was charged with ice water (2000 mL) with stirring which led to the formation of slurry.

The
precipitates were collected, washed with water, and dried under a vacuum to give 29 g (76%) of
3-(4-cyanobenzoyl)indolizine. Rf 0.3 (10% ethyl acetate in hexanes); mp 156-157 C
(recrystallized from ethyl acetate).

Shi Epoxidation

Org. Process Res. Dev., 11 (1), 44 -51, 2007.

The potassium trans-alkenoate solution from the Suzuki cross-coupling was adjusted to pH 10.5
with 25% aqueous H2SO4. The solution was cooled to between -5 to 5 oC and D-Epoxone (4.3 g,
0.017 mol), as a solution in acetonitrile (20 mL) was added. While the mixture was stirred with
vigorous agitation, Oxone (45.3 g, 0.074 mol) in water (160 mL) was added to the mixture. The
temperature was maintained below 10 oC by control of the Oxone solution charge rate, and the
pH was maintained at 10.0-11.0 by the addition of 20% KOH as necessary. After the addition
was complete, the mixture was held at 10-15 oC for 1 h. The mixture was adjusted to pH 2 with
25% H2SO4. Toluene (233 mL) was added, the mixture was heated to 75-80 oC, and the layers
were separated. The organic layer was filtered and concentrated until the pot volume was
approximately 100 mL. The solution was cooled to 20-30 oC, and heptane (67 mL) was added
over approximately 1 h to crystallise the product. The solids were filtered, washed with cold
heptane (~15 mL), and dried at 35-40 oC to afford a 55% yield of hydroxylactone in 86%.

3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one Synthesis

 
0 C, filtered, and washed with 50 mL of methanol. The product was dried in the vacuum oven at 50 C overnight to
provide 11.0 g (61% yield) of desired product.

Shestopalov pyridine ring construction

Organic Process Research & Development 2006, 10, 1157-1166

Knoevenagel condensation of aldehyde with methyl cyanoacetate, Michael addition of the

pyridinium yield to the condensation product, and cyclization of the Michael adduct.

5-Cyano-1,2,3,4-tetrahydro-6-hydroxy-4-(2-methylphenyl)- 2-oxo-1,3-bipyridinium,
Inner Salt .  A 3000 mL four-necked flask (with a 250 mL pressure equilibrating addition
funnel/dry N2 adapter, septum with a Teflon-coated thermocouple, Teflon paddle stirrer/glass
shaft, and stopper) is charged with 115.6 mL (120.15 g, 1.0 mol) of o-tolualdehyde, 87.9 mL
(99.09 g, 1.0 mol) of methyl cyanoacetate, the suspension of 172.61 g (1.0 mol) of pyridinium
salt in 300 mL of isopropanol , and 1.7 L of methanol. The addition funnel is charged with 153.3
mL (111.3 g, 1.1 mol) of triethylamine. The amine is added over 24 min at 170 rpm and 20-
25 C (intermittent ice-water bath). The resulting mixture is stirred at 25-30 C for 24 h. The
precipitate is suction filtered, washed with 500 mL of 25 C methanol, 500 mL of 25 C toluene,
and 500 mL of 25 C hexanes, and then air-dried 18 h at 25 C to afford 284.69 g (93.2%)
of product as a bright yellow solid.

