Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([N:26]2[CH2:27][CH2:28][CH:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:24][CH2:25]2)[C:3]1=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(C2CCNCC2)cc1
Reactant: O=C1C(Br)CCN1Cc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCN(C3CCN(Cc4ccccc4)C3=O)CC2)cc1
Yield: 75.3 %

Procedure:
A solution of 3-bromo-1-benzyl-pyrrolidin-2-one (1.4 g, 5.1 mmol)(intermediate 3), 4-(4-methoxyphenyl)-piperidine (0.98 g, 5.1 mmol) and DIPEA (3.6 mL, 20.6 mmol) in acetonitrile (15 mL) was heated at 90° C. for 18 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (150 mL), washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated to yield 2.1 g of crude product, which was purified by flash chromatography on silica gel (24 g) using 100% EtOAc to yield 1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (1.4 g, 71%). 1H NMR: 400 MHz, DMSO-d6: δ ppm 1.51-1.65 (m, 2H) 1.66-1.77 (m, 2H) 1.86-1.98 (m, 1H) 2.02-2.12 (m, 1H) 2.27-2.45 (m, 2H) 2.66-2.83 (m, 2H) 2.99-3.23 (m, 3H) 3.45-3.54 (m, 1H) 3.72 (s, 3H) 4.29-4.46 (m, 2H) 6.85 (d, J=9.04 Hz, 2H) 7.16 (d, J=9.04 Hz, 2H) 7.19-7.24 (m, 2H) 7.28 (s, 1H) 7.32-7.39 (m, 2H). LCMS: R.T. 1.76 min. LCMS (ES-API), 365.2 m/z (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:8]([C:9](O)=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([CH3:15])=[N:5]1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:8]([C:9]([Cl:19])=[O:10])=[C:7]([N+:12]([O-:14])=[O:13])[C:6]([CH3:15])=[N:5]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nn(CC(F)(F)F)c(C(=O)O)c1[N+](=O)[O-]
Product: Cc1nn(CC(F)(F)F)c(C(=O)Cl)c1[N+](=O)[O-]

Procedure:
The above acid (22 g, 0.11 mol) is added in portions at 70°-90° C. to a stirred acid mixture prepared by adding 30 ml conc. sulfuric acid to 15 ml of 90% nitric acid. After stirring two hours at 95°, the mixture is poured into 75 g of ice. The collected precipitate is dried to give 23 g, 1-(2,2,2-trifluoroethyl)-3-methyl-4-nitropyrazole-5-carboxylic acid, mp 135°-138° C. This nitro acid (23 g, 0.09 mol) is mixed with 21 g (0.1 mol) of phosphorus pentachloride and heated on a steam bath for 2.5 hr, filtered, and evaporated in vacuo to give 20 g of 1-(2,2,2-trifluoroethyl-3-methyl-4-nitropyrazole-5-carbonyl chloride as an oil. The acid chloride (20 g) in 30 ml of acetone is added dropwise to 130 ml cold concentrated ammonium hydroxide and the mixture is filtered after stirring one hour to give 16 g of 3-methyl-4-nitro-1-(2,2,2-trifluoroethyl)-5-pyrazolecarboxamide, mp 205°-207° C. from ethyl acetate.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[S-:13][C:14]#[N:15].[K+].BrBr.O>CO.[Br-].[K+]>[CH:1]([C:4]1[C:12]([S:13][C:14]#[N:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: N#C[S-]
Reactant: CC(C)c1cc2ccccn2n1
Agent: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1nn2ccccc2c1SC#N
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution of 3 g of 2-isopropylpyrazolo[1,5-a]pyridine in 56 ml of methanol was added 5.74 g of potassium thiocyanate and stirred at room temperature. 3.3 g of bromine was dissolved in 13 ml of methanol saturated with potassium bromide and added dropwise to the previous solution. Then, the mixture was stirred at room temperature for an hour, poured into 130 ml of water and resulting precipitate was filtered and dried. This crude precipitate was recrystallized from methanol to give 3.53 g (yield 87%) of the aimed compound as pale yellow prismatic crystals. mp 91°-92.5° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](B(O)O)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3].Br[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[CH:10][C:9]=2[CH:16]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)Cc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Cc1ccc2oc(-c3ccc(C=O)cc3)cc2c1
Yield: 64.2 %

