Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CN([CH:21]=[C:22]([C:30](=O)C)[C:23](OC(C)(C)C)=O)C.CCN(CC)CC>C(#N)C>[F:1][C:2]1[C:3]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17][C:22]([CH3:30])([CH3:23])[CH3:21])=[O:16])[CH:11]=[N:10]2)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(-n2ncc(C(=O)O)c2C)c1F
Reactant: CC(=O)C(=CN(C)C)C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccnc(-n2ncc(C(=O)OC(C)(C)C)c2C)c1F
Temperature: 85 °C

Procedure:
1-(3-Fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid: To a solution of tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.123 g, 0.575 mmol) in acetonitrile (2 mL) was added TEA (0.080 mL, 0.575 mmol) and Intermediate 43A (0.073 g, 0.517 mmol). The orange solution was heated to 85° C. for 1 h. Additional tert-butyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.160 mL) and Et3N (0.080 mL) were added into the solution and the reaction was heated at 85° C. for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography to give tert-butyl 1-(3-fluoro-4-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate as yellow oil. MS(ESI) m/z: 292.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J=4.8 Hz, 1H), 8.02 (s, 1H), 7.29 (t, J=4.8 Hz, 1H), 2.54 (s, 3H), 2.43 (d, J=1.5 Hz, 3H), 1.58 (s, 9H). To the oil was added 4 N HCl in dioxane (2 mL) and the reaction was stirred at rt for 4 h. The clear orange solution was evaporated to dryness followed by coevaporation with toluene (2×) to give the desired product (15 mg, 11%) as sticky pink solid. MS(ESI) m/z: 236.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O>>[Cl:27][C:25]1[CH:26]=[C:18]2[C:19]([C:20](=[O:22])[N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:16])([F:1])[F:15])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[C:13](=[O:14])[NH:17]2)=[CH:23][CH:24]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Yield: 32.9 %

Procedure:
1.67 g (6.67 mmol) of 4-trifluoromethylbenzenesulfonylisocyanate and 1.14 g (6.67 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 888 mg of the above-identified compound (yield 32.9%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):7.13 (1H,s), 7.23 (1H,d), 7.87 (1H,d), 8.06 (2H,d), 8.39 (2H,d), 11.78 (1H,br).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH2:12][O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH2:28])[CH:25]=3)[NH:20][CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[C:6]1([CH2:12][O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:25]=3)[NH:20][CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 1 h

Procedure:
Methanesulphonyl chloride (0.3 ml) was added in 3 portions over 3 h to a stirred, ice-cold solution of phenylmethyl[2-[5-(aminomethyl)-1H-indol-3-yl]ethyl]carbamate (0.45 g) in dry pyridine (15 ml). After a further 1 h, the mixture was partitioned between ice-cooled hydrochloric acid (1N, 300 ml) and ethyl acetate (200 ml). The organic layer was washed with brine (80 ml) and potassium carbonate solution (ca. 40%; 50 ml), dried (Na2SO4) and evaporated in vacuo to leave a yellow gum (0.45 g). Chromatography on silica gel (MFC: 18 g), eluting with increasing concentrations of ether in dichloromethane, gave the title compound (0.3 g) as an almost colourless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:4]=[CH2:5].[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>C(O)C>[C:12]([C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH2:3][CH:4]=[CH2:5])[CH2:18][CH2:17][C:19](=[O:20])[CH3:21])([O:14][CH2:15][CH3:16])=[O:13]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: C=CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: C=CCC(CCC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 22 h
Yield: 87.8 %

Procedure:
To an ethanol solution (10.4 ml) containing sodium hydride (0.049 g, 1.13 mmol, 55% in oil) were added diethyl allylmalonate (3.0 g, 15 mmol) and methyl vinyl ketone (1.39 g, 19.9 mmol). The reaction liquid was stirred at room temperature for 22 hours. After treatment and purification as in Referential Example 1, there was obtained 3.56 g of 5,5-dicarboethoxy-7-octen-2-on (yields: 88%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22]#[N:23])([CH3:21])[CH2:17][CH:18]1[CH2:20][CH2:19]1)([CH3:12])([CH3:11])[CH3:10]>O.C(O)C>[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22](=[NH:23])[NH:7][OH:8])([CH3:21])[CH2:17][CH:18]1[CH2:19][CH2:20]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C#N)(CC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(CC1CC1)C(=N)NO
Temperature: 80 °C
Yield: 65 %