Tisler triazolopyrimidine cyclization

Organic Process Research & Development 2006, 10, 1178-1183

Laboratory Procedure of Hydrogenation to Obtain the Indole. To a mixture of

enamine (5.00 g, 15.4 mmol), iron(II) acetate (28 mg, 0.154 mmol), and 5% Rh/C (317 mg,
0.154 mmol), tetrahydrofuran (THF) (100 mL) was added. After the atmosphere was displaced
with N2 followed by H2, the mixture was stirred for 15 h at rt under atmospheric pressure of H2.
After the atmosphere was replaced with N2, aqueous NH3 (_14%, 20 mL) was added. The
following workup operations were conducted under N2. After stirring for 20 min, the mixture
was filtered to remove the catalyst, which was washed with THF (50 mL). The combined
solutions were extracted with toluene (50 mL). The organic layer obtained was washed with
aqueous citric acid (10%, 50 g), aqueous sodium bicarbonate (5%, 50 g), and brine (20%, 50 g).
The yield of the target indole was determined by HPLC (3.30 assay g, 96% yield). The solution
was concentrated in vacuo. The residue was dissolved in toluene (100 mL) and filtered through a
pad of SiO2 (5 g), and the silica gel was washed with toluene (100 mL). The combined toluene
solutions were analyzed by HPLC (3.22 assay g, 94% yield), and then concentrated in vacuo.
The residual solids were suspended in toluene (5 mL) and heptane (13 mL) and heated to 90 C
to dissolve the solids. The homogeneous solution was cooled to 63 C, followed by seeding with
a crystal of indole to form a seed bed. The slurry formed was stirred for 1 h at 60-65 C, heptane
(37 mL) was added over a period of 2 h, and the solution was gradually cooled to rt. After
standing overnight, the slurry was filtered, washed with heptane-toluene (10:1) (5.5 mL) and
heptane (5.5 mL), and dried in vacuo at 40 C overnight. The target indole was obtained as
colorless crystals (2.94 g, 86% yield with 99.9 area % purity by HPLC).

Knorr Cyclization Pyrrole

Organic Process Research & Development 2006, 10, 899-904

3-(4-Bromophenyl)-4-cyano-5-ethyl-1H-pyrrole-2-carboxylic Acid Ethyl Ester. Preparation of enolate: Under a

nitrogen atmosphere, potassium tert-butoxide (13.097 kg, 117.29 mol) was dissolved in THF (68.2 L) at 20 C. To
the resulting mixture, a mixture of ethyl propionate 12.2 L, 106.63 mol) and acetonitrile (6.68 L) was added over
0.75 h at 18 to 21 C and stirred for 1 h at this temperature (NMR (10 íL of reaction mixture in 1 mL of DMSO-d6)
indicated noester remaining). Preparation of pyrrole: In a separate reactor under a nitrogen atmosphere, R-
isonitroso-â-ketoester (12.8 kg, 42.65 mol) was dissolved in EtOH (110 L) at 20 C. The solution was cooled to
1 C, and zinc (6.429 kg, 98.01 mol) was added portionwise over 0.5 h. A solution of acetic acid (19.5 L), water (2.5
L), and EtOH (11.5 L) was prepared. About 1 to 2% of the ethanolic aqueous acetic acid solution was added to the
mixture of R-isonitroso-â-ketoesterand zinc in EtOH at 0 C to give a slight exotherm and initiate the reduction. The
rest of the ethanolic aqueous acetic acid solution was added to the mixture of R-isonitroso-â-ketoester and zinc in
EtOH over 1.5 h between -2 to 2 C. The suspension was cooled to -5 C and stirred for 0.25 h (HPLC indicated
98.3% conversion of R-isonitroso-â-ketoester). The potassium enolate suspension was added over 0.5 h to the zinc
suspension at -9 to -2 C. The reaction was stirred at -4 C for 3.0 h, warmed to 20 C over 10 h, and stirred at 20 C
 

Organic Process Research & Development 2006, 10, 893-898

2-Chloro-1-phenylethanol. A 75-mL jacketed reaction flask equipped with an addition port, reflux condenser and a
magnetic stir bar was first purged with argon for 10 min and then charged with a solution of 0.025 mmol of CBS
reagentin 5 mL of THF. A BH3âTHF solution containing 4.8 mmol of BH3 (10 mL) was added portionwise over 10
min. The reaction flask was heated to 30 C and a solution of 1.24 g (8 mmol) of starting material ketone in 10 mL
of THF was added via syringe pump at a rate of 0.15 mL/min. After the addition was complete, the reaction mixture
was stirred for 45 min and cooled to ambient, and the remaining hydride was decomposed by the addition of 2 mL
of dry methanol. The reaction mixture was passed through a short bed of SiO2 and the solvent evaporated giving the
chloro alcohol, desired product, in 95% yield; HPLC purity >95%, HPLC ee ) 95%.

