Name: 140462-76-6|(Z)-2-(11-(3-(Dimethylamino)propylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid hydrochloride|98%
Brand: Ambeed
SKU: A143866
Price: 6.0 USD
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1
[ 64168-10-1 ]
[ 140462-76-6 ]
[ 872040-96-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: diethyl-(2-[4]piperidyl-ethyl)-amine; olopatadine hydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 23℃; for 16h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water	2 EXAMPLE 2 1-[4-(2-Diethylamino-ethyl)-piperidin-1-yl]-2-{11-[3-dimethylamino-prop-(Z)-ylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl}-ethanone fumaric acid salt Olopatadine hydrochloride (0.26 g, 0.7 mmol), HOBT (0.12 g, 0.9 mmol), 4-(2-diethylamino-ethyl)-piperidine (0.16 g, 0.8 mmol) and triethylamine were dissolved in THF (20 mL). EDCl (0.15 g, 0.79 mmol) was added the solution stirred for 16 hr at 23° C., poured into dilute aqueous NaHCO3 (50 mL), extracted with ethyl acetate (2*20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel [eluent: methanol/DCM (20%)], to furnish 1-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-2-{11-[3-dimethylamino-prop-(Z)-ylidene]-6, 11-dihydro-dibenz[b,e]oxepin-2-yl}-ethanone (0.37 g, 0.7 mmol) in 99% yield. The purified amide (0.10 g, 0.2 mmol) was dissolved in methanol (5 mL) and fumaric acid (0.023 g, 0.2 mmol) added. The solution was concentrated under vacuum to afford 1-[4-(2-diethylamino-ethyl)-piperidin-1-yl]-2-{11-[3-dimethylamino-prop-(Z)-ylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl}-ethanone fumaric acid salt. Mass spectra: m/z 505 [M+H]+. 1H NMR (D2O, 600 MHz) δ 7.46 (m, 3H), 7.42 (m, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.13 (s, 1H), 7.01 (d, J=7.8 Hz, 1H), 6.67 (s, 3H), 5.80 (t, J=8.4 Hz, 1H), 4.38 (d, J=13.2 Hz, 1H), 3.92 (m, 1H), 3.86 (d, J=15.6 Hz, 1H), 3.77 (d, J=15.6 Hz, 1H), 3.36 (t, J=7.8 Hz, 2H), 3.06 (bm, 6H), 2.74 (bs, 8H), 2.72 (t, J=10.8 Hz, 1H), 1.75 (d, J=13.2 Hz, 1H), 1.55 (m, 3H). 13C NMR (CDCl3, 150 MHz) δ 175.39, 146.57, 137.85, 132.47, 131.44, 130.59, 129.29, 127.93, 123.09, 73.76, 59.84, 50.30, 50.14, 49.53, 45.63, 42.06, 35.71, 34.02, 32.12, 27.73, 11.22.

Reference： [1]Current Patent Assignee: ALCON, INC. - US2005/288283, 2005, A1 Location in patent: Page/Page column 3

2
[ 67-56-1 ]
[ 140462-76-6 ]
[ 113806-01-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: methanol; olopatadine hydrochloride With acetyl chloride In methanol at 23℃; for 2h; Stage #2: With sodium hydrogencarbonate In methanol; water	1 {11-[3-Dimethylamino-prop-(Z)-ylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl}-acetic acid methyl ester Olopatadine hydrochloride [(0.25 g, 0.67 mmol)] was dissolved in methanol (10 mL) and treated with excess of acetyl chloride (0.2 g, 2.5 mmol) at 23° C. The solution was stirred for 2 hr, then poured into dilute aqueous NaHCO3 (50 mL), extracted with ethyl acetate (2*20 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel [eluent: methanol/DCM gradient (5%-20%)], to furnish {11-[3-Dimethylamino-prop-(Z)-ylidene]-6,11-dihydro-dibenz[b,e]oxepin-2-yl}-acetic acid methyl ester (0.22 g, 0.63 mmol) in 94% yield. Mass spectra: m/z 352 [M+H]+. 1H NMR (CDCl3, 600 MHz) δ 7.31 (m, 1H), 7.24 (m, 3H), 7.07 (d, J=2.4 Hz, 1 H), 7.05 (dd, J=8.4 Hz, 1 H), 6.80 (d, J=8.4 Hz, 1 H), 5.71 (t, J=7.2 Hz, 1H), 3.70 (s, 3H), 3.53 (s, 2H), 2.58 (dd, J=14.4, 72 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.23 (s, 6H). 13C NMR (CDCl3, 150 MHz) δ 172.15, 154.58, 145.60, 139.67, 133.64, 132.00, 130.81, 129.90, 129.04, 127.44, 127.43, 126.29, 125.68, 123.93, 119.74, 70.40, 59.49, 51.96, 45.40, 40.25, 28.06.

Reference： [1]Current Patent Assignee: ALCON, INC. - US2005/288283, 2005, A1 Location in patent: Page/Page column 3

3
[ 113806-05-6 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
95.6%	With hydrogenchloride In water; acetone at 5 - 25℃; for 2 - 15h;	6.1.c; 6.2.c Step c: Conversion of Olopatadine (Free Base) to Olopatadine Hydrochloride To a suspension of the above obtained Olopatadine (of 30.0 g, 0.078 mol; HPLC assay: 87.70%) in acetone (226 g) was added concentrated hydrochloric acid (9.73 g, 0.085 mol; assay: 32%). After the addition of hydrochloric acid, the suspension became viscous and further acetone (226 g) was added. The mixture was stirred for one hour at 20-25° C., cooled to <5° C., and stirred for an additional hour at this temperature. After filtration, the white solid washed with acetone (96 g) and dried under vacuum for 15 hours at 60° C. to give white fine powdery Olopatadine Hydrochloride (yield: 28.04 g, 0.065 mol; assay: 99.39% (NaOH), HPLC purity: 99.92%, Z/E-Isomers: 99.98/0.02, yield: 95.60%, polymorphic form A). Overall yield for Olopatadine hydrochloride based on Olo-IM2: 51.5%. Calculated volume yield for the synthesis of Olopatadine-HCl: 1.48%
88.1%	With hydrogenchloride In water; acetone at 0 - 25℃; for 16 - 22h;	12.1; 12.2; 12.3; 12.4 Example 12 This example relates to the formation of olopatadine HCl from olopatadine (free base). Addition of hydrochloric acid (assay 32%) to a suspension of olopatadine in acetone. Table 10 below shows various results achieved when starting material containing different ratios of (Z)/(E) isomers are employed. Table 11 shows the results achieved when from 1 to 3 equivalents of the HCl are used to convert olopatadine (free base) to olopatadine hydrochloride. And, Table 12 shows the influence of temperature on the conversion to olopatadine hydrochloride.As the results show, olopatadine-HCl salt formation according to applicant's process is robust and efficient. A content of the undesired E-isomer up to 2.4% could be separated from olopatadine during the HCl salt formation using 1-3 equivalents HCl and at a temperature in a range of 0° C. to 35° C. In all cases the resultant olopatadine HCl product contained less than 0.15% of the E-isomer.
81.2%	With hydrogenchloride In water; acetone at 20 - 60℃;	5 EXAMPLE 5; A RBF is charged with 100 g of Olopatadine free base (of Example 4) , 60 mL of purified water, 100 mL of acetone and, keeping T=20-25°C, add in 10/15 minutes 44 mL of hydrochloric acid 32% (w/w) . Keeping T=20- 25°C, add to the mixture in about 30 minutes 1800 mL of acetone. Heat the slurry at reflux (T about 600C) in about 30 minutes and stir for at least 30 minutes. Cool down the slurry at T=20-25°C and stir for at least 1 hour then cool at T=0-5°C in about 1 hour and stir for at least 2 hours. The slurry is filtered and the cake is washed with 400 mL of acetone previously cooled at T = 0-50C. The product Olopatadine hydrochloride is dried under vacuum at T=50°C for at least 6 hours obtaining 90.0 g (molar yield = 81.2%) . HPLC purity: 99.94% (Area %) and all impurities are lower than 0.05% (HPLC Area %) (according HPLC method of example 7) . Bromide ion = not detected (0 ppm)(according to the IC method of Example 6) . m.p. = 253°C (DSC Onset) .Olopatadine hydrochloride bromide free of crystalline form A and pharmaceutically acceptable grade is thus obtained.

