Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([CH3:27])[CH:18]=3)[N:8]=2)[CH:6]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[C:19]([CH3:27])[CH:18]=4)[N:8]=3)[CH:6]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)ccc1C(F)(F)F
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cccc(S(=O)(=O)NC(C)(C)C)c4)c3)n2)ccc1C(F)(F)F

Procedure:
N-tert-Butyl-3-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.73) (0.50 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as an off white solid (0.118 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].O=C[C@H]([C@H]([C@H](CO)O)O)O>>[C:1]([O:4][C@H:5]1[O:17][C@@H:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1OC(OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Product: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
A 100-ml four-necked flask was subjected to nitrogen substitution. 2.97 g (purity: 98 wt %; corresponding to 10 mmol of L-ribose) of the 2,3,5-tri-O-acetyl-1-O-methyl-L-ribofuranose obtained at a yield of 93.5% from L-ribose was added to the flask by the same method as that of Example B1(1). Thereafter, 1.85 ml (2.0 equivalents) of acetic anhydride, 1.14 ml (2.0 equivalents) of acetic acid, and 0.64 ml (0.8 equivalents) of pyridine were added thereto. While stirring in an ice bath, 2.2 g (2.2 equivalents) of concentrated sulfuric acid was added dropwise thereto at an internal temperature of 0±5° C. The temperature was increased to room temperature, and the reaction solution was stirred for 1.5 hours. Thereafter, the reaction solution was maintained at a temperature of 0±5° C. again in an ice bath, and 10 ml of diisopropyl ether was added thereto, followed by stirring in an ice bath for 4 hours. Thereafter, the reaction product was maintained at 5° C. or lower in a refrigerator overnight. While stirring in an ice bath, 3.60 g of sodium acetate was added to the reaction product, and the obtained mixture was then stirred in an ice bath for 30 minutes. 30 ml of ethyl acetate and a saturated sodium bicarbonate aqueous solution were added to the reaction solution at room temperature until the aqueous layer was neutralized, followed by liquid separation. The aqueous layer was extracted with 30 ml of ethyl acetate, and organic layers were then gathered. The gathered layers were washed with 20 ml of a saturated sodium bicarbonate aqueous solution and then with 20 ml of a saturated sodium chloride aqueous solution 2 times. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was then removed by filtration, concentrated under reduced pressure. Thus, 3.67 g of crude 1,2,3,5-tetra-O-acetyl-L-ribofuranose was obtained in the form of yellow oil. The obtained compound was analyzed by HPLC. As a result, it was found that the crude product contained 2.63 g of 1,2,3,5-tetra-O-acetyl-L-ribofuranose, that the ratio of α-/β-anomers was 6/94, and that the total reaction yield of the β-anomer from L-ribose was 73%.
Reaction SMILES: ClC1C(C2C=CN=CC=2NC)=CC=CN=1.F[C:17]1[CH:22]=[CH:21]C=[C:19](OC)[C:18]=1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N:31]([CH2:48]C(F)(F)F)[C:32](=[O:47])[C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:34]=1.CCN(C(C)C)C(C)C.[NH4+:62].[Cl-:63]>C(Cl)Cl>[Cl:63][C:19]1[C:18]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N:31]([CH3:48])[C:32](=[O:47])[C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([S:43]([CH3:46])(=[O:44])=[O:45])[CH:34]=2)=[CH:17][CH:22]=[CH:21][N:62]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Agent: CNc1cnccc1-c1cccnc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1cccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-N-methyl-3,4′-bipyridin-3′-amine (0.2 g, 910 μmol, example 313, intermediate a) in CH2Cl2 (5 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (522 mg, 1.82 mmol, example 223, intermediate d) and DIPEA (471 mg, 636 μL, 3.64 mmol) and the light yellow solution was stirred at room temperature for 16 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted four times with CH2Cl2. The organic layers dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (0.393 g; 91%). MS (ESI): m/z=470.06 [M+H]+.
Reaction SMILES: CC1(C)O[CH2:6][C:5]([CH2:20][N:21]2[CH:25]=[C:24]([CH2:26][O:27]COC)[N:23]=[C:22]2[N+:31]([O-:33])=[O:32])([CH2:8][O:9]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][O:3]1.C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.[F-:61].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:3][CH2:4][C:5]([CH2:8][OH:9])([CH2:6][F:61])[CH2:20][N:21]1[CH:25]=[C:24]([CH2:26][OH:27])[N:23]=[C:22]1[N+:31]([O-:33])=[O:32]
Reactant: COCOCc1cn(CC2(COS(=O)(=O)c3ccc(C)cc3)COC(C)(C)OC2)c([N+](=O)[O-])n1
Reactant: [F-]
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1nc(CO)cn1CC(CO)(CO)CF
Temperature: 80 °C
Reaction time: 0.83 h