Noyori hydrogenation

Organic Process Research & Development 2006, 10, 893-898

(S)-2-Succinimido-1-phenylethanol. Twenty mmol (4.34 g) of starting material was placed in a 250-mL jacketed,

glass reactor vessel,14 and the air in the reactor was completely replaced by argon using multiple fill/release cycles.
Degassed methanol (250 mL) was added to the reactor via cannula and the mixture stirred at 30 C to dissolve the
ketone. Four milliliters of the Noyori catalyst solution (8 ímol of Ru) and 12 mL of the K-OtBu solution (3 mmol)
were injected into the reactor using gastight syringes. The argon in the reactor was replaced with hydrogen
(fill/release cycles) and the reactor pressurized to 60 psig with hydrogen. The reaction mixture was stirred at 1000
rpm overnight at 30 C with the hydrogen uptake recorded as described previously. The reaction mixture was passed
through a short alumina column and the solvent removed to give desired product, with an HPLC ee of 99% at
100% conversion. HPLC purity >97%.

Asymmetric Hydrogenation of a beta-Enamine Amide

Organic Process Research & Development 2006, 10, 723-726

Hantzsch pyridine synthesis

In a typical process, 3-cyanobenzaldehyde (1 equiv) and ammonium acetate (2.5 equiv) are slurried together in
ethanol (18 rel vols). A solution of dione (0.9 equiv) in ethanol (6 rel vols) is added slowly, followed by allyl ester
(1.1 equiv) and more ammonium acetate (2.5 equiv) in ethanol (11 rel vols). The mixture is heated to reflux for 3.5
h, and then excess ethanol is removed by distillation under vacuum until 18 rel vols remains. Water (24 rel vols) is
added to precipitate the product, which is isolated by filtration and washed with water (6 rel vols) and MTBE (6 rel
vols, twice).

Reductive alkylation

Organic Process Research & Development 2006, 10, 814821

(R)-2-(4-(2-(2-Cyclopentyl-5-((5,7-dimethyl-[1,2,4]triazolo[ 1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-6-oxo-3,6-
dihydro- 2H-pyran-2-yl)ethyl)-2-fluorophenyl)-2-methylpropanenitrile. A 100-gal reactor was charged
with aldehyde (6.5 kg, 36.9 mol). A separate 50-gal reactor was charged with beta-ketoester (9.1 kg, 24.5 mol),
BH3/NMe3 (2.7 kg, 37 mol), MeOH (7 gal), and THF (5 gal). The solution in the 50-gal reactor was transferred to
the 100-gal reactor, and a slight exotherm was observed to 28 C. The mixture was allowed to stir at room
temperature for 30 min and was then charged with concentrated aqueous HCl (0.25 gal). The reactor was charged
with water (13.7 kg) and then seeded with 1 (2 g) to initiate crystallization. The mixture was stirred for 20 h and
then was filtered; the cake rinsed with THF (4 gal) and then water (7 gal). The wet cake was transferred to a clean
reactor and charged with water (18 gal) and stirred for 2 h. The slurry was filtered, washed with water (12 gal), and
dried at 50 C for 5 days to provide 7.3 kg (56%) of desired product as a white crystalline solid (purity 90% by
HPLC analysis).