Procedure:
A mixture of 5-isobutylbenzofuran-2-ylboronic acid (70 mg, 0.33 mmol), 4-bromobenzaldehyde (61 mg, 0.33 mmol), triethylamine (1.7 mL, 12.6 mmol) and bis(triphenylphosphine)palladium(II)chloride (12 mg, 0.017 mmol) in ethanol (10 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was treated with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo (the aqueous work-up is optional). Purification by silica gel chromatography on ISCO system gave the title compound (59 mg, 65% yield): >99% purity by LCMS, ESI-MS: 279.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:17][O:18]C(=O)C(C)C)[CH2:10][O:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([CH2:10][O:11][C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])[CH2:17][OH:18]
Reactant: CC(C)C(=O)OCC(O)(COC(=O)C(C)C)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CC(C)C(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Yield: 94.8 %

Procedure:
A 200 ml reaction vessel was charged with 2 g of 2-(2,4-difluorophenyl)-1,3-diisobutyryloxy-2-propanol, 100 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizopus delemer, Enzyme No. 6), 90 ml of 50 mM acetate buffer (pH 5) and 10 ml of cyclohexane. The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethyl acetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and further dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by means of column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2) to give 1.51 g of oily (R)-2-(2,4-difluorophenyl)-3-isobutyryloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as Example 35.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.C([O:16][C:17](=[O:32])[C@@H:18]([O:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28]Br)=[CH:22][CH:21]=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:28][CH2:27][O:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][C@H:18]([O:30][CH3:31])[C:17]([OH:32])=[O:16])=[CH:25][CH:24]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of biphenyl-4-ol (0.39 mmol, 68 mg) in 10 ml of DMF in was treated with (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester obtained in Step 2 (0.33 mmol, 100 mg) and cesium carbonate (0.66 mmol, 214 mg) in a round bottom flask. The reactants were filtered and was washed with DMF several times and the solvent was evaporated under vacuo. The residue was reconstituted in a mixture of ethanol (20 ml) and NaOH (1M) (8 ml), and then stirred at room temperature until TLC indicated the disappearance of starting material. Ethanol was removed under vacuum, and the aqueous solution was diluted with 20 ml of brine and washed with diethyl ether (3×15 mL). The aqueous phase was acidified with
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.II.[I:14]([O-])(=O)(=O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][C:7]=1[I:14]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1ccc(N)cn1
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N)c(I)n1
Temperature: 60 °C
Reaction time: 48 h
Yield: 152.9 %

Procedure:
A mixture of methyl 5-aminopyridine-2-carboxylate (2.92 g), iodine (3.9 g) and sodium periodate (1.64 g) in N,N-dimethylformamide (24 mL) was stirred at 60° C. for 2 days. The reaction mixture was cooled to room temperature. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 10 minutes. The crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give methyl 5-amino-6-iodopyridine-2-carboxylate (3.26 g). To sodium hexamethyldisilazide (1.03 mol/L tetrahydrofuran solution, 7.68 mL) was added a solution of methyl 5-amino-6-iodopyridine-2-carboxylate (1 g) in tetrahydrofuran (5 mL) in a dropwise manner at −14° C., and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of di(tert-butyl)dicarbonate (0.82 g) in tetrahydrofuran (3 mL) in a dropwise manner, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (13.6 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added 2-propanol (2.8 mL) and water (3.4 mL), and the mixture was stirred at 80° C. for 30 minutes, and then stirred at room temperature for 30 minutes. The crystals were collected by filtration. The collected crystals were washed with a mixed solvent (2-propanol/water=5/6), and dried under reduced pressure to give the title compound (0.82 g).
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[C:22]1[O:26][N:25]=[CH:24][CH:23]=1.[NH2:28][CH2:29][CH2:30][NH:31][S:32]([C:35]1[C:36]2[CH:37]=[CH:38][N:39]=[CH:40][C:41]=2[CH:42]=[CH:43][CH:44]=1)(=[O:34])=[O:33]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:28][CH2:29][CH2:30][NH:31][S:32]([C:35]2[C:36]3[CH:37]=[CH:38][N:39]=[CH:40][C:41]=3[CH:42]=[CH:43][CH:44]=2)(=[O:34])=[O:33])=[C:16]([C:22]2[O:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: COC(=O)COc1ccc(Br)cc1-c1ccno1
Agent: CC(C)C[AlH]CC(C)C
Product: O=S(=O)(NCCNCCOc1ccc(Br)cc1-c1ccno1)c1cccc2cnccc12

