Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=O)C.[CH:12](=O)[C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>O1CCCC1.O>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[C:8]1[CH2:9][CH2:10][NH:6][C:7]1=[O:11]
Reactant: COc1ccccc1C=O
Reactant: CC(=O)N1CCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C=C1CCNC1=O
Yield: 11.8 %

Procedure:
Sodium hydride (16 g) was suspended in tetrahydrofuran (100 ml) and a solution of N-acetylpyrrolidone (25 g) and o -anisaldehyde (26.8 g) in tetrahydrofuran (100 ml) was added dropwise under ice-cooling. After completion of the reaction, the reaction mixture was poured into water. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give oily 3-(2′-methoxybenzylidene)-2-pyrrolidone (4.7 g). The oil was dissolved in methylene chloride (60 ml). By demethylation using boron tribromide under ice-cooling, 3-(2′-hydroxybenzylidene)-2-pyrrolidone (4.0 g) was obtained as yellow crystals. To the crystals (1.5 g) were added dimethylformamide (50 ml) and potassium carbonate (2.2 g). (S)-Glycidyl nosylate (2.3 g) was added and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate to give an oily compound (1.8 g). By the reaction of the oil (0.5 g) and 4-(5,6,7,8-tetrahydronaphthalen-2-yl)piperidine (0.5 g) in methanol in the same manner as in Example 307, the title compound (0.4 g) was obtained, melting point 157-159° C.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(O)(C)(C)C>[C:8]([O:7][C:1](=[O:12])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of tert-butyl alcohol (650 mL) and di-tert-butyl carbonate (24 g) was added 2-Aminopyridine (9.4 g) slowly. This mixture was stirred at room temperature for 24 hours. This reaction solution was concentrated under a reduced pressure, and the residue thereof was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (18 g).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][NH:20][N:19]=1.CCN(C(C)C)C(C)C.[CH3:32][Si:33]([CH2:36][CH2:37][O:38][CH2:39]Cl)([CH3:35])[CH3:34]>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:39][O:38][CH2:37][CH2:36][Si:33]([CH3:35])([CH3:34])[CH3:32])[N:19]=1
Reactant: CC(=O)Nc1cc(-c2cc(-c3nc[nH]n3)c(Br)o2)c(C)cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
Temperature: 0 °C
Yield: 13.5 %

