Name: 146137-76-0|2-Fluoro-5-iodobenzaldehyde|98%
Brand: Ambeed
SKU: A200354
Rating: 96 (35 reviews)

1
[ 2365-48-2 ]
[ 146137-76-0 ]
[ 146137-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride 1.) DMSO, 20 deg C, 2.) DMSO, 2-5 min; Yield given. Multistep reaction;
	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	7 A mixture of 5.00 g of 2-fluoro-5-iodobenzaldehyde, 2.76 g of methyl thioglycolate, 5.53 g of potassium carbonate,and 50 ml of N,N-dimethylformamide was stirred for 2 hours at 80°C. The reaction mixture was cooled to roomtemperature, and then the precipitated solids were separated by filtration. Concentrated hydrochloric acid was addedto the filtrate, and the precipitated solids were collected by filtration and dried under reduced pressure, thereby obtaining953 mg of 5-iodobenzo[b]thiophene-2-carboxylic acid (hereinafter, described as a "compound 15 of the present invention").
	With triethylamine In dimethyl sulfoxide at 20 - 70℃; for 5h; Inert atmosphere;	Methyl 7-iodobenzo[b]thiophene-2-carboxylate (11) General procedure: The crude starting material (10) was dissolved in DMSO (25 mL) and methyl thioglycolate (2.6 mL, 1.1 equiv.) was added dropwise under Ar at RT. Triethylamine (7.45 mL, 2.2 equiv.) was then added and the mixture was heated at 70 °C for 5 hours. The reaction mixture was cooled to RT and poured slowly into vigorously stirred ice-water (250 mL). After 30 min of stirring, a light yellow precipitate was collected by filtration, rinsed with H2O, and dried in vacuo to afford a crude yellow solid (6.40 g, 80% crude yield). The product was used for the next reaction without further purification.

Reference： [1]Bridges, Alexander J.; Lee, Arthur; Maduakor, Emmanuel C.; Eric Schwartz [Tetrahedron Letters, 1992, vol. 33, # 49, p. 7499 - 7502]
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP2926660, 2015, A1 Location in patent: Paragraph 0264
[3]Hur, Wooyoung; Rosen, Hugh; Gray, Nathanael S. [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 1, p. 1 - 5]

2
[ 352-34-1 ]
[ 33513-42-7 ]
[ 146137-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium diisopropyl amide 1.) hexane, THF, -78 deg C, 2.) -78 deg C; Yield given. Multistep reaction;
	Stage #1: 4-fluoro-1-iodobenzene With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.166667h; Inert atmosphere; Stage #2: N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 0.166667h; Inert atmosphere;	2-Fluoro-3-iodobenzaldehyde (10) General procedure: To a stirred solution of 1-fluoro-2-iodobenzene (4.6 mL, 39 mmol) in THF (39 mL)at -78°C was added 1.8 M LDA solution (22.8 mL, 1.05 equiv.) dropwise over 10 minunder Ar. After 10 min, DMF (3.65 mL, 1.2 equiv.) was added dropwise and the reactionwas stirred for 10 min at -78°C. The reaction was quenched at -78°C by the rapid additionof 10 mL of acetic acid followed by 80 mL of H2O. The cooling bath was removed, andthe aqueous phase was extracted with diethyl ether (70 mL x 3). The organic layers werecombined and washed with 0.5 N HCl solution (150 mL x 2), H2O (150 mL x 2), and brine(150 mL). The organic solution was dried over MgSO4, filtered, and concentrated underreduced pressure. The resulting brown solid (6.25 g, 64% crude yield) was dried in vacuoand used for the next reaction without further purification.

Reference： [1]Bridges, Alexander J.; Lee, Arthur; Maduakor, Emmanuel C.; Eric Schwartz [Tetrahedron Letters, 1992, vol. 33, # 49, p. 7499 - 7502]
[2]Hur, Wooyoung; Rosen, Hugh; Gray, Nathanael S. [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 1, p. 1 - 5]

