Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH:37]([NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:46])[NH:35][CH2:36][CH:37]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=1)[NH:45][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1cccc(Cl)c1

Procedure:
(2-(3-Chloro-phenyl)-2-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester (from Example 4 supra) by following the method in Example 61.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[C:9]([N+:8]([O-:18])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[N+]([O-])=Cc1ccccc1

Procedure:
Following the general procedure of Example 1, N-benzyl-N-tert-butylamine is oxidized using a solution of 3-chloroperoxybenzoic acid dissolved in methylene chloride to give N-tert-butyl-alpha-phenyl nitrone as a white solid melting at 70°-72° C. This is the nitrone described in Japanese Sho No. 59-11345.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])=[N:9][N:10]=2)[N:7]=1.[CH2:23]([N:25]1[C:29]([CH2:30][OH:31])=[N:28][CH:27]=[N:26]1)[CH3:24].[H-].[Na+]>CN(C=O)C>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:8]1[N:6]2[N:7]=[C:2]([O:31][CH2:30][C:29]3[N:25]([CH2:23][CH3:24])[N:26]=[CH:27][N:28]=3)[C:3]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: CC(C)(C)c1cc2nnc(-c3c(F)cccc3F)n2nc1Cl
Reactant: CCn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3c(F)cccc3F)nnc2cc1C(C)(C)C

Procedure:
This compound was prepared from 6-chloro-3-(2,6-difluorophenyl)-7-(1,1-dimethylethyl)-1,2,4-triazolo[4,3-b]pyridazine and (2-ethyl-2H-1,2,4-triazol-3-yl)methanol following the procedure (sodium hydride, DMF) described in WO 98/04559. Data for the title compound: m.p. 182° C.; 1H NMR (400 MHz, CDCl3) δ1.39-1.45 (12H, m), 4.10-4.16 (2H, m), 5.46 (2H, s), 7.09-7.15 (2H, m), 7.52-7.59 (1H, m), 7.92 (1H, s), 8.00 (1H, s); MS (ES30) m/e 414 [MH]+; Anal. Found: C, 58.19; H, 5.05; N, 23.80%. C20H21F2N7O requires: C, 58.10; H, 5.12; N, 23.72%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cu].ClC1C=CC=CC=1Cl>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 7 h
Yield: 81.4 %

Procedure:
To 30 ml of o-dichlorobenzene, 4.5 g (27 mmol) of diphenylamine, 11.0 g (51 mmol) of p-iodotoluene, 5.5 g (40 mmol) of anhydrous sodium carbonate and 1.1 g of copper powder were added. The mixture was heated and refluxed with stirring for 7 hours. After the reaction was completed, the reaction solution was filtered. The filtrate was successively washed with an aqueous 3 to 5% sodium thiosulfate solution and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and thereafter the solvent was removed. The resulting crude reaction product was recrystallized from ethanol to obtain 4-methyltriphenylamine in an amount of 5.7 g (yield: 81.4%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.O[N:16]=[C:17]([C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[NH2:18]>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:12]([C:3]3[CH:2]=[CH:11][C:10]([C:2]4[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=4[CH3:12])=[C:5]([CH2:6][O:8][CH3:9])[CH:4]=3)[O:13][N:16]=2)=[CH:20][N:21]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: COc1ccc(C(N)=NO)cn1
Product: COCc1cc(-c2nc(-c3ccc(OC)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and N′-hydroxy-6-methoxypyridine-3-carboximidamide (UkrOrgSynthesis BBV-066226). After purification by precipitation from MeOH, the title compound was obtained as a white powder. HPLC (Method A), Rt: 5.8 min (purity: 99.8%). UPLC/MS, M+(ESI): 388.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.91 (d, J=2.2 Hz, 1H), 8.34 (dd, J=8.7, 2.2 Hz, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.16 (dd, J=7.9, 1.4 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.36-7.26 (m, 3H), 7.14 (d, J=7.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.22 (d, J=12.8 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.96 (s, 3H), 3.24 (s, 3H), 2.03 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[CH3:20][O:21][CH2:22]Br>C1COCC1>[CH3:20][O:21][CH2:22][CH:15]1[C:16](=[O:19])[CH2:17][CH2:18][O:13][CH2:14]1
Reactant: COCBr
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCC1COCCC1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
To a solution of diisopropylamine (6.1 g, 60 mmol) in THF (100 mL) cooled in an ice bath was added a 1.6 M solution of n-butyllithium in hexanes (37 mL, 60 mmol). The resulting solution was cooled to −78° C. To it was added tetrahydro-4H-pyran-4-one (5 g, 50 mmol) followed by phosphorous hexamethyltriamide (10 mL, 55 mmol). After 10 min, a solution of bromomethyl methyl ether (25 g, 200 mmol) in THF (50 mL) was added. Stirring was continued at 0° C. for 1 h and at room temperature overnight. The reaction was quenched by addition of a saturated solution of ammonium chloride in water. The resulting solution was extracted with ether three times. The combined extracts were dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 20% ether/petroleum ether afforded the desired product (0.9 g oil). 1H NMR (CDCl3) δ 4.2 (2H, m), 4.1 (3H, s), 3.6-3.4 (4H, m), 2.4-2.3 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI.Cl>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH3:11]
Reactant: Oc1c(Cl)cc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Cl)cc(Cl)cc1Br
Temperature: 0 °C
Yield: 113.1 %