Procedure:
Sodium bicarbonate (247.52 mg, 2.94 mmol) was dissolved in water (2 mL) and hydroxylamine hydrochloride (204.747 mg, 2.94 mmol) was added. A solution of (1-cyano-2-cyclopropyl-1-methyl-ethyl)-carbamic acid tert-butyl ester (600 mg, 2.69 mmol) in ethanol (10 mL) was added thereto and the resulting reaction mixture was heated at 80° C. for 12 hours. After evaporation of solvents, the residue was dissolved with ethyl acetate (20 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, 25 g, 3:7 ethyl acetate/n-hexane) to give the title compound (450 mg, 66%) as white solid; LC-MS (UV peak area, ESI) 100%, 258.4 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][CH:25]=[C:2]([NH:1][C:27](=[O:28])[NH:26][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:3]=1)#[N:22]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (120 mg, 0.342 mmol) produced in Example 3(vi) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (63 mg, 0.445 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (methanol/ethyl acetate=0/100→5/95). The obtained solution was concentrated under reduced pressure to give the title compound (173 mg, 94%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16](Cl)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1.O>CN(C=O)C>[CH3:10][O:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: COc1ccc(S)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 4-methoxy thiophenol (5 mL, 40.7 mmol) and methyl-3-nitro-4-chlorobenzoate (10.52 g, 48.8 mmol) in DMF (40 mL) was added CsCO3 (26.5 g, 81.4 mmol) and the reaction mixture heated at 80° C. for 3 hours. After cooling, the solution was poured into water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum to afford the title compound after chromatography on silica gel using ethyl acetate/hexanes as eluent (10.93 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[CH:14]1(B(O)O)[CH2:16][CH2:15]1>ClCCl>[CH:14]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7]([CH:12]=[O:13])=[CH:8]2)[CH2:16][CH2:15]1
Reactant: OB(O)C1CC1
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Solvent: ClCCl
Product: COc1ccc2c(C=O)cn(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
Dihydroxo-bis[N,N,N′,N′-tetramethylenediamine)copper (II) chloride (26 mg, 0.057 mmol) was added to a stirred room temperature mixture of 6-methoxy-1H-indole-3-carbaldehyde (100 mg, 0.568 mmol) and cyclopropylboronic acid (98 mg, 1.13 mmol) in dichloromethane (3 mL). Molecular sieves (4 A°, 100 mg) were added and the mixture was stirred under oxygen at room temperature for 48 hours. The reaction mixture was filtered over a pad of silica gel, washed with dichloromethane, partitioned between dichloromethane (10 mL) and 10% ammonium hydroxide (2×10 mL). The organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 25 M), eluting with EtOAc/hexanes to give the title compound (50 mg) as a oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:13])([F:12])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=O)[O:29]C1C=CC([N+]([O-])=O)=CC=1)[CH3:26])=[O:24].[F:40][C:41]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:42][NH2:43]>ClCCl.C(OC(=O)C)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[C@@H:3]1[NH:22][C:23]([C@@H:25]([O:27][C:28](=[O:29])[NH:43][CH2:42][C:41]([F:48])([F:40])[C:44]([F:47])([F:46])[F:45])[CH3:26])=[O:24]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Yield: 86 %

Procedure:
0.065 g (0.12 mmol) carbonic acid 4-nitro-phenyl ester (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester and 0.26 ml 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-40/0-60) yielded 0.06 g (86%) (2,2,3,3,3-Pentafluoro-propyl)-carbamic acid (S)-1-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester as white foam, MS: m/e: 554.3 (M+H+), [α] 589=−4.40° (0.75% in CHCl3).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH:14]([OH:17])([CH3:16])[CH3:15].[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35](O)=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)Cl>[O:18]=[C:19]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][C:26]([C:35]([O:17][CH:14]([CH3:16])[CH3:15])=[O:36])=[C:25]2[N:20]1[CH2:21][CH2:22][C:23]1[CH:40]=[CH:39][S:38][C:24]=12
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2
Reactant: CC(C)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2

