Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:7]1)C.[OH-].[Na+].Cl.C1(C)C=CC=CC=1>C(O)C>[Cl:20][C:17]1[S:16][C:15]([C:13]([NH:12][CH:8]2[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:21])=[O:3])[CH2:7]2)=[O:14])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)CN1CCCC(NC(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
9.2 To a stirred solution of {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid ethyl ester at r.t. in 5 ml ethanol were added 5 ml 1 N NaOH. The slurry slowly turned to a clear solution. Stirring at r.t. was then continued for 5 h. The mixture was neutralized by adding 5 ml of 1 N HCl (pH ˜7). The light orange solution was concentrated to leave an off-white solid. This residue was coevaporated several times with toluene to remove the remaining H2O, and dried overnight (r.t., 0.5 mbar) to give 1.07 g {3-[(5-chloro-thiophene-2-carbonyl)-amino]-piperidin-1-yl}-acetic acid (containing 2 mol equivalents of sodium chloride). Off-white solid. MS 301.3 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.O.C(O)(=O)C.[CH:17](N)=[NH:18]>COCCO>[F:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:17][NH:18][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: N=CN
Reactant: Nc1cnc(F)cc1C(=O)O
Solvent: COCCO
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cnc(F)cc12

Procedure:
A suspension of 39.0 g (246 mmol) of 5-amino-2-fluoropyridine-4-carboxylic acid hydrated with 0.15 equivalents of water, 52.01 g (500 mmol) of formamidine acetate, and 500 mL of 2-methoxyethanol was heated at reflux for 6 hours, then concentrated to a solid. The solids were treated carefully with 100 mL of 10% aqueous sodium bicarbonate while maintaining vigorous stirring. The resultant suspension was filtered, and the collected brown solids were washed well with water, then dried over P2O5 to afford 31.3 g (77%,) of product that was used directly in the next reaction. Recrystallization of a small sample from methanol gave product of mp 287° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.ON1C2C=CC=CC=2N=N1.[Br:34][CH2:35][CH2:36][CH2:37][C:38](O)=[O:39].O>CN(C)C=O.Cl.CN(C)CCCN=C=NCC>[Br:34][CH2:35][CH2:36][CH2:37][C:38]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)=[O:39]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: O=C(O)CCCBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)CCCBr)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
Methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (450 mg) was suspended in N,N-dimethylformamide (5 ml) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (391 mg), 1-hydroxybenzotriazole (276 mg) and 4-bromobutanoic acid (318 mg) were added, which was followed by stirring at room temperature for 24 hr. Water (50 ml) was added to the reaction mixture under ice-cooling and the precipitated crystals were collected by filtration and dried under reduced pressure with heating to give methyl 3-(4-((4-bromobutyryl)amino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (436 mg) as pale-yellow crystals.
Reaction SMILES: ClB.CSC.C[SiH](C[CH2:10][Si:11]([CH3:19])([CH3:18])[CH2:12][CH2:13]CCC=C)C.OO.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:19][Si:11]([CH3:18])([CH2:10][Si:11]([CH3:18])([CH3:12])[CH3:10])[CH2:12][CH2:13][CH2:24][CH2:23][CH2:22][CH2:26][OH:25]
Reactant: C1CCOC1
Reactant: C=CCCCC[Si](C)(C)CC[SiH](C)C
Agent: BCl
Agent: OO
Solvent: CSC
Product: C[Si](C)(C)C[Si](C)(C)CCCCCCO
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Monochloroborane-methyl sulfide (2.03 ml, 2.15 g, 19.5 mmol) was added dropwise to a stirred, cooled (0° C.) solution of compound 10 (2.96 g, 13.0 mmol) in THF (20 ml). The reaction mixture was stirred at 0° C. for 24 h, and a solution of hydrogen peroxide (13 ml, 30% in water) added dropwise and the reaction mixture stirred at 0° C. for 4 h, washed with water and the organic layer extracted into hexane/ethyl acetate (3×30 ml, 1:1). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield colorless oil. The crude product was purified by column chromatography [silica gel eluted with hexane/ethyl acetate (4:1)] to yield a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=1)#[CH:14].N1C=CN=C1.[C:30]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])([CH3:32])[CH3:31]>C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Si:34]([O:1][C:2]1[CH:11]=[C:10]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#Cc1ccc(OCOC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#Cc2ccc(C(=O)OC)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of methyl 2-hydroxy-4-iodobenzoate (6.55 g, 23.6 mmol), 1-ethynyl-4-(methoxymethoxy)benzene (4.58 g, 28.3 mmol) and copper(I) iodide (450 mg, 2.36 mmol) in triethylamine (50 mL) was added bis(triphenylphosphine)palladium(II) chloride (1.66 mg, 2.36 mmol), and the mixture was stirred under an argon stream at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in DMF (30 mL). Imidazole (2.42 g, 35.4 mmol) and tert-butyl(chloro)dimethylsilane (4.27 g, 28.3 mmol) were added thereto, and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:2) to give the title compound (8.50 g, yield 84%) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.CS(O)(=O)=O.FC1C=CC=CC=1C1OC(C([NH:36][C:37]([NH2:39])=[NH:38])=O)=CC=1>CO.[Cl-].[Na+].O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[O:6][C:5]([C:3]([NH:38][C:37]([NH2:39])=[NH:36])=[O:2])=[CH:9][CH:8]=2)=[CH:11][CH:12]=1
Reactant: N=C(N)NC(=O)c1ccc(-c2ccccc2F)o1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)o1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(N)NC(=O)c1ccc(-c2ccc(F)cc2)o1
Yield: 51.4 %