Procedure:
2-Bromo-4,6-dichlorophenol (Preparation 24, 4.6 g, 19 mmol), potassium carbonate (4.5 g, 32.3 mmol) and methyl iodide (1.8 ml, 20.5 mmol) were combined in 46 ml acetone and heated to reflux for 18 hours. The reaction was cooled to 0° C., 1N HCl (aqueous) was added to give pH 3, and the reaction was extracted into 50 ml ethyl acetate. The organic layer was washed with brine (2×20 ml), dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown solid (5.5 g).
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:17][CH:10]([CH2:11]3)[N:9]3[C:5](=[N:6][C:7]([C:20](O)=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1.[Cl-].[NH4+:24]>>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[CH:12]3[CH2:11][CH:10]([CH2:17]3)[N:9]3[C:5](=[N:6][C:7]([C:20]([NH2:24])=[O:21])=[C:8]3[CH:18]=[O:19])[C:4]=2[CH:3]=1
Reactant: O=Cc1c(C(=O)O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: [NH4+]
Agent: [Cl-]
Product: NC(=O)c1nc2n(c1C=O)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxylic acid (0.09 g) was reacted with ammonium chloride similar to as described in Example 2 to give 60 mg of 9-bromo-10-fluoro-3-formyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7(12),8,10-pentaene-4-carboxamide.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:6]2[C:11]=1[C:10](=O)[NH:9][CH:8]=[N:7]2)[CH3:2].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[Cl:28][C:10]1[C:11]2=[C:3]([CH2:1][CH3:2])[C:4]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][N:6]2[N:7]=[CH:8][N:9]=1
Reactant: CCc1c(C(=O)OC)cn2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(C(=O)OC)cn2ncnc(Cl)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
A 1 L round bottomed flask was charged with methyl 5-ethyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (25.0 g, 113 mmol), toluene (375 mL) and diisopropylethylamine (11.8 g, 91.6 mmol). Phosphorous oxychloride (20.7 g, 135 mmol) was then added drop-wise at room temperature (exothermic). Once the addition was complete the reaction mixture was heated to 100° C. for 20 hrs. Analysis of an aliquot by HPLC indicated that the starting material had been completely consumed (Rt starting material=10.6 min, Rt product=15.2 min). The reaction was then cooled and slowly poured into a mixture of saturated sodium hydrogen carbonate solution (500 mL), toluene (500 mL) and ice water (350 mL). After stirring for 30 minutes the organic layer was separated and washed with saturated sodium hydrogen carbonate solution (500 mL). Drying over sodium sulfate, filtration and concentration afforded 30.5 g (>100%) of crude methyl 4-chloro-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate. This material was dissolved in acetonitrile (800 mL) and the solution charged to a 2 L round bottomed flask. Sodium hydrogen carbonate (15.1 g, 180 mmol) and 5-amino-1-benzylindazole (27.8 g, 124 mmol) were then added followed by additional acetonitrile (400 mL). The resulting suspension was then stirred at room temperature for 16 h. HPLC analysis after this time indicated that approximately 17% of the starting indazole remained. The mixture was then heated to reflux for 1 hr after which time only 5% of the starting indazole remained. After cooling, the mixture was concentrated and the residue partitioned between methylene chloride (800 mL) and water (300 mL). The lower organic layer was separated and washed further with water (300 mL). Drying over sodium sulfate, filtration and concentration under reduced pressure afforded 51.3 g (100%) of methyl 4-(1-benzyl-1H-indazol-5-ylamino)-5-ethylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate, which was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>[N+](C)([O-])=O>[OH:19][C:18]([C:7]1([O:6][CH3:5])[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)([CH3:20])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Aluminium chloride (162 g, 12,2 mmol) was added in 3 portions to a solution of 2-methoxynaphthalene (1,28 g, 8,09 mmol) in nitromethane (20 mL) at 5° C. Ethyl pyruvate (1,41 g, 12,2 mmol) in nitromethane (10 mL) was added over 1 hour at this temperature. The reaction was allowed to proceed for 1 hour and warmed to 20° C. for 2 hours. Ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate was formed with a selectivity of 16% at 52% conversion of the starting material.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[NH:10][C:11]1([C:14](=[O:16])[NH2:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:23]([O:25][C:26](=[O:31])[C:27](=O)[CH2:28]Br)[CH3:24]>C1COCC1>[CH2:23]([O:25][C:26]([C:27]1[N:15]=[C:14]([C:11]2([NH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:17])[CH2:12][CH2:13]2)[O:16][CH:28]=1)=[O:31])[CH3:24]
Reactant: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C2(NC(=O)OCc3ccccc3)CC2)n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 48.1 %