Procedure:
7.1 ml of tri-n-butylamine and 6.1 ml of isopropanol were added to a suspension of 2.0 g of 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid and 3.8 g of N-methyl-2-chloropyridinium iodide in 12.5 ml of methylene chloride, the reaction mixture was stirred under reflux for 24 hours, evaporated in vacuo and the residue was chromatographed on silica gel with toluene/ethyl acetate (9:1). After crystallization from methanol, there was obtained pure isopropyl 4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate of m.p. 165.5°166°.
Reaction SMILES: [CH2:1](N(CC)CC)C.ClCCl.C(OC(NC(C)(C)CN(C(OC(C)(C)C)=O)CCCO)=O)C1C=CC=CC=1.[C:38]([O:42][C:43]([N:45]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:46][C@@H:47]([NH:49][S:50]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[CH:59]=[N:58][CH:57]=[CH:56]2)(=[O:52])=[O:51])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39]>O>[C:38]([O:42][C:43]([N:45]([CH2:63][CH2:64][CH2:65][OH:66])[CH2:46][C:47]([NH:49][S:50]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[CH:59]=[N:58][CH:57]=[CH:56]2)(=[O:52])=[O:51])([CH3:1])[CH3:48])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCN(CC)CC
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Agent: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NS(=O)(=O)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.7 mL of triethylamine was added to a dichloromethane (20 mL) solution of 550 mg of 2-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl-3-hydroxypropylamino)-2-methylpropane (Reference Compound 37). To this reaction solution, a dichloromethane solution (100 mL) of 6-chlorosulfonylisoquinoline (Reference Compound 2) synthesized according to Reference Example 2 was added, and the mixture was stirred at room temperature for 16 hours. After the completion of reaction, water was added, followed by extraction with dichloromethane (20 mL×3). The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by silica gel chromatography (acetone:hexane=1:1) to obtain 140 mg of the compound of interest as a brown oil (14%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1)[CH3:2].Cl.O1CCOCC1>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)Cc1cccc(CN)c1
Reaction time: 20 h

