Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15](F)([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.O[C@@]1([C@]2(C)[C@H]([C@H]3C(=CC2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1=C)C(=O)C>>[O:26]1[C@@H:16]2[C@:15]31[C@H:5]([C@H:4]1[C@:18]([CH3:25])([CH2:17]2)[C@@:19]([OH:24])([C:20](=[O:21])[CH2:22][OH:23])[C@H:2]([CH3:1])[CH2:3]1)[CH2:6][CH2:7][C:8]1[C@:14]3([CH3:28])[CH:13]=[CH:12][C:10](=[O:11])[CH:9]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
Dexamethasone (9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione) can also be prepared from 17β-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione (VI) by first transforming it to 17α,21-dihydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione 21-acetate as described above and next transforming it to 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate by the process of U.S. Pat. No. 3,130,209. 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate is then epoxidized by means well known to those skilled in the art, see for example U.S. Pat. No. 3,980,778, Examples 2 and 7 to produce 9β,11β-epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione which is transformed to dexamethasone 21-acetate by the process of U.S. Pat. No. 3,007,932, Example 2.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2C([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([Br:16])=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+]>O.C(O)(=O)C.[Hg]=O>[Br:16][C:5]1[CH:6]=[C:7]([C:14]([OH:15])=[O:13])[C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][CH:9]=2
Reactant: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Agent: O=[Hg]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)cc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of bromo anhydride 21 (22.8 g, 82.4 mmol) and sodium hydroxide (13.2 g, 330 mmol) in water (500 mL) was added a solution of mercury(II) oxide (23.2 g, 107 mmol) in water (70 mL) and glacial acetic acid (24 mL). The reaction mixture was heated at reflux for 4 days and then cooled to room temperature. The resulting solid was filtered and dried in vacuo.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[C@@H:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH3:11])[CH3:10])[C@H:4]([C:18]2[NH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([C:39]5[NH:43][C:42]([C@@H:44]6[CH2:48][CH2:47][CH2:46][N:45]6C(OC(C)(C)C)=O)=[N:41][CH:40]=5)=[CH:35][CH:34]=3)[CH:27]=[CH:26]4)=[CH:21][N:22]=2)[CH2:3]1.Cl.[CH3:57][O:58][C:59]([NH:61][C@H:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63]([OH:65])=O)=[O:60].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[OH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:17])[C@@H:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH3:11])[CH3:10])[C@H:4]([C:18]2[NH:19][C:20]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([C:33]3[CH:38]=[CH:37][C:36]([C:39]5[NH:43][C:42]([C@@H:44]6[CH2:48][CH2:47][CH2:46][N:45]6[C:63](=[O:65])[C@H:62]([NH:61][C:59](=[O:60])[O:58][CH3:57])[C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)=[N:41][CH:40]=5)=[CH:35][CH:34]=3)[CH:27]=[CH:26]4)=[CH:21][N:22]=2)[CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 22.5 %

Procedure:
To (S)-tert-butyl 2-(5-(4-(6-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (61 mg, 0.082 mmol) in MeOH (2.5 mL) was added HCl (4M in dioxane, 0.5 mL). The solution stirred o/n, and the solvent was removed. The intermediate was dissolved in DMF (2 mL). (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (19 mg, 0.09 mmol), COMU (39 mg, 0.082 mmol), and DIPEA (0.07 mL, 0.41 mmol) were added sequentially. The solution was stirred o/n and the mixture was purified by HPLC to yield product (15.5 mg). LCMS-ESI+: calc'd for C47H50N8O7: 838.95 (M+); Found: 839.29 (M+H+).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.N1C2C(=CC=C(C(OC)=O)C=2)C=C1.C([O-])([O-])=O.[K+].[K+].