1.

2.
3.
4.
5.
6.

1.
2.
3.
4.
5.
6.
7.

1.
2.
3.
4.
5.
6.
7.

HPLC
TLC

8. PH
9.
10.
11.

1.
2.
3.
4. /

1.
2.
3.
1


1.
To a mixture (suspension / solution / slurry) of compound 12 (487 mg, 1 mmol) and
o-plenylenediamine (948 mg, 6 mmol) in CH2Cl2 (15 ml) being coolen to 0 was
added the DCC (226 mg, 1.1 mmol).
Anhydrous lithium iodide (1.38 g, 10.3 mmol) was added the five portions (dropwise /
in one portion / in portions) to a stirred solution of compound 12 (10.90 g, 51.5 mmol)
in CH2Cl2 (120 ml).
A round-bottom flask was changed with compound 3 (1.75 g, 5.27 mmol), LiCl (1.17
g, 26.3 mmol), DMSO (100 Ml) and H2O (378 ul)
in portions/portionwise
in one portion
dropwise
2.
Et3N (20 mL, 142 mmol) and a catalytic amount of DMAP were added the solution of
compound 1 (4.549 g, 46.4 mmol) in CH2Cl2120 ml at 0
3.
To a stirred -78 solution of trimethylsilyacetylene (4.44g, 45.5 mmol)in THF (10 ml)
under argon was added dropwise n-butylithium (1.6M in hexane, 28.25 ml).
4.
An ozone-enrichen steam of oxygen was bubbled through a cold (-78) solution of
compound 9 (128 mg, 1.409 mmol) in CH2Cl2 (5 ml) until it turned light blue. The
solution was purged with argon at -78 for 10 min to remove the excess O3 .
5.
The mixture was added to a sulotion of compound 2 (3.00 g, 12.8 mmol) in THF (48
ml) via cannula over a period of 30 min.
A solution of compound 29 (100 mg, 0.19 mmol, 1.0 equiv) in dry DMSO (1.5 ml)
was cannulated under argon to a vigorously stirred mixture of powered potassium
superoxide (62 mg, 0.87 mmol, 4.5 equiv) and 18-crown-6-ether (23 mg, 0.087 mmol,
0.45 equiv) in dry DMSO 0.5 ml.
2

6.
To a stirred solution of compound 15 (8.61 g, 21.2 mmol) was added a solution of
p-toluenesulfonic acid (6.0 g) in CH2Cl2 via syringe over 5 min.
7.
A solution of compound 1 (10 g, 1 mol) in EtOAc (20 ml) was added dropwise (via
addition funnel or syringe) to the above mixture at 10
(while maintaining gentle reflux;
while keeping internal temperature between 10 - 30).

1. /
a. The reaction mixture (solution or suspension) was stirred at 5 for 2 hrs and
then kept at room temperature (or ambient temperature) for another 2 hrs (or
overnight)
b. The reaction mixture (solution or suspension) was refluxed (or heated to reflux)
for 2 hrs (or overnight)

c. The reaction mixture (solution or suspension) was heated at 60 for 2 hrs (or
overnight)
d. The reaction mixture (solution or suspension) was allowed to reflux (or heat to
reflux) for 2 hrs (or overnight)
2.
a. After 1 h, TLC analysis (CH2Cl2 / hexane 3:1) showed the complete consumption of
compound 15.
b. The reaction was complete (incomplete or messy) detected by TLC (Petroleum
ether/EtOAc = 4:1),LC-MS, HPLC or NMR.

3. /
The mixture was left standing overnight.
The mixture was allowed to stand at room temperature for 1 day.
The mixture was allowed to stand in a freezer at -15 .
3

4. /
Compound A (1.97 g, 6.63 mmol) was coevaporated with toluene five times to
remove the water. The residue was subjected to toluene azeotrope to give the
corresponding acid choride as brown oil. The aqueous portion was concentrated under
reduced pressure followed by azeotropic removal of water with absolute EtOH.
5.
A mixture of compound 1 (190 g, 0.88 mmol) and Raney Ni (20 g) in ethanol (1500
ml) and ethyl acetate (500 ml) was stirred under 1 atm at room temperature for an
hour.
6.
A mixture of TsOH.H2O (56.91 g. 0.3 mol) and toluene (400 mL) was heated to reflux
to remove water by Dean-Stark trap.
7. /
The reaction was exothermic / endothermic .
8.
The sealed vial was irradiated in the microwave on a Biotage Smith Synthesis at
150 for 10 min.
9.
The mixture was degassed for 10 min and refilled with N 2 .
10.
The device for absorbing the evolved hydrogen bromide was attched to the reaction
flask. [care!! The reaction evolves HBr and is best connected to a HBr gas trap
(bubber containing 1 M NaOH solution)].
11.
To the solution which is protected from light was added dropwise Br 2 (3.45 g, 22
mmol) in CH2Cl2 (10 mL) over 5 min and the mixture was stirred for 1 h.
A mixture of compound 8 (213 mg, 0.186 mmol) and compound 9 (220 mg, 0.279
mmol) was refluxed for 20h under dark in a nitrogen atmsophere.
4


1.
The mixture was filtered through a Celite pad, and the filtrate was concentrated to
give the crude product.
2.
The reaction mixture was quenched by the addition of the saturated aqueous NH4Cl.
3.
The residue was triturated with ether and filtered to afford a white solid.
4.
After quenching the reaction, the reaction mixture was poured into separator funnel
and separated.
5.
The residue was partitioned between ethyl acetate (100 ml) and HCl (1N, 50 ml).The
organic layer was washed with water, dried (MgSO4) and evaporated to dryness.
Ethyl acetate (100 ml) and HCl1 M aq, 50 mL were added to the residue, and the
layers were separated.
6.
The crude product was purified by prep-HPLC to give compound 4 as colorless thick
oil, which was solidfied on standing.
7.
The white solid was re-crystallized from water, dried by hyophilization to give a
white solid.
7.
7.1
The crude produt was chromatographed on silica gel (CH2Cl2 / MeOH
20:110:15:1) to give the compond 8 (0.282 g, 51%) as a white solid.
5

The crude product was purified by column chromatography on silica gel eluted with
(CH2Cl2 / MeOH 20:110:15:1) to give the compound 8 (0.282 g, 51%) as a white
solid.
7.2 HPLC
Be purified by prep-HPLC to afford/give/yield
7.3 TLC
Be purified by prepare TLC to afford/give/yield
7.4
Recrystallized from
8. PH
The pH was adjusted to around 9 by progressively adding solid NaHCO3.
The mixture was adjusted to pH 9 with solid NaHCO3.
: be acidified to

: be basified to

: be neutralized

9.
The aqueous layer was extracted with ethyl acetate (100 mL4).
10.
The mixture was evaporated to afford the crude product.
The mixture was concentrated afford the crude product.
The solvent was removed to afford the crude product.
11.
11.1
The organic layer was dried over MgSO 4 , and concentrated.
11.2
The precipitate was filtered and dried (in/under vacumm; under reduced pressure).
6


1.
A gentle reflux appeared throughout the addition.
The temperature was increased from 25 to 50 during the addition.
2.
Solid was precipitate out after 1h reaction.
The reaction mixture was cooled to -10, and solid was precipitate out.
3.
XX was added to the mixture, and the resulting suspension was stirred for 2h.
4.
The suspension was heated to 90 and stirred until all solid was dissolved.
5./
The reaction mixture became sticky after 2hrs reaction/stirring.
After 2hrs stirring, the mixture turned into black/brown/gray/yellow/red color.

1.
No further operation
2.
The work-up of this batch was together with the other batches that recorded in the
following pages.
3.
IPC check showed this condition is better/bad for this reaction. No further operation /
screen reaction.

Processs
1.
XX(): XX()
XX(): XX()
XX(): XX()
XX(): XX()

2.

3.
dropwise, quicklyin portions

4. TLCHPLC,LC-MS
TLC TLC
3 TLC

HPLC LC-MC
X% X%
5.

X% pH
pH 9, pH
6.
7.

HPLC
MC HPLC MS

Notebook
1.

2. Sourse M. W; W.T; Mole eq.

Note Source batch
NO; domestic
ID Aidrich 163767
3.

4. TLC

5. /
6.

7.
8.
9.
Continued to page
10.

11.

12.