	With hydrogenchloride In water	7 HCI 2N (2ml, 4.10mmo.) was added to a solution of the acid in water. The mixture was stirred and concentrated to dryness. The solution of resultant oil in acetone (25m.) was refluxed for SOmin and the suspension obtained was cooled, filtered, washed and dried to obtain 0.88g (70% global) of (Z)-[11-(3-Dimethylamino-propylidene)-6,11-dihydro-dibenzo[b,e]oxepin-2-yl]-acetic acid hydrochloride (99.17% of purity by HPLC).
	With hydrogenchloride In tetrahydrofuran; water at 15 - 20℃; for 0.75 - 0.833333h; Heating / reflux;	7 Active carbon (Norit SX Ultra) was added to a stirring solution of 6g (17.78mmol) of (Z)-[11-(3-dimethylamino-propyliden)-6,11-dihydro-dibenzo[b,e]oxepin-2-yl]acetic acid in tetrahydrofurane (282mL) at room temperature. The slurry was filtered, washed with tetrahydrofurane, HCl 12N was added until pH 0-1 and the mixture was heated at reflux temperature of the solvent for 15-20min. After that, the reaction mixture was cooled (15-20°C) and stirred for 30min, centrifuged, washed at first time in tetrahydrofurane (30mL) and followed by acetone, the obtained product was dried at 55-60 °C to obtain 6.20g of (Z)-[11-(3-dimethylamino-propyliden)-6,11-dihydro-dibenzo[b,e]oxepin-2-yl]acetic acid hydrochloride. (99.74% chromatographic purity; Z/E: 99.8:0.2). A suspension of 5g (13.37mmol) of (Z)-[11-(3-dimethylamino-propyliden)-6,11-dihydro-dibenzo[b,e]oxepin-2-il]acetic acid hydrochloride in acetone (50mL) was heated at reflux temperature until the dissolution of Olopatadine hydrochloride, following this, acetone (250mL) was slowly added and was concentrated under reduced pressure distillation. The reaction mixture was cooled at 18-22 °C for 2h, centrifuged, washed with acetone, dried under vacuum to obtain 4.3g (Z)-[11-(3-dimethylamino-propyliden)-6,11-dihydro-dibenzo[b,e]oxepin-2-yl]acetic acid hydrochloride. (99.98% chromatographic purity; Z/ E: 99.99:0.01).

Reference： [1]Current Patent Assignee: UNIVERSITY OF ZURICH - US2007/232814, 2007, A1 Location in patent: Page/Page column 25; 26
[2]Current Patent Assignee: UNIVERSITY OF ZURICH - US2007/232814, 2007, A1 Location in patent: Page/Page column 30
[3]Current Patent Assignee: HOLDING F.I.S. S.P.A. - WO2010/121877, 2010, A2 Location in patent: Page/Page column 27-28
[4]Current Patent Assignee: URIACH S.A. - WO2006/10459, 2006, A1 Location in patent: Page/Page column 15
[5]Current Patent Assignee: URIACH S.A. - EP1908758, 2008, A1 Location in patent: Page/Page column 6

Yield	Reaction Conditions	Operation in experiment
99%	In cyclohexane at 79℃; for 3.16667h;
95%	In tert-butyl methyl ether at 55℃; for 2.5h;
94%	In tetrahydrofuran at 65℃; for 3.41667h;

94%	In α,α,α-trifluorotoluene at 101℃; for 3h;
93%	In ethyl acetate at 78℃; for 3h;
91%	In dichloromethane at 38℃; for 2.5h;
90%	In di-isopropyl ether; N,N-dimethyl-formamide at 20 - 25℃;
90%	In Hexafluorobenzene; dimethyl sulfoxide at 20 - 25℃;
87%	In tert-butyl methyl ether; N,N-dimethyl-formamide at 20 - 25℃;
87%	In 1,2-dimethoxyethane at 86℃; for 2h;
73%	In ethanol at 25 - 78℃; for 0.5h;
38%	In N,N-dimethyl-formamide; 4-methyl-2-pentanone at 0 - 25℃;
35%	In toluene at 25 - 109℃;
18%	In acetonitrile at 25 - 81℃;
9%	In butanone at 25 - 78℃; for 1.5 - 2.66667h;
9%	In ethyl acetate; N,N-dimethyl-formamide at 20 - 25℃;

Yield	Reaction Conditions	Operation in experiment
	In water Recrystallization;
	In methanol; toluene at -20 - 5℃; for 2h;
	In tetrahydrofuran; methanol; hexane; water at 0 - 5℃;

	In methanol; chloroform at 0 - 5℃;
	In water Reflux;	7 Example 7; Preparation of Olopatadine Hydrochloride Form BA 0.5 g sample of olopatadine hydrochloride was dissolved in 1.5 mL of water at reflux. Thereafter, olopatadine hydrochloride Form B seed crystals were added to the hot solution. The mixture was then cooled to room temperature without agitation. The resulting solid precipitate was then dried under vacuum for 2 hours at room temperature to yield 0.45 g of olopatadine hydrochloride Form B. (Yield 90%).Analytical data: XRD (2θ): 10.42°, 12.94°, 14.81°, 18.52°, 19.22°, 19.45°, 20.95°, 22.99°, 28.77° (substantially identical to FIG. 4);); M.p.: 244.1-244.7° C.
	In water; acetone Reflux;	1.IV Step - IV: Purification of crude 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11- dihydro dibenz [b, e] oxepin -2 - yl - acetic acid hydrochloride:To 375 ml of acetone, charged 75 gm of crude cis - olopatadine hydrochloride and raised the temperature of the reaction to attain reflux. Charged DM water (112. 5 ml) to the slurry at reflux temperature to get clear solution. Charcoalised the clear solution and filtered through charcoal bed. Charged filtrate in the flask and raised the temperature to reflux. Diluted the filtrate with acetone (1125 ml) at reflux temperature. After the addition maintained the reaction mass at reflux temp for 30 minutes. Cooled the reaction mass to 0 -5°C and maintained for two hours. Filtered the white solid and dried till constant weight to get pure cis - olopatadine hydrochloride.Yield = 60 gm
	With hydrogenchloride; pyrographite In water; acetone at 35 - 40℃; for 0.25h;	17 A solution of (Z)-l l-[3-(dimehylan ino)propylidene]-6,l l-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride (2 g) in 10% aqueous acetone (35 ml) was heated to 40-45°C and stirred for 30 minutes at same temperature. Aqueous hydrochloric acid was added to the reaction mixture at 35-40°C. Carbon (0.2 g) was added to the reaction mixture and stirred for 15 minutes at same temperature. Filtered the reaction mixture through highflow bed and washed with 10% aqueous acetone. Distilled off the solvent from the filtrate under reduced pressure and co-distilled twice with acetone. The reaction mixture was cooled to 25-30°C, added acetone to it and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone. Acetone and water were added to the obtained wet compound and heated the reaction mixture to 50-60°C. Filter the reaction mixture and the obtained filtrate was heated to 40-45°C. Acetone was slowly added to the reaction mixture at 40-45°C. Cooled the reaction mixture to 0-5°C and stirred for 90 minutes at same temperature. Filtered the precipitated solid, washed with acetone and dried the compound to get the pure title compound.Yield: 1.6 grams; Purity by HPLC: 99.95%. (Z-isomer)

