Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=1.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:36]=1)[C:33](Cl)=[O:34].CC(O)C>CCOCC>[Br:27][C:28]1[CH:36]=[C:32]([C:33]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[NH:9][CH:8]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2c(Cl)ncnc21
Reactant: O=C(Cl)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(c1cncc(Br)c1)c1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
n-BuLi (11.3 mL, 2.5 M in Hexane, 28.3 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine (10.0 g, 25.7 mmol) in Et2O (250 mL) at −78° C. and stirred for 0.5 h. 5-Bromo-nicotinoyl chloride (6.8 g, 30.8 mmol) was added to the reaction mixture slowly and stirred for 3 h, warmed to room temperature, and stirred for an additional 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl (150 mL) and stirred for 30 min. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (300 mL), dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude solid. Trituration with 2-propanol provided the title compound as a pure white solid (7.5 g, 86%). MS: 337.5/339.5 (MH+); HPLC Rf: 4.02 min. (HPLC method 4).
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CCN(c2ccc(C(=O)OCC)cc2)CC1
Reaction time: 0.25 h

Procedure:
A 0° C. solution of methyltriphenylphosphonium bromide (500 mg, 1.4 mmol) in THF (1.5 mL) was treated dropwise with 1M sodium hexamethyldisilazide in THF (1.4 mL), stirred for 15 minutes, and added dropwise to a 0° C. solution of Example 158B (0.25 g, 1.0 mmol) in THF (2.1 mL). After stirring for 15 minutes, the reaction was quenched with water and was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated The concentrate was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide the desired product. MS (DCI) m/e 246 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][NH:6][C:5](=O)[C:4]=1[F:10])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]([F:10])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCc1nc[nH]c(=O)c1F
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1ncnc(Cl)c1F
Yield: 66 %

Procedure:
A mixture of the product of part (i) (6.4 g, 45 mmol) and phosphoryl chloride (30 ml) was heated under reflux for 3 hours. The excess phosphoryl chloride was removed by distillation under reduced pressure and the residue was poured into ice-water. The resulting mixture was extracted with methylene chloride (3×50 ml) and the combined organic extracts were washed with water and dried over magnesium sulphate. The solvent was removed under reduced pressure and the resulting oil was distilled under reduced pressure to provide the title compound (4.81 g, 66%), b.p. 74° C. at 22 mm Hg, which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH:20]([CH3:22])[CH3:21])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Si:24]([CH3:40])([CH3:39])[CH2:25][CH2:26][O:27][CH2:28]N1C2C=NNC(=O)C=2C=C1.[Cl-].[NH4+]>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:40])([CH3:39])[CH3:23])[C:18](=[O:19])[C:13]=2[C:12]([CH:20]([CH3:22])[CH3:21])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]ncc21
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)c1cn(COCc2ccccc2)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 0 °C
Yield: 62 %

Procedure:
Reaction was carried out in the same manner as in Reference example 18-(a) except for using 0.98 g (3.3 mmol) of 1-benzyloxymethyl-3-isopropyl-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Reference example 21-(e) in place of 1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction mixture was poured into ice-water, neutralized with a saturated aqueous solution of ammonium chloride and extracted with toluene. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=3:2 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 0.87 g of the title compound as a slightly yellowish oil. (Yield: 62%)
Reaction SMILES: N[C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N(OC(C)(C)C)=O.[NH4+].[Cl-:20]>C(#N)C.Cl[Cu]>[Cl:20][C:2]1[S:3][C:4]([I:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(N)sc1I
Reactant: [Cl-]
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Agent: [NH4+]
Solvent: CC#N
Product: COC(=O)c1nc(Cl)sc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of methyl 2-amino-5-iodothiazole-4-carboxylate (8A) (9 g, 31.7 mmol) in acetonitrile (60 mL) was added CuCl (4.75 g, 48 mmol) followed by t-butyl nitrite (6.19 g, 60 mmol). The mixture was stirred at rt for 2 hours. NH4Cl was then added slowly to the stirring mixture to quench the reaction. The mixture was extracted with EtOAc and the combined extracts were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% EtOAc in hexanes to provide 7.5 g (78%) of the desired product methyl 2-chloro-5-iodothiazole-4-carboxylate (88): LC/MS (APCI): m/z 304.0 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]=[O:17]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][OH:17]
Reactant: C=O
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Agent: [Na+]
Agent: [OH-]
Product: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reaction time: 8 h