3
[ 146137-76-0 ]
[ 334971-55-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 2-Fluoro-5-iodo-benzaldehyde With sodium hydroxide; hydroxylamine hydrochloride In ethanol; water at 25 - 30℃; for 2h; Ice cooling; Stirring; Stage #2: With hydrogenchloride In ethanol; water at 25 - 30℃;	50 PREPARATIONS; Preparation 50; 2-Fluoro-5-iodobenzaldehyde Oxime To a mixture of 2-fluoro-5-iodobenzaldehyde (9.4 mmol) in H2O (5 ml), EtOH (5 ml), and ice (4.5 g) was added hydroxylamine hydrochloride (0.67 g, 10.3 mmol, 1.1 eq.). Then, 23.6 mmol of 50% NaOH (1 g in 1 ml H2O, 2.5 eq.) was added with stirring. Enough ice to keep the temperature at 25-30° C. was added. The reaction was stirred for 2 h, acidified with conc. HCl to pH 4 (ice was added to keep the temperature at 25-30° C.), and extracted with Et2O. The combined organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel using (1-10%) ethyl acetate in hexanes to give 2-fluoro-5-iodobenzaldehyde oxime (2.06 g, 78% over 2 steps). [00443] MS (ES) (m/z) 264.0 [M-1]. IR (KBr) 3575.39, 1478.30, 1262.00, 1238.75, 1109.23, 964.08, 810.03, 809.87 cm-1.
	With hydroxylamine hydrochloride; sodium carbonate In methanol; water at 20℃; for 2h;	1.1.1 General procedure of preparation of 2 General procedure: To a mixture of aldehyde 1 (10.0 mmol) in 30% methanol aqueous solution, NH2OH·HCl (0.695 g, 10.0 mmol) was added slowly. After the NH2OH·HCl was fully dissolved, Na2CO3 (0.53 g 5.0 mmol) was added and then the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried to afford intermediate 2 as white solids.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US6670373, 2003, B1 Location in patent: Page column 55
[2]Pang, Guang Xian; Niu, Chao; Mamat, Nuramina; Aisa, Haji Akber [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 12, p. 2674 - 2677]

4
[ 699016-02-9 ]
[ 146137-76-0 ]
[ 699016-31-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 60℃; for 2h;	117 Preparation 117 Under nitrogen at room temperature, to a solution of 2,2,2-trifluoro-N-[(1R)-2-(4-mercaptophenyl)-1-methylethyl]acetamide (2.0 g) in N,N-dimethylformamide (20 ml) was added 2-fluoro-5-iodobenzaldehyde (2.09 g) and potassium carbonate (1.15 g), and the mixture was stirred at 60° C. for 2 hours.The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate.The organic layer was washed successively with water (two times) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel (hexane/chloroform=1:3 to only chloroform) to give 2,2,2-trifluoro-N-[(1R)-2-[4-[(2-formyl-4-iodophenyl)thio]phenyl]-1-methylethyl]acetamide (3.06 g). (+)ESI-MS (m/z): 516 (M+Na)+
	With potassium carbonate In DMF (N,N-dimethyl-formamide) at 60℃; for 2h;	117 Under nitrogen at room temperature, to a solution of 2,2, 2-TRIFLUORO-N-[(LR)-2-(4-MERCAPTOPHENYL)-1- methylethyl] acetamide (2.0 g) in N, N-dimethylformamide (20 ml) was added 2-FLUORO-5-IODOBENZALDEHYDE (2.09 g) and potassium carbonate (1.15 g), and the mixture was stirred at 60°C for 2 hours. The resulting mixture was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic layer was washed successively with water (two times) and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/chloroform = 1: 3 to only chloroform) to give 2,2, 2- TRIFLUORO-N- [ (1R)-2- [4- [ (2-FORMYL-4-IODOPHENYL) THIO] PHENYL]- 1-METHYLETHYL] ACETAMIDE (3.06 g). (+) ESI-MS (m/z): 516 (M+Na) +

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US2004/106653, 2004, A1 Location in patent: Page/Page column 43
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2004/45610, 2004, A1 Location in patent: Page/Page column 139

