Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[CH3:9][NH:10][CH:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][N:14]([CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[CH2:15]2.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:27]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:14]2[CH2:15][CH:16]3[CH:11]([N:10]([CH3:9])[S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])[CH:12]([CH2:18][CH2:17]3)[CH2:13]2)=[CH:30][CH:29]=1)#[N:28]
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A solution of 1-butanesulfonyl chloride (39.1 mg, 0.25 mmol) in MeCN (2 mL) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Preparation G; 74.6 mg, 0.25 mmol) in CHCl3 (0.5 mL). K2CO3 was added and the mixture was stirred at rt for 24 h. The mixture was filtered through a silica plug (500 mg), which plug was then eluted with MeCN:CHCl3 (80:20; 3×2.5 mL), followed by CHCl3:MeOH (95:5), to give the title compound in 35% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:8]1>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH:9]([OH:7])[CH2:10][C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:17])[F:16])[CH2:2][CH2:3]1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CC1CO1
Reactant: C1COCCN1
Product: OC(CN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h
Yield: 93.2 %

Procedure:
To 8.7 g of morpholine, 27.6 g of 1,2-epoxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane was added dropwise. The mixture was then stirred at 80° C. for 10 hours. The reaction mixture was directly purified by silica gel column chromatography, obtaining 33.8 g of 1-morpholino-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol (yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C:43]1[S:44][CH:45]=[C:46]([CH2:48]O)[N:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.ClCCl>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:48][C:46]5[N:47]=[C:43]([CH3:42])[S:44][CH:45]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: Cc1nc(CO)cs1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OCc2csc(C)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 76.3 %

Procedure:
A mixture of 6-methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.100 g, 0.315 mmol) and triphenylphosphine (0.123 g, 0.47 mmol) was maintained under vacuum for 10 minutes. The mixture was flushed with nitrogen and then charged with dry THF (8 mL) and (2-methylthiazol-4-yl)methanol (Example 1A, 0.049 g, 0.38 mmol). The mixture was warmed to 50° C. and sonicated for 5 minutes. The cooled mixture was treated with a solution of DIAD (0.096 g, 0.47 mmol) in dry THF (2 mL) added in three portions dropwise over 20 minutes. The mixture was homogeneous after 40 min. and was stirred at 22° C. for 6 h. The reaction mixture was diluted with dichloromethane (250 mL), washed with sat. sodium bicarbonate, brine and dried over anhydrous MgSO4. Evaporation gave a semi-solid residue which was purified by chromatography on silica gel (2.5×10 cm, dichloromethane/EtOAc 8:2) to provide the title material (0.103 g, 76%) as white cubes. LC (Method A): 2.224 min. HRMS (ESI) calcd for C19H17N4O4S2 [M+H]+ m/z 429.0686. found 429.0605. 1H NMR (CDCl3, 600 MHz) δ 7.82 (s, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.67 (m, 1H), 6.39 (d, J=1.89 Hz, 1H), 5.25 (d, J=0.9 Hz, 2H), 4.18 (s, 3H), 3.82 (s, 3H), 2.72 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:16][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 79.7 %

