Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5][CH2:6][C:7](=O)[CH2:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)N)=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:13][O:12][C:10](=[O:11])[C:9]([CH3:15])([CH3:14])[CH2:8][C:7]1[N:31]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[C:28]2[C:27]([C:6]=1[S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2
Reactant: COC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 39 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in a mixture of 300 mL of toluene and 150 mL of glacial acetic acid was added 15 g of NaOAc and 50 g of 1-(4-methoxyphenyl)-1-(p-chlorobenzyl)hydrazine hydrochloride. The reaction was maintained with stirring at room temperature for 3 days under argon in the dark. The mixture was poured into 3 L of H2O and extracted with 3×500 mL of EtOAc. The ethyl acetate was washed with 3×500 mL of water then solid NaHCO3 was added. The mixture was filtered and the filtrate washed twice with water. The organic phase was dried over MgSO4 and evaporated to dryness to provide the title compound. m.p. 102°-103° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:41]=[N:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 85.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 2-methoxy-5-pyridineboronic acid (110 mg, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (110 mg, 83%) as a white solid: LC/MS m/e calcd for C26H25N3O3S [M+H]+ 460.57, observed 460.0.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[Br:18][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reaction time: 20 h

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n-hexane (100 mL) and washed with a saturated NaHCO3 solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1:4 gave the title compound. MS (DCI) m/z 295 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([P:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][I:33]>>[I-:33].[CH3:32][P+:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=1
Reactant: FC(F)(F)c1cccc(P(c2cccc(C(F)(F)F)c2)c2cccc(C(F)(F)F)c2)c1
Reactant: CI
Product: C[P+](c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Product: [I-]
Yield: 82.5 %

Procedure:
Starting from 2.39 g (5.13 mmol) of tris(3-trifluoromethylphenyl)phosphine and 1.10 g (7.75 mmol, 1.51 eq) of methyl iodide, 2.57 g (4.23 mmol, 82.4%) of methyltris(3-trifluoromethylphenyl)phosphonium iodide was obtained: mp 225.1°-229.3° C. (dec).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.NC[C:21]1[CH:37]=[CH:36][C:35]2[C:26]3[NH:27][C:28](=[O:34])[C:29]4[N:30]([CH:31]=[CH:32][N:33]=4)[C:25]=3[CH2:24][C:23]=2[CH:22]=1>CN(C)C=O>[O:34]=[C:28]1[NH:27][C:26]2[C:35]3[CH:36]=[CH:37][CH:21]=[C:22]([CH2:1][NH:3][C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:23]=3[CH2:24][C:25]=2[N:30]2[CH:31]=[CH:32][N:33]=[C:29]12
Reactant: NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)NCc1cccc2c1Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 16 h

Procedure:
1.4 ml of triethylamine and 0.9 ml of phenylacetyl chloride are added to a suspension of 1 g of 8-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 40 ml of dimethylformamide. After reacting for 16 hours at a temperature in the region of 20° C., the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is suspended in 50 ml of acetone. After filtration and drying under reduced pressure (1 mbar) at 60° C., 100 mg of N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)methyl]phenylacetamide are obtained in the form of a beige solid melting above 260° C. (1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm: 3.51 (2H, s, CH2 -Ph), 3.97 (2H, s, CH2), 4.35 (2H, d, J=4 Hz, NCH2), between 7.20 and 7.40 (6H, m, arom. H), 7.43 (1H, s, arom. CH), 7.60 (1H, s, arom. CH), 7.78 (1H, d, J=7 Hz, arom. CH), 7.98 (1H, s, arom. CH), 8.63 (1H, broad t, NH), 12.3 (1H, s, NH)).
Reaction SMILES: O=[C:2]1[CH2:5][N:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[CH2:9]([O:8][C:6]([N:4]1[CH2:5][CH:2]([N:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]2)[CH2:3]1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H]1CN(C2CN(C(=O)OCc3ccccc3)C2)CCN1C(=O)OC(C)(C)C
Yield: 64.5 %