5
[ 146137-76-0 ]
[ 438050-27-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 2-Fluoro-5-iodo-benzaldehyde With sodium tetrahydroborate In methanol at 0 - 20℃; for 1.33333h; Stage #2: With water In ethyl acetate	17.1 Step 1) (2-Fluoro-5-iodo-phenyl)-methanol Step 1) (2-Fluoro-5-iodo-phenyl)-methanol To an ice cooled solution of 2-Fluoro-5-iodo-benzaldehyde (1.0 g, 4.0 mmol) in CH3OH (10 mL) was added NaBH4 (0.182 g, 4.8 mmol) in two portions over 10 min. The reaction mixture was stirred for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed sequentially with 2*H2O (20 mL) and brine (20 mL). The organic layer was dried (MgSO4), and concentrated. The crude material was purified by flash chromatography (30% Ethyl acetate/Petroleum Ether) to afford the titled compound (1.0 g, 99%) as a white solid, identified by NMR and mass spectral analyses. Mp: 42° C. MS (EI+): 252 (M+).
88%	With sodium tetrahydroborate In tetrahydrofuran; methanol	33 Dissolve 2-fluoro-5-iodobenzaldehyde, (prepared essentially as described in Tet. Lett., 33, 7499, (1992)), (6. 54 g, 26. 1 mmol) in 4 : 1 tetrahydrofuran : methanol (200 mL) and treat with sodium borohydride (1. 98 g, 52. 3 mmol) and stir overnight. Concentrate the reaction mixture, then partition between ethyl acetate and water. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify the crude oil by silica gel chromatography, eluting with 85 : 15 hexanes : ethyl acetate, to give the title compound as a white crystalline solid (5. 8 g, 88%). 1HNMR (400 MHz, DMSO-d6) 6 4. 46 (d, J = 5. 7 Hz, 2H), 5. 31 (t, J = 5. 7 Hz, 1H), 6. 96 (dd, J = 10. 1, 8. 8 Hz, 1H), 7. 58 (ddd, J = 8. 6, 4. 8, 2. 4 Hz, 1H), 7. 72 (dd, J = 6. 8, 2. 4 Hz, 1H).

Reference： [1]Current Patent Assignee: PFIZER INC - US2009/48320, 2009, A1 Location in patent: Page/Page column 36
[2]Current Patent Assignee: ELI LILLY & CO - WO2005/94822, 2005, A1 Location in patent: Page/Page column 41

6
[ 866683-29-6 ]
[ 146137-76-0 ]
[ 866683-74-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With tetrabutyl ammonium fluoride; triethylamine In tetrahydrofuran at -78 - 60℃; for 2.16667h;	38 Combine 5-trimethylsilanylethynyl-nicotinonitrile (1. 30 g, 11. 5 mmol), (prepared as described in PREPARATION 3), 2-fluoro-5-iodobenzaldehyde (3. 45 g, 13. 8 mmol, (prepared essentially as described in Tet. Lett., 33, 7499, (1992)), bis (triphenylphosphine) palladium (II) dichloride (404 mg, 0. 575 mmol), copper (I) iodide (219 mg, 1. 15 mmol), and triethylamine (22. 4 mL, 161 mmol) in tetrahydrofuran (9 mL). Cool the suspension to-78 °C and treat with a 1. 0 M solution of tetrabutylammonium fluoride (11. 5 mL) in tetrahydrofuran. After 10 min, heat to 60 °C for 2 h. Cool to room temperature and filter through diatomaceous earth washing with ethyl acetate. Purify the crude product by silica gel chromatography, eluting with a gradient from 80 : 20 to 60 : 40 hexanes : ethyl acetate, to give the title compound as an off-white crystalline solid (1. 3 g, 45%). 1HNMR (400 MHz, DMSO-d6) 6 7. 51 (dd, J = 10. 5, 8. 8 Hz, 2H), 7. 93 (ddd, J = 8. 7, 4. 9, 2. 3 Hz, 1H), 8. 02 (dd, J = 6. 6, 2. 2 Hz, 1H), 8. 56 (t, J = 2. 2 Hz, 1H), 9. 01 (d, J = 2. 2 Hz, 1H), 9. 02 (d, J = 2. 2 Hz, 1H), 10. 16 (s, 1H) ; MS (ES) : 7n/z = 251. 0 [M-H]-.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/94822, 2005, A1 Location in patent: Page/Page column 43