Procedure:
By following a similar procedure as described in Example 34, DIBAL-H reduction of (4-bromo-2-isoxazol-5-yl-phenoxy)-acetic acid methyl ester, and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine of the title compound as a white solid. ESIMS: m/z 517 [(M+H)+, 79Br], 519 [(M+H)+, 81Br].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3OC)[C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:31][N:30]=[CH:29][N:28]=3)(=[O:24])=[O:25])=[CH:20][CH:21]=2)[N:16]([CH3:43])[CH:15]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: COc1ccc(B(O)O)c(Cl)c1
Product: COc1ccc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c(Cl)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (2-chloro-4-methoxyphenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(2-chloro-4-methoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.82 (s, 3 H) 3.92 (s, 3 H) 6.96-7.04 (m, 1 H) 7.17 (d, J=2.63 Hz, 1 H) 7.42 (d, J=8.59 Hz, 1 H) 7.45-7.53 (m, 2 H) 7.71 (s, 1 H) 7.93 (s, 1 H) 8.19 (s, 1 H). m/z (ESI) 434.0 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:13]([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19](=[O:27])[C:18]2([CH3:29])[CH3:28])[CH:14]=[N:15][CH:16]=1)=O)C>C1COCC1>[OH:9][CH2:10][C:12]1[N:13]([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19](=[O:27])[C:18]2([CH3:29])[CH3:28])[CH:14]=[N:15][CH:16]=1
Reactant: CCOC(=O)c1cncn1C1c2ccccc2NC(=O)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2ccccc2C1n1cncc1CO
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A solution of LiAlH4 (1 M in ether, 1.98 mL, 1.98 mmol) is added dropwise to a solution of 3-(3,3-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-4-yl)-3H-imidazole-4-carboxylic acid ethyl ester (621 mg, 1.98 mmol) in THF (10 mL) at −10° C. After 4 h at this temperature, the reaction is quenched by the addition of water (0.3 mL), NaOH solution (15%, 0.3 mL) and water (1 mL). The resulting mixture is filtered, and the solid is washed by ether (10 mL×3). The combined solution is concentrated under vacuum, and the residue is purified by reverse phase HPLC (5% to 40% acetonitrile/water with 0.1% NH4OH over 15 min) to give the title compound (445 mg). 1H NMR (400.3 MHz, MeOD): δ 7.43 (d, J=8.0 Hz, 1H) 7.39 (s, 1H), 7.35 (t, J=8 Hz 1H), 7.09-7.03 (m, 2H), 6.91 (s, 1H), 5.39 (s, 1H), 4.72 (d, J=8.0 Hz, 2H) 1.30 (s, 3H), 1.05 (s, 3H), 13C NMR (100.6 MHz, MeOD): δ 175.93, 138.02, 136.50, 133.43, 131.20, 130.68, 127.52, 124.80, 123.29, 117.07, 61.88, 54.40, 25.68, 19.97. HRMS: calculated for C15H17N3O2: 272.1399. Found: 272.1407.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C=Cc1ccc(CO)cc1
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a solution of methyl 4-formylcinnamate (5.58 g) in methanol (100 ml) was added sodium borohydride (0.4 g), and the mixture was stirred at room temperature for an hour. The reaction mixture was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave methyl 4-(hydroxymethyl)cinnamate (5.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([Cl:30])=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)cc(Cl)c1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 4-benzyloxy-3-chloro-5-methoxybenzoic acid (541 mg), toluene (5.4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (578 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([N:5]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[CH2:9][S:10][C:11]1[NH:12][C:13]2[C:14]([N:19]=1)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:6])[CH:2]([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([N:5]([C:7]1[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=1[CH2:9][S:10]([C:11]1[NH:12][C:13]2[C:14]([N:19]=1)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:32])[CH3:6])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN(C)c1ccccc1CSc1nc2ncccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)CN(C)c1ccccc1CS(=O)c1nc2ncccc2[nH]1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-isobutyl-N-methylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution in the presence of sodium hydroxide to obtain 2-[2-(N-isobutyl-N-methylamino)benzylthio]imidazo[4,5-b]pyridine in the same manner as in Example 1-(2). The obtained 2-[2-(N-isobutyl-N-methylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner as in Example 9-(3) to give 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 116°-118° C. (decompn.)
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=[CH:6][CH:5]=1.[C:34](OC1C=CC=CC=1)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:1]=[N:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][C:16]=2[O:30][CH3:31])=[CH:6][CH:5]=1)(=[O:36])[CH3:35]
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C=NN)cc1
Reactant: CC(=O)Oc1ccccc1
Solvent: ClCCl
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(CN=NC(C)=O)cc1
Reaction time: 3 h