Procedure:
Methyl(4S)-4-[(tert-butoxy)carbonylamino]-5-[(4-methylphenyl)sulfonyloxy]pentanoate (4.93 mmol, 1.98 g) was dissolved in DMF (15 mL) and sodium azide (14.8 mmol, 0.961 g) were added. The reaction was heated at 50° C. for 3 hours. The reaction mixture was filtered and the solvent was removed in vacuo. The crude was purified by flash chromatography (SiO2, ethyl acetate) to yield the title compound (1.07 g, 80% yield). ES-MS: 273 (M+1).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[OH:12]N1C2C=CC=CC=2N=N1.Cl.[CH:23]([N:26]1[C:30]2[C:31](=[O:40])[NH:32][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:34][C:29]=2[CH:28]=[N:27]1)([CH3:25])[CH3:24].[CH:41]([N:44]1[C:48]2C(=O)N[C:51]3([CH2:57]CN[CH2:54][CH2:53]3)[CH2:52][C:47]=2[CH:46]=[N:45]1)(C)C>CN(C)C=O.O>[CH:23]([N:26]1[C:30]2[C:31](=[O:40])[NH:32][C:33]3([CH2:39][CH2:38][N:37]([C:57]([C:51]4[CH:53]=[CH:54][C:46]5[C:47](=[CH:48][N:44]([CH3:41])[N:45]=5)[CH:52]=4)=[O:12])[CH2:36][CH2:35]3)[CH2:34][C:29]=2[CH:28]=[N:27]1)([CH3:25])[CH3:24]
Reactant: On1nnc2ccccc21
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncc2c1C(=O)NC1(CCN(C(=O)c3ccc4nn(C)cc4c3)CC1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-2H-indazole-5-carboxyllic acid (28 mg, 0.16 mmol) in dry dimethylformamide was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (37 mg, 0.19 mmol) and 1-hydroxybenzotriazole (26 mg, 0.19 mmol) N,N-diisopropylethylamine (84 μL, 0.48 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one hydrochloride was added (Intermediate 2, 30 mg, 0.12 mmol) and the reaction was stirred for 16 hours. The mixture was poured into chilled water and the resulting precipitate was collected by vacuum filtration. The obtained solid was triturated from diethyl ether to afford 1′-isopropyl-1-(2-methyl-2H-indazole-5-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one (25 mg). +ESI (M+H) 407.3; 1H NMR (400 MHz, DMSO-d6, δ): 8.41 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 5.40 (m, 1H), 4.18 (s, 3H), 3.60 (br. s., 4H), 2.85 (s, 2H), 1.70 (br. s., 4H), 1.35 (d, 6H).
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[N:6]=1)=[O:4].[NH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)[N:6]=[C:5]([C:3]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Yield: 39.8 %

Procedure:
A mixture of 1-benzyl-5-(5-fluoro-pyridin-3-yl)-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (23 mg, 0.056 mmol), glycine (417 mg, 5.6 mmol) and NaOMe solution (9 mL, 4.4 mmol) was refluxed for 16 h. After cooling to r.t., solvent was evaporated. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH about 3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 10 mg of the title compound. MS: (+) m/z 449.34 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20]I>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:20])[C:6]=2[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CI
Reactant: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Product: CN1C(=O)COc2ccc(Br)c(Oc3ccccc3)c21

Procedure:
This compound was synthesized according to the procedure of Example 83, Step 1, using 6-bromo-5-phenoxy-2H-1,4-benzoxazin-3(4H)-one and methyl iodide as the starting materials. LCMS calculated for C18H13BrNO3 (M+H)+: m/z=334.0, 336.0. found: 333.9, 335.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:18][N:17]([C@@H](C3C=CC=CC=3)C)[C:16](=O)[CH2:15]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:15][CH2:16][NH:17][CH2:18]2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)CC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C[C@H]2CCNC2)CCC1

Procedure:
10% Palladium on carbon catalyst (water content 53.8%, 650 mg) was added to ethanol (40 ml) solution of 3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]pyrrolidine (isomer B2) (645 mg, 1.80 mmol), and the mixture was subjected to 5 hours of catalytic hydrogenation at an external temperature of 50° C. in an atmosphere of hydrogen under atmospheric pressure. The reaction solution was filtered and the solvent was evaporated under a reduced pressure, thereby obtaining 458 mg (quantitative) of the title compound as colorless crystals. This product was used in the subsequent reaction without purification.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH3:16])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>>[CH3:16][O:15][C:10](=[O:14])/[CH:11]=[C:12](/[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)\[CH3:13]
Reactant: OCc1ccc(Br)cc1
Reactant: C/C=C/C(=O)OC
Product: COC(=O)/C=C(\C)c1ccc(CO)cc1