7
[ 7103-09-5 ]
[ 146137-76-0 ]
[ 931430-31-8 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 4-but-1-enylmagnesium bromide; 2-Fluoro-5-iodo-benzaldehyde In tetrahydrofuran at -78 - -30℃; for 1.66667h; Stage #2: With ammonium chloride In tetrahydrofuran; water	83.a.1 Step a) Preparation of 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene A stirred solution of 2-fluoro-5-iodo-benzaldehyde (0.714 g, 2.86 mmol) in dry THF at -78° C. under nitrogen was treated over 10 min with 0.5 M 3-butenyl magnesium bromide in THF (6.85 mL, 3.43 mmol), stirred for 0.5 h, allowed to warm to -30° C. over 1 h, quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The extracts were combined, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue by flash chromatography (5% to 10% ethyl acetate/petroleum ether) gave 1-(2-fluoro-5-iodo-phenyl)pent-4-en-1-ol as a clear oil, 565 mg (65% yield). A portion of this oil (0.25 g, 0.82 mmol) was dissolved in dry methylene chloride, cooled to 0° C., treated with boron triflouride etherate (0.1 mL, 0.81 mmol), stirred for 15 minutes under a nitrogen atmosphere, warmed to room temperature for 1 h, and quenched with saturated sodium bicarbonate. The reaction mixture was partitioned between methylene chloride and H2O; and the aqueous phase was extracted with methylene chloride. The organic phase and the extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to give 1-fluoro-4-iodo-2-pent-4-en-1-ylbenzene as a clear oil, 0.18 g (76% yield).

Reference： [1]Current Patent Assignee: PFIZER INC - US2007/72925, 2007, A1 Location in patent: Page/Page column 45

8
[ 146137-76-0 ]
[ 30923-92-3 ]
[ 1028459-44-0 ]

Yield	Reaction Conditions	Operation in experiment
25%	Stage #1: 2-Fluoro-5-iodo-benzaldehyde; cyclopentylhydrazine With caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; Stage #2: With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at 150℃; for 5h;	32 l-Cyclopentyl-5-iodo-lH-indazole (32c); A mixture of 2-fluoro-5-iodobenzaldehyde (500 mg, 2 mmol), cyclopentylhydrazine (273 mg, 2 mmol), and cesium carbonate (1.91 g, 5 mmol) in NMP (5ml) was stirred at 100 0C overnight. Then KOfBu (560 mg, 5 mmol) and DMF (10 ml) were added, and the mixture was stirred at 150 0C for 5 h. After cooling to room temp., the mixture was diluted with ethyl acetate (100 ml), and washed with water (3 x 50 ml), and dried. Eveporation of solvent afforded balch residue, which was dissolved in acetonitrile (50 ml), and the insoluble material was removed vy filtration. Flash chromatography on silica gel («- heptane/ethyl acetate) afforded yellow oil, 158 mg (25 %). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J= 0.9 Hz, IH), 7.91 (s, IH), 7.59 (dd, J= 8.8, 1.5 Hz, 1 H), 7.26 (d, J = 9.4 Hz, 1 H, partially covered tiwh the signal of solvent), 4.95 (quintet, J= 7.4 Hz, IH), 2.17 (m, 4H), 1.98 (m, 2H), 1.75 (m, 2H). APCI-MS: m/z 313 [MH+]
25%	Stage #1: 2-Fluoro-5-iodo-benzaldehyde; cyclopentylhydrazine With caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; Stage #2: With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at 150℃; for 5h;	130 A mixture of 2-fluoro-5-iodobenzaldehyde (500 mg, 2 mmol), cyclopentylhydrazine (273 mg, 2 mmol), and cesium carbonate (1.91 g, 5 mmol) in NMP (5ml) was stirred at 100 °C overnight. Then KOffiu (560 mg, 5 mmol) and DMF (10 ml) were added, and the mixture was stirred at 150 °C for 5 h. After cooling to r.t, the mixture was diluted with ethyl acetate (100 ml), and washed with water (3 x 50 ml), and dried. Eveporation of solvent afforded balch residue, which was dissolved in acetonitrile (50 ml), and the insoluble material was removed by filtration. Flash chromatography on silica gel (ϖ-heptane/ethyl acetate) afforded yellow oil, 158 mg (25 %). APCI-MS: m/z 313 [MH^]1HNMR (400 MHz, CDCl3) δ 8.08 (d, J= 0.9 Hz, IH), 7.91 (s, IH), 7.59 (dd, J= 8.8, 1.5 Hz, IH), 7.26 (d, J= 9.4 Hz, IH, partially covered tiwh the signal of solvent), 4.95 (quintet, J = 7.4 Hz, IH), 2.17 (m, 4H), 1.98 (m, 2H), 1.75 (m, 2H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/63116, 2008, A1 Location in patent: Page/Page column 54
[2]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/76048, 2008, A1 Location in patent: Example 130

9
[ 4930-98-7 ]
[ 146137-76-0 ]
[ 1028459-62-2 ]