Procedure:
3.6 mg (7.6 μmol equivalents) of 2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane was dissolved in 1 mL of acetonitrile, 17 mg (34.5 μmol equivalents) of Kryptofix 222 (trade name, Merck), 5.8 mg (100 μmol equivalents) of potassium fluoride, and 1.8 mg (23 μmol equivalents) of potassium carbonate were added thereto, and the mixture was refluxed while heating for 3 hours. After completion of the reaction, water was added, and the mixture was extracted three times with chloroform. The combined chloroform layers were dried with anhydrous sodium sulfate and then concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1). 1 mL of 1 mol/L hydrochloric acid was added dropwise to a fraction thus obtained, and the mixture was heated to 80° C. in an oil bath and then stirred for 50 minutes. After completion of the reaction, the mixture was concentrated under vacuum to give a trace amount of 1-(2,2-dihydroxymethyl-3-fluoropropyl)-4-hydroxymethyl-2-nitroimidazole.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9](/[CH:23]=[CH:24]/[CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>O.CCO>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][CH:15]=2)[N:10]=[C:9](/[CH:23]=[CH:24]/[CH3:25])[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: C/C=C/c1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C=C/c1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 90 °C
Yield: 85.7 %

Procedure:
560 mg (13.9 mmol) NaOH flocs were added to a solution of 450 mg (1.4 mmol) (E)-4-methyl-2-(prop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a water/EtOH mixture (in each case 21 ml) at 0° C. The mixture was subsequently heated to 90° C. for 16 h. It was then concentrated in a vacuum and the residue was taken up with water (20 ml) and washed with EtOAc. Thereafter, the aqueous phase was set to pH ˜2 with a 2M hydrochloric acid and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in a vacuum. 350 mg (1.2 mmol, 85%) (E)-4-methyl-2-(prop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:10]=[C:11]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH:27]([F:29])[F:28])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=2[CH3:15])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:30]=O>[BH4-].[Na+].C(#N)C>[ClH:1].[F:28][CH:27]([F:29])[O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([N:2]2[CH2:8][CH2:7][CH2:6][N:5]([CH3:30])[CH2:4][CH2:3]2)[CH:10]=1)(=[O:19])=[O:18]
Reactant: C=O
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2OC(F)F)cc1N1CCCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(NS(=O)(=O)c2ccccc2OC(F)F)cc1N1CCCN(C)CC1

Procedure:
The title compound was prepared from the title compound of Example 2 under reductive amination conditions employing an aqueous solution of formaldehyde and sodium borohydride in acetonitrile as solvent.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH2:4][S:5][CH2:6][CH2:7][C:8]([O:10]C)=[O:9].O.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[C:3]([CH2:4][S:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])([OH:12])=[O:2]
Reactant: COC(=O)CCSCC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of methyl 3-((2-methoxy-2-oxoethyl)thio)propanoate (5.0 g, 26 mmol) in THF/MeOH/water (60 mL, 4:1:1) was added lithium hydroxide monohydrate (4.375 g, 101 mmol). The resulting mixture was stirred at room temperature overnight before it was concentrated under reduced pressure. The residue obtained was diluted with water (˜100 mL) and the resulting solution was acidified with 6N HCl. The mixture was partitioned between water and ethyl acetate. The organic extract was washed with more water, separated, dried over sodium sulfate, filtered and evaporated to afford 3-((carboxymethyl)thio)propanoic acid (3.64 g, 85%) as a white solid. 1H NMR, DMSO-d6) δ ppm 2.55-2.57 (t, 2H) 2.75-2.79 (t, 2H) 3.27 (s, 2H) 12.41 (s, 2H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]4[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18]1)=[N:9][C:8]([O:34][CH3:35])=[CH:7][CH:6]=2.[CH2:36]1[O:38][C@H:37]1[CH2:39][OH:40]>C1COCC1.CO>[OH:38][C@@H:37]([CH2:39][OH:40])[CH2:36][N:13]([CH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:34][CH3:35])[N:9]=2)[N:4]=[CH:3][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1
Reactant: OC[C@H]1CO1
Reactant: COc1ccc2ncc(F)c(CNCCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c2n1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(F)c(CN(CCCC3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)C[C@@H](O)CO)c2n1
Temperature: 70 °C
Yield: 52 %