Beta-ketoester synthesis
Organic Process Research & Development 2006, 10, 493-499

4-(4-Nitrobenzyl)morpholine To a 2-L, three-neck, round-bottom flask, fitted with mechanical stirring,

thermocouple, 250-mL addition funnel, and nitrogen inlet were charged 4-nitrobenzylbromide (100 g, 463
mmol) (Caution. Strong irritant and lachrymator! Weigh in hood with door down and transport in stoppered
flask!) and 500 mL of toluene. A solution of morpholine (121 g, 1389 mmol) in 100 mL of toluene was added
dropwise, keeping the temperature less than 50 C. The solution was rinsed in with 50 mL of toluene. The resulting
solution was stirred at less than 50 C until the reaction was complete. TLC analysis; add 1 mL of reaction mixture
to 1 mL of water, spot upper layer and elute with 1:1 ethyl acetate/heptane, visualize with UV. When complete, 500
mL of water was added, and the phases were separated. The organic phase was washed with 500 mL of saturated
sodium bicarbonate. The organic phase was concentrated to less than 150 mL volume on the rotovap with a 60-
70 C bath. Isopar C (500 mL) was added to crystallize the product. The slurry was stirred at 20-25 C for 30 min,
filtered, and washed with 100 mL of Isopar C. The product was dried at 45 C in a vacuum oven overnight. The
yield was 96.0 g, 93%, of desired product: mp 80.3-82.1 C. HPLC purity 95%.

mild conversion of a quinoline N-oxide to a 2-aminoquinoline

Organic Process Research & Development 2006, 10, 534-538

2-Amino-quinoline-6-carboxylic Acid Benzyl Ester. To a solution of 1-oxy-quinoline-6-carboxylic acid benzyl

ester (4.1 kg, 14.7 mol) in methylene chloride (20 L) was added p-toluenesulfonyl chloride (3.9 Kg, 21 mol) under
nitrogen, and the mixture was stirred for 45 min at 22-25 C. This solution was added very slowly (400 mL/min) to
a suspension of ammonium chloride (2.4 kg, 44 mol) in methylene chloride (12 L) and triethylamine (6.8 L, 48 mol)
while keeping the temperature at 25-30 C. The reaction mixture was stirred for an additional hour at 22-25 C
before cooling to -5 C for 1 h and filtered. The filtered solids were rinsed with pre-cooled methanol (4.5 L) at -
5 C. This solid material was then triturated in water (45 L) for 20 min at 20-25 C, filtered, and washed with
precooled methanol (9 L) at -5 C. The product was dried in a vacuum oven at 35-40 C for 24 h to yield 1.85 kg
(45.1%) of the title compound.

Transfer alkylation
The reaction was stirred for 30 min after the addition was complete and after a sample showed the reaction was
complete (>98% conversion by HPLC, analysed as N-benzyl urea derivative of the isocyanate). To the above
mixture was added benzyl alcohol (17.7 kg, 164 mol), and the mixture was heated to reflux at 110 C for 5 h. When
the reaction was complete, it was cooled to 20-25 C and washed with water (50 L) and then twice with 10% brine
(50 L). The toluene solution was solvent switched first to 2-propanol and then to n-heptane by vacuum distillation
(to an end-point of less than 2% IPA in the n-heptane in the pot). The mixture was cooled to 50 C, seeded with 200
g of desired product suspended in n-heptane (300 mL), and then cooled to 20 C at 0.2 C/min. After 8 h at this
temperature the mixture was cooled further to -5 C and filtered on a 36-in. Nutsche. The cake was washed with n-
heptane and dried in a vacuum oven. The yield of product was 44.7 kg (80%).

LAH reduction

Organic Process Research & Development 2006, 10, 262-271

3-(4-Fluorobenzyl)piperidine. A solution of (S)-3-(4-fluorobenzyl)-2-piperidone (6.4 kg, 30.8 mol) in 120 L of

toluene was cooled to 10 C. Lithium aluminum hydride bis(tetrahydrofuran) solution in toluene (1.0 M, 27.8 kg,
31.8 L, 31.8 mol) was added at a temperature below 15 C. The batch was heated to 40 C and stirred for 3 h. The
batch was quenched by slow addition to a Rochelle salt solution (16.4 kg in 90 L of water) and stirred for 15 min.
The organic phase was washed with 10% brine followed by water. The toluene solution was concentrated by
vacuum distillation to a volume of about 60 L. The resultant solution contained product (5.0 kg, 25.9 mol, 84%).