Procedure:
A solution of N-{4-[5-bromo-4-(1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (6.0 g, 16.6 mmol) in dry DMF (150 mL) was allowed to stir at 0° C. To this cooled solution was added DIEA (6.5 g, 5.0 mmol) portionwise over 20 min under an atmosphere of nitrogen. The reaction mixture was allowed to stir for 10 min at 0° C. and then SEM-Cl (5.5 g, 33.2 mmol) in dry DMF was add dropwise over 10 min. The reaction mixture was allowed to stir at 0° C. for 10 min and then allowed to warm to rt and allowed to stir for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (1.1 g, 21%) plus an additional SEM regioisomer (1.7 g, 25%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]#[N:9])#[N:2].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Cl.O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][N:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]#[N:9])[N:6]=[CH:5]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1nc[nH]c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ncn(Cc2ccc(Cl)c(Cl)c2)c1C#N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
4,5-Dicyanoimidazole (93 g, described by Woodward, U.S. Pat. No. 2534331 (1950)) was dissolved in dry dimethylformamide (500 ml) with stirring. Sodium hydride (20 g) was added to the solution in portions at such a rate that the temperature after the addition was 90° C. When effervescence had ceased the solution was heated on a steam bath for 15 minutes and then allowed to cool to 60° C. 3,4-Dichlorobenzyl chloride (230 g, described by Beilstein & Kuhlberg, Ann., 146, 326 (1867)) was added over 30 minutes to the solution, which was heated on a steam bath for 6 hours and then at 150° C. for 10 minutes. The cooled reaction mixture was poured into water (2 liters) and a brown solid was filtered off and washed with water. The damp solid was recrystallised from ethanol (1 liter) to give 1-(3,4-dichlorobenzyl)-4,5-dicyanoimidazole, m.p. 132°-134° C., (114 g) as off-white crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1[NH:22][C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([C:23]4[NH:22][N:21]=[CH:25][N:24]=4)=[CH:34][CH:33]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc(-c2ncn[nH]2)cc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(-c2ncn[nH]2)cc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-4-(2H-[1,2,4]triazol-3-yl)-benzamide was prepared starting from intermediate D and 4-(2H-[1,2,4]triazol-3-yl)-benzoic acid. MS calcd. for C25H18ClN5O2 [(M+H)+] 455.9, obsd. 456.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][O:20][CH3:21])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([CH:15]=O)=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].Cl.NO.C([N:27](CC)CC)C.C(OC(=O)C)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][O:20][CH3:21])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([C:15]#[N:27])=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8]
Reactant: COCOc1ccc(Cl)cc1C(=O)c1ncccc1C=O
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: COCOc1ccc(Cl)cc1C(=O)c1ncccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a mixture of 2-(5-chloro-2-methoxymethoxybenzoyl)-3-formylpyridine (2.34 g), hydroxylamine hydrochloride (532 mg) and triethylamine (775 mg) was added acetonitrile (30 ml), which was stirred for 1.5 hour at room temperature. The reaction mixture was concentrated, which was partitioned with ethyl acetate/water. The organic layer was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated to give 2-(5-chloro-2-methoxymethoxybenzoyl)-3-hydroxylminomethylpyridine (2.39 g). A mixture of this compound and acetic anhydride (15 ml) was heated for one hour under reflux, followed by distilling off acetic anhydride under reduced pressure. The residue was purified by means of 10 a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-chloro-2-methoxymethoxybenzoyl)-3-cyanopyridine (1.51 g) (Compound E-12).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:26](I)[CH:27]([CH3:29])[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Reactant: CC(C)CI
Product: COc1ccc(-c2cc(=O)n(CC(C)C)nc2-c2ccc(OC)c(F)c2)cc1F

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and isobutyl iodide as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1([CH3:34])[CH2:32][NH:31][C:30](=[O:33])[NH:29]1>>[CH3:27][C:28]1([CH3:34])[N:29]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]5)[CH2:12][CH2:11]3)[CH:3]=2)[C:30](=[O:33])[NH:31][CH2:32]1
Reactant: CC1(C)CNC(=O)N1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5C(=O)NCC5(C)C)c4)CC3)cccc2n1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 4,4-dimethyl-2-imidazolidinone.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([SH:14])=[N:13][C:8]2=[CH:7][CH:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:4][C:5]1[N:10]=[C:9]2[S:11][C:12]([S:14][CH:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C:17]([OH:19])=[O:18])=[N:13][C:8]2=[CH:7][CH:6]=1
Reactant: Sc1nc2ccc(Cl)nc2s1
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Sc1nc2ccc(Cl)nc2s1)c1ccc(Cl)cc1
Yield: 68.2 %

