Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccnc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc[n+]([O-])c(Cl)c1
Yield: 90 %

Procedure:
2-Chloro-4-t-butylpyridine (5.0 g, 30 mmol) was dissolved in chloroform (75 mL), treated with MCPBA, ca. 75% (8.3 g, 36 mmol, 1.2 equivalents) and heated to reflux for 19 h. The mixture was stirred with sodium bisulfate solution until testing with starch-iodide paper indicated consumption of oxidant. The pH was adjusted to 7 with saturated aqueous NaHCO3 solution, the phases separated and the aqueous phase extracted once with CH2Cl2. The organic phases were pooled and washed twice with H2O, once with brine, dried (Na2SO4) and concentrated in vacuo to afford 2-chloro-4-t-butylpyridine-N-oxide (5.0 g, 90%), which crystallized to long white needles on standing.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:10]([C:6]1[CH:5]=[C:4]([Br:8])[N+:3]([O-:9])=[C:2]([Br:1])[CH:7]=1)([O-:12])=[O:11]
Reactant: [O-][n+]1c(Br)cccc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])c(Br)c1
Temperature: 90 °C
Yield: 16 %

Procedure:
2,6-dibromopyridine-N-oxide (6.28 g) was dissolved in concentrated sulphuric acid (20 ml) with stirring. A mixture of concentrated sulphuric acid (20 ml) and concentrated nitric acid (10 ml) was then continuously added dropwise. The solution was then heated at 90° C. for 3 hours with stirring, poured onto ice and then basified with sodium hydroxide. The solution was then continuously extracted with ether, and recrystallised from ethanol to give pale yellow leaflets of 4-nitro-2,6-dibromopyridine-N-oxide (1.2 g, 16%), m.p. 222° C.-224° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[C:15]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]1.O.[OH-].[Na+].CN([CH:25]=[O:26])C>>[CH:25]([C:8]1[C:9]2[C:14](=[C:13]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=2)[NH:6][CH:7]=1)=[O:26]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2c(C=O)c[nH]c12

Procedure:
2.9 ml of phosphorus oxychloride are added slowly to 7 ml of N,N-dimethylformamide in a nitrogen atmosphere (formylation solution). 5 g (0.029 mol) of methyl indole-7-carboxylate are dissolved in 7 ml of DMF and added slowly to the formylation solution, during which the temperature does not rise above 30 degrees. The mixture is then warmed at 100° for one hour. After cooling, the mixture is poured into water and neutralised using sodium hydroxide solution, and the deposited crystals are filtered off with suction. m.p. 154°. Yield 5.3 g (89.9% of theory).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Br:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:8])[CH3:7].[N+:21]([O-])([OH:23])=[O:22]>O>[C:6]([NH:9][C:10]1[C:19]([N+:21]([O-:23])=[O:22])=[C:14]([C:13]([Br:20])=[CH:12][CH:11]=1)[C:15]([O:17][CH3:18])=[O:16])(=[O:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc(NC(C)=O)ccc1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1c(Br)ccc(NC(C)=O)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 62 %

Procedure:
To conc. sulfuric acid (150 mL), methyl 5-acetylamino-2-bromobenzoate (Reference Compound No. 1-(2), 18.5 g, 68.1 mmol) was added at 0° C. portionwise, and conc. nitric acid (150 mL) was added dropwise thereto over 1 hour. The reaction mixture was stirred for 30 minutes, poured into iced water (1 L), and then extracted with ethyl acetate (500 mL, 2 times). The organic layer was washed with water (1 L, 2 times), saturated aqueous sodium hydrogen carbonate solution (1 L), and saturated brine (1 L) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (13.4 g) as a yellow solid. (Yield 62%)
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=1>C(O)C>[CH2:3]([O:15][C:16]1[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCBr
Reactant: OCCCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCOc1cccc(CCCO)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
A 15 N aqueous sodium hydroxide solution (2 ml) and a solution (10 ml) of 8.0 g of undecyl bromide in ethanol was added to a solution (30 ml) of 4.56 g of 3-(3-hydroxyphenyl)propanol in ethanol and the mixture was stirred at 70° C. for 12 hours. The solvent was distilled away and the residue was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogencarbonate and brine, and dried over magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20-1:3) to give 7.37 g of 3-(3-undecyloxyphenyl)propanol as a colorless, oily substance.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].Cl>C1COCC1.C(OCC)(=O)C>[F:26][C:27]([F:29])([F:28])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1nccs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1nccs1)C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of 2 g (17.68 mmol) of thiazole-2-carboxaldehyde and 0.88 ml (0.88 mmol) of a 1M solution of tetrabutylammonium fluoride in THF, in 88 ml of THF, is admixed slowly at approximately 0° (ice bath) with 2.7 g (19.44 mmol) of trifluoromethyltrimethylsilane (TMS-CF3). Stirring is continued at ambient temperature for 2 hours. The reaction mixture is admixed with 25 ml of 1N aqueous hydrochloric acid and ethyl acetate. The aqueous phase is separated off and extracted twice with ethyl acetate, and the combined organic phases are washed successively with saturated aqueous sodium bicarbonate solution and than with saturated aqueous sodium chloride solution and are dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>>[CH:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: C1=C(c2ccccc2)CCCC1
Reactant: [H][H]
Product: c1ccc(C2CCCCC2)cc1