Yield	Reaction Conditions	Operation in experiment
33%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 20 - 150℃; for 5h;	44 5-Iodo-l- (2-pyridinyl) indazole; Cesiumcarbonate (29.86 g, 91.6 mmol) is added to a suspension of 2-fluoro-5- iodobenzaldehyde (11.45 g, 45.8 mmol) and 2-pyridylhydrazine (5 g, 45.8 mmol) in 230 mL N-methylpyrrolidon. The reaction mixture is stirred two hours at room temperature. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for three hours at 150 °C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured into ice water. After vigorously stirring at room temperature for 15 minutes the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried over Na2SO4, the solvent is removed i.vac, and the product purified by chromatography on silica gel. Yield 4.8 g (33 %). ES+MS : 322 (MH+) 1H-NMR (CDCl3); δ = 7.18 (ddd, IH), 7.75 (dd, IH), 7.84 (ddd, IH), 8.05 (d, IH), 8.11 (s, IH), 8.14 (d, IH), 8.53 (m, IH), 8.66 (IH).
5%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃;	118 2-Fluoro-5-iodobenzaldehyde (527 mg, 2.11 mmol), 2-hydrazinopyridine (237 mg, 2.17 mmol), cesium carbonate (2.06 g, 6.32 mmol) and NMP (10 ml) werer charged in a 10 ml vial which was sealed and stirred (magnetic bar) over night at 100°C. Water and ethylacetate were added and the phases was separated. The organic layer was washed three times with brine and concentrated. Purification on silica with ethylacetate+/-eptane 5:95 to 10:90 over 15 min, 10 ml/min, followed by evaporation afforded 31 mg (5%) of 5-iodo-l-pyridin-2-yl-lH-indazole.APCI-MS m/z: 321.8 [MH+]1H NMR (300 MHz, CDCl2) δ 8.64 (dt, IH), 8.50 (dq, IH), 8.13 (dd, IH), 8.11 (d, IH), 7.87- 7.81 (m, IH), 7.74 (dd,lH).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/63116, 2008, A1 Location in patent: Page/Page column 71-72
[2]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/76048, 2008, A1 Location in patent: Example 118

10
3-hydrazinylpyridine dihydrogenchloride [ No CAS ]
[ 146137-76-0 ]
[ 1028459-64-4 ]

Yield	Reaction Conditions	Operation in experiment
93.9%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 20 - 160℃;	45 5-Iodo-l-pyridin-3-yllH-indazole; Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5- iodobenzaldehyde (6.87 g, 27.46 mmol) and 3-pyridylhydrazine dihydrochloride (5 g, s 27.46 mmol) in 136 mL N-methylpyrrolidon. The reaction mixture is stirred overnight at room temperature. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for four hours at 160 °C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured on 1000 mL ice water. After vigorously stirring at room temperature for 45 minutes, the precipitated product is sucked off via a o glass microfibre filter, washed with water and dried at the evaporator at 45 °C. 8.28 g (93.9%) of the title compound are obtained. MS (CI+): m/z 322 (M+)1H-NMR (400 MHz, DMSO [d6]): δ = 7.62 (IH), 7.72 (2H), 8.20 (IH), 8.32 (IH), 8.49 (IH), 8.61 (IH), 9.01 (IH).
93.9%	With caesium carbonate In 1-methyl-pyrrolidin-2-one; water at 20 - 160℃; for 4.75h;	114 Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5- iodobenzaldehyde (6.87 g, 27.46 mmol) and 3-pyridylhydrazine dihydrochloride (5 g, 27.46 mmol) in 136 mL ν-methylpyrrolidon. The reaction mixture is stirred overnight at r.t. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for 4 h at 160 0C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured on 1000 mL ice water. After vigorously stirring at r.t. for 45 min, the precipitated product is sucked off via a glass microfibre filter, washed with water and dried at the evaporator at 45 °C. 8.28 g (93.9%) of the title compound are obtained. MS (CI+): 322 (M+)1H-NMR (400 MHz, DMSO [d6]): δ = 7.62 (IH), 7.72 (2H), 8.20 (IH), 8.32 (IH), 8.49 (IH), 8.61 (IH), 9.01 (IH).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/63116, 2008, A1 Location in patent: Page/Page column 73
[2]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/76048, 2008, A1 Location in patent: Example 114

