Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)(C)[C:3]([NH2:5])=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[N:10]=1.C([Li])CCC.BrCCBr.C(OCCCC)(=O)C=C>[Pd]>[NH:10]1[C:9]2[C:14](=[CH:1][CH:2]=[CH:3][N:5]=2)[CH2:13][CH2:12][C:11]1=[O:15].[ClH:8]
Reactant: CC(C)(C)C(N)=O
Reactant: COc1cccc(Cl)n1
Agent: [Pd]
Agent: C=CC(=O)OCCCC
Agent: [Li]CCCC
Solvent: BrCCBr
Product: Cl
Product: O=C1CCc2cccnc2N1

Procedure:
In step (a) trimethylacetamide may be reacted with 2-chloro-6-(methyloxy)pyridine. In step (b) the product of step (a) may be treated with n-butyl lithium and 1,2-dibromoethane. The product from step (b) may be treated in step (c) with n-butyl acrylate. Hydrogenation in the presence of palladium on carbon in step (d) can yield the hydrogenated product. The product of step (d) may be cyclised in step (e) to yield the 3,4-dihydro-1,8-naphthyridin-2(1H)-one by treatment with hydrochloric acid. In step (f) the oxirane may be formed by reaction with sodium hydride then with (2S)-2-oxiranylmethyl 3-nitrobenzenesulfonate. Cyclisation to the imidazonaphthyridine may be done by heating the oxirane, or microwave power. Step (h) to attach the 4-(N-tert-butoxycarbonylamino) piperidine moiety may be performed by formation of the methanesulfonate, then reaction with the corresponding amine. Aromatisation of the ring in step (i) may be done by treatment with DDQ followed by heating. The amine may then be deprotected using acid hydrolysis, step (j) to yield the amine (IIA), which may then be reacted with a compound of Formula IIB e.g. an aldehyde to form the compound of Formula (I).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14](=[O:18])[C:15](Cl)=[O:16].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)[CH:21]=1.C(N(CC)CC)C>ClCCl.CC(C)=O>[CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14](=[O:18])[C:15]([NH:39][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[N:23]=3)[CH2:28][CH2:29]2)=[CH:38][CH:37]=1)=[O:16]
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Reactant: Cc1cc(-c2ccccc2)c(C(=O)C(=O)Cl)n1C
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc(C)n4C)cc3)CC2)c1
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A solution of (1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-oxo-acetyl chloride (46 g, 0.176 mol) in dry dichloromethane (300 mL) was added to a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (40 g, 0.140 mol) and triethylamine (14.2 g, 0.140 mol) in dry dichloromethane (300 mL) over 15 min. After stirring for 1 h the reaction mixture was quenched into water (200 mL) and the organic phase separated. The aqueous layer was extracted with dichloromethane (2×50 mL) and the combined organic layers were washed successively with water (2×200 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated to give a solid. This was dissolved in acetone (580 mL) and silica gel was added (72.5 g, 100-200 mesh). The mixture was stirred at room temperature for 1 h, filtered and the solids washed with acetone (75 mL). The silica treatment was repeated a second time. The filtrate was concentrated to ˜300 mL (˜4 vols), activated carbon (8 g) was added and heated at reflux for 15 min. The mixture was cooled to 45-50° C. and filtered over celite, washing with acetone (75 mL). The solution was again concentrated to ˜300 mL and petroleum ether (725 mL, 10 vols) was added, slowly, at reflux. The resulting suspension was cooled to room temperature, stirred for 15 min, then cooled to 0° C. and stirred for 1 h. The solid was filtered off, washed with petroleum ether (150 mL) and dried under vacuum to afford 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-acetamide (53.5 g, 74%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[C:7]([I:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])([O-])=O.N>C(O)C>[N+:12]([C:5]1[CH:6]=[C:7]([I:11])[C:8]([I:10])=[CH:9][C:4]=1[NH2:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(I)c(I)cc1[N+](=O)[O-]
Agent: N
Solvent: CCO
Product: Nc1cc(I)c(I)cc1[N+](=O)[O-]

Procedure:
A solution was prepared from 3 gms. of 1,2-dinitro-4,5-di-iodobenzene in 150 ml. of ethanol. Gaseous ammonia was passed into the solution while heating to refluxing temperature. This procedure was continued until TLC indicated that all starting material had reacted (about 8 hours). The volume of the solution was then reduced to 1/3 of the original volume and the solution was cooled. 2-nitro-4,5-di-iodoaniline formed in the above reaction precipitated and was collected by filtration; mp=196°-7° C.; yield=1.70 g.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC1C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>COCCOC>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:19][CH:32]=[N:31][CH:30]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 85 °C