Procedure:
To a solution of (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (3.0 g, 8.1 mmol) in THF (100 mL) was added NaHCO3 (9.7 g, 120 mmol) and 3-bromo-2-oxo-propionic acid ethyl ester (8.1 mL, 64.0 mmol). The reaction was heated at 70° C. for 15 h. The resulting orange suspension was filtered through celite and concentrated under reduced pressure. The resulting orange oil was dissolved in THF (10 mL) and to this was added trifluoroacetic anhydride (1 mL). The mixture was stirred at room temperature for 24 h. The reaction was quenched with satd NaHCO3 and extracted with EtOAc (3×50 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered, concentrated and purified by reverse phase HPLC. The combined HPLC fractions were extracted with EtOAc (3×100 mL). The extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give 2-(1-benzyloxycarbonylamino-cyclopropyl)-oxazole-4-carboxylic acid ethyl ester (1.3 g, 3.9 mmol) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]#[N:9].[OH2:17].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:8]([NH2:9])=[O:17]
Reactant: O
Reactant: N#CC(N)c1ccc(F)cc1
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(F)cc1
Reaction time: 3 h
Yield: 38 %

Procedure:
Then, 30 g of concentrated sulfuric acid was added to 1.45 g of water, to which 20 g of 2-amino-2-(4-fluorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 8.4 g (yield, 38%) of 2-amino-2-(4-fluorophenyl)acetamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].[CH:22]([S:25](Cl)(=[O:27])=[O:26])([CH3:24])[CH3:23]>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:25]([CH:22]([CH3:24])[CH3:23])(=[O:27])=[O:26])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNS(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A solution of the compound of Example 51, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.50 mmol) in 30 mL of pyridine was chilled in an ice water bath. The stirred solution was treated dropwise with isopropylsulfonyl chloride (0.39 mL, 3.50 mmol) and the reaction was allowed to gradually warm to room temperature. After 18 h, the reaction was concentrated. The crude product was purified by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) and then triturated in hexanes to give 314 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}propane-2-sulfonamide as a white solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[CH2:33][OH:34])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)C>C(Cl)Cl>[CH2:12]([O:19][C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:24]=1[CH:33]=[O:34])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1CO)OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(C(F)(F)F)cc1NC(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Molecular Sieves 4A (20 g) and pyridinium chlorochromate (6.8 g, 31.5 mmol) were added to a solution of 2-benzyloxycarbonylamino-4-trifluoromethyl-1-hydroxymethylbenzene (6.83 g, 21.0 mmol), prepared in step (c), in methylene chloride (200 ml), and the mixture was stirred under ice cooling for 45 min. Diethyl ether was added to the reaction mixture, and the mixture was filtered through Florisil and silica gel. The solvent was then removed under reduced pressure to give 2-benzyloxycarbonylamino-4-trifluoromethylbenzaldehyde (5.43 g, 80%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24]O>S(=O)(=O)(O)O>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCCc1ccc(C(=O)CCCc2ccccc2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccc(C(=O)CCCc2ccccc2)cc1