Reductive Amination

Organic Process Research & Development 2006, 10, 262-271

 In a 100-gal glass reactor were warmed sodium triacetoxyborohydride (18.5 kg, 87.3 mol) and DMSO (71 kg) to
40 C until homogeneous. The batch was cooled to 12 C, and (S)-3-(4-fluorobenzyl)piperidine 2-(R)-mandelate salt
(20.2 kg, 58.5 mol) was added. In a separate reactor, (1R,2R)-2-
(benzyloxycarbonylamino)cyclohexanecarboxaldehyde (15.3 kg, 58.5 mol) and DMSO (33 kg) were mixed to give a
homogeneous solution. The aldehyde solution was added over 2 h to the piperidine solution while keeping the
temperature at 10-14 C. After the addition the reaction was stirred for an additional hour and then quenched with 6
N aqueous HCl solution (8.4 kg) at 20-24 C. To the quenched reaction mass were sequentially added iPrOAc (59
kg), water (67 kg), and 15% aqueous sodium hydroxide solution (50 kg). The mandelic acid was removed in the
aqueous solution. The product was extracted into the iPrOAc, which was washed with 10% brine (40 kg) and water
(45 kg). This iPrOAc solution containing (1R,2S)-1-(benzyloxycarbonyl) amino-2-[3(S)-(4
fluorobenzyl)piperidinyl]methyl-cyclohexane was used in next reaction without purification.
Imidazole synthesis from aldehyde

Org. Process Res. Dev., 10 (1), 36 -45, 2006

3-Methyl-5-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazole. Hydroxybenzotriazole hydrate (2.06

kg, 13.4 mol) was suspended in acetonitrile (25 L), and 2.5 L was distilled off at 1 atm under
nitrogen to azeotropically remove water. [CAUTION: Hydroxybenzotriazole will decompose,
possibly violently, if heated above its melting point (155-160  C).] After cooling to 25-30  C,
4-methylsulfonylphenylacetic acid (2.5 kg, 11.67 mol) was added, followed by EDC
hydrochloride (2.68 kg, 14.0 mol). The resulting mixture was stirred at 20-30  C for 30 min.
Methylamidoxime (1.14 kg, 14.0 mol) was added to the slurry over 10 min. The resulting
mixture was then heated at reflux for 12 h. The solution was solvent switched to ethyl acetate
under reduced pressure (100-200 mBar, 40-50  C) by continuous distillation of ~40 L of ethyl
acetate and concentrated to a final volume of ~27 L. After cooling to ~20  C, aqueous
NaHCO3 (1 M, 20 L) was added slowly with vigorous stirring. The aqueous layer was removed,
and the organic layer was washed with DI water (7.5 L). The aqueous solutions were back
extracted with 17.5 L of ethyl acetate. The combined ethyl acetate solution was concentrated to
~7 L (100-200 mBar, 50-70  C) and diluted with 2-propanol (17.5 L). The solution was further
concentrated to ~12.5 L. The solution was allowed to cool to 10-20  C, and the desired product
precipitated. After stirring for 2 h the mixture was filtered; the solid was washed with 2 × 2.5 L
of 2-propanol and then air-dried for 2 h. The solid was further dried in an oven at 30-35  C
under vacuum (N2 sweep) to constant weight. Isolated yield: 2.6 kg, 88%.

Friedel-Crafts acetylations

Org. Process Res. Dev., 10 (1), 135 -141, 2006

N-(5-Acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide. Regioselective
Friedel-Crafts Acetylation of starting material in Dichloromethane. A 1-L, four-
necked, round-bottomed flask (rinsed with dichloromethane), equipped with a
mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was
charged with aluminum chloride (102.0 g, 765.0 mmol) and dichloromethane (280.0
mL) at 20-25  C. The slurry was cooled to an internal temperature at 0-5  C, and
acetyl chloride (72.0 g, 917.0 mmol) was added over 20 min while maintaining the
temperature at 0-5  C. The white suspension was stirred at 0-5  C for 15 min and N-(