6
[ 60548-16-5 ]
[ 27710-82-3 ]
[ 949141-22-4 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
< 0.5%; > 99%		Charged 238 gms [3 - (Dimethylamino) propylamine] triphenyl phosphonium bromide hydrobromide in 1400 ml tetrahydrofuran under nitrogen atmosphere. Slowly charged 130.5 gms sodium hydride and raised the temperature to reflux to maintain for 3.0 hrs. The <n="13"/>suspension cooled and chilled to 00C and charged solution of 100 gms benzyl ester of 1 1 - oxo - 6, 1 1 - Dihydrodibenz [b, e] oxepin - 2 - acetic acid in 400 ml tetrahydrofuran and stirred the reaction mass at 25 - 300C for 3.0 hours. Cooled the reaction mass to -10 to 50C and quenched in 1700 ml water. The organic layer separated and washed with water. Combined aqueous layer washed with diisopropyl ether and acidified with dilute hydrochloric acid to pH 2. The acidified aqueous layer extracted with dichloromethane 2500 ml. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was taken in the mixture of 500 ml dichloromethane and diethyl ether solvent. The product was filtered and dried. The HPLC purity of the product Olopatadine hydrochloride obtained; Cis / Z Isomer = > 99.0%; Trans / E Isomer = < 0.5%.

Reference： [1]Patent: WO2009/81417,2009,A2 .Location in patent: Page/Page column 11-12

7
[ 113806-03-4 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydrogenchloride; water In acetone for 10h; Reflux;	4.B The compound (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid ethyl ester (residue obtained in Part A) was dissolved in 100 ml of acetone in a reaction flask. 3.4 ml (0.040 moles) of HCl were added to this solution. The reaction was heated under reflux for 10 hours, in which time the reaction passed from being a solution to being a suspension. After this time, the reaction was cooled until reaching 20-25°C. The solid was filtered, washed and the resulting product was dried in an oven with air circulation at 50-55°C, obtaining 5.2 g (0.015 moles, 50%) of a white solid identified as (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid, isolated as hydrochloride, the spectroscopic properties of which are the following: 1H-NMR (DMSO, 400MHz), δ: 2.69 (s, 6H); 2.77 (m, 2H); 3.24 (m, 2H): 3.56 (s, 2H); 5.15 (bs, 2H); 5.62 (t, 1H); 6.76 (d, 1H); 7.06 (m, 2H); 7.30 (m, 4H) ppm. 13C-NMR (DMSO, 400MHz), δ: 25.12; 40.13; 42.44(2); 56.02; 70.26; 119.95; 123.43; 126.62; 127.64; 128.03; 128.47(2); 129.85; 131.34; 132.57; 134.12; 141.63; 145.25; 154.52; 173.67 ppm. MS, M'+1: 338.17

Reference： [1]Current Patent Assignee: CURIA INC; CRYSTAL DRUG - EP2145882, 2010, A1 Location in patent: Page/Page column 14

8
[ 55453-87-7 ]
[ 27710-82-3 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3; Preparation of Olopatadine Hydrochloride Form A Through Wittig Reaction Using Sodium Hydride3-[bromo(triphenyl)phosphoranyl]-N,N-dimethyl propan-1-amine hydrobromide (phosphonium salt) (205 g; 0.40 mol) was suspended in 545.5 g (615 mL) of tetrahydrofuran under a nitrogen atmosphere. After stirring for 40 minutes, 64.48 g (1.61 mol) of sodium hydride 60percent in mineral oil was added over five minutes. After addition of the sodium hydride, the reaction mixture was heated to reflux (approximately 65° C.) with continuous stirring and maintained at this temperature for 1 hour. An intense orange suspension was obtained. The reactor contents were then cooled to room temperature and 36 g (0.13 mol) of (11-oxo-6,1'-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (Compound II, R1H) was added with stirring. The mixture was then stirred for 15 hours at room temperature.Thereafter, a mixture of 153.5 g (153.5 mL) of deionized water and 136.1 g (153.5 mL) of tetrahydrofuran was slowly added with continuous stirring. Next, 615 g (615 mL) of deionized water was added, and stirring was continued for 20 minutes. The resulting two phase mixture was then acidified with hydrochloric acid (37percent) with stirring to adjust the pH to approximately 3 (actual reading 2.27). The aqueous and organic phases were then separated, and the aqueous phase was salified with 180 g of sodium chloride and extracted with 607.5 g (750 mL) of 1-butanol. The phases were then separated, and the organic phase was washed three times with water.The solvent of the organic phase was then removed by distillation under reduced pressure to yield 119.61 g of an orange oil. To this oil was added 157 g (200 mL) of 2-propanol, which produced a yellow suspension. The mixture was then stirred and maintained at this temperature for 1 hour. Thereafter, the suspension was filtered, and the collected wet solid was dried under vacuum at 60° C. until constant weight to yield 37.23 g (0.10 mol, 74.21percent) of olopatadine hydrochloride. (HPLC Purity: 54.28percent, cis: 6.44percent, trans; Cis/Trans Ratio: 8.43).A 36 g portion of the olopatadine hydrochloride obtained was then suspended in 226.08 g (288 mL) of 2-propanol. The mixture was heated to reflux (approximately 82° C.) with continuous stirring and maintained at this temperature for a minimum 20 minutes. The reactor was then cooled to room temperature, and the suspension was filtered to yield a slight yellow solid that was dried under vacuum at 60° C. (Partial Yield 37.62percent; HPLC Purity: 97.23percent cis, 0.76percent trans; Cis/Trans Ratio: 128. 50).A 17 g portion of the olopatadine hydrochloride obtained in the previous step was then treated with 120.1 g (153 mL) of 2-propanol. The white to white off suspension obtained was stirred and heated to reflux for 55 minutes. Then, it was allowed to cool to room temperature. The suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. (Partial Yield 35.67percent; HPLC Purity: 99.56percent cis, 0.18percent trans; Cis/Trans Ratio: 538.54).A 15 g portion of the olopatadine hydrochloride obtained in the previous step was then treated with 58.8 g (75 mL) of 2-propanol. The resulting white suspension was stirred and heated to reflux for 30 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 14.42 g of olopatadine hydrochloride. (Global Yield 34.29percent; HPLC Purity: 99.73percent cis; 0.10percent trans; Cis/Trans Ratio: 760.46).A 10 g portion of the olopatadine hydrochloride obtained in the previous step was treated with a mixture of 23.5 g (30 mL) of 2-propanol and 15 g of deionized water. The resulting white suspension was stirred and heated to reflux for 15 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 7.49 g of olopatadine hydrochloride. (Global Yield 25.68percent; HPLC Purity: 99.98percent cis; 0.02percent trans; Cis/Trans Ratio: 4999.35).A 6.7 g portion of the olopatadine hydrochloride obtained in the previous step was treated with a mixture of 15.8 g (20 mL) of 2-propanol and 10 g of deionized water. The resulting white suspension was then stirred and heated to reflux for 10 minutes. Thereafter, the reactor content was cooled to room temperature. The white suspension was then filtered, and the solid was washed with 2-propanol and dried under vacuum at 60° C. to yield 3.44 g of olopatadine hydrochloride Form A. (Global Yield 13.18percent; HPLC Purity: 99.91percent cis, 0.01percent trans; Cis/Trans Ratio: 11708.08).Analytical data: HPLC purity: 99.91percent; Assay: 101.62percent; XRD (2psi): 6.33°, 10.92°, 12.66°, 15.44°, 17.60°, 18.30°, 19.04°, 19.34°; 20.61°, 24.08°, 25.45°, 28.34° (substantially identical to FIG. 1); ...
		Example-1: Preparation of ll-[(Z)-3-(dimethylamino)propylidene]-6-ll-dihydro dibenz[b,e] oxepin-2-aceticacid hydrochloride compound of formula-lan-Butyl lithium (100 ml) was added to the solution of 3-dimethylaminopropyl)- triphenyl phosphoniumbromide HBr compound of formula-3 (37.94 grams) in tetrahydrofuran (200 ml) at 0-5 °C under nitrogen atmosphere. The reaction mixture was stirred for an hour at the same temperature. A mixture of l l-oxo-6, 11-dihydrobenz (b,e)oxepin-2-acetic acid compound of formula-2 (10 grams) and tetrahydrofuran (30 ml) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 65-70°C and then hated to reflux. The reaction mixture was stirred for 12 hours at 65-70°C. After completion of the reaction, the reaction mixture was cooled to 5-10°C. The reaction mixture was quenched with aqueous hydrochloric acid at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for an hour. Both organic and aqueous layers were separated. The aqueous layer was washed with toluene and then the aqueous layer was neutralizing with aqueous sodium carbonate solution at 5-10°C. The reaction mixture was washed with ethyl acetate. Hydrochloric acid (20 ml) and acetic acid (40 ml) was added to the reaction mixture at 25-30°C. The reaction mixture was stirred for 15 minutes and then dichloromethane was added to it. Both organic and aqueous layers were separated. The organic layer was washed with brine solution and the organic layer was distilled off under reduced pressure. Acetone (100 ml) was added to the residue at 25-30°C and stirred the reaction mixture for 45 minutes at 25-30°C. The solid was filtered, washed with acetone and dried to get the title compound. Yield: 5 grams,M.P: 238-241°C (Decomposition)Purity by HPLC: 97.7percent (Z-isomer), 1.15percent (E-isomer)