Procedure:
A mixture of 4-hydroxy-7-trifluoromethylquinoline (30.0 g.), 40% aqueous formaldehyde solution (36 ml.) and 1 M aqueous sodium hydroxide solution (250 ml.) was stirred at 40°-50° for 8 hours. The solid product was collected and dried to give the novel 4-hydroxy-3-hydroxymethyl-7-trifluoromethylquinoline, m.p. 302°-304°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[O:31])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][OH:31])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=1)([C:13]#[N:14])[CH3:12])[N:9]=2
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C=O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: CC(C#N)(Cn1nc2cc(Cl)cc(CO)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.4 %

Procedure:
To a solution of N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (150 mg) in ethanol (2 mL) cooled in an ice bath was added sodium triacetoxyborohydride (0.22 g). After 6 hour at room temperature, more sodium triacetoxyborohydride (0.29 g) was added and the mixture stirred overnight at room temperature. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (100 mg, 67%). Rf=0.4 (3:1 EA/heptane). MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz, CHLOROFORM-d): 1.87 (s, 3H), 5.06 (s, 2H), 5.15 (d, J=13.8 Hz, 1H), 5.43 (d, J=13.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.43 (dt, J=1.8, 1.0 Hz, 1H), 7.47 (s, 1H), 7.80 (d, J=1.8 Hz, 1H) and 7.88 (d, J=8.8 Hz, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:13][C:14]3[CH:15]=[N:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:18]([CH3:20])[CH:19]=3)=[C:8]([CH:12]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>ClCCl>[C:9]([C:8]1[CH:12]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[CH:6][C:7]=1[NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N+:16]([O-:35])[CH:15]=1)([OH:11])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Nc2ccc(C3CC3)cc2C(=O)O)cnc1-c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Nc2ccc(C3CC3)cc2C(=O)O)c[n+]([O-])c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-cyclopropyl-2-(5-methyl-6-phenylpyridin-3-ylamino)benzoic acid (0.29 mmol, 0.1 g) in 4 ml of dichloromethane was added mCPBA in portions, at 0° and under argon atmosphere. After the addition the mixture was stirred overnight at room temperature. The solvent was evaporated and the solid residue was triturated with a water/ethyl acetate mixture. The solid was filtered off affording 0.035 g (33% of yield) of the expected product.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:23](=[O:28])[CH2:24][S:25]([CH3:27])=[O:26])=[C:17]([CH:22]=1)[N:18]([CH3:21])[CH:19]=[O:20]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:23](=[O:28])[CH2:24][S:25]([CH3:27])(=[O:6])=[O:26])=[C:17]([CH:22]=1)[N:18]([CH3:21])[CH:19]=[O:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)=O
Solvent: ClCCl
Product: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (0.63 g) was added to a solution of 5'-fluoro-N-methyl-2'-methylsulphinylacetylformanilide (0.78 g), prepared in a similar manner to that described in Example 8, in dichloromethane (25 ml). The mixture was stirred at ambient temperature for 2 hours and then washed with saturated aqueous sodium hydrogen carbonate solution (2×20 ml) and water (2×20 ml). Evaporation in vacuo gave an oil which was crystallised from toluene gave to give 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide, m.p. 95°-97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:19]([CH:20]=O)=[CH:18][C:17]2[C:12](=[C:13]([CH3:22])[CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH2:23]([NH2:32])[C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:29][O:28][C:27]1[CH:30]=[CH:31][C:24]([CH2:23][NH:32][CH2:20][C:19]2[C:10]([C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:22])=[CH:25][CH:26]=1
Reactant: COc1cccc(F)c1-c1nc2c(C)cccc2cc1C=O
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2c(F)cccc2OC)cc1