[C:40]([O:44][C:45]([N:47]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C:48](=[CH2:53])[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41]>CC#N>[C:40]([O:44][C:45]([N:47]([C:54]([O:56][C:57]([CH3:58])([CH3:60])[CH3:59])=[O:55])[CH:48]([C:49]([O:51][CH3:52])=[O:50])[CH2:53][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[Br:1])=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: COC(=O)c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared from commercially available methyl indole-6-carboxylate as described in WO 2004/087714) in MeCN (0.2 M), 6.0 eq of K2CO3 and 1.0 eq of methyl 2-[bis(tert-butoxycarbonyl)amino]acrylate were added and the mixture was stirred overnight at RT. The mixture was then filtered and the filtrate concentrated in vacuo to afford the title compound (98%). MS (ES+) m/z 636 (M+H)+, MS (ES+) m/z 638 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[CH:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7].[F:29][C:30]1[CH:43]=[CH:42][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])=[CH:32][CH:31]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][CH2:4][O:5][C:6]([C:8]3[CH:9]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=4)[C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=3[CH3:14])=[O:7])[CH2:38][CH2:37]2)=[O:35])=[CH:42][CH:43]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCl)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCC(C(=O)c3ccc(F)cc3)CC2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A mixture of 16.4 g of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-chloropropyl ester and 16.6 g of 4-(p-fluorobenzoyl)-piperidine is kept for 1 hour under argon in a bath heated to 145°. After cooling, 100 ml of ethyl acetate and 50 ml of 2N hydrochloric acid are added and the mixture is stirred until the reaction mass has completely dissolved. The partly oily aqueous-acidic phase is adjusted to pH 10 with 50% potassium carbonate solution; methylene chloride is added and the whole is filtered with suction. The methylene chloride phase of the filtrate is separated off and concentrated by evaporation and the residue is dissolved in ethyl acetate; the solution is dried over sodium sulphate and filtered. Filtration is then carried out over 1 kg of silica gel Merck 9385 using a hexane/ethyl acetate/methanol mixture (4:2:0.5) as eluant. The 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester 3-[4-(p-fluorobenzoyl)-piperidino]-propyl ester obtained after working up is converted by means of ethereal hydrogen chloride solution into the hydrochloride which, after recrystallisation from isopropanol, melts at 198°-205° with the evolution of gas.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][C@H:29]1[O:34][C@@H:33]([CH3:35])[CH2:32][NH:31][CH2:30]1>CN(C)C=O.C(OCC)(=O)C>[CH3:35][CH:33]1[CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:30][CH:29]([CH3:28])[O:34]1
Reactant: COC(=O)c1ccc(-c2ccc(OCCCBr)cc2)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCCCN3CC(C)OC(C)C3)cc2)cc1
Yield: 45.8 %

Procedure:
A solution of methyl 4-[4′-(3-bromopropyoxy)phenyl]benzoate (1.5 g), potassium carbonate (1.2 g) and cis-2,6-dimethylmorpholine (990.6 mg) in N,N-dimethyformamide was stirred for 15 hours at room temperature, then diluted with ethyl acetate and washed with water (5x), dried over magnesium sulfate, evaporated, then purified by silica gel chromatography (20:1 dichloromethane-ethanol elution) to give methyl 4-[4′-[3-(2,6-dimethylmorpholino)propoxy]phenyl]benzoate (755 mg).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:23][C:24]1[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(C(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 34 %

Procedure:
To a solution of p-dodecylbenzenesulfonyl chloride (260 mg, 0.75 mmol) in pyridine (3 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl was added to quench the reaction. The mixture was extracted with ethyl acetate (3×40 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with CH2Cl2:methanol 49:1 to give the product as a solid, mp 96-97° C., in 34% yield (95 mg, 0.20 mmol); 1H NMR (300 MHz, CDCl3) δ 0.85 (t, 3H, J=6.6 Hz), 1.20-1.35 (m, 21H), 1.57 (m, 2H), 2.60 (t, 2H, J=7.0 Hz), 4.43 (q, 2H, J=7.2 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.77 (d, 2H, J=7.7 Hz); 13C NMR (300 MHz, CDCl3) δ 14.1, 22.7, 29.3, 29.4, 29.6, 29.6, 31.1, 31.9, 35.9, 63.4, 126.6, 128.9, 136.9, 145.8, 159.9, 163.7, 167.9; MS (LCQ, ESI+) Calcd for C23H36N3O4S2 482.2, found 482.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C23H36N3O4S2 482.2140, found 482.2134 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([CH2:15][CH2:16][OH:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[H-].[Na+].[CH3:26]I.O>CN(C)C=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]([CH2:15][CH2:16][O:17][CH3:26])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1