11
[ 619-67-0 ]
[ 146137-76-0 ]
[ 1034155-00-4 ]

Yield	Reaction Conditions	Operation in experiment
78.32%	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; water; at 20 - 150℃; for 4.5h;	4-etaydrazinobenzoic acid (11.32 g, 60 mmol) and cesiumcarbonate (58.65 g, 180 mmol) are added to 2-fluoro-5-iodobenzaldehyde (15 g, 60 mmol) in 300 mL N-methylpyrrolidon. After 1 h stirring at r.t., the reaction is heated for 4 h at 150 C. The reaction mixture is allowed to cool off and poured on 1 L ice water. The reaction mixture is acidified with citric acid and vigorously stirred at r.t. for 30 min. The precipitate is filtered off and given in ethyl acetate. The slurry is vigorously stirred for 1 h and sucked off. The filter residue (few material) is <n="157"/>discarded and the filtrate evaporated. This residue which is contaminated with N- methylpyrrolidine is treated with 300 mL of a mixture of ethyl acetate/ hexane (1:3) and stirred overnight. The precipitated crystals are sucked off and dried. 17.11 g (78.32%) of 4-(5- iodoindazole-l-yl)-benzoic acid are obtained.K2CO3 (7.35 g, 53.2 mmol) is suspended in 110 mL DMF. 4-(5-iodoindazole-l-yl)-benzoic acid (17.6 g, 48.33 mmol), dissolved in 25 mL DMF, is added dropwise. The reaction mixture is stirred for 30 min at r.t. Subsequently CH3I (3.31 mL, 53.2 mmol) is added dropwise (temperature rises to 30 C). The reaction mixture is stirred overnight at r.t. and then poured on ice water. It is three times extracted with ethyl acetate. The combined organic extracts are washed twice with water and brine. After drying over Na2SO4 and filtration the solvent is evaporated. The residue is purified by chromatography (silicagel, eluents: ethyl acetate/ hexane) yielding 14.03 g (76.8%) of the title compound. MS (CI+): 496 (M+)1H-NMR (300 MHz, DMSO [d6]): delta = 3.92 (3H), 7.75-7.92 (2H), 7.93-8.03 (2H), 8.10-8.25 (2H), 8.38 (IH), 8.44 (IH).

Reference： [1]Patent: WO2008/76048,2008,A1 .Location in patent: Example 116

12
4-hydrazinylpyridine dihydrochloride [ No CAS ]
[ 146137-76-0 ]
[ 1034154-94-3 ]

Yield	Reaction Conditions	Operation in experiment
92.3%	With caesium carbonate In 1-methyl-pyrrolidin-2-one; water at 20 - 160℃; for 4.75h;	115 Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5- iodobenzaldehyde (6.87 g, 27.46 mmol) and 4-pyridylhydrazine dihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. The reaction mixture is stirred overnight at r.t. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for 4 h at 160 °C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured on 1000 mL ice water. After vigorously stirring at r.t. for 45 min, the precipitated product is sucked off via a glass microfibre filter, washed with water and dried at the evaporator at 45 °C. The title compound is obtained with a yield of 92.3% (8.14 g). 1H-NMR (300 MHz, DMSO [d6]): δ = 7.83 (IH), 7.89-7.92 (2H), 7.99 (IH), 8.39 (IH), 8.48 (IH), 8.70-8.78 (2H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC; BAYER AG - WO2008/76048, 2008, A1 Location in patent: Example 115

13
[ 104308-26-1 ]
[ 146137-76-0 ]
[ 1075176-96-3 ]
[ 1075176-95-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,6-dimethylbenzyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran; dichloromethane at 0℃; for 0.25h; Stage #2: 2-Fluoro-5-iodo-benzaldehyde In tetrahydrofuran; dichloromethane at -78 - 20℃;	46.1 To a solution of 2, 6-dimethylbenzyltriphenylphosphonium bromide (2.21 g, 4.8 mmol) in CH2Cl2 (30 mL) was added a solution of potassium tert-butoxide (5 mL of a 1 M solution in THF, 5 mmol) and the mixture was stirred at 0 °C for 15 min. The mixture was cooled to -78 °C and 6-fluoro-3-iodobenzaldehyde (1.0 g, 4.0 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was partitioned between EtOAc and water and the combined organics were washed with 1 M HCl and brine, dried over Na2Sθ4 and concentrated under reduced pressure. Purification by flash chromatography (100% hexanes) gave (E)-2-(2-fluoro-5-iodostyryl)-1,3-dimethylbenzene (0.280 g) and (Z)-2- (2-fluoro-5-iodostyryl)-1,3-dimethylbenzene (0.472 g) with additional product collected as an E/Z mixture (0.45O g). Total yield (1.2O g, 85%). Trans-isomer: 1H NMR (400 MHz, DMSO-d6) δ 8.12 (dd, J= 7.2, 2.4 Hz, 1H), 7.63 (dq, J= 8.8, 2.4 Hz, 1H), 7.34 (d, J= 16.8 Hz, 1H), 7.04-7.09 (m, 4H), 6.61 (d, J= 16.8 Hz, 1H),2.30 (s, 6H).