Procedure:
The invention also relates to a hydrogenation and oxidation process in which a feed comprising cyclohexenylbenzene is contacted with hydrogen in the presence of a hydrogenation catalyst under hydrogenation conditions to form cyclohexylbenzene. The cyclohexylbenzene is then reacted with oxygen (e.g., air) in the presence of an oxidation catalyst under oxidation conditions to form cyclohexylbenzene hydroperoxide.
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH2:10]([OH:12])[CH3:11]>C(OCC)(=O)C>[ClH:1].[CH2:10]([O:12][C:2](=[NH:3])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:11]
Reactant: CCOC(=O)CC#N
Reactant: CCO
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=N)CC(=O)OCC
Yield: 90 %

Procedure:
Anhydrous hydrogen chloride (2.0 mol) is added to a mixture of ethyl cyanoacetate (1.0 mol) and ethanol (1.1 mol) in ethyl acetate (1 L) at 0° C. over a period of three hours. The mixture is then stirred at 5°-10° C. for ten additional hours. Removal of the solvent under reduced pressure gives the intermediate ethyl 3-ethoxy-3-iminopropanoate hydrochloride in a yield of about 90%. The appropriate o-aminophenol (1.0 mol) is added with vigorous stirring below 15° C. to a solution of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.0 mol) in methanol and allowed to react for ten hours at less than 20° C. After removal of the methanol, the residue is extracted with acetone and the extract is concentrated and diluted with cold 2-propanol to precipitate the ethyl 2-benzoxazolylacetate intermediate (m.p. 50°-53° C.) which is collected by filtration in a yield of 85%. A mixture of the ethyl 2-benzoxazolylacetate (1.0 mol), a benzaldehyde compound (1.0 mol), piperidine (10 ml) and acetic acid (2.5 ml) in toluene (1 L) is refluxed with agitation for four hours while removing the water of reaction. The reaction mixture is then cooled and filtered to obtain the product. This general procedure may be used to prepare the following compounds:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([OH:13])([CH3:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.I[CH3:15]>CN(C=O)C>[Br:3][C:4]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]([O:13][CH3:15])([CH3:11])[CH3:12])[CH:5]=1
Reactant: CC(C)(O)c1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
To a mixture of NaH (240 mg, 6.02 mmol) in DMF (dry, 4 mL) at 0° C. is added the solution of 2-(5-bromo-pyridin-3-yl)-propan-2-ol (500 mg, 2.31 mmol) in DMF (dry, 4 mL). The mixture is stirred at 0° C. for 15 min then raised to room temperature and stirred for 1 h. The mixture is then cooled back to 0° C. and iodomethane (397 mg, 2.80 mmol) iss added. The reaction mixture is stirred at room temperature overnight and is quenched by adding water dropwise. The mixture is partitioned between DCM and water. The DCM phase is separated and then washed with water twice. The DCM phase is evaporated under high vacuum. The residue is separated by silica gel flash column (EtOAc/Hepane 0 to 40% gradient, then 40%) to obtain 371 mg 3-bromo-5-(1-methoxy-1-methyl-ethyl)pyridine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:18]
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cccc(O)c1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 3-(3-hydroxyphenyl)propionic acid (20.0 g, 120 mmol) in ethanol was dropwise added thionyl chloride (8.8 ml, 120 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and submitted to flash chromatography (10% ethyl acetate in toluene eluent) to give 23.3 g of 3-(3-hydroxy-phenyl)propionic acid ethyl ester.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][NH2:7])[CH3:5].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:23])[C:10]=1[C:24](=O)[CH2:25][CH3:26]>O.C(O)C>[CH2:4]([O:6][N:7]=[C:24]([C:10]1[C:11](=[O:23])[CH2:12][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=2)[CH2:14][C:9]=1[OH:8])[CH2:25][CH3:26])[CH3:5]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of sodium hydroxide (0.15 g) in water (5 ml) and then ethoxyamine hydrochloride (0.37 g) were added to a solution of 3-hydroxy-5-(4-methylthiophenyl)-2-propionylcyclohex-2-en-1-one (1.0 g) in ethanol (40 ml). The mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the solvent was removed by distillation under reduced pressure. The residue was treated with dichloromethane and the organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(4-methylthiophenyl)cyclohex-2-en-1-one (0.95 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(N)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of 5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (7.95 g, 34.1 mmol) in acetic acid (250 mL) was added zinc dust (11.7 g, 179 mmol) in portions under cooling in an ice bath over a period of 10 minutes. After stirring for 30 min at room temperature, solids were filtered of through celite. Filtrate was concentrated and residue was purified by SiO2 column chromatography (Eluent: methylene chloride/methanol 20:1) to give 4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (4.34 g, 21.4 mmol, 62%) as an oil. LCMS m/z (%)=204 (M+H). 1H NMR (400, CDCl3) δ: 7.51 (d, J=1.8 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.76 (dd, J=2.8, 8.7 Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.22 (d, J=1.8 Hz, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.24-3.55 (broad s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added pyrrolidine (9.2 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (13.6 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-(pyrrolidin-1-ylcarbonyl)-cyclohexanecarboxylate (11.8 g).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[NH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8].[CH3:20][C@H:21]1[CH2:23][C@@H:22]1[CH2:24]Br>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C[C@H]1C[C@@H]1CBr>[CH:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]([CH2:20][C@H:21]2[CH2:23][C@@H:22]2[CH3:24])[C:10]=1[C:16]([O:18][CH3:19])=[O:17])=[O:8]
Reactant: C[C@H]1C[C@@H]1CBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
Potassium tert-butoxide (3.49 g, 35.1 mmol) was added to a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5.79 g, 31.9 mmol) and 18-crown-6 (0.41 g, 1.55 mmol) in tetrahydrofuran (130 ml) and the mixture was stirred at room temperature for 1 hour. After dropwise addition over 30 minutes of (1S,2S)-2-methylcyclopropylmethyl bromide (5.71 g, 38.3 mmol) to the reaction mixture at 50° C., the mixture was heated under reflux for 3 hours. Potassium tert-butoxide (0.36 g, 3.22 mmol) and (1S,2S)-2-methylcyclopropylmethyl bromide (0.48 g, 3.21 mmol) were further added to the mixture and this mixture was heated for 1 hour. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to afford the desired compound (8.26 g, 100%) as a pale brown oil.
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N+:31]([O-])([O:33]C(C)C)=[O:32]>CO>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:31]([O-:33])=[O:32])[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:2][CH2:3]1
Reactant: CC(C)O[N+](=O)[O-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1

Procedure:
17β-cyclopropyloxy-androst-4-en-3-one (9.70 g, 29.5 mM), potassium tert-butoxide (7.0 g, 62.4 mM), and isopropyl nitrate (2.99 ml) are reacted by the method of Example 1 to yield 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one, m.p. 137-38° C. (methanol)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[C-:10]#[N:11].[Na+].[I-].[Na+].O>CN(C=O)C>[O:6]1[CH2:7][CH2:8][O:9][CH:5]1[CH2:4][CH2:3][CH2:2][C:10]#[N:11]
Reactant: ClCCCC1OCCO1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCC1OCCO1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 2-(3-chloropropyl)-1,3-dioxolane (15.88 g; 0.1054 moles), sodium cyanide (6.46 g; 0.132 moles) and sodium iodide (1.57 g; 0.0105 moles) in DMF (100 mL) was heated at 80° C., with magnetic stirring, under a nitrogen atmosphere for 15 hours. The mixture was allowed to cool, added to water (300 mL) and extracted with ethyl acetate (3×200 mL). The combined extracts were washed with water (200 mL) and saturated aqueous sodium chloride solution (100 mL) and then dried over sodium sulfate. Filtration and evaporation of solvent gave a crude yellow oil which was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (5:2). Removal of solvent under vacuum gave the product 4-(1,3-dioxolan-2-yl)-butanenitrile (11.28 g; 76%) as a colorless oil. 1H NMR (CDCl3) δ 4.89–4.91 (1H, m), 3.92–4.01 (2H, m), 3.82–3.90 (2H, m), 2.40–2.46 (2H, m), 1.77–1.85 (4H, m).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH2:17][OH:18]>C(O)CCC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][CH2:17][OH:18])([O-:14])=[O:13]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO

Procedure:
A mixture of 50 parts of 1-chloro-2-nitro-4-(trifluoromethyl)benzene, 37 parts of 2-aminoethanol and 100 parts of 1-butanol is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is taken up in a diluted hydrochloric acid solution. The product is extracted with methylbenzene. The layers are separated and the aqueous phase is extracted with methylbenzene. The combined methylbenzene-phases are washed successively with a diluted hydrochloric acid solution and twice with water, dried, filtered and evaporated. The solid residue is crystallized from petroleumether. The product is filtered off and dried, yielding 2-{[2-nitro-4-(trifluoromethyl)phenyl]amino}ethanol; mp. 74.9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (75%). MS 329 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:12]=[CH:11][N:10]=3)[CH:7]=2)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13](OC)=[O:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CC1=C(C)Cc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1=C(CCO)c2cc(F)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
To a solution of 14b (24 g) in dry THF (300 ml), LiAlH4 (6.9 g) was added in portions. The mixture was stirred at room temperature for 1.5 hours. Excess LiAlH4 (LAH) was destroyed with saturated Na2SO4 solution. The organic phase was concentrated in vacuo, and the crude product was purified via silica gel column chromatography eluting with methylene chloride. The product was recrystallized from hexane to give 5-fluoro-2-methyl-1H-3-indenyl-(2-hydroxy)ethane (15b) (14.9 g, 63% yield): m.p. 65°-66.5° C.