Reference： [1]Patent: US2010/137619,2010,A1 .Location in patent: Page/Page column 5-6
[2]Patent: WO2011/128911,2011,A2 .Location in patent: Page/Page column 14

9
[ 19070-16-7 ]
[ 55453-87-7 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4; Preparation of Olopatadine Hydrochloride Form A Through Grignard Reaction(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid (Compound II, R1H) (22.2 g; 0.0827 mol) was suspended in 216 g (222 mL) of tetrahydrofuran under a nitrogen atmosphere. After stirring the yellow solution for 40 minutes, 102.27 g (0.16471 mol) of 3-dimethylaminopropylmagnesium chloride solution was added over approximately two hours. The reaction mixture was then stirred and maintained at room temperature for 15 hours.Thereafter, 475 mL of aqueous ammonium chloride solution was slowly added to the reaction mixture with continuous stirring. The resulting white aqueous phase and yellow organic phase were then acidified with hydrochloric acid (37percent) with stirring in order to adjust the pH to approximately 1. The mixture was then stirred at room temperature for approximately 15 hours. Next, the mixture was heated to reflux for 2 hours and 45 minutes in order to ensure the complete evolution of the reaction (i.e., complete dehydration). The aqueous and organic phases were then separated, and the aqueous phase was extracted five times with 142 g (160 mL) of tetrahydrofuran. The resulting organics phases were then washed with brine. The phases were then separated, and the solvent of the organic phase was removed by distillation under reduced pressure to yield 46.87 g of an orange residue.Next, 220 g of deionized water and 192 g (220 mL) of isopropyl acetate were added to the residue. The mixture was then stirred for 30 minutes, and the phases were separated. The solvent of the organic phase was then removed by distillation under reduced pressure. Next, 7.9 g (10 mL) of acetone was added to the residue and then removed by distillation under vacuum.The residue obtained was then suspended in 79.1 g (100 mL) of acetone and heated with continuous stirring to reflux for 45 minutes. Thereafter, the resulting suspension was allowed to cool and was stirred overnight at room temperature. The suspension was then filtered, and the resulting yellowish solid was washed with acetone and dried under vacuum at 45° C. to yield 20.55 g of solid. (Global Yield 66.42percent; HPLC Purity: 16.06percent cis, 82.34percent trans; Cis/Trans Ratio: 0.1984).A 1 g portion of the solid obtained was treated with 3.95 g (5 mL) of acetone and 4.05 g (5 mL) of 1-butanol. The mixture was stirred and heated to reflux for 30 minutes and then allowed to cool to 0-5° C. for 2 hours. The suspension was filtered, and the resulting white solid was washed with acetone and dried under vacuum for two hours at 60° C. to yield 0.11 g of olopatadine hydrochloride Form A. (Partial Yield 11.00percent; Global Yield 6.75percent; HPLC Purity: 95.37percent cis, 4.08percent trans; Cis/Trans Ratio: 23.37).Analytical data: HPLC Purity: 95.37percent; XRD (2psi): 6.28°, 11.03°, 12.61°, 15.44°, 17.47°, 18.99°, 19.34°, 19.34°, 20.52°, 24.03°, 25.27°, 28.21° (substantially identical to FIG. 1); IR: substantially identical to FIG. 2; DSC (open pan): substantially identical to FIG. 3.

Reference： [1]Patent: US2010/137619,2010,A1 .Location in patent: Page/Page column 6

10
[ 55453-87-7 ]
[ 140462-76-6 ]

Reference： [1]Patent: WO2011/33532,2011,A1
[2]Patent: EP2385045,2011,A1

11
[ 113805-63-3 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In chlorobenzene at 80 - 85℃; for 5h;	1.III Step III: Preparation of 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 11 - dihydro dibenz [b, e] oxepin -2 - yl - acetic acid hydrochloride [Cis - Olopatadine hydrochloride].Charged 1250 ml of chlorobenzene to 120 gm of olopatadine. Raised the temperature of the reaction mixture to 80 - 85°C and started passing dry hydrochloric acid gas for 5 hours. Stopped passing hydrochloric acid gas and cooled the reaction mixture to 25 - 30°C and maintained 2.0 hours at 25 - 30°C. Filtered the solid separated and washed with cooled acetone to isolate crude 11 - (Z) - [3 - (Dimethylamino) propylidene] - 6, 1 1- dihydro dibenz [b, e] oxepin -2 - yl - acetic acid hydrochloride (Cis - Olopatadine HCl).Dried the solid till constant weight.Yield = 90.0 gm
	With hydrogenchloride at 90℃; for 5h;	2 (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid • hydrochloride Example 2 (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid • hydrochloride To a flask, 2 g (5.63 mmol) of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid and 25.37 g (11.26 mmol) of a 2.42% hydrogen chloride-toluene solution were added, and the mixture was stirred at 90°C for 7 hours. The E isomer/Z isomer ratio of the reaction mixture, when measured by HPLC, was 61.28 : 38.82. Toluene (8 mL) was distilled off at an inner pressure of 430 to 500 hPa and a temperature of 90 to 95°C, and then water was distilled off. The concentrated viscous reaction mixture was transferred to a pressure-resistant container equipped with a 100-mL teflon inner cylinder, and 5.03 g (3.38 mmol) of a 2.42% hydrogen chloride-toluene solution was added thereto. The mixture was stirred at 90°C for 5 hours. The E isomer/Z isomer ratio of the reaction mixture, when measured by HPLC, was 3.24 : 96.76. The reaction mixture was cooled to room temperature, and crystals were filtered and washed with acetone (20 mL). The crystals were dried under reduced pressure to obtain 1.46 g of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid • hydrochloride. The yield was 69.4%. The proportions of the Z isomer and the E isomer, when measured by HPLC, were 99.13% and 0.87%, respectively. 1H NMR (400 MHz, DMSO-d6) δ 2.73 (s, 6H), 2.77 (td, J = 7.6, 7.2 Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H) , 3.55 (s, 2H), 5.21 (brs, 1H), 5.65 (t, J = 7.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.0, 2.0 Hz, 1H), 7.28-7.40 (m, 4H), 10.28 (brs, 1H), 12.31 (brs, 1H)