Reference： [1]Current Patent Assignee: KUBOTA PHARMACEUTICAL HOLDINGS CO LTD - WO2008/131368, 2008, A2 Location in patent: Page/Page column 158

14
[ 29786-93-4 ]
[ 352-34-1 ]
[ 108-18-9 ]
[ 33513-42-7 ]
[ 146137-76-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: n-butyllithium; diisopropylamine In tetrahydrofuran at 0 - 5℃; for 0.333333h; Nitrogen gasification; Stirring; Stage #2: 4-fluoro-1-iodobenzene; N,N-dimethyl-formamide In tetrahydrofuran at -78℃; for 1.3h; Stirring;	49 PREPARATIONS; Preparation 49; 2-Fluoro-5-iodobenzaldehyde To a solution of diisopropylamine (1.54 ml, 11 mmol, 1.1 eq.) in THF (20 ml) under N2 stirring at 0-5° C. was added dropwise over 10 minutes 1.6M n-BuLi (6.25 ml, 10 mmol) and stirred at this temperature for 10 min. The reaction mixture was cooled to -78° C. in a dry ice/acetone bath and dropwise added 1-iodo-4-fluorophenyl (1.12 ml, 10 mmol) over 5 min. The reaction was stirred at this temperature for 1 h, and DMF (0.8 ml, 11 mmol, 1.1 eq.) was added dropwise over 5 minutes, and stirred for 10 minutes. Acetic acid (2 ml) was added, followed by H2O and extracted with Et2O. The combined organic solution was washed with 0.1 N HCl, brine, dried (MgSO4), filtered and concentrated. The crude 2-fluoro-5-iodobenzaldehyde (2.36 g) was taken onto the next step without purification. [00440] 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.14 (d, 1H), 7.89-7.86 (m, 1H), 6.95 (t, 1H). GC[100 C (5 min.)→180 C (5 min.) 20 C/min], Rt=7.375.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - US6670373, 2003, B1 Location in patent: Page column 55

15
[ 288-16-4 ]
[ 146137-76-0 ]
[ 1202766-44-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[288-16-4]isothiazol</strong>e (A.157) (3.0 g, 35.3 mmol) in 50 mL THF at -78 0C under argon was added n-butyllithium (1.6 M in hexane, 22.1 mL, 35.3 mmol) dropwise over 10 minutes. The mixture stirred at -780C for 1.5 hours. A solution of 2-fluoro-5-iodobenzaldehyde (A.156)(7.35 g, 29.4 mmol) in 30 mL THF was added dropwise over 15 minutes, and the reaction stirred an additional 2 hours at -78 0C. Water was added to quench the reaction, and the mixture warmed to 0 0C. The solution was neutralized with 2 N HCl to pH 7, partitioned between water and dichloromethane, and the aqueous layer further extracted with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4 and condensed. Purification by flash chromatography (0-15-100% ethyl acetate in hexane) gave 7.19 g (2- fluoro-5-iodophenyl)(<strong>[288-16-4]isothiazol</strong>-5-yl)methanol A.158. IH NMR (500 MHz, CHLOROFORM- d) delta ppm 8.30 (1 H, s), 7.76 (1 H, dd, J=6.8, 2.2 Hz), 7.56 (1 H, ddd, J=8.6, 5.0, 2.3 Hz), 6.97 (1 H, s), 6.79 (1 H, dd, J=9.8, 8.8 Hz), 6.37 (1 H, s)

Reference： [1]Patent: WO2009/158011,2009,A1 .Location in patent: Page/Page column 88