Procedure:
5-(4-fluorophenyl)furan-2-carboxylic acid methyl ester (220 mg, 1.0 mmol) was dissolved in methanol (4 ml), to which 2 M guanidine solution (3.0 ml, 6.0 mmol) prepared in Example 1 was added, and the mixture was heated at reflux for 12 hours. After completion of the reaction, the solution was added with saturated brine (20 ml) and extracted with ethyl acetate (30 ml×3). The organic layer was washed with 10% brine, dried over anhydrous magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane), to give 127 mg of a title compound (yield: 51%).
Reaction SMILES: [CH3:1][C@@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][CH2:4][CH3:5].O1CCOCC1>CO>[NH2:25][C:9]1[N:8]=[C:7]([O:6][C@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][O:19]1
Reactant: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Solvent: CO
Solvent: C1COCCO1
Product: CCC[C@@H](C)Oc1nc(N)c2[nH]c(=O)n(CCC3CCCO3)c2n1
Temperature: 37 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-9-[2-(tetrahydro-2-furanyl)ethyl]-9H-purin-6-amine (50 mg, 0.143 mmol) in methanol (10 ml) at room temperature was added 4M HCL in 1,4 dioxane (0.894 ml, 3.58 mmol) to give a pale straw coloured solution. The reaction mixture was stirred at 37° C. for 3 hours, and the solvent removed on a nitrogen blowdown unit overnight. The residue was dissolved in methanol and loaded onto a 2 g aminopropyl SPE cartridge and eluted with methanol. The appropriate fractions were combined and dried under a stream of nitrogen in a blowdown apparatus to give the title compound as a white solid (26 mg).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8][CH2:9][CH3:10])=O.Cl.O1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=O)[CH:18]=[CH:17]1>C(O)C>[O:1]=[C:2]1[C:10]2[CH:21]=[C:22]3[CH2:23][CH2:24][CH2:25][CH2:20][CH2:19][C:18]3=[CH:17][C:9]=2[O:8][C:6]([C:5]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=c1ccoc2ccccc12
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2cc3c(cc2o1)CCCCC3
Temperature: 25 °C

Procedure:
A solution of the product from step (b) (10 gm) in ethanol (50 ml) was added to sodium ethoxide solution (prepared by dissolving sodium (5.75 gm) in ethanol (150 ml)) and stirred at room temperature for ten minutes. Diethyl oxalate (17.5 gm) in ethanol (30 ml) was added dropwise and the reaction mixture was refluxed for 90 minutes, cooled, poured into dilute hydrochloric acid and extracted with chloroform. Removal of the chloroform in vacuo yielded a brown oil which was refluxed with ethanol (150 ml) containing conc. hydrochloric acid (80 ml) for five hours. The bulk of the solvent was removed in vacuo and the residues were poured into water and extracted with ethyl acetate. After washing with brine and water the ethyl acetate was removed in vacuo yielding a brown oil which was found to contain the chromone ester and the chromone acid. Trituration of the oil with 40°/60° C. petroleum ether yielded the title compound, a fawn coloured solid which was crystallised from aqueous ethanol. Wt 0.34 gm. Mpt. 74°-75 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH:12](=[N:1]/[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][O:5][C:6]2=[O:11])\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c1COC2=O
Solvent: CO
Product: O=C1OCc2c(/N=C/c3ccccc3)cccc21
Yield: 63.2 %