Procedure:
To 2-fluoro-5-(3-formylpyridin-2-yloxy)benzoic acid (230 mg, 0.881 mmol) and TosMIC (172 mg, 0.881 mmol) in DME (8.0 mL) was added DBU (0.29 mL, 1.9 mmol). The mixture was heated to 85° C. for 2.5 hours in a sealed tube. After concentrated, the residue was diluted with saturated sodium carbonate and extracted with EtOAc. The aqueous layer was acidified with TFA (pH˜3) and the resulting solid was filtered and dried to yield 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoic acid as a beige solid. MS m/z=301 [M+1]+. Calc'd for C15H9FN2O4: 300.25.
Reaction SMILES: Cl[CH:2]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[O:5][C:4]=1[CH3:15].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31]C)=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:16]1([CH:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=2)[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[O:5][C:4]=2[CH3:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1oc(-c2ccc(F)cc2)cc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2ccc(F)cc2)cc1C(Nc1ccc(C(=O)O)nc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 3-[chloro(cyclohexyl)methyl]-5-(4-fluorophenyl)-2-methylfuran (1.3 g), methy 5-aminopyridine-2-carboxylate (0.7 g), sodium carbonate (0.5 g) and sodium iodide (1.4 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 10 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (5 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid. To the obtained 5-({cyclohexyl[5-(4-fluorophenyl)-2-methylfuran-3-yl]methyl}amino)pyridine-2-carboxylic acid (694 mg) were added ethyl β-alaninate hydrochloride (261 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (326 mg), hydroxybenzotriazole monohydrate (260 mg), triethylamine (237 μl) and N,N-dimethylformamide (10 mL), and the obtained mixture was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (521 mg, 60%) as an amorphous compound.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[NH2:13][C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:13]/[C:14]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])=[N+:2]=[N-:3]
Reactant: N#Cc1cccc(Cl)c1N
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (2.86 g, 17.2 mmol) and 2-amino-3-chlorobenzonitrile (2.62 g, 17.2 mmol) in DCM (60 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (7.2 mL, 51.6 mmol) was added, followed by dropwise additiona of titanium (IV) chloride solution (1 N in DCM, 10.3 mL, 10.3 mmol). The reaction mixture was stirred at 0° C. for 2 hours, then at room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue obtained was used in the following step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[C:10](=[O:11])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1.S(=O)(=O)(O)O>C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[C:10](=[O:11])[CH2:9][CH:8]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: CNc1nc(Cl)nc2c1C(=O)CC2c1ccccc1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1C(=O)CC2c1ccccc1

Procedure:
A solution of 2-chloro-4-(methylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5-one (Preparation AN) (7 mg) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (7 mg) in THF (0.2 mL) and sulfuric acid (4 mg) was heated at 85° C. for 12 h. THF was removed in vacuo, and the residue was purified by reverse phase preparative to give the title compound (as its TFA salt) as a yellowish oil (9 mg). LC-MS (M+H)+=461.12. 1HNMR (500 MHz, CD3OD) δ ppm 7.80 (m), 7.1-7.4 (m), 4.50 (1H, m), 3.25 (1H, m), 2.56 (1H, m), 3.50 (3H, s), and 3.19 (3H, s).
Reaction SMILES: C[O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH:19]=O>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:21])[C:18]=1[CH2:19][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[C:3]([OH:2])=[O:11]
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1c(Cl)cncc1Cl
Product: O=C(O)c1ccccc1NCc1c(Cl)cncc1Cl

Procedure:
Prepared by a similar procedure as described for preparation 1J, starting from anthranilic acid methyl ester and 3,5-dichloro-4-pyridinecarboxaldehyde (Aldrich). 13C-NMR (DMSO-d6) δ 170.1, 149.7, 147.9, 142.6, 133.5, 132.2, 131.7, 115.1, 113.2, 110.9, 41.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=O)[CH2:9][CH2:10][C:11]1[S:12][C:13]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:14]=2[N:15]=1)[CH3:7])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26]>C1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=[S:26])[CH2:9][CH2:10][C:11]1[S:12][C:13]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:14]=2[N:15]=1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)C(=O)CCc1nc2c(F)c(F)cc(F)c2s1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccccc1
Product: CCOC(=O)CN(C)C(=S)CCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 60 °C
Yield: 35.2 %