16
C₂₅H₂₂N₃O₃Pol [ No CAS ]
[ 146137-76-0 ]
C₃₂H₂₄FIN₃O₃Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethyl orthoformate In dichloromethane at 20℃; for 12h;

Reference： [1]Wilk, Wolfram; Noeren-Mueller, Andrea; Kaiser, Markus; Waldmann, Herbert [Chemistry - A European Journal, 2009, vol. 15, # 44, p. 11976 - 11984]

17
[ 1415115-02-4 ]
[ 146137-76-0 ]
[ 1415115-19-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 2-pyridyl fluoroiodomethyl sulfone With diethylzinc In hexane; N,N-dimethyl-formamide at -30 - -25℃; for 0.0833333h; Inert atmosphere; Stage #2: With copper(l) iodide In hexane; N,N-dimethyl-formamide at -15℃; for 0.25h; Inert atmosphere; Stage #3: 2-Fluoro-5-iodo-benzaldehyde In hexane; N,N-dimethyl-formamide at 20℃; for 8h; Inert atmosphere;

Reference： [1]Zhao, Yanchuan; Gao, Bing; Ni, Chuanfa; Hu, Jinbo [Organic Letters, 2012, vol. 14, # 23, p. 6080 - 6083]

18
[ 823-85-8 ]
[ 534-17-8 ]
[ 146137-76-0 ]
[ 1025762-98-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-fluorophenyhydrazine hydrochloride; 2-Fluoro-5-iodo-benzaldehyde In 1-methyl-pyrrolidin-2-one at 20℃; for 5h; Industrial scale; Stage #2: caesium carbonate In 1-methyl-pyrrolidin-2-one at 115℃; for 3.5h; Industrial scale;	4.iv 1-(4-fluorophenyl)-5-iodo-indazole (iv) l-(4-Fluorophenyl)-5-iodo-indazole A mixture of 2-fluoro-5-iodobenzaldehyde (3.70 kg, 14.2 mol; 96.1% assay by mass) and 4-fluorophenylhydrazine hydrochloride (2.50 kg, 14.2 mol; 92.4% assay by mass) in N-methylpyrrolidone (25 L) was stirred for 5 hours at 20 °C. Caesium carbonate (13.89 kg, 42.6 mol) was charged and the mixture stirred at 115 °C for 3.5 hours. Water (18.3 L) was charged after adjusting the reaction temperature to 80 °C and once the solids were dissolved, the mixture was allowed to separate into layers. The lower layer was discarded. The upper layer and an N-methylpyrrolidone (2 L) rinse were transferred into stirring water (11.3 L), maintained at 62 °C throughout the addition. After cooling to 20 °C, l-(4-fluorophenyl)-5-iodo-indazole was filtered off, washed with two portions of water (16.0 L and 17.5 L) followed by 2-methylpentane (16.5 L), and suction dried for around 18 hours at 20 °C. Yield 6.28 kg (11.9 mol, 84% by moles). 64% Assay (LC), 20% water, both by mass. 98.6% LC purity (λ = 254 nm). 1H NMR (400 MHz, d6-DMSO) δ 8.31 (d, J= 0.9 Hz, 1H), 8.28 (dd, J= 0.7, 1.6 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.70 (dd, J= 1.6, 8.8 Hz, 1H), 7.61 (ddd, J= 0.7, 0.9, 8.9 Hz, 1H), 7.45 - 7.38 (m, 2H).

Reference： [1]Current Patent Assignee: BAYER AG; ASTRAZENECA PLC - WO2013/1294, 2013, A1 Location in patent: Page/Page column 48

19
[ 146137-76-0 ]
[ 100-63-0 ]
5-iodo-1-phenyl-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With potassium carbonate In N,N-dimethyl-formamide for 16h; Reflux;

Reference： [1]Sambiagio, Carlo; Munday, Rachel H.; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C. [Chemistry - A European Journal, 2014, vol. 20, # 52, p. 17606 - 17615]

20
[ 41052-75-9 ]
[ 146137-76-0 ]
C₁₃H₈ClIN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide for 16h; Reflux;

Reference： [1]Sambiagio, Carlo; Munday, Rachel H.; Marsden, Stephen P.; Blacker, A. John; McGowan, Patrick C. [Chemistry - A European Journal, 2014, vol. 20, # 52, p. 17606 - 17615]

21
[ 19763-90-7 ]
[ 146137-76-0 ]
C₁₃H₇Cl₂IN₂ [ No CAS ]