Procedure:
4-aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), benzaldehyde (427 mg, 4 mmol) were added to methanol (20 mL) and stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residue was dried in vacuum. 600 mg of crude product (E)-4-(benzylideneamino)isobenzofuran-1(3H)-one was obtained which was used for the next synthetic step without further purification.
Reaction SMILES: [O-][CH2:2]C.[Na+].[Na].[C:6]([CH2:8][C:9](OCC)=[O:10])#[N:7].Cl.[CH3:15][O:16][CH2:17][CH2:18][C:19]([NH2:21])=[NH:20]>C(O)C>[NH2:7][C:6]1[N:20]=[C:19]([CH2:18][CH2:17][O:16][CH2:15][CH3:2])[NH:21][C:9](=[O:10])[CH:8]=1
Reactant: CC[O-]
Reactant: CCOC(=O)CC#N
Reactant: COCCC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOCCc1nc(N)cc(=O)[nH]1
Reaction time: 8 h

Procedure:
To a solution of sodium ethoxide in ethanol, prepared from sodium (47.5 g.) and dry ethanol (675 ml.), was added, slowly with cooling and stirring, ethyl cyanoacetate (74 ml.), followed by a solution of 3-methoxypropionamidine hydrochloride (96 g.) in dry ethanol (173ml.). The mixture was stirred and heated under reflux for 40 hours, evaporated to dryness in vacuo, the residue triturated with water (67.5 ml.), acidified to pH 6 with concentrated hydrochloric acid, left to stand at 0° C. overnight and filtered. The aqueous filtrate was extracted continuously with ethyl acetate for 3 days and the extract dried and evaporated to dryness to give crude 4-amino-2-(2-ethoxyethyl)pyrimid-6-one (11.38 g.), m.p. 167°-170° C., sufficiently pure for use in the next stage. A sample was purified by chromatography on silica gel, followed by recrystallisation from ethanol, to give pure 4-amino-2-(2-ethoxyethyl)pyrimid-6-one, m.p. 191°-194° C.
Reaction SMILES: [C:1]1([CH:7]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>CCOC(C)=O.C(#N)C>[Cl-:29].[O:32]=[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(NS(=O)(=O)c1ccccc1)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(NS(=O)(=O)c1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(phenylsulfonamido)acetate (C64) (96 mg, 0.24 mmol) in EtOAc (1.6 ml) and acetonitrile (0.8 ml), was added 2-chloro-1-phenylethanone (40.8 mg, 0.26 mmol). The solution was stirred at RT overnight. The solution was concentrated under vacuum and the crude was purified by flash chromatography (DCM/MeOH=95/5 to 9/1) to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(phenylsulfonamido)acetoxy)-1-azoniabicyclo[2.2.2]octane chloride (99 mg; 74% yield).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:5])C.[NH:17]([C:19]1[N:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[NH2:18].O>ClCCl.CO>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]2[N:17]([C:19]3[N:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:18]=[C:4]([CH3:5])[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(C)=NC(=O)c1ccc(OC)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cn2)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
N-(1-ethoxy-ethylidene)-4-methoxy-benzamide 462 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(4-methoxy-phenyl)-3-mehtyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (397 mg, yield: 55%) was obtained as a solid phase.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14](O)[CH3:15].S(=O)(=O)(O)O>C(Cl)CCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([O:10][CH2:14][CH3:15])=[O:9])=[CH:12][CH:13]=1
Reactant: CCO
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C