Reference： [1]Current Patent Assignee: INDOCO REMEDIES LIMITED - WO2011/33532, 2011, A1 Location in patent: Page/Page column 15
[2]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP2385045, 2011, A1 Location in patent: Page/Page column 6

12
C₂₃H₂₈N₂O₂ [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: hydrogenchloride; water / 90 - 95 °C 1.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 2.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C

Reference： [1]Current Patent Assignee: INDOCO REMEDIES LIMITED - WO2011/33532, 2011, A1

13
[ 87486-90-6 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: dichloromethane / 0 - 20 °C / pH 9.5 - 10 2.1: tetrahydrofuran / 1 h / 0 - 5 °C 2.2: 0 - 35 °C 2.3: 0 - 5 °C / pH 9 - 10 3.1: hydrogenchloride; water / 90 - 95 °C 3.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 4.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C

Reference： [1]Current Patent Assignee: INDOCO REMEDIES LIMITED - WO2011/33532, 2011, A1

14
N, N-dimethyl-2-(11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-yl)acetamide [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 1 h / 0 - 5 °C 1.2: 0 - 35 °C 1.3: 0 - 5 °C / pH 9 - 10 2.1: hydrogenchloride; water / 90 - 95 °C 2.2: 0.5 h / 10 - 15 °C / pH 6.8 - 7.2 3.1: hydrogenchloride / chlorobenzene / 5 h / 80 - 85 °C

Reference： [1]Current Patent Assignee: INDOCO REMEDIES LIMITED - WO2011/33532, 2011, A1

15
[ 156-38-7 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 120 - 135 °C 1.2: 5 - 10 °C 2.1: acetic acid / 2.5 h / 70 - 75 °C 3.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 0 °C / Reflux 3.3: 0.25 h / 25 - 30 °C
	Multi-step reaction with 3 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 120 - 135 °C 1.2: 5 - 10 °C 2.1: acetic acid / 2.5 h / 70 - 75 °C 3.1: iodine; magnesium; ethylene dibromide / tetrahydrofuran / 1 h / Inert atmosphere; Reflux 3.2: 5 - 30 °C 3.3: 25 - 30 °C
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide; methanol / 1 h / Reflux 2.1: phosphorus pentoxide / 1 h / 110 °C 2.2: 2 h / 110 °C 3.1: sodium hydroxide / 1 h / Reflux 4.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / 0 °C 4.2: 12 h / Reflux 4.3: 1 h / 20 °C

Multi-step reaction with 4 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide; methanol / 1 h / Reflux 2.1: phosphorus pentoxide / 1 h / 110 °C 2.2: 2 h / 110 °C 3.1: sodium hydroxide / 1 h / Reflux 4.1: dimethyl sulfoxide; sodium hydride / tetrahydrofuran / 4 h / 30 - 48 °C / Inert atmosphere; Large scale 4.2: 20 h / Inert atmosphere; Large scale

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/128911, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/128911, 2011, A2
[3]Current Patent Assignee: SICHUAN ZIREN PHARMACEUTICAL - CN113620920, 2021, A
[4]Current Patent Assignee: SICHUAN ZIREN PHARMACEUTICAL - CN113620920, 2021, A

16
[ 55453-87-7 ]
[ 109-54-6 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 14: Preparation of (Z)-ll-[3-(dimehylamino)propylidene]-6,ll- dihydrodibenz[b,e] oxepin-2-acetic acid hydrochlorideIodine (0.5 g) was added to a mixture of magnesium (43 g) and tetrahydrofuran (150 ml) under nitrogen condition. Heated the reaction mixture to reflux temperature. 3- dimethyl amino propyl chloride (5 ml) followed by 1,2-dibromo ethane (2 g) were added to the reaction mixture at same reflux temperature. A solution of 3 -dimethyl amino propyl chloride (225 g) in tetrahydrofuran (200 ml) was added drop wise to the reaction mixture at reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C, further cooled to 5-10°C. A solution of l l-oxo-6,11- dihydrobenz[b,e]oxepin-2-acetic acid (50 g) in tetrahydrofuran (150 ml) was added to the reaction mixture slowly at 5-10°C and stirred for 45 minutes at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred the reaction mixture for 5 hours at same temperature. After completion of the reaction, the reaction mixture was quenched with aqueous acetic acid. Aqueous hydrochloric acid [hydrochloric acid (300 ml) in water (100 ml)] was added to the reaction mixture at a temperature below 25 °C and stirred for 10 minutes at 25-30°C. Toluene was added to the reaction mixture and stirred for 10 minutes. Both the toluene and aqueous layers were separated and the aqueous layer was washed with toluene. Both the toluene layers were combined and washed with hydrochloric acid. Both the aqueous layer and hydrochloric acid layers were combined. Heated the aqueous layer to 90-95 °C and stirred for 24 hours at same temperature Cooled the reaction mixture to 25-30°C and dichloromethane was added to the reaction mixture. Stirred the reaction mixture for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both the dichloromethane layers were combined and then dried with sodium sulfate. Distilled off the solvent completely under reduced pressure and co- distilled with acetone. Acetone was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the precipitated solid, washed with acetone and then dried to get the title compound.Yield: 30 grams; Purity by HPLC: 98.9percent (Z-isomer)

Reference： [1]Patent: WO2011/128911,2011,A2 .Location in patent: Page/Page column 22-23

17
[ 87-41-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 120 - 135 °C 1.2: 5 - 10 °C 2.1: acetic acid / 2.5 h / 70 - 75 °C 3.1: n-butyllithium / tetrahydrofuran / 1 h / 0 - 5 °C / Inert atmosphere 3.2: 0 °C / Reflux 3.3: 0.25 h / 25 - 30 °C
	Multi-step reaction with 3 steps 1.1: sodium methylate / N,N-dimethyl-formamide; methanol / 120 - 135 °C 1.2: 5 - 10 °C 2.1: acetic acid / 2.5 h / 70 - 75 °C 3.1: iodine; magnesium; ethylene dibromide / tetrahydrofuran / 1 h / Inert atmosphere; Reflux 3.2: 5 - 30 °C 3.3: 25 - 30 °C
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide; methanol / 1 h / Reflux 2.1: phosphorus pentoxide / 1 h / 110 °C 2.2: 2 h / 110 °C 3.1: sodium hydroxide / 1 h / Reflux 4.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / 0 °C 4.2: 12 h / Reflux 4.3: 1 h / 20 °C

Multi-step reaction with 4 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide; methanol / 1 h / Reflux 2.1: phosphorus pentoxide / 1 h / 110 °C 2.2: 2 h / 110 °C 3.1: sodium hydroxide / 1 h / Reflux 4.1: dimethyl sulfoxide; sodium hydride / tetrahydrofuran / 4 h / 30 - 48 °C / Inert atmosphere; Large scale 4.2: 20 h / Inert atmosphere; Large scale

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/128911, 2011, A2
[2]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/128911, 2011, A2
[3]Current Patent Assignee: SICHUAN ZIREN PHARMACEUTICAL - CN113620920, 2021, A
[4]Current Patent Assignee: SICHUAN ZIREN PHARMACEUTICAL - CN113620920, 2021, A

18
[ 55453-89-9 ]
[ 140462-76-6 ]