Procedure:
For the above synthesis, (E)-3-{4-[3-(4-nitrophenyl)-2H-oxo-2-pyridin-1-yl]phenyl}but-2-enoic acid methyl ester was prepared from P3 and (E)-3-(4-methanesulfonyloxymethylphenyl)but-2-enoic acid methyl ester by the method of Preparation 7, and (E)-3-(4-methanesulfonyloxymethylphenyl)but-2-enoic acid methyl ester was prepared from (E)-3-(4-hydroxymethylphenyl)but-2-enoic acid methyl ester and methanesulfonyl chloride analogously to the method of Preparation 6 (in this case mostly the mesylate was isolated rather than the chloride). (E)-3-(4-hydroxymethylphenyl)but-2-enoic acid methyl ester was prepared analogously to the method of Preparation 4 from 4-bromobenzyl alcohol and methyl crotonate.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>>[F:10][C:8]1[CH:9]=[C:2]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=Cc1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 92.8 %

Procedure:
2-bromo-4-fluorobenzaldehyde (1.53 g, 7.5 mmol) was reacted with (3,5-bis(trifluoromethyl)phenyl)boronic acid (2.3 g, 9 mmol) according to the procedure as described in Example 56, Step A to give the title compound as a white solid (2.34 g, 92%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][CH:2]([C@H:4]1[C@@H:7]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[NH:6][C:5]1=[O:14])[CH3:3].N1C=CC=CC=1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[O:23]>C(Cl)Cl>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:22]([NH:1][CH:2]([C@H:4]1[C@H:7]([CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[NH:6][C:5]1=[O:14])[CH3:3])=[O:23])([O-:34])=[O:33]
Reactant: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)OCC[C@H]1NC(=O)[C@H]1C(C)N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)NC(=O)OCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
Trans and cis-3-(1-aminoethyl)-4-(2'-acetoxyethyl)-2-azetidinone (0.6575 g, 0.00328 mole) is dissolved in 10 ml CH2Cl2, cooled to 0° C., and treated with 1.1 mole each of pyridine and o-nitrobenzyl chloroformate. The reaction mixture is stirred at 0° for 20 min, the ice bath is removed and stirring continued for another 30 min. The solution is diluted with CH2Cl2, washed with H2O, dried and evaporated in vacuo. Column chromatography ##STR207## of the residue gives 0.7790 g (0.00206 mole, 63% yield) of the product.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+]>C(O)C.ClCCl>[OH:2][CH2:1][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: O=[N+]([O-])c1cccc(-c2ncccc2CO)c1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a suspension of 3-(3-formylpyridin-2-yl)nitrobenzene (0.6 g) in ethanol (20 ml) was added sodium borohydride (40 mg), and the mixture was stirred for 5 minutes. The mixture was diluted with dichloromethane and washed with water. The separated aqueous layer was extracted with dichloromethane. The combined organic extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3-(3-hydroxymethylpyridin-2-yl)nitrobenzene (606 mg).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:32][C:33]#[N:34].C1CCCCC1>C(OCC)(=O)C>[C:33]([CH2:32][C@@:18]1([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:13]=2)[N:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])#[N:34]
Reactant: N#CCBr
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COC(=O)[C@]1(CC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared (2.71 g, 76%) using a similar procedure t as set out earlier in Description 7 using crude 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D6, 3.25 g, 7.89 mmol) and bromoacetonitrile (3.3 ml, 47.38 mmol in 40 ml THF); Rt (HPLC): 6.4 min; Rf (cyclohexane:ethyl acetate=7:3): 0.40; MS: (ES/+) m/z: 473 [M+Na+]; C26H30N2O5 requires 450; 1H NMR (500 MHz, DMSO-d6) δ(ppm): 7.46-7.24 (m, 7H); 6.94 (d, 2H); 5.11 (s, 2H); 4.94-4.78 (m, 1H); 3.78 (s, 3H); 3.33 (d, 1H); 3.22 (d, 1H); 2.66-2.52 (m, 1H); 2.42-2.29 (m, 1H); 2.29-2.16 (m, 1H); 1.92-1.77 (m, 1H); 1.38-0.97 (br. s, 9H); NOE between the aromatic protons and the methyl ester could be observed.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:15]([O:17][CH3:18])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[N+:11]([O-:24])[C:10]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncccc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)ccc[n+]1[O-]
Yield: 94.6 %