Procedure:
Prepared according to Procedure F using 2-(2-fluoro-6-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (1.086 g, 3.68 mmol), DCE (18 mL), PMBNH2 (0.95 mL, 7.36 mmol, 2.0 eq), and NaBH(OAc)3 (2.3387 g, 11.03 mmol, 3 eq) After purification, N-(4-methoxybenzyl)(2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine was obtained as yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.42 (1H, s), 7.84 (1H, d, J=7.4 Hz), 7.55-7.62 (1H, m), 7.43-7.54 (2H, m), 7.13 (2H, d, J=8.6 Hz), 6.90-7.01 (2H, m), 6.77-6.85 (2H, m), 3.71 (3H, s), 3.65 (3H, s), 3.47-3.62 (4H, m), 2.64 (3H, s), 2.43 (1H, s). Mass Spectrum (ESI) m/e=417.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1>C1COCC1.CO.[Pd]>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N)c(N)c1
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To a stirred mixture of methyl 6-amino-5-nitronicotinate (2 g, 10.15 mmol) in a mixture of THF (30 mL) and MeOH (10 mL) at rt was added palladium (10 wt % on activated carbon, 100 mg), and the mixture stirred under hydrogen gas (1 atmosphere) for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford methyl 5,6-diaminonicotinate (1.69 g, 100%) as a yellow solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=2.1 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 6.27 (br s, 2H), 4.92 (br s, 2H), 3.74 (s, 3H). LCMS (ESI) m/z 168 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH3:24][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:13]3[C:14]([CH3:21])=[C:15]([O:20][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][C:10]2([CH3:22])[CH3:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N(C)C)cc1)C(C)(C)O2
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(N(C)C)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
Using 3-[4-(dimethylamino)phenyl]-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: Br.[N:2]1([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:5]1[CH2:6][CH2:7][CH2:8][N:2]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:4]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NN1CCCNCC1)c1ccc(F)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCCN(NC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(1-homopiperazinyl)-4-fluorobenzamide hydrobromide (455 mg) in 1N aqueous solution of sodium hydroxide (3.2 ml) was added acetic anhydride (0.2 ml) at 0° C., and the solution was stirred at ambient temperature for 1.5 hours. The reaction mixture was extracted with a mixture of ethyl acetate and n-butanol. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and ethyl acetate (1:15) to give oil. The oil was crystallized when treated with ethyl acetate below 0° C. to give N-(4-acetyl-1-homopiperazinyl)-4-fluorobenzamide (137 mg).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C:27]1[C:28]2[C:35]([I:36])=[CH:34][N:33]([C@@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@H:39]([CH2:49][O:50][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:38]3)[C:29]=2[N:30]=[CH:31][N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C:27]1[C:28]2[C:35]([I:36])=[CH:34][N:33]([C@@H:37]3[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@H:39]([CH2:49][OH:50])[CH2:38]3)[C:29]=2[N:30]=[CH:31][N:32]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncnc2c1c(I)cn2[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Silica gel-carrying tetrabutyl ammonium fluoride (700 mg) (up to 1.5 mmol/g) was added to a solution of (2S,4S)-tert-butyl 4-(4-(bis(tert-butoxycarbonyl)amino)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((tert-butyldiphenylsilyloxy)methyl)pyrrolidine-1-carboxylate (237.5 mg) obtained in Step 3 in THF (5 ml), and the resulting mixture was stirred at room temperature overnight. Silica gel was separated by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow, amorphous substance (185 mg). Physical properties: m/z [M+H]+ 660.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28].CO>N1C=CC=CC=1>[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](=[O:31])[O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)[CH3:28]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CCN(CC)C(=O)OC1CCN(c2ccc(/C=C(\C#N)c3ccc(OC)c(OC)c3)s2)CC1
Yield: 21.4 %