Procedure:
A solution of (3-cyano-phenyl)-acetic acid ethyl ester (6.3 g, 33.29 mmol) in EtOH (50 mL) was added to a mixture of 10% Pd/C (1.26 g) in EtOH (50 mL) under Nitrogen. Additional EtOH (150 mL) was added followed by a solution of HCl in dioxane (4 M, 11.4 mL, 45.6 mmol). The mixture was hydrogenated on a Parr shaker at 45 psi for 20 h and the catalyst was removed by filtration through celite. The solution was concentrated to afford (3-aminomethyl-phenyl)-acetic acid ethyl ester as the hydrochloride salt (7.31 g). 1H NMR (400 MHz, CD3OD) δ 7.42–7.32 (m, 4H), 4.12 (q, 2H), 4.09 (s, 2H), 3.68 (s, 2H), 1.23 (t, 3H).
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[C:12]([OH:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:20])([CH3:19])[C:9]1=[O:21])C1C=CC=CC=1.[H][H].Cl>C(O)(=O)C.[C].[Pd].C(OCC)(=O)C>[OH:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[C:10]([CH3:20])([CH3:19])[C:9](=[O:21])[NH:8]2
Reactant: [H][H]
Reactant: Cc1ccc(O)c2c1N(Cc1ccccc1)C(=O)C2(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(O)c2c1NC(=O)C2(C)C
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
41.0 g (146 mmol) of 1-benzyl-2,3-dihydro-4-hydroxy-3,3,7-trimethyl-1H-indol-2-one was dissolved in 11 of acetic acid. After the addition of 82 g of a 10% palladium-carbon catalyst, the reaction atmosphere was replaced with hydrogen and 40 ml (160 mmol) of 4N hydrogen chloride solution in ethyl acetate was added, following which the mixture was stirred for 2.5 hours over a water bath at 80° C. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 4:1 mixture of chloroform and methanol) and recrystallized (ether) to obtain 27.58 g (yield, 98.9%) of colorless prisms of the title compound.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][N:14]([CH3:23])[CH3:13])[CH2:18][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCN1CCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(CCN(C)C)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and 1-[2-(dimethylamino)ethyl]piperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:18]O.O>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N+:14]([O-:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCCCc2cccnc2)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: [O-][n+]1cccc(CCCOCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
3-(3-Benzyloxypropyl)pyridine (34.28 g) was dissolved in acetic acid (260 ml), followed by the addition of a 30% aqueous solution of hydrogen peroxide (52 ml), and the mixture was stirred at 50° C. overnight. After cooling as it was, water (52 ml) was added to the reaction solution, which was then evaporated. The resulting residue was dissolved in chloroform, washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the title compound as a yellow oil (30.23 g, yield; 88%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].[F:13][C:14]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:15]=1[C:16](Cl)=[O:17]>O1CCCC1>[C:3]([CH:5]([C:16](=[O:17])[C:15]1[CH:19]=[C:20]([F:25])[C:21]([F:24])=[C:22]([F:23])[C:14]=1[F:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (12.8 g) was added to tetrahydrofuran (400 ml) and the mixture cooled with stirring using an ice bath. tert-Butyl cyanoacetate (22.8 g) was added dropwise over a 20 minute period with continued ice bath cooling such that the temperature remained below 10° C. 2,3,4,5-Tetrafluorobenzoyl chloride (34 g) was then added dropwise over a one hour period while maintaining the temperature between -5° C. and 0° C. using an ice-acetone bath. The cooling bath was removed and stirring continued for another 30 minutes while the mixture was warmed to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (1.5 liter) and toluene (100 ml) were added with stirring. The layers were separated and the aqueous layer extracted again with toluene (100 ml). The aqueous layer was acidified to pH 1 using 36% hydrochloric acid. The crystals were collected and washed with excess water and dried under vacuum at room temperature to give tert-butyl 2-cyano-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (47 g, 93%), mp 90°-92° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3([OH:34])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[C:35]1([C@@H:41]2[CH2:43][C@H:42]2[C:44](Cl)=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3([OH:34])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:44]([C@@H:42]4[CH2:43][C@H:41]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:45])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
To a mixture of tert-butyl 4-{[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00017 mol) in pyridine (4 mL) was added trans-2-phenyl-cyclopropane carbonyl chloride (0.035g, 0.00019 mol) at −5° C. The mixture was stirred at −5° C. for 10 minutes then warmed up to room temperature to stir for 1 hours. The mixture was quenched with an aqueous 1N solution of sodium hydroxide. Pyridine was removed under reduced pressure. The residue was partitioned between water and dichloromethane (50 mL). The organic layer was washed with water. The solvents were removed under reduced and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield trans tert-butyl 4-{[4-amino-3-(3-methoxy-4-{[(2-phenylcyclopropyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00013 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.7 min. MS: MH+ 614.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1.[CH2:29]([OH:32])[CH2:30][OH:31].[OH-].[K+].O>ClCCl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:31][CH2:30][CH2:29][O:32][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1
Reactant: OCCO
Reactant: Fc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: OCCOc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Temperature: 120 °C
Yield: 91.6 %

Procedure:
A round bottom flask was charged with 0.2 g (0.438 mmol) of 9-(4-fluoro-phenyl)-thianthrenium hexafluorophosphate, and 5.0 g of ethylene glycol. The mixture was heated up to 120° C. and stirred until complete dissolution. 50 mg of potassium hydroxide were added to this solution; the solution was stirred for 1 hour and then poured into water. Dichloromethane was added and the organic layer separated, washed with water and dried (Na2SO4). After drying the solvent was removed under vacuum to give a white solid (0.2 g, 92%).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][NH:14][NH2:15]>C1(C)C=CC=CC=1>[CH2:10]([C:9]1[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:14]([CH3:13])[N:15]=1)[CH3:11]
Reactant: CNN
Reactant: CCOC(=O)C(=O)CC(=O)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(CC)nn1C
Temperature: -20 °C

Procedure:
To a solution of compound 2 (3.8 g, 22 mmol) in toluene (20 mL) was added methylhydrazine (1.8 g, 0.039 mol) cooled to −20° C. After completion of the reaction, the reaction liquid was washed with water and the solvent was removed by evaporation to obtain crude product, the crude product was purified by silica gel column chromatography (PE:EA=5:1) to give the desired product as a white oil.