Reference： [1]Patent: WO2011/128911,2011,A2

19
[ 203188-29-8 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride With hydrogenchloride In water at 25 - 95℃; Stage #2: With acetic acid In water at 25 - 30℃;	9 Example-9: Preparation of Z-isomer of ll-[3-(dimethylamino)propylidene]-6-ll- dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride from the mixture of E&Z isomersAdded aqueous hydrochloric acid (15 ml) into the mixture of E&Z isomers of 1 l-[-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e]oxepin-2-aceticacid hydrochloride (5 grams) at 25-30°C and then heated the reaction mixture to 90-95°C. Stirred the reaction mixture for 12 hours at the same temperature. The reaction mixture was cooled to 25-30°C and then added acetic acid (10 ml) to it. The reaction mixture was washed with toluene and then reaction mixture was extracted with dichloromethane. Distilled off the solvent from the organic layer under reduced pressure and co-distillation with ethyl acetate. Ethyl acetate HC1 (5 ml) was added to the obtained residue at 40-45°C and stirred the reaction mixture for 30 minutes at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure and acetone (15 ml) was added to the obtained residue at 25-30°C. The reaction mixture was stirred for 45 minutes at the same temperature. The obtained solid was filtered, washed with acetone and dried get pure Z-isomer of l l-[(Z)-3-(dmiemylammo)propylidene]-6-l l-dihydrodibenz[b,e] oxepinr2-aceticacid hydrochloride.Yield: 3 gramsPurity by HPLC: 96.93% (Z-isomer), 0.9% (E-isomer)

Reference： [1]Current Patent Assignee: MSN LABORATORIES PRIVATE LIMITED - WO2011/128911, 2011, A2 Location in patent: Page/Page column 20

20
[ 19070-16-7 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: toluene; tetrahydrofuran / 2.08 h / 5 - 18 °C 2: hydrogenchloride; acetic anhydride / toluene / 6 h / 100 °C / Sealed tube

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP2385045, 2011, A1

21
11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With hydrogenchloride; acetic anhydride In toluene at 100℃; for 6h; Sealed tube;	1 (Z)-11-(3-dimethylaminopropylidene)-6,1-1-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride Example 1 (Z)-11-(3-dimethylaminopropylidene)-6,1-1-dihydrodibenz[b,e] oxepin-2-acetic aCid • hydrochloride To a pressure-resistant container equipped with a 100-mL) teflon inner cylinder, 25.37 g of a toluene solution in which 3 g (8.44 mmol) of 11-hydroxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, 0.95 g (9.3 mmol) of acetic anhydride and 0.62 g (16.9 mmol) of hydrogen chloride were dissolved was added, and then the container was hermetically sealed. This container was heated up to 100°C, and the solution was stirred for 6 hours. The container was cooled to room temperature, and, thereafter, crystals were filtered, washed with 15 mL of acetone, and then dried under reduced pressure to obtain 2.51 g of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihycirodibenz[b,e]oxepin-2-acetic acid • hydrochloride. The yield was 79.5%. When measured by HPLC, the proportions of the Z isomer and the E isomer were 99.40% and 0.60%, respectively.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP2385045, 2011, A1 Location in patent: Page/Page column 6

22
[ 1354633-17-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: hydrogenchloride / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2
	Multi-step reaction with 6 steps 1.1: hydrogenchloride / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2
	Multi-step reaction with 6 steps 1.1: hydrogenchloride; water / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2

Multi-step reaction with 6 steps 1.1: hydrogenchloride; water / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[3]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[4]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

23
[ 1354633-33-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium carbonate / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2
	Multi-step reaction with 6 steps 1.1: potassium carbonate / methanol 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2
	Multi-step reaction with 6 steps 1.1: Alkaline conditions; Enzymatic reaction 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2

Multi-step reaction with 6 steps 1.1: Alkaline conditions; Enzymatic reaction 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[3]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[4]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

24
[ 1354633-20-7 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide 2.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2
	Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide 2.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

25
[ 916243-38-4 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 2.1: pyridine / 5 - 20 °C 3.1: methanol; water / 3 h / Reflux 4.1: water; sodium hydroxide / methanol / 2 h / Reflux 4.2: pH 2
	Multi-step reaction with 4 steps 1.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 2.1: pyridine / 5 - 20 °C 3.1: methanol; water / 3 h / Reflux 4.1: water; sodium hydroxide / methanol / 2 h / Reflux 4.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

26
[ 833485-11-3 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: iodine; silver sulfate / methanol / 2 h / 18 °C 2.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 3.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2
	Multi-step reaction with 6 steps 1.1: iodine; silver sulfate / methanol / 2 h / 18 °C 2.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 3.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 4.1: pyridine / 5 - 20 °C 5.1: methanol; water / 3 h / Reflux 6.1: water; sodium hydroxide / methanol / 2 h / Reflux 6.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

27
[ 916243-37-3 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 2.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2
	Multi-step reaction with 5 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 2.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 3.1: pyridine / 5 - 20 °C 4.1: methanol; water / 3 h / Reflux 5.1: water; sodium hydroxide / methanol / 2 h / Reflux 5.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

28
[ 916243-39-5 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: pyridine / 5 - 20 °C 2.1: methanol; water / 3 h / Reflux 3.1: water; sodium hydroxide / methanol / 2 h / Reflux 3.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

29
methyl 2-{11-[(Z)-3-(methanesulfonyloxy)propylidene]-6,11-dihydrodibenzo[b,e]oxepin-2-yl}acetate [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: methanol; water / 3 h / Reflux 2.1: water; sodium hydroxide / methanol / 2 h / Reflux 2.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

30
[ 14199-15-6 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: iodine; silver sulfate / methanol / 2 h / 18 °C 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: iodine; silver sulfate / methanol / 2 h / 18 °C 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: hydrogenchloride / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2

	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: hydrogenchloride; water / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: pyridine 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: potassium carbonate / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: pyridine 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: Alkaline conditions; Enzymatic reaction 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: hydrogenchloride / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: potassium carbonate / N,N-dimethyl-formamide 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: hydrogenchloride; water / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: pyridine 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: potassium carbonate / methanol 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 9 steps 1.1: bromine; acetic acid 2.1: pyridine 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 4.1: Alkaline conditions; Enzymatic reaction 5.1: potassium carbonate / N,N-dimethyl-formamide 6.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 7.1: pyridine / 5 - 20 °C 8.1: methanol; water / 3 h / Reflux 9.1: water; sodium hydroxide / methanol / 2 h / Reflux 9.2: pH 2
	Multi-step reaction with 4 steps 1.1: potassium carbonate / ethanol / 24 h / Reflux 2.1: potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride / ethanol / 3 h / Reflux; Large scale 2.2: pH 1 - 2 / Large scale 3.1: acetic anhydride / 2 h / 80 - 90 °C / Large scale 4.1: sodium hydride / tetrahydrofuran / 4 h / 20 - 60 °C / Inert atmosphere; Large scale 4.2: Large scale

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[3]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[4]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[5]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[6]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[7]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[8]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[9]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[10]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[11]Current Patent Assignee: SHIJIAZHUANG CHUANGJIAN PHARMACEUTICAL TECHNOLOGY - CN104262318, 2016, B

31
Methyl-4-acetoxy-3-brom-phenylacetat [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: potassium carbonate / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: Alkaline conditions; Enzymatic reaction 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: potassium carbonate / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2

Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: Alkaline conditions; Enzymatic reaction 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[3]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[4]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

32
[ 34918-57-5 ]
[ 140462-76-6 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[2]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[3]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[4]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[5]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[6]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[7]Organic Process Research and Development,2012,vol. 16,p. 225 - 231
[8]Organic Process Research and Development,2012,vol. 16,p. 225 - 231

33
[ 100126-08-7 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: hydrogenchloride / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: hydrogenchloride; water / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: hydrogenchloride / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2

Multi-step reaction with 7 steps 1.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide 2.1: hydrogenchloride; water / methanol 3.1: potassium carbonate / N,N-dimethyl-formamide 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[3]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[4]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

34
[ 113806-01-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
88.4%	Stage #1: (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenz<b,e>oxepin-2-acetic acid methyl ester With water; sodium hydroxide In methanol for 2h; Reflux; Stage #2: With hydrogenchloride In water
66%	Stage #1: (Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenz<b,e>oxepin-2-acetic acid methyl ester With sodium hydroxide In methanol; water at 20℃; for 3h; Stage #2: With hydrogenchloride In tetrahydrofuran; water for 0.0833333h;