Procedure:
Compound 6 (150 mg) was dissolved in pyridine (1 mL), and diethylcarbamoyl chloride (55 mg) was added to the solution, followed by stirring under reflux for 2 hours. After completion of reaction, methanol was added to the reaction mixture, followed by stirring for 30 minutes. The solvent was evaporated to dryness, and the residue was extracted with chloroform and purified water. The organic layer was dried over sodium sulfate anhydrate, and the solvent was evaporated to dryness. The residue was recrystallized from ethyl acetate, to thereby yield the target product (yield: 40.6 mg, 21.3%).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>CCO>[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: C1CNCCNC1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: CS(=O)(=O)c1ccc(CN2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To a 2-neck, 2-L round bottom flask containing anhydrous EtOH (800 mL) and equipped with a mechanical stirrer and condenser was added acetyl chloride (20.2 mL, 0.267 mol, 1.1 equiv). The solution was stirred for 0.5 h and homopiperazine (24.3 g, 0.243 mol) was added, The mixture was heated to reflux for 2 h. The reaction mixture was cooled to 25° C., 4-(methylsulfonyl)benzyl chloride (25 g, 0.122 mol, 0.5 equiv) was added and the reaction mixture heated to reflux for 16 h. The reaction mixture was cooled to 25° C. and the solvent was removed under vacuum. The residue was diluted with EtOAc (500 mL) and was washed with 2N KOH (2×500 mL). The aqueous layer was extracted with EtOAc (1×500 mL). The organic phase was combined, washed with 2N KOH (1×300 mL), dried (MgSO4) and concentrated. The crude solid was washed with hot EtOAc to yield pure desired product (8.03 g, 32.7 g theoretical, 25%) as an off-white solid, TLC R1 0.04 (10% CH3OH—CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 9.82 (br s, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.60 (d, J=7.7 Hz, 2H), 3.80 (br s, 2H), 3.36 (br m, 2H), 3.07 (s, 3H), 2.93 (br s, 2H), 2.80 (br s, 2H), 2.12 (br m, 2H).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=CC(S(OCC(C)CC)(=O)=O)=[CH:3][CH:2]=1.[C:17]1([CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1)[OH:18].[OH-].[Na+]>O.C(O)CCC>[CH3:6][CH:1]([CH2:2][CH3:3])[CH2:16][O:18][C:17]1[CH:24]=[CH:23][C:21]([OH:22])=[CH:20][CH:19]=1
Reactant: CCC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CCC(C)COc1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Into a n-butanol suspension containing 37 mmol (9.0 g) of 2-methylbutyl p-toluenesufonate prepared by tosylating S-(-)-2-methylbutanol and 74 mmol (8.2 g) of hydroquinone, added dropwise was a solution of 50 mmol (2.1 g) of sodium hydroxide dissolved in a solvent mixture of 3 ml of water and 10 ml of n-butanol. After conclusion of the dropping, the mixture was then stirred for 8 hours at 120° C. After addition of water, the reaction solution was extracted with ether, and the extracted solution was dried and concentrated. The concentrate was purified by column chromatography, to obtain 4.8 g of the objective ether compound (Yield: 72%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:17]([CH3:20])([CH3:19])[O:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCNCC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCNCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 173.2 %

Procedure:
Scheme 1, step C reagent. To a solution of 4-hydroxypiperidine (2.00 g, 9.89 mmoles) in CH2Cl2 (30 mL) is added 1H-imidazole (2.69 g, 39.55 mmoles) followed by t-butyldimethylchlorosilane (3.58 g, 23.73 mmoles) and the reaction mixture is stirred at room temperature. After 12 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 100% CH2Cl2 to 10% 7N ammonia in MeOH/90% CH2Cl2 to afford the title compound (3.69 g, 86.3%). Mass spectrum (m/z): 216.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(N)ccc1Oc1ccccc1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
To 52.1 g of N-(5-nitro-2-phenoxyphenyl)methanesulfonamide was added 51 ml of an aqueous solution containing 2.7 g of ammonium chloride, and then 42.5 g of an iron powder was added thereto with heating at 80° C. with stirring, followed by stirring for 2 hours. To the reaction cooled to 50° C. were added ethyl acetate and water, and the precipitate was filtered. After extraction with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give 29.6 g of N-(5-amino-2-phenoxyphenyl)methanesulfonamide.