Procedure:
A solution of the compound of Example 78 (0.05 g, 0.1 mmol) in THF/MeOH (1:1, 0.5 mL) was treated with (S)-glycidol (0.06 mL, 5 eq.). The mixture was heated at 70° C. for 3 h, concentrated in vacuo and purified by FC (EA/MeOH 19:1+1% NH4OH) to give the title compound as a colourless solid (0.03 g, 52% yield).
Reaction SMILES: [O:1]=[C:2]([C@@:17]1([OH:58])[CH2:34][C@H:33]([O:35][C@@H:36]2[O:50][C@@H:49]([CH3:51])[C@H:39]3[O:40][C@H:41]4[N:46]([C@H:38]3[CH2:37]2)[CH2:45][CH2:44][O:43][C@@H:42]4[O:47][CH3:48])[C:32]2[C:19](=[C:20]([OH:57])[C:21]3[C:22](=[O:56])[C:23]4[C:28]([C:29](=[O:53])[C:30]=3[C:31]=2[OH:52])=[C:27]([O:54][CH3:55])[CH:26]=[CH:25][CH:24]=4)[CH2:18]1)[CH2:3][O:4][CH:5]1[O:10][CH:9]([CH2:11][O:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][CH2:7][CH2:6]1.O[N:60]1[C:64](=[O:65])[CH2:63][CH2:62][C:61]1=[O:66].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:1]=[C:2]([C@@:17]1([OH:58])[CH2:34][C@H:33]([O:35][C@@H:36]2[O:50][C@@H:49]([CH3:51])[C@H:39]3[O:40][C@H:41]4[N:46]([C@H:38]3[CH2:37]2)[CH2:45][CH2:44][O:43][C@@H:42]4[O:47][CH3:48])[C:32]2[C:19](=[C:20]([OH:57])[C:21]3[C:22](=[O:56])[C:23]4[C:28]([C:29](=[O:53])[C:30]=3[C:31]=2[OH:52])=[C:27]([O:54][CH3:55])[CH:26]=[CH:25][CH:24]=4)[CH2:18]1)[CH2:3][O:4][CH:5]1[O:10][CH:9]([CH2:11][O:12][CH2:13][C:14]([O:16][N:60]2[C:64](=[O:65])[CH2:63][CH2:62][C:61]2=[O:66])=[O:15])[CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1O
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1CCCC(COCC(=O)O)O1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1CCCC(COCC(=O)ON2C(=O)CCC2=O)O1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of the acid intermediate 49 obtained from step 3 of the process (2 mg, 0.0024 mmol) in dry dichloromethane (1 ml) cooled at 0° C., N-hydroxysuccinimide (1 mg, 0.00792 mmol) and N,N′-dicyclohexylcarbodiimide (1 mg, 0.004556 mmol) were added. The reaction mixture was stirred at 0° C. for 2.5 h, until disappearance of the starting material (HPLC-MS analysis). The solvent evaporated under vacuum and the residue treated with ethyl ether (2×4 ml). The suspension was stirred for 10 minutes, the solid removed by filtration and the organic solution concentrated in vacuo, affording 2 mg of 50 (red solid) as a mixture of diastereoisomers. MS (ESI): 911 [M+H]+. Retention time=6.12, 6.30, 6.42 min (method 1).
Reaction SMILES: C(N=[C:10]=[S:11])(=O)C1C=CC=CC=1.[C:12]([C:15]1[NH:19][CH:18]=[N:17][C:16]=1[NH:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)(=[O:14])[NH2:13].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl.CO>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[NH2:23][CH2:22][CH2:21][N:20]1[C:16]2[N:17]=[CH:18][NH:19][C:15]=2[C:12](=[O:14])[NH:13][C:10]1=[S:11]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCNc1nc[nH]c1C(N)=O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
Benzoyl isothiocyanate (1.3 mL, 9.8 mmol) was added to tert-butyl {2-[(5-carbamoyl-1H-imidazol-4-yl)amino]ethyl}carbamate (2.5 g, 9.3 mmol, obtained from Example 26(a)) in dichloromethane (25 mL) and methanol (0.050 mL) at 0° C. The mixture was allowed to reach r.t. and stirred for 3 h. After removal of solvents, the residue was dissolved in ammonia (7 N in methanol, 30 mL) and subjected to microwave heating at 80° C. for 5 h. The solvent was then evaporated and the Boc-protected product was purified by silica gel column chromatography (dichloromethane/methanol 95:5) which gave 1.5 g (52% yield). This material (1.5 g, 4.9 mmol) was dissolved in dichloromethane (50 mL) and treated with trifluoroacetic acid (7 mL). After 2 h, the mixture was concentrated, diethyl ether was added and the solid was collected and dried in vacuo to afford 1.1 g (67% yield) of the title compound as its trifluoroacetic acid salt.
Reaction SMILES: Cl.C(N=C=N[CH2:7][CH2:8][CH2:9]N(C)C)C.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:20]=2)[CH:15]=[CH:14]1.C(O)C=C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][C:23]([O:25][CH2:9][CH:8]=[CH2:7])=[O:24])[CH:20]=2)[CH:15]=[CH:14]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccc2cc[nH]c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C=CCO
Solvent: ClCCl
Product: C=CCOC(=O)Cc1ccc2cc[nH]c2c1
Yield: 86.8 %