Procedure:
2-(4-hydroxyphenoxy)propionic acid (9.0 g), ethanol (15 ml) and concentrated sulfuric acid (0.5 ml) were added to ethylene dichloride (40 ml) and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and the ethylene dichloride layer was separated and washed twice with water and twice with aqueous 2% NaHCO3. The organic fraction was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure to give the product, ethyl 2-(4-hydroxyphenoxy)-propionate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:23]1[CH:27]=[C:26]([CH2:28][OH:29])[O:25][N:24]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>ClCCl>[CH2:11]([C:23]1[CH:27]=[C:26]([CH:28]=[O:29])[O:25][N:24]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCc1cc(CO)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCCCc1cc(C=O)on1
Temperature: -60 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution of oxalyl chloride (28.8 ml) in dry dichloromethane (100 ml) was cooled to -60° C. and a solution of dimethylsulfoxide (8.9 ml) in dichloromethane (30 ml) was added, followed by a slurry of 3-(1-dodecyl)-5-isoxazolemethanol (14.0 g) in dry dichloromethane (200 ml). The mixture was stirred at -60° C. for 1 hr, quenched with triethylamine (87 ml) and allowed to warm to room temperature. The solution was poured into water (300 ml) and extracted with dichloromethane. The organic phases were washed with dilute citric acid solution, dried, filtered, and the filtrate was evaporated. The residue was passed through a short pad of silica gel using dichloromethane as the eluent. The solution was evaporated and the residue was recrystallized from ether-hexane to give 11.5 g (78%) of product, mp 53°-54° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([CH2:24][CH3:25])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[O:13])[CH3:2].[CH2:26]([OH:29])[CH2:27][CH3:28].[CH2:30]1[CH2:35]CCC[CH2:31]1>>[CH2:24]([C:14]1[CH:15]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:17]=[C:3]([CH2:1][CH3:2])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([O:29][CH2:26][CH2:27][CH3:28])[O:13][CH2:31][CH2:30][CH3:35])[CH3:25]
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Reactant: CCCO
Reactant: C1CCCCC1
Product: CCCOC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)OCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A mixture of 0.39 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 0.24 g of 1-propanol and 10 ml of cyclohexane was stirred at room temperature, to which 0.038 g of p-tolunesulfonic acid hydrate and 0.40 g of powdered molecular sieves SA were added. After stirring at room temperature for 30 minutes, the reaction mixture was filtered. The filtrate was added to water and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-dipropyloxyethoxy)butyloxy)benzene (yield, 77%), nD23.5 1.4975.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28].O>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:17][C:15]1[CH:14]=[CH:13][C:5]2[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:2]([N+:27]([O-:32])=[O:28])[O:3][C:4]=2[CH:16]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: Cc1ccc2c(-c3ccccc3)c(Br)oc2c1
Agent: O=C(O)C1CC=CCC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc2c(-c3ccccc3)c([N+](=O)[O-])oc2c1
Reaction time: 16 h

Procedure:
To a stirred solution of 4 g (0.014 mole) of 2-bromo-6-methyl-3-phenylbenzofuran in 50 ml of acetic acid and 50 ml of chloroform is added 1.8 g (0.015 mole) of cyclohexene-4-carboxylic acid and a solution of 1.4 g (0.015 mole) of dinitrogen tetroxide in 10 ml of acetic acid. After sitting for about 16 hours the mixture is poured into water. This mixture is extracted with chloroform and the extracts are washed with water and 10% sodium bicarbonate solution and dried. Evaporation of the solvent and recrystallization of the residue from cyclohexane provides yellow crystals of 6-methyl-2-nitro-3-phenylbenzofuran, m.p. 142°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]([Cl:15])([Cl:14])[C:11](Cl)=[O:12]>>[Cl:9][C:10]([Cl:15])([Cl:14])[C:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12]
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: O=C(Oc1ccc(Cl)cc1)C(Cl)(Cl)Cl
Temperature: 120 °C

Procedure:
A 25.6 gram (g) (0.2 mole) sample of 4-chlorophenol was mixed with 40 g of trichloroacetyl chloride at room temperature. The resulting solution was heated under reflux conditions at 120° C. for 10 hours. The temperature was gradually increased to 180° C. over a period of 16 hours. The reaction mixture was then allowed to cool to room temperature. An insoluble solid product was collected by filtration and dried in vacuo. The solid was identified by vapor phase chromatography as 4-chlorophenyl trichloroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22]#[N:23])=[CH:16][CH:15]=3.C([O-])(=O)C.[Na+].Cl.[OH:36][NH-:37]>C(Cl)Cl.CO>[NH2:23][C:22]1[O:36][N:37]=[C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)[CH:21]=1
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(C(=O)CC#N)ccc3n(C)c21
Reactant: [NH-]O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc(N)on4)ccc3n(C)c21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution containing 300 mg (0.707 mmol) of compound 3-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-3-oxopropionitrile from Example 20A, 238 mg (2.9 mmol) of sodium acetate and 152 mg (2.2 mmol) of hydroxylamide hydrochloride in 4 ml of CH2Cl2 and 4 ml of MeOH is stirred at 50° C. for 24 h and then at ambient temperature for 18 h. The reaction medium is concentrated by adsorbing it onto silica, and purification is carried out on a silica column, elution being carried out with EtOAc/20% cyclohexane and then 100% EtOAc.