Procedure:
To a suspension of 2.10 g of 4-[4-(4-phenylbutyryl)phenyl]butyric acid in 15 ml of methanol, 0.1 ml of sulfuric acid was added, and the mixture was heated under reflux for 4 hours. After the reaction solution was removed under reduced pressure, the residue was dissolved in ethyl acetate and then washed successively with water, aqueous potassium carbonate and water. After the ethyl acetate layer was dried, the solvent was removed under reduced pressure. The residue was washed with isopropyl ether to yield 1.87 g of colorless crystals. Recrystallization from methanol gave colorless flakes, mp 61°~62° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[SH:21][C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.[OH-].[Na+]>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:21][C:22]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(SCCCSc2nc3ccccc3[nH]2)ccnc1CSc1ccncc1
Yield: 83 %

Procedure:
According to the procedure indicated in Example 5, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 2-mercaptobenzimidazole in the presence of sodium hydroxide solution gives, after crystallization from dichloromethane/diisopropyl ether, the title compound; m.p. 128-129° C.; yield 83% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13](=[O:22])[C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][CH2:10]Cl.[H-].[Na+].O>CN(C)C=O>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:13]1[O:22][CH2:10][CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[N:12]=1
Reactant: O=C(NC(CCCl)c1ccccc1Br)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccc(F)c1C1=NC(c2ccccc2Br)CCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 10.0 g of N-[1-(2-bromophenyl)-3-chloropropyl]-2,6-difluorobenzamide in 60 ml of N,N-dimethylformamide at a temperature of from 5° C. to 10° C., was added portionwise 1.1 g of 60% dispersion in mineral oil of sodium hydride. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 7.4 g of 2-(2,6-difluorophenyl)-4-(2-bromophenyl)-5,6-dihydro-4H-1,3-oxazine. ND23.0 1.5750
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].C1(O)C=CC=CC=1>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccccc1OCc1ccccc1
Yield: 47.8 %

Procedure:
To a stirred solution of 2-benzyloxyphenol (1) (4.0 g, 20 nM) and ethyl 4-bromobutyrate (2) (5.6 g, 28.7 mM) in dried acetone (100 mL) was added anhydrous ground potassium carbonate (6.0 g, 44 mM) and the resultant mixture heated at reflux under nitrogen until TLC analysis showed the absence of the starting phenol. Flash chromatography (silica gel, 15% ethyl acetate/hexane as eluant) of the filtered and concentrated mixture yielded 3.0 g of product (3) as a clear oil.
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13](Br)[CH:12]=1.[OH-].[K+]>C(OC(=O)C)C>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:12]=1
Reactant: COc1ccc(F)cc1Br
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 4-fluoro-2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow liquid (47%). 1H-NMR (400 MHz, CDCl3) δ(ppm) 7.82 (s, 1H), 7.21 (m, 1H), 7.17 (m, 1H), 7.07 (m, 2H), 7.00 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(CCN(C)C)C.[Li]C(CC)C.C1CCCCC1.[CH3:30][Si:31](Cl)([CH3:33])[CH3:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:31]([CH3:33])([CH3:32])[CH3:30])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C[Si](C)(C)c1cccc(Cl)c1C(=O)O
Temperature: -100 °C
Yield: 63 %

Procedure:
2-Chlorobenzoic acid (3.91 g, 25 mmol), THF (60 mL), and TMEDA (8.6 mL, 57 mmol) were stirred under nitrogen and cooled to -100° C. 1.3M s-BuLi in cyclohexane (0.055 mol, 42.3 mL) was added dropwise keeping the temperature below -80° C. After the addition was complete TMSCl (2.7 g, 25 mmol) was added dropwise and the resulting mixture was allowed to stir and slowly warm to -30 C. 25% citric acid (100 mL) was added and the mixture was extracted with two 50 mL portions of ether, which were then combined and washed three times with water, dried (MgSO4) and concentrated. The crude product was purified by HPLC, eluting with 2:3 ethyl acetate/hexanes. The product was recovered as a white solid in 63% yield. m.p. 129°-131° C.