Procedure:
A solution of methyl 3-benzyloxypicolinate (4.86 g) and 3-chloroperoxybenzoic acid (5.75 g, 60% peracid) in CH2Cl2 (100 mL) was stirred at room temperature for 40 hours. The reaction mixture was then extracted with 5% sodium bisulfite solution (100 mL) then with 0.5N NaOH solution (150 mL). After drying (MgSO4), the solvent was evaporated to give 4.9 g of methyl 3-benzyloxypicolinate-1-oxide as a white solid. Recrystallization from methylcyclohexane/toluene gave a crystalline solid, m.p. 104-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH2:17]([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH3:18]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([NH:8][C:9](=[O:10])[N:19]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:17][CH3:18])([CH3:7])[CH3:6]
Reactant: CCNC1CCCCC1
Reactant: CC(C)(N=C=O)c1ccc(Cl)c(Cl)c1
Agent: [C-]#N
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)NC(C)(C)c1ccc(Cl)c(Cl)c1)C1CCCCC1
Yield: 72.8 %

Procedure:
A solution of 2.3 g of 3,4-dichloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, in 10 ml of chloroform was added to 1.5 g of N-ethylcyclohexylamine. The solvent was then removed by distillation and the resulting white crystals were recrystallized from a mixture of benzene-n-hexane to obtain 2.6 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-morpholinopyridin-3-amine (0.3282 g, 1.272 mmol) in dry DMF (10.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (0.125 g, 3.12 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.46 g, 1.57 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the black residue was treated with MeOH and placed on the rotovap. (without vac.) in a 45° C. water bath. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as N-(5-bromo-2-morpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=512.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:28])[C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=1.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:28])[C:25]([N:38]([CH3:39])[CH3:37])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-oxo-acetic acid. (100 mg, 0.20 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 531 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([CH3:8])=[CH2:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:19]2[CH:20]=[C:15]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:16]=[CH:17][C:18]=2[OH:21])([CH3:8])[CH3:7])=[CH:4][CH:3]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)c1ccc(O)c(C(C)(C)c2ccc(Cl)cc2)c1

Procedure:
4-Chloro-α-methylstyrene (50 g) and 45 g of 4-tert-butylphenol are reacted according to the procedure of Example 3 to afford the title compound in a yield of 66.6 g as a colorless oil. The structure is confirmed by 1 Hnmr and mass spectroscopy.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16](Cl)=[O:17]>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Product: CN(CCC#Cc1ccccn1)C(=O)c1c(Cl)cccc1Cl
Yield: 45.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 47 mg of 2,6-dichloro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 45%).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:6]2[N:7]=[CH:8][N:9]=[C:10](O)[C:5]=2[C:4]=1[CH3:13])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:10]1[C:5]2[C:4]([CH3:13])=[C:3]([CH2:1][CH3:2])[NH:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1[nH]c2ncnc(O)c2c1C
Product: CCc1[nH]c2ncnc(Cl)c2c1C
Yield: 66 %

Procedure:
A mixture comprising 1.18 g (6.64 mmol) 6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol (prepared according to intermediate example 1b) and 37.1 mL phosphorus oxychloride was heated at 100° C. for 1 hour. The reagent was removed and the residue purified by chromatography. The product was further purified by digestion with diethyl ether to give 855 mg (66%) of the title compound.