Reference： [1]Location in patent: experimental part Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Location in patent: experimental part Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

35
[ 3433-80-5 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: iodine; silver sulfate / methanol / 2 h / 18 °C 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 4.1: piperidine; formic acid; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 3 h / 92 °C / Inert atmosphere 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2
	Multi-step reaction with 7 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 25 °C 2.1: iodine; silver sulfate / methanol / 2 h / 18 °C 3.1: copper(l) iodide; bis-triphenylphosphine-palladium(II) chloride; triethylamine / N,N-dimethyl-formamide / 5 h / 25 °C / Inert atmosphere 4.1: piperidine; formic acid; 1,3-bis-(diphenylphosphino)propane; palladium diacetate / acetonitrile / 60 °C 5.1: pyridine / 5 - 20 °C 6.1: methanol; water / 3 h / Reflux 7.1: water; sodium hydroxide / methanol / 2 h / Reflux 7.2: pH 2

Reference： [1]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]
[2]Nishimura, Koichiro; Kinugawa, Masahiko [Organic Process Research and Development, 2012, vol. 16, # 2, p. 225 - 231]

36
[ 875050-49-0 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h

	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[3]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[4]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[5]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[6]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

37
methyl [4-(2-formylbenzyloxy)-3-iodophenyl]acetate [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h
	Multi-step reaction with 3 steps 1.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 1.2: 2.5 h / 20 °C 2.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 2.2: 24 h / 60 °C 3.1: sodium hydroxide / methanol; water / 3 h / 20 °C 3.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

38
[ 875050-51-4 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 1.2: 24 h / 60 °C 2.1: sodium hydroxide / methanol; water / 3 h / 20 °C 2.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

39
(Z)-methyl 3-[4-(dimethylamino)but-1-enyl]-4-(2-iodobenzyloxy)phenylacetate [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 1.2: 24 h / 60 °C 2.1: sodium hydroxide / methanol; water / 3 h / 20 °C 2.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

40
(Z)-methyl 4-{2-[4-(dimethylamino)but-1-enyl]benzyloxy}-3-iodophenylacetate [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 1.2: 24 h / 60 °C 2.1: sodium hydroxide / methanol; water / 3 h / 20 °C 2.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

41
[ 60633-91-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

42
[ 61874-04-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[3]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[4]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[5]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[6]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

43
[ 5407-04-5 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium iodide / acetonitrile / 132 h / Reflux 1.2: 0.5 h / 20 - 45 °C 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: sodium iodide / acetonitrile / 132 h / Reflux 1.2: 0.5 h / 20 - 45 °C 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: sodium iodide / acetonitrile / 132 h / Reflux 1.2: 0.5 h / 20 - 45 °C 2.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[3]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

44
[ 59473-45-9 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: lithium hexamethyldisilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[3]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[4]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[5]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[6]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

45
[ 352469-17-1 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h
	Multi-step reaction with 4 steps 1.1: potassium carbonate; sodium iodide / acetonitrile / 3 h / 20 °C / Reflux 2.1: potassium hexamethylsilazane / toluene / 1 h / 20 °C 2.2: 2.5 h / 20 °C 3.1: tetrabutyl-ammonium chloride; potassium carbonate / water; acetonitrile / 0.25 h / 20 °C 3.2: 24 h / 60 °C 4.1: sodium hydroxide / methanol; water / 3 h / 20 °C 4.2: 0.08 h

Reference： [1]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]
[2]Bosch, Joan; Bachs, Jordi; Gomez, Antonia M.; Griera, Rosa; Ecija, Marta; Amat, Mercedes [Journal of Organic Chemistry, 2012, vol. 77, # 14, p. 6340 - 6344]

46
[ 113805-63-3 ]
[ 949141-22-4 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In isopropyl alcohol at 27℃; Overall yield = 80 %; Overall yield = 0.93 g;	7 The salt was added portionwise to aqueous NaHCO3, with ice cooling and the resultant solution was neutralized with 4 N HC1. The crude product was desalinated with HP-10and recrystallized successively from 2-propanol and water to give 1.14 g (66%) of the free base 8 mp 188-189.5 “C; ‘H NMR (DMSO-d6): 2.15 (s,6 H), 2.40-2.60 (m, 4 H), 3.45 (8, 2 H), 5.00-5.55 (br, 2 H), 5.66 (t, J = 6.7 Hz, 1 H), 6.75 (d, J = 8.1 Hz, I H),7.0-7.1 (m, 2 H), 7.2-7.4 (m, 4 H); MS mlz 337 (M+). The free base 8 (1.14 g, 35 mmol) was added to a 8 N solution of HC1 in 2-propanol (0.8 mL, 64 mmol) and themixture was stirred at room temperature (27°C). After being concentrated, the residue was recrystallized from acetone-water (2/1) to give 0.93 g (80%) of 8 as hydrochloride salt: rnp 248 °C dec. (Compound 1). The E/Z ratio was determined by analyzing the ‘H NMR spectrum of compound 7, by integration of characteristic protons at ö 5.69 (Z) and ö 6.02 (E) which appear as triplets.

Reference： [1]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2014/147647, 2014, A1 Location in patent: Paragraph 0029

47
(E,Z)-11-<3-(dimethylamino)propylidene>-6,11-dihydrodibenz<b,e>oxepin-2-acetic acid methyl ester [ No CAS ]
[ 949141-22-4 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydroxide; water / methanol / 1 h / Reflux 1.2: 27 °C 2.1: sodium hydrogencarbonate / water 3.1: hydrogenchloride / isopropyl alcohol / 27 °C

Reference： [1]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2014/147647, 2014, A1

48
6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid trimethyl-silyl ester [ No CAS ]
[ 27710-82-3 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
		At room temperature and under an argon atmosphere, a solution of 6,1 1-dihydro-li- oxo-dibenz[b,e]oxepin-2-acetic acid (5.0 g, 18.64 mmol, I eq) in anhydrous THF (20 ml) was prepared. N,O-bis(trimethyl-silyl)acetamide (4.56 ml, 18.64 mmol, 1 eq) was added and the solution stirred for 1 hour. At room temperature and under an argon atmosphere, a suspension of 3-dimethylaminopropyltriphenylphosphoniumbromide hydrobromide (23.7 g, 46.6 mmol, 2.5 eq) in anhydrous THF (80 ml) was prepared. To this suspension the previously prepared solution of trimethylsilyl ester was then added, followed by the sodium hydride (60% in mineral oil, 6.08 g, 152.1 mmol, 7.85 eq). The resulting mixture was heated at 60C for 3 hours and the consumption of the starting material was followed by LC-MS. The reaction mixturewas cooled to 0C and carefully quenched with 40 ml of THF/H20 1/1 (v/v). After dilution with water (100 ml), the mixture was washed with toluene (100 ml) and two times with 2-methylTllF (100 ml). The aqueous phase was acidified to pH 1 with 37% hydrochloric acid (8 ml) and then washed with toluene (100 ml). Sodium acetate was added up to pH 5 and the aqueous phase was extracted two times with a mixture of 2-methylTHF/2-propanol 2:1 (v/v) (300 ml). The organic layer wasevaporated under reduced pressure. The crude material (8.7 g) was taken up with acetone (90 ml) and acidified with 37% hydrochloric acid, obtaining the precipitation of the cis isomer of olopatadine hydrochloride. The white solid was filtered and washed with acetone. Yield = 55%.