Procedure:
A stirred solution of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide (40.0 g, 87.7 mmol) in 500 mL anhydrous methylene chloride is treated with phenyl acetate (11.1 mL, 87.7 mmol). The solution is stirred 3 hours, concentrated in vacuo and the resulting liquid is purified by chromatography on silica gel (850 g) with 30% ethyl acetate/hexane as the eluent to afford 4-[5-[4-(acetyliminoaminomethyl)phenoxy]pentyloxy]-3-methoxy-N,N-bis(1-methylethyl)benzamide as a colorless foam; CHN calculated for C28H39N3O5 :
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([OH:18])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:21]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[C:12]([O:18][CH3:21])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1oc2c(Cl)cc(Cl)c(O)c2c1C
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc2c(Cl)cc(Cl)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To 120 mg of 5,7-dichloro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester was added 1 mL of iodomethane, 200 mg of K2CO3 and 4 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent in vacuo gave 125 mg (99% yield) of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([CH3:32])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([O:15]C)[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)C=O.C1C=C(Cl)C=C([C:40](OO)=[O:41])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:32][C:17]1[CH:18]=[C:19]([O:21][Si:22]([CH:26]([CH3:27])[CH3:28])([CH:23]([CH3:24])[CH3:25])[CH:29]([CH3:30])[CH3:31])[CH:20]=[C:2]([CH3:1])[C:3]=1[CH2:4][C:5]1[CH:12]=[CH:9][C:8]([O:13][CH2:14][O:41][CH3:40])=[C:7]([OH:15])[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc(C=O)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxy-methoxy-benzaldehyde (compound 15, step e; 0.460 g, 1.01 mmol) in dichloromethane 30 mL was add mCPBA (0.870 g, 2.52 mmol) and saturated sodium bicarbonate solution (2 mL). After stirring at rt overnight, the reaction mixture was poured into dichloromethane 50 mL and washed 3× with 10 mL of saturated aqueous sodium bicarbonate. The dichloromethane was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was combined with methanol (10 mL) and 2 mL of 1 N NaOH and stirred for 1.5 hours at room temperature. The reaction was acidified with 12 N HCl (pH<3) and poured into 50 mL ethyl acetate. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Flash column chromatography using silica and a step gradient of hexane/ethyl acetate [20:1], hexane/ethyl acetate [9:1] provided 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-phenol (0.189 g, 42%): 1H NMR (300 MHz, DMSO-d6): δ 8.95(s, 1H), 6.86(d, 1H, J=8.1 Hz), 6.56(s, 2H), 6.41(d, 1H, J=2.1 Hz), 6.34(dd, 1H, J=2.1 Hz and J=8.7 Hz), 5.05(s, 2H), 3.78(s, 2H), 3.38(s, 3H), 2.13(s, 6H), 1.11(m, 3H), 1.00(m, 18H); Uniplate silica gel, 250 microns; Mobile phase=10% ethyl acetate in hexane: Rf=0.15
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]([CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7]([Cl:14])=[O:8]
Reactant: Cc1oc(C)c(C(=O)O)c1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(C)c(C(=O)Cl)c1C

Procedure:
2,4,5-Trimethyl-3-furancarbonyl chloride was prepared by refluxing 2,4,5-trimethyl-3-furancarboxylic acid (20.0 g) with thionyl chloride (20 ml) in toluene (75 ml) for 3 hours. The toluene and excess thionyl chloride were removed on a rotary evaporator and the residue distilled (b.p. 95°-97° C. at ca. 12 mm).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13]
Reactant: CCI
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1C
Yield: 74.5 %

Procedure:
A mixture of 2-methyl-5-nitrophenol (450 mg, 2.94 mmol), ethyl iodide (356 μl, 4.41 mmol) and potassium carbonate (609 mg, 4.41 mmol) in 15 mL of acetone was heated at reflux for 2 days. The reaction mixture was filtrated, concentrated under vacuum, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the title compound (397 mg) which was directly used in the next step.