Procedure:
750 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to a solution of 450 mg of 2-(indol-6-yl)acetic acid [synthesized according to the procedures described in Chem. Pharm. Bull., 20, 2163 (1972)], 0.27 ml of allyl alcohol and 480 mg of 4-dimethylaminopyridine in 20 ml of methylene chloride, at room temperature, and the resulting mixture was stirred overnight. After completion of the reaction, the reaction mixture was acidified by the addition of a 3% aqueous solution of hydrochloric acid, followed by extraction with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 10 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 480 mg of the title compound as an oil.
Reaction SMILES: Cl.Cl.NC1CCN(S(C2C=C3C(=CC=2)C=NC=C3)(=O)=O)CC1.[C:23]([O:27][C:28](N(CCCO)C[C@@H](NS(C1C=C2C(=CC=1)C=NC=C2)(=O)=O)C)=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.Cl.[Br:54][C:55]1[C:64]([S:65]([N:68]2[CH2:75][CH2:74][CH2:73][CH2:72][NH:71][CH2:70][C@H:69]2[CH3:76])(=[O:67])=[O:66])=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]=[CH:60]2>>[Br:54][C:55]1[C:64]([S:65]([N:68]2[CH2:75][CH2:74][CH2:73][CH2:72][N:71]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:70][C@H:69]2[CH3:76])(=[O:67])=[O:66])=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]=[CH:60]2
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Reactant: C[C@@H]1CNCCCCN1S(=O)(=O)c1ccc2cnccc2c1Br
Agent: Cl
Agent: NC1CCN(S(=O)(=O)c2ccc3cnccc3c2)CC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCCCN1S(=O)(=O)c1ccc2cnccc2c1Br

Procedure:
The compound of interest was synthesized (colorless oil, 41%) according to the production method of Step 1 of Example 12 using Reference Compound 4 instead of Reference Compound 2 and using Reference Compound 23 instead of Reference Compound 9.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([CH:11]=O)=[CH:9][N:8]=[C:7]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:6]=23)[CH2:3][CH2:2]1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C>[CH:1]1([NH:4][C:5]2[C:10]([CH:11]=[N:19][OH:20])=[CH:9][N:8]=[C:7]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:6]=23)[CH2:3][CH2:2]1
Reactant: CCn1ncc2c(NC3CC3)c(C=O)cnc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCn1ncc2c(NC3CC3)c(C=NO)cnc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a stirred solution of 4-cyclopropylamino-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (300 mg, 0.00129 mole) in ethanol, hydroxylamine hydrochloride (359 mg, 0.0051 mole) and sodium acetate (424 mg, 0.0051 mole) were added. The reaction mixture was allowed to stir at room temperature for about 50 minutes. Ethanol was removed under reduced pressure and residue was poured in water. The organic compound was extracted with ethyl acetate. Ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure to afford white solid compound. Yield: 270 mg. m/z: (M++1) 246.1.