Reference： [1]Patent: WO2015/63579,2015,A1 .Location in patent: Paragraph 7; 8

49
[ 55453-87-7 ]
3-dimethylaminopropyltriphenylphosphine hydrobromide [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
1.120 kg		Taking example 2 step 4 the obtained intermediate IV (Z/E = 65.12/32 . 82) 2 kg (5.9mol) dissolved in 10L acetone, dropping 600mL8NHCl, precipitating a large amount of white solid. After the add, continue to stir 1h, filtering, because 2L acetone washing, drying the white solid obtained 1120g, olopatadine hydrochloride for the final product, the yield is 56percent. (Purity 99.79percent, Z/E=99.79/0 . 08)

Reference： [1]Patent: CN104262318,2016,B .Location in patent: Paragraph 0045; 0046

50
[ 1009378-92-0 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium hydroxide; N-benzyl-N,N,N-triethylammonium chloride / ethanol / 3 h / Reflux; Large scale 1.2: pH 1 - 2 / Large scale 2.1: acetic anhydride / 2 h / 80 - 90 °C / Large scale 3.1: sodium hydride / tetrahydrofuran / 4 h / 20 - 60 °C / Inert atmosphere; Large scale 3.2: Large scale

Reference： [1]Current Patent Assignee: SHIJIAZHUANG CHUANGJIAN PHARMACEUTICAL TECHNOLOGY - CN104262318, 2016, B

51
[ 34040-62-5 ]
[ 140462-76-6 ]

Reference： [1]Patent: CN104262318,2016,B

52
[ 55453-87-7 ]
N-(3-chloropropyl)-N,N-dimethylamine hydrochloride [ No CAS ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
90.5%		Under nitrogen was added to the reaction flask N, of N- dimethylamino-chloropropane hydrochloride (150mmol) 23.71g ,, was added potassium bromide (300mmol) 35.7g, stirred for 1 hour, hexamethylphosphoramide (200mmol) 35.84g, dimethyl sulfoxide 150ml, was heated at reflux, the reaction was stirred for 2 hours. after completion of the reaction, dimethyl sulfoxide was dissolved in 30ml of <strong>[55453-87-7]Isoxepac</strong> (100mmol) 26.83g of the solution, first at room temperature for 1 hour, then 20 reaction temperature, after completion of the reaction the reaction solution was added 150ml of water, the solvent was removed by distillation under reduced pressure, the residue was added 30percent hydrochloric acid was dissolved in ethanol, the crystallization is added petroleum ether, filtered and washed to obtain olopatadine hydrochloride (90.5 mmol) 33.84g, yield 90.5percent, HPLC purity 99.3percent, E-type content of 0.05percent.

Reference： [1]Patent: CN105693685,2016,A .Location in patent: Paragraph 0056; 0057

53
[ 55453-87-7 ]
[ 18355-96-9 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
60.6%		(1) Add 200g (3-dimethylaminopropyl)triphenylphosphine bromide to the three-necked flask, and then add 400g of anhydrous tetrahydrofuran, turn on the stirring, and control the temperature to 20-22 C.After adding 40 g of NaH, the temperature was raised to reflux after the addition, and the reaction was carried out for 1 h.Then add 100g of isoc acid, stir under reflux for 2 hours, then lower the temperature to 0 ~ 15 , slowly add 30g of anhydrous methanol,Then, 400 g of a 50% mass concentration tetrahydrofuran aqueous solution was added, and finally 1600 g of water was added to quench the reaction.The reaction solution was adjusted to pH 6 ± 0.2 with concentrated hydrochloric acid, and then distilled to dryness under reduced pressure.The solid was dissolved in 1400 g of acetone, stirring was started, 40 g of concentrated hydrochloric acid was added, and a white solid was precipitated.After the dropwise addition was completed, the temperature was lowered to 10 to 15 C and stirred for another 10 hours.Suction filtration to obtain a white solid, dried in an oven to constant weight. The product was crude olopatadine hydrochloride,The purity is 98.67% (Z / E = 98.67: 0.82), the yield is 62.4g, and the yield in this step is 60.6%.

Reference： [1]Patent: CN110343086,2019,A .Location in patent: Paragraph 0012; 0023

54
[ 55453-90-2 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydroxide / 1 h / Reflux 2.1: dimethyl sulfoxide; sodium hydride / tetrahydrofuran / 4 h / 30 - 48 °C / Inert atmosphere; Large scale 2.2: 20 h / Inert atmosphere; Large scale

Reference： [1]Current Patent Assignee: SICHUAN ZIREN PHARMACEUTICAL - CN113620920, 2021, A

55
[ 55453-87-7 ]
[ 27710-82-3 ]
[ 113806-05-6 ]
[ 140462-76-6 ]

Yield	Reaction Conditions	Operation in experiment
9.09%	Stage #1: anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h; Stage #2: isoxepac In tetrahydrofuran; hexane for 12h; Reflux; Stage #3: olopatadine With hydrogenchloride In tetrahydrofuran; hexane; isopropyl alcohol at 20℃; for 1h;	4-5 In a 250mL three-necked flask , Add 14.4g (28mmol) of 3-dimethylaminopropyl triphenylphosphonium hydrobromide, 80mL of THF, and slowly add 1.92mol/L of n-butyllithium to 40mL of n-hexane solution under ice-salt bath cooling, add After completion, the reaction was stirred for 1 hour below 0°C, 4g (14mmol) of compound 6 was added in 20mL THF solution, heated to reflux for 12 hours, cooled, evaporated to remove THF, the residue was dissolved with 20mL of water, extracted with ether (15mL×2), and the aqueous solution Adjust the pH to 2 with concentrated hydrochloric acid, extract with ethyl acetate (15mL×2), and then neutralize the aqueous solution with 4mol/L sodium hydroxide solution to a pH of 7, and concentrate to remove water to obtain 3.1g of the crude product of compound 7. 65%. The crude product was recrystallized twice with isopropanol to obtain (Z)-70.97g, with a yield of 31.2%; Dissolve 0.45 g of olopatadine prepared above in 2 mL of isopropanol, pass hydrogen chloride gas, stir at room temperature for 1 h, concentrate, and recrystallize the residue with acetone. 0.25 g of white powdery solid was obtained, the yield was 50%, and the total yield was 9.09%.

Reference： [1]Current Patent Assignee: SICHUAN ZIREN PHARMACEUTICAL - CN113620920, 2021, A Location in patent: Paragraph 0039; 0044-0045

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	140462-76-6	MDL No. :	MFCD00875716
Formula :	C₂₁H₂₄ClNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HVRLZEKDTUEKQH-NOILCQHBSA-N
M.W :	373.87	Pubchem ID :	5282402
Synonyms :	KW4679;ALO4943A;Patanase;Pataday;Olopatadine (hydrochloride);Olopatadine hydrochloride	Chemical Name :	(Z)-2-(11-(3-(Dimethylamino)propylidene)-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetic acid hydrochloride

Num. heavy atoms :	26
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.29
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	106.19
TPSA :	49.77 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.97 cm/s

[ CAS No. 140462-76-6 ] {[proInfo.proName]}

Quality Control of [ 140462-76-6 ]

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Physicochemical Properties

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Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 140462-76-6 ]

Application In Synthesis of [ 140462-76-6 ]

[ 140462-76-6 ] Synthesis Path-Downstream 1~55

Precautionary Statements-General

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Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.27
Log Po/w (WLOGP) :	4.24
Log Po/w (MLOGP) :	3.1
Log Po/w (SILICOS-IT) :	4.05
Consensus Log Po/w :	2.73

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-3.6
Solubility :	0.094 mg/ml ; 0.000251 mol/l
Class :	Soluble
Log S (Ali) :	-2.95
Solubility :	0.418 mg/ml ; 0.00112 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.9
Solubility :	0.000467 mg/ml ; 0.00000125 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.93

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P264-P270-P273-P301+P310+P330-P391-P405-P501	UN#:	2811
Hazard Statements:	H301-H400	Packing Group:	Ⅲ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling