 0.39 mmol). The reaction mixture was stirred for 2 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the subsequent step without further purification. LCMS (Method 4): Rt 3.30 min, m/z 759 [MH+].