Procedure:
To a mixed solution of benzyl 3-oxoazetidine-1-carboxylate (30.0 g, 146 mmol), which is a known and commercially available product, THF (100 mL) and acetic acid (60 mL) was added a commercially available product of tert-butyl(2S)-2-methylpiperazine-1-carboxylate (32.2 g, 161 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hour. To the reaction mixture was added sodium triacetoxyborohydride (46.5 g, 219 mmol) at 0° C. The resultant mixture was stirred at room temperature for 1 hour and 30 minutes. To the reaction mixture were added sodium hydrogen carbonate and water at 0° C. The resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (36.7 g, yield: 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH2:26][CH2:27][C:28]([O:30][CH2:31]C)=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[CH2:33]1N2CCN(CC2)C1.C(=O)(OC)OC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:33])[C:21]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2[nH]1
Reactant: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Product: COC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Temperature: 25 °C
Yield: 58.8 %

Procedure:
A solution of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]propanoate (D33) (114 mg), DABCO (56 mg) and dimethyl carbonate (2 mL) in N,N-dimethylformamide (DMF, 2 mL) was stirred at 90° C. for 2 days. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate. The organic solution was washed with water. The organic solution was dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford methyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (D113) (67 mg). MS (ES): C24H24ClN3O4 requires 453; found 454.2 (M+H+).
Reaction SMILES: [CH2:1]([C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[H][H]>[Pd].C(O)(=O)C>[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCCCC(=O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccc(O)cc1

Procedure:
16.75 g of dodecyl chloride was dropwise added to 7.0 g of phenol and the resulting mixture was subjected to reaction at 90° C. for 30 minutes. And then, 12.0 g of AlCl3 powder was added thereto and the resulting mixture was further subjected to reaction at 100° C. for 4 hours. The reaction mixture was cooled and added to dilute hydrochloric acid. The resulting mixture was then subjected to extraction with two 50-ml portions of ethyl acetate. To the resulting solution of the reaction product in the ethyl acetate was added 80 ml of 3% aqueous sodium hydroxide solution, and the aqueous layer was then separated. To the aqueous layer was added conc hydrochloric acid to adjust the pH to 2, and the crystal, thus precipitated was filtered and washed with water to obtain 9.35 g of 4-hydroxyphenyl undecyl ketone. Subsequently, 8.0 g of the 4-hydroxyphenyl undecyl ketone thus obtained was mixed with 650 mg of a 5% active carbon-supported palladium and 100 ml of acetic acid, and the resulting mixture was subjected to reaction in a hydrogen gas stream at 50° C. for 15 hours to reduce the ketone. The reaction mixture was cooled and filtered, and acetic acid was distilled off to obtain 7.50 g of white, solid 4-dodecylphenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (10 mL) was added to 4-methoxybenzoic acid (306 mg, 2.0 mmol) and the mixture was stirred at reflux for 3 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to obtain 4-methoxybenzoyl chloride (320 mg). 3-Hydroxyanthranilic acid (167 mg, 1.0 mmol) and pyridine (158 mg, 2.0 mmol) were added to dichlormethane (10 mL) and the mixture was stirred at room temperature for 30 min. Then 2 (320 mg, 2.0 mmol) was added. The mixture was stirred at room temperature overnight and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=20:1 to 10:1) to yield methyl 3-hydroxy-2-(4-methoxybenzamido)benzoate as a solid (178 mg, yield 59%). LC-MS (ESI) m/z 302 [M+1]+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:3](=[O:5])[CH3:2])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (16 mg, 0.029 mmol) and triethylamine (20. μL, 0.14 mmol) in dichloromethane (1 mL) was added acetic anhydride (4.0 μL, 0.043 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.4 mg, 13%). LCMS calculated for C19H25N4O2S (M+H)+: m/z=373.2. Found: 373.1.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@H:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:25]1
Reactant: C[C@H]1CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: C[C@@H]1CCCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylpiperidine (1.2 equiv) to give 163 (13.8 mg, M+1 395.1)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C@@H:9]1[C:14]2=[C:15]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=[C:13]2[O:12][C:11]([CH3:36])([CH3:35])[C@@H:10]1[O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23](=[O:29])[C:22]1[CH:21]=[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]2=[CH:18][C:17]=1[N:16]3[CH3:34]>N1C=CC=CC=1>[C:1]([O:8][C@@H:9]1[C:14]2=[C:15]3[C:24](=[C:25]([O:27][CH3:28])[CH:26]=[C:13]2[O:12][C:11]([CH3:36])([CH3:35])[C@@H:10]1[O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:23](=[O:29])[C:22]1[CH:21]=[C:20]2[CH:30]=[CH:31][CH:32]=[CH:33][C:19]2=[CH:18][C:17]=1[N:16]3[CH3:34])(=[O:3])[CH3:2]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)[C@@H](O)[C@@H](OC(=O)c1ccccc1)C(C)(C)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4cc1n3C)[C@@H](OC(C)=O)[C@@H](OC(=O)c1ccccc1)C(C)(C)O2
Reaction time: 12 h

Procedure:
2.5 ml of acetic anhydride are added to a solution of 0.1 g of the compound of Example 20 in 2.5 ml of pyridine. After reacting for 12 hours at room temperature, the reaction mixture is concentrated under reduced pressure. Chromatography on silica gel (eluant: dichloromethane) allows the expected product to be isolated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](=O)([O-])[O-].[K+].[K+].O.[C:14](O)(=O)[CH2:15][C:16]([CH2:21][C:22](O)=O)([C:18]([OH:20])=O)O>CN(C=O)C>[N:1]1([C:15]2[CH:14]=[CH:7][CH:22]=[CH:21][C:16]=2[CH:18]=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: C1CCNCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1N1CCCCC1
Temperature: 130 °C

Procedure:
To a solution of the aldehyde 3a (20 g, 161.1 mmol) in dry DMF (160 mL), piperidine (19.1 mL, 193.4 mmol, 1.2 eq) and potassium carbonate (26.73 g, 193.4 mmol, 1.2 eq) were successively added. The suspension was heated at 130° C. for 3 h. The reaction mixture was then poured into cold water and acidified with citric acid up to pH 5. The aqueous layer was extracted 3X with EtOAc and the combined organic extract was successively washed with water, saturated NaHCO3 and brine. After drying the organic extract over MgSO4, filtration and concentration, the desired 2-piperidinobenzaldehyde 3b was isolated as a red oil (28.23 g, 92% yield).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[NH2:8][C:9]1[N:13]=[CH:12][NH:11][N:10]=1>C(O)(=O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]=1)[CH3:7]
Reactant: CCC(=O)CC#N
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CCc1cc(N)n2ncnc2n1
Temperature: 150 °C
Yield: 11.3 %

Procedure:
A mixture of 3-oxopentanenitrile (1.0 g, 103 mmol) and 3-amino-1,2,4-triazole (0.91 g, 10.8 mmol) in 10 mL of acetic acid was heated in a pressure tube at 150° C. for 24 h. The reaction mixture was allowed to cool to room temperature, and solvent was removed in vacuo. The solid was removed via filtration. The filtrate partially solidified upon standing at room temperature, and the solid was collected via filtration to give the title compound (200 mg, 12% yield).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:8][C:7]1=[O:23])(=O)[CH2:2][CH2:3][CH3:4].[CH2:24]([O:27][NH2:28])[CH:25]=[CH2:26]>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:8][C:7]1=[O:23])[CH2:2][CH2:3][CH3:4])[CH:25]=[CH2:26]
Reactant: C=CCON
Reactant: CCCC(=O)C1C(=O)CC(CCS(C)(=O)=O)C(C(=O)OC)C1=O
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCS(C)(=O)=O)C(C(=O)OC)C1=O

Procedure:
3.5 g of 2-butyryl-5-(2-methylsulfonylethyl)-4-methoxycarbonyl-cyclohexane-1,3-dione was allowed to react with 0.9 g of allyloxyamine at room temperature for 5 hours in 20 ml of ethanol. After completion of the reaction, the resulting reaction solution was treated as in Example 1 to obtain 3.1 g of white crystal of the desired compound. m.p. 96.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[C:20](Cl)[N:19]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=1.[NH2:28][NH2:29]>CC(O)C.O>[NH2:25][C:24]1[C:21]2[C:20](=[N:19][C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[F:27])(=[O:10])=[O:9])=[CH:13][CH:14]=3)=[CH:23][N:22]=2)[NH:29][N:28]=1
Reactant: N#Cc1ncc(-c2ccc(NS(=O)(=O)c3cc(Cl)ccc3F)cc2)nc1Cl
Reactant: NN
Solvent: O
Solvent: CC(C)O
Product: Nc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cc(Cl)ccc4F)cc3)cnc12
Temperature: 120 °C
Yield: 22 %

Procedure:
5-Chloro-N-[4-(6-chloro-5-cyano-pyrazin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (160 mg) was suspended in a mixture of 1 ml iPrOH and 1 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT and the crude reaction mixture was evaporated to dryness, redissolved in DMF and purified by preparative HPLC (C18 reversed phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield 38 mg (22%) of the title compound in the form of N-[4-(3-amino-1H-pyrazolo[3,4-b]pyrazin-6-yl)phenyl]-5-chloro-2-fluoro-benzenesulfonamide hydrochloride after lyophilizing with aqueous hydrogen chloride.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=2)[CH2:9]1)(C)(C)C.C(O)([C:23](F)([F:25])[F:24])=O.FC(F)C(O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][C@@H:8]([NH:7][C:6](=[O:5])[CH:23]([F:25])[F:24])[CH2:9]2)=[N:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCN(c2ccc(Br)cn2)C1)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Dissolve [(R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (4.24 g, 12.43 mmol) in CH2Cl2 (10 mL) and add TFA (5 mL). Stir at RT for 1 h. Evaporate the excess reagent. Dissolve the resulting crude material in CH2Cl2 (50 mL) and cool to 0° C. Add difluoroacetic acid (1.78 g, 18.64 mmol), EDCI (3.57 g, 18.64 mmol), HOBt (2.52 g, 18.64 mmol) and Et3N (5.2 mL, 37.3 mmol). Stir the reaction at 0° C. for 30 min and at RT overnight. Dilute with CH2Cl2 (100 mL) and wash with 0.1 M NaOH (2×50 mL) and H2O (100 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material, eluting with 100% EtOAc to give 1.98 g (50%) of the title compound. MS/ES m/z (79Br) 321.0 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:12]#[N:13])[O:10][CH:11]=1.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:7]1[CH:8]=[C:9]([C:12]#[N:13])[O:10][CH:11]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: N#Cc1cc(Br)co1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1coc(C#N)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
n-Butyllithium (1.6M, 3.7 mL, 5.93 mmol) was added to a solution of 4-bromofuran-2-carbonitrile (850 mg, 4.94 mmol) in anhydrous ether (15 mL) stirred at −78° C. under nitrogen. After 10 min, tri-n-butylstannyl chloride (1.61 g, 4.94 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue. Purification by flash chromatography using a gradient of ammoniated methanol in chloroform gave the sub-title compound as a yellow oil (1.0 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]([F:24])=[CH:13][C:14]([Cl:23])=[C:15]([CH:22]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(C(C)=O)C>[C:1]([NH:10][C:11]1[C:12]([F:24])=[CH:13][C:14]([Cl:23])=[C:15]([CH:22]=1)[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Solvent: CCC(C)=O
Product: CC(C)OC(=O)c1cc(NC(=O)c2ccccc2)c(F)cc1Cl
Yield: 90 %

Procedure:
A solution of benzoyl chloride (2.94 g, 0.021 mole) and 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (4.62 g, 0.020 mole) in methyl ethyl ketone (50 ml) was stirred at room temperature for 3 days. Evaporation of the solvent and crystallization of the solid residue from ethyl ether gave colorless needles, m.p. 117°-119° C. (6 g, 90% yield).