Procedure:
To benzene (10 ml) was added N-[3-(4,5,7-trifluorobenzothiazol-2-yl)propionyl]-N-methylglycine ethyl ester (610 mg, 1.7 mmol) obtained in Example 3-ii) and phosphorus pentasulfide (378 mg, 1.7 mmol) and the mixture was heated at 60° C. for 3 hours. The organic phase was decanted and the residue was extracted with ether. All the organic phases were combined, washed with water, dried and evaporated to yield a residue, which was crystallized from hexane-isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)-1-thioxopropyl]N-methylglycine ethyl ester (225 mg, 35%) as colorless crystals.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]2[CH:15]=[N:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]2[CH2:6][NH:5]1.[CH3:23]I.O>CN(C)C=O.C(O)(=O)C>[CH3:23][N:5]1[C:4](=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]2[CH:15]=[N:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]2[CH2:6]1
Reactant: CI
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
70 mg (1.6 mmol) of sodium hydride (55 percent oil dispersion) are suspended in 5 ml of dry dimethylformamide and treated with 135 mg (0.5 mmol) of ethyl 5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate. After completion of the gas evolution, 0.15 ml (2.3 mmol) of methyl iodide is added and the mixture is stirred at room temperature for 1 hour. The mixture is poured into ca 50 ml of water, neutralised with glacial acetic acid and extracted three times with ca 30 ml of chloroform each time. The combined chloroform phases are washed with ca 20 ml of water, dried over magnesium sulphate and evaporated. After column chromatography and recrystallisation from ethyl acetate, there is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 166°-167° C.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1.[CH2:16]([CH:24]1[CH2:26][O:25]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[OH:25][CH:24]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: c1ccc(CCC2CO2)cc1
Reactant: Oc1ccc(SC2CCCNC2)cc1
Agent: Br
Product: Oc1ccc(SC2CCCN(CC(O)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=358.2 (M+H+) was prepared from (RS)-4-(piperidin-3-yl-sulfanyl)-phenol hydrobromide and (RS)-2-phenethyl-oxirane.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[K+].[Br-].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>C(#N)C>[Br-:10].[CH2:11]([C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH3:19])[C:29]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCBr
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. 1-bromopentane (1.1 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a yellow precipitate (1.793, 49% yield). 1H NMR (500 MHz, DMSO-d6) 9.66 (1H, s, NCHN), 8.02 (4H, m, Ar), 7.57 (3H, m, Ar), 5.66 (2H, s, NCH2), 4.24 (2H, t, NCH2), 1.80 (2H, tt, CH2), 1.37 (2H, tq, CH2), 0.93 (3H, t, CH3). 13C{1H} NMR (125 MHz, DMSO-d6) 136.4 (NCN), 132.8 (Ar), 132.6 (Ar), 130.0 (Ar), 128.8 (Ar), 127.8 (Ar), 127.7 (Ar), 127.6 (Ar), 126.8 (Ar), 126.7 (Ar), 125.5 (Ar), 120.9 (Ar), 114.1 (Ar), 112.9 (Ar), 51.6 (CH2), 48.5 (CH2), 27.8 (CH2), 27.4 (CH2), 21.4 (CH2), 13.6 (CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: CC(C)(C)NO
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1C=[N+]([O-])C(C)(C)C
Temperature: 25 °C
Reaction time: 70 h
Yield: 78 %

Procedure:
2-Ethoxybenzaldehyde (12.0 g, 79.90 mmol) and N-tert-butylhydroxylamine (10.69 g, 119.86 mmol) were mixed in chloroform with molecular sieves (50 g, 4A) and silica gel (10 g). The mixture was sealed under argon gas and stirred for 70 h at room temperature. The mixture was then filtered and the solid washed with ethyl acetate and the combined solution was rotary evaporated. Pentane (50 mL) was added to the liquid residue and isolation of the resulting solid afforded 13.79 g (78.0% yield) of the title compound as white crystals, m.p. 58.3+ C. (Rf=0.55 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: C(C(C(=O)C)[C:5]([C:7]1[CH:12]=[CH:11]C=CC=1)=[O:6])(C)C.C[O:17][C:18](C)(C(C)C)[C:19]1C=CC=C[CH:20]=1>C(C1C=CC=CC=1C(C)C)(C)C>[C:18]([O:6][CH2:5][CH2:7][CH2:12][CH3:11])(=[O:17])[CH:19]=[CH2:20]
Reactant: CC(=O)C(C(=O)c1ccccc1)C(C)C
Reactant: COC(C)(c1ccccc1)C(C)C
Agent: CC(C)c1ccccc1C(C)C
Product: C=CC(=O)OCCCC