Reactant: CI
Reactant: COCOc1cc(CCO)c(-c2ccccc2)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCc1cc(OCOC)cc(OCOC)c1-c1ccccc1
Temperature: 4 °C
Reaction time: 0.07 h
Yield: 89.4 %

Procedure:
2-[3,5-Bis(methoxymethoxy)-2-phenylphenyl]ethanol (1.2 g, 3.7 mmol) obtained in Example 3, Step 3 was dissolved in N,N-dimethylformamide (15 mL), and a 60% sodium hydride dispersion in mineral oil (0.30 g, 7.5 mmol) was added thereto in an atmosphere of nitrogen, followed by stirring at 4° C. for 4 minutes. After methyl iodide (0.70 mL, 11 mmol) was added dropwise to the reaction mixture, the mixture was stirred at 4° C. for 1 hour, followed by further stifling for 48 hours, while the temperature of the mixture was raised to room temperature. To the reaction mixture was added water (10 mL) and a saturated aqueous solution of ammonium chloride (20 mL), and the mixture was extracted with ethyl acetate (0.10 L). The organic layer was washed with water (0.10 L) and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/2) to obtain 3,5-bis(methoxymethoxy)-1-(2-methoxyethyl)-2-phenylbenzene (1.1 g, 91%).
Reaction SMILES: [CH2:1]([C:3](=[CH2:6])[CH:4]=O)[CH3:2].[NH2:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Reactant: C=C(C=O)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Glacial acetic acid 100 g and 2-ethyl-2-propenal 30 g (0.357 mol) were placed in a 200 ml four neck distillation flask: with a reflux condenser and heated on an oil bath. When the inside temperature reached 90° C., ethyl β-amino-β-ethoxycarbonylacrylate 60 g (0.321 mol) was added dropwise thereto at 90° to 95° C. over a period of 4 hours. After completion of the dropping, the mixture was reacted at 90° to 95° C. for 3 hours. After completion of the reaction, the reaction mixture was distilled to give 36.2 g of 5-ethyl-2,3-diethoxycarbonylpyridine (bp2 : 151° to 152° C.).
Reaction SMILES: FC1C=C(C(Cl)=O)C=CC=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH2:14].[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:36]=[C:37]([C:41]([N:43]=[C:44]=[S:45])=[O:42])[CH:38]=[CH:39][CH:40]=1.[Cl:11][C:12]1[CH:18]=[C:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:13]=1[NH:14][C:44]([NH:43][C:41](=[O:42])[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([F:34])[CH:36]=1)=[S:45]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: O=C(Cl)c1cccc(F)c1
Agent: O=C(N=C=S)c1cccc(F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(F)c4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
3-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 58%).
Reaction SMILES: [Mg].[CH2:2]1[O:14][C:5]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)([CH3:6])[O:4][CH2:3]1.C1OC(C2C=CC=CC=2)(CBr)OC1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>O1CCCC1>[CH3:6][C:5]1([C:7]2[CH:12]=[CH:11][C:10]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:9][CH:8]=2)[O:14][CH2:2][CH2:3][O:4]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: BrCC1(c2ccccc2)OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C2(C)OCCO2)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a suspension of 12.4 g (0.51 g-atoms) magnesium turnings in 190 ml tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of a solution of 103 g (0.424 mole) of 4'-bromoacetophenone ethylene ketal in 130 ml dry tetrahydrofuran. The reaction is started and the remainder of the bromoacetophenone ethylene ketal solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for one hour. The resulting Grignard solution is added dropwise to a cold solution of 51.1 g (0.424 mole) pivaloyl chloride in 120 ml of dry tetrahydrofuran at a rate that maintains the temperature at 0° C. After addition the resulting solution is stirred for 1 hour at -60° C and then 1 additional hour at -10° C. The mixture is then poured onto ice and extracted with ether, the ether is washed with 2N sodium hydroxide and salt water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is triturated with petroleum ether to give 4'-(2-methyl-2-dioxolanyl)pivalophenone, m.p. 75°-82° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:13][C:14]#[N:15])[CH2:10][CH2:11]1
Reactant: COCCCN1CCNCC1
Reactant: N#CCBr
Product: COCCCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-(3-Methoxy-propyl)-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=198.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.30 (s, 3H), 2.45-2.20 (m, 12H), 1.65-1.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([I:11])[CH:10]=1)[NH2:6].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[I:11][C:9]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([CH3:20])(=[O:23])=[O:22])=[C:4]([CH:10]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(I)ccc1NS(C)(=O)=O
Reaction time: 0.75 h
Yield: 46 %

Procedure:
To a solution of 5-iodoanthranilic acid methyl ester (1.00 g) and triethylamine (1.01 mL) in CH2Cl2 (25 mL) is added methanesulfonyl chloride (0.59 ml) at 0° C. The ice bath is removed and after 3 h at room temperature the solution is poured into water (20 mL) and extracted with CH2Cl2 (2×20 mL). The organic layers are combined, dried over MgSO4 and the solvent removed in vacuo. The resulting residue is dissolved in CH3OH (20 mL) and sodium methoxide (20 mL) is added. After 45 min, the solvent is removed in vacuo. The residue is diluted with Et2O (20 mL) and washed with water (20 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude black liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 0.58 g (46%) of the title compound as a brown solid. Physical characteristics: m.p. 119-120° C.; 1H NMR (300 MHz, CDCl3) δ10.41, 8.36, 7.82, 7.52, 3.94, 3.06; IR (diffuse reflectance) 1700, 1682, 1483, 1385, 1335, 1328, 1307, 1249, 1213, 1159, 1147, 1093, 1086, 978, 971 cm−1; MS (FAB) m/z 356 (MH+); HRMS (FAB) m/z 355.9447 (C9H10INO4S+H). Anal. Found: C, 30.49; H, 2.88; N, 3.96.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]1.C1(C[NH2:30])C=CC=CC=1>CO.[Pd]>[NH2:30][CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH2:12][CH2:13]1
Reactant: NCc1ccccc1
Reactant: CC(C)C(=O)CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(N)CN1CCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 24 h
Yield: 4.4 %

Procedure:
A mixture of 1-[4-(1H-benzimidazol-2-ylamino)-1-piperidinyl]-3-methyl-2-butanone (0.03 mol) and benzenemethanamine (0.09 mol) in methanol (200 ml) was hydrogenated at 40° C. under a 3 bar pressure for 48 hours with palladium on activated carbon (1.3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH3OH and the filtrate was evaporated. Hydrogenation was continued for 24 hours. After uptake of hydrogen, the catalyst was filtered through celite, washed with CH3OH and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/14/1; 20–45 μm). The desired fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.4 g of (±)-N-[1 (2-amino-3-methylbutyl)-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 138° C. (interm. 37).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[NH4+:15]>>[NH2:15][C:8]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: [NH4+]
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: [OH-]
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
20 g (108 mmol) of 2,4-difluoro-5-nitrobenzonitrile was added to 200 ml of 25% ammonium hydroxide and the mixture was stirred for 90 min. at room temperature. The yellow precipitate was isolated by filtration and washed with water and a small amount of cold ethanol to give 18.8 g (96%) of the title compound. M.p. 197°-199° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C@H:4]([C:5](O[C@@H](C2C=CC=C(OC3C=CC=CC=3)C=2)C#N)=[O:6])[C@@H:3]1/[CH:24]=[C:25](\[Cl:30])/[C:26]([F:29])([F:28])[F:27].[Cl:32]/C(/C(F)(F)F)=C\[C@@H]1[C@H](C(O)=O)C1(C)C>>[Cl:30]/[C:25](/[C:26]([F:29])([F:28])[F:27])=[CH:24]\[C@@H:3]1[C@H:4]([C:5]([Cl:32])=[O:6])[C:2]1([CH3:31])[CH3:1]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C(\Cl)C(F)(F)F
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
In order to produce gamma-cyhalothrin on an industrial scale it is desirable to find methods of making the final product that avoid the use of expensive reagents and have as few chemical stages as possible. The present invention provides a direct process to meet these requirements. There is therefore provided a process for the preparation of gamma-cyhalothrin (IV) comprising a) chlorinating 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid (I) to give 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride (II) and b) esterifying 1R cis-Z 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl cyclopropanecarboxylic acid chloride (II) with the (S)-cyanohydrin of 3-phenoxy benzaldehyde (III).