Procedure:
A methylene chloride solution of 6.0 g (0.03 m) of 5-chloro-2-mercaptothiazolo[5,4-b]pyridine, 7.5 g (0.03 m) α-bromo-α-(p-chlorophenyl)acetic acid and 6.0 g (0.06 m) triethylamine is heated to gentle reflux overnight. The solution is extracted twice with a dilute hydrochloric acid solution and then once with water. After drying over anhydrous MgSO4, the solvent is removed and the residual solid is recrystallized from acetonitrile. 7.5 g (68% yield) of title compound, melting at 144°-6° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.I([O-])(=O)(=O)=[O:23].[Na+]>[Ru](=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N:8]2[CH:12]=[N:13][N:14]=[C:7]2[CH3:6])=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3)c3cc(Br)ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Br)cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 3, 7-bromo-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-bromo-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[O:17][N:16]=1.[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:21][C:22]1[N:23]=[C:24]([N:32]2[CH2:36][CH2:35][N:34]([CH2:14][C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[C:33]2=[O:37])[S:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Cc1cc(CBr)no1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3cc(C)on3)C2=O)nc1C
Yield: 78 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(bromomethyl)-5-methylisoxazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 78% yield: MS (ES+) m/z 351.2 (M+1).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.F[B:21]([C:31]1[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=1[CH3:39])[C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30]>CCCCCC.C1COCC1>[C:1]1([CH3:4])[CH:3]=[C:36]([CH3:35])[CH:31]=[C:32]([CH3:33])[C:2]=1[B:21]([C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=1[CH3:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([B:21]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][C:32]=3[CH3:39])[C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: [Li]C(C)(C)C
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(c2ccc(-c3ccc(B(c4c(C)cc(C)cc4C)c4c(C)cc(C)cc4C)cc3)cc2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
28.5 ml (48 mmol) of a 1.7 M solution of tert-butyllithium in n-hexane was added dropwise to a well-stirred suspension of 3.12 g (10 mmol) of 4,4′-dibromobiphenyl in 200 ml of absolute THF which had been cooled to −78° C. over a period of 20 minutes at such a rate that the temperature of the reaction mixture did not exceed −65° C. The suspension was stirred at −78° C. for another 1 hour and a solution of 6.44 g (24 mmol) of fluorodimesitylborane in 100 ml of absolute THF was then added dropwise over a period of 20 minutes at such a rate that the temperature of the reaction mixture did not exceed −65° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([NH:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].ClCCl>C(#N)C>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH2:31][CH:32]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:11]3[C:12]([O:14][CH3:15])=[C:13]4[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:17])[CH2:38][CH2:37]2)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CCNCC2)CC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1c(N2CCC(NC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 62.5 °C
Yield: 17.9 %

Procedure:
To a stirred solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (295 mg, 1.0 mmol) in acetonitrile (5 mL) was added 4-(piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (339 mg, 1.2 mmol) followed by the addition of 8-diazabicyclo[5.4.0]undec-7-ene (DBU, 182 mg, 1.2 mmol). The resulting stirred solution was then heated in a 60-65° C. oil bath for two days. The cooled reaction mixture was filtered through a fritted funnel. The filtrate was condensed to dryness. Dichloromethane was added into this residue and washed with water twice. The resulting organic layer was washed one more time with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give crude material as light brown syrup. This crude product was further purified with 10% methanol in dichloromethane by preparative TLC plate to afford pure title product as yellow solid (100 mg). ESI MS m/z 559 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.76 (d, J=12.4 Hz, 1H), 3.98 (m, 3H), 3.71 (s, 3H), 3.51 (d, J=12.1 Hz, 2H), 3.17 (t, J=12.3 Hz, 2H), 2.76 (br s, 1H), 1.92 (d, J=11.8 Hz, 2H), 1.83 (d, J=11.6 Hz, 2H), 1.49 (q, J=8.6 Hz, 2H), 1.38 (s, 9H), 1.20 (q, J=7.9 Hz, 2H), 1.15 (d, J=7.1 Hz, 2H), 0.94 (d, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mg].C(=O)([O:15][CH2:16][CH3:17])OCC.Cl>C(OCC)C>[CH2:1]([C:16]([CH2:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCCCCC(O)(CCCCCCCC)CCCCCCCC
Temperature: 30 °C
Reaction time: 1 h

Procedure:
This compound may be prepared in the following manner. Three moles of n-octylbromide are slowly added to 3 moles of magnesium turnings in 0.6 liters of anhydrous ethyl ether (nitrogen atmosphere). One mole of diethyl carbonate in 0.151 anhydrous ethyl ether is slowly added to the mixture. The mixture is stirred for one hour at 30° C., then the mixture is slowly poured into 1.8 liters of a cold 10% HCl solution. The organic layer is dried with magnesium sulfate and the ethyl ether is evaporated off to give tri-n-octylcarbinol.
Reaction SMILES: [H-].[Na+].[CH2:3]([S:5][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4].CI.[C:27](=O)(O)[O-].[Na+]>O.C1COCC1>[CH2:3]([S:5][C:6]1[C:7]([C:12]([N:14]([CH3:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:4]
Reactant: CCSc1cccnc1C(=O)Nc1ccc(C(F)(F)F)cn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CCSc1cccnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.9 g of 60% sodium hydride (oil-based) was added to a mixture of 0.65 g of 3-ethylsulfanyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 2) and 4 mL of THF under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was ice-cooled, 1.0 g of methyl iodide was added thereto, and then the mixture was stirred at 30° C. for 2 hours. Water and a saturated aqueous sodium bicarbonate solution were poured to the reaction mixture cooled to room temperature, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.27 g of 3-ethylsulfanyl-N-methyl-N-(5-trifluoromethyl-pyridin-2-yl) picolinamide (hereinafter, referred to as Compound of Present Invention 16).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:9]=[C:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:7]=[C:6](O)[CH:5]=1.P(Cl)(Cl)([Cl:24])=O>COCCOC.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[Cl:24][C:6]1[CH:5]=[C:4]([O:3][CH:2]([F:21])[F:1])[N:9]=[C:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:7]=1
Reactant: Oc1cc(OC(F)F)nc(SCc2cccc(F)c2F)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Product: Fc1cccc(CSc2nc(Cl)cc(OC(F)F)n2)c1F