Procedure:
In a mixture of diisopropyl benzene, isopropyl acetyl acetophenone, and dimethyl isopropyl phenyl carbinol
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([N+:11]([O-])=O)[C:3]=1[OH:14].[H][H]>CO.[Ni]>[ClH:1].[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([NH2:11])[C:3]=1[OH:14]
Reactant: [H][H]
Reactant: CCc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Agent: [Ni]
Solvent: CO
Product: CCc1c(Cl)cc(N)c(O)c1Cl
Product: Cl
Temperature: 20 °C
Yield: 157.7 %

Procedure:
2,4-Dichloro-3-ethyl-6-nitrophenol (20 g, 98.4% purity) was dissolved in methanol (80 g), to which Raney nickel (0.8 g) and activated carbon (0.2 g) were added and into which hydrogen gas was introduced at a hydrogen pressure of 4 kg/cm2 at 40° to 45° C. until no absorption of hydrogen gas was found. After completion of the reaction, Raney nickel was removed in air, and hydrochloric acid (17.7 g) was added dropwise, and the reaction mixture was cooled to 20° C., which resulted in a deposition of crystals. The deposited crystals were washed with acetone (28 g) and dried, which afforded 16.2 g of 2,4-dichloro-3-ethyl-6-aminophenol hydrochloride. To this hydrochloride salt, the above distillation-purified acid chloride compound (23.4 g) was added in air, and the mixture was heated under reflux in acetonitrile (162 g) for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C., and the deposited crystals were filtered, washed with acetonitrile (16 g) and dried, which afforded 30.1 g of the desired amide compound (m.p., 145°-146° C., 98.9% purity). These crystals were recrystallized from acetonitrile (150 g), and 28.2 g of crystals having a purity of 99.3% were obtained (82.2% yield in the amidation step).
Reaction SMILES: O[CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.S(Cl)([Cl:19])=O.O>C(Cl)Cl>[ClH:19].[Cl:19][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2CCc2ncccc21
Solvent: ClCCl
Solvent: O
Product: Cl
Product: ClC1c2ccccc2CCc2ncccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.11 g of 5-hydroxy-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine was suspended in 10 ml of methylene chloride. To the suspension was added 3.57 g of thionyl chloride with water-cooling. The mixture was stirred for 1 hour at room temperature. The solvent was removed by distillation under reduced pressure to obtain crystals of 5-chloro-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine hydrochloride. The crystals were suspended in 10 ml of methylene chloride.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].N[C:13]1([O:22]O)[CH2:18][CH:17]([CH3:19])[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14]1>C(O)C>[C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][CH:17]1[CH2:16][C:15]([CH3:21])([CH3:20])[CH2:14][C:13](=[O:22])[CH2:18]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C1CCCC1
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred mixture of cyclopentanone (33.8 g.) and ethanol (100 c.c.) containing ammonium acetate (3.2 g.) and kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (44.6 g., 68% pure). After storing at 0°C overnight the reaction mixture was worked up as in the previous Examples to give unreacted cyclopentanone and dihydroisophorone together with a fraction (20.0 g.) b.p. 82° - 86°/0.5 mm.Hg. This last fraction was redistilled to give: material b.p. 74° - 76°C/0.3 mm.Hg., peroxide equivalent 202, shown by mass spectroscopy to be a mixture of the peroxide ##SPC61##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([O:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][CH:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([NH:37][S:34]([CH:32]([CH3:33])[CH3:31])(=[O:36])=[O:35])=[O:10])=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:20][C:21]1[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=1
Reactant: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Oc2cccc(Cl)c2C(=O)NS(=O)(=O)C(C)C)n1
Yield: 38.5 %

Procedure:
A stirred solution of 0.43 grams (0.001 mole) of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzoate (prepared in Steps F and G), 0.12 gram (0.001 mole) of 1-methylethylsulfonamide, and 0.14 gram (0.001 mole) of potassium carbonate in 5 mL of acetonitrile was heated at reflux for five hours. The reaction mixture was then cooled and concentrated under reduced pressure to a residue. The residue was stirred with ethyl acetate and water, and the aqueous layer was separated. The aqueous layer was acidified with aqueous dilute hydrochloric acid and then was extracted with ethyl acetate. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was crystallized from diethyl ether. The solid was collected by filtration to yield 0.16 gram of 2-[3-chloro-2-(1-methylethylsulfonylaminocarbonyl)phenoxy]-4,6dimethoxypyrimidine; m.p. 150°-152° C., Compound 10 in Table 1. The nmr spectrum was consistent with the proposed structure.