Procedure:
To a solution of 6-(difluoromethoxy)-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinol (product of step i) (0.4 g) in 1,2-dimethoxyethane was added benzyltriethylammonium chloride (3 mg) and phosphorous oxychloride (0.23 mL). The resulting mixture was heated to reflux for 16 hours. The reaction mixture was cooled then diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and dried (MgSO4), filtered and evaporated. Purification was by column chromatography on silica gel using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.35 g
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:17]3[CH2:18][CH2:19][CH2:20][N:16]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CCCN1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)N(C1=NCCC1)c1ccccc1O2

Procedure:
Reaction of 2-chlorophenoxazine, 2-pyrrolidinone, and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-CHLORO-10-(1-PYRROLIN-2-YL)PHENOXAZINE as a distillable oil, b.p. 150-165° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(1-PYRROLIN-2-YL)-PHENOXAZINE HYDROCHLORIDE, m.p. 209.5-213.5° C. (corr.), in a 40% overall yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[C:14](Br)[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CC(O)=O.O.[Zn]>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:17])=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc(Br)c(Br)c2CC1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)N1CCc2scc(Br)c2CC1
Yield: 73.7 %

Procedure:
The product of step (e) (1.3 g, 3.39 mmol) was dissolved in 1:1 HOAc:water (40 mL), treated with Zn dust (0.44 g, 6.79 mmol), and heated to reflux for 1 hour. The reaction was cooled, diluted with water and extracted 2×EtOAc. The organic extracts were dried over MgSO4 and concentrated to give 0.76 g of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.C(OO)(=[O:12])C.[OH-].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N+:3]=1[O-:12]
Reactant: CCc1cccc(Br)n1
Reactant: CC(=O)OO
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1cccc(Br)[n+]1[O-]
Temperature: 50 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8 mmol) (S. G. Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans. 1, 1991, 3, 501) in acetic acid (15 ml) was added peracetic acid (26 ml of a 39% solution) maintaining T<50° C. After complete addition the mixture was stirred at 50° C. for 5 hr and then cooled to room temperature (rt). Crushed ice (40 g) was added and the pH was adjusted to pH 12 with 40% aqueous KOH solution. After extraction with CHCl3 (6×60 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 20.0 g (>100%) of the title compound, MS: m/e=201 (M+) as a yellow oil.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:5]([F:7])=[O:6].S(O[CH2:23][CH3:24])(OCC)(=O)=O>CN(C)C=O>[C:4]([C:5]([O:6][CH2:23][CH3:24])([F:1])[F:7])([C:8]([F:10])([F:9])[F:11])([C:12]([F:13])([F:14])[F:15])[F:3]
Reactant: [F-]
Reactant: O=C(F)C(F)(C(F)(F)F)C(F)(F)F
Reactant: CCOS(=O)(=O)OCC
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Yield: 75.7 %

Procedure:
The title compound was prepared essentially as in Example 1 using anhydrous potassium fluoride (31.9 g, 0.55 mole), anhydrous dimethyl formamide (184 g), perfluoroisobutryl fluoride (112.3 g of 77% purity, 0.4 mole), and diethyl sulfate (100.1 g, 0.65 mole). The resulting mixture was worked up essentially as in Example 3 to yield 80 g of the title compound. The product identity was confirmed by IR, GCMS, and 1H and 19F NMR.