Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.I[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]([C@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH2:17]2)[N:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]([CH3:52])[C:30]2[O:34][C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39](B4OC(C)(C)C(C)(C)O4)=[CH:38][CH:37]=3)=[N:32][C:31]=2[CH:51]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:8]([C@H:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH2:17]3)[N:7]=[C:6]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33]4[O:34][C:30]5[C:29]([CH3:52])=[CH:28][C:27]([CH3:26])=[CH:51][C:31]=5[N:32]=4)=[CH:41][CH:40]=3)[C:14]=12
Reactant: COCCN1CCC[C@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COCCN1CCC[C@H](n2nc(-c3ccc(Nc4nc5cc(C)cc(C)c5o4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Yield: 85.7 %

Procedure:
A mixture of (S)-3-iodo-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.64 g, 0.0014 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.64 g, 0.00175 mol, 1.2 eq.), tetrakis(triphenylphosphine)palladium (0.081 g, 0.00007 mol) and sodium carbonate (0.37 g, 0.0035 mol) in N,N-dimethylformamide (15 mL) and water (7 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water (25 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish oil, which was purified by flash column chromatography on silica using 2%-10% methanol/dichloromethane as a mobile phase to give (S)-N2-(4-{4-amino-1-[1-(2-methoxyethyl)-3-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (0.60 g, 0.0012 mol).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][P:4](Cl)(=[O:8])[O:5]CC.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH2:16](N(CC)CC)[CH3:17]>C(OCC)C>[CH2:16]([CH:11]1[CH2:12][O:13][CH2:14][CH2:15][N:10]1[P:4]([CH2:3][CH2:2][Cl:1])(=[O:8])[OH:5])[CH3:17]
Reactant: CCOP(=O)(Cl)CCCl
Reactant: C1COCCN1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: CCC1COCCN1P(=O)(O)CCCl

Procedure:
A solution of 19.1 grams (0.1 mol) ethyl 2-chloroethylphosphonochloridate (from Example 2) in 200 ml. dry diethyl ether was cooled to 5°C. and a solution of 8.7 grams (0.1 mol) morpholine and 10.1 grams (0.1 mole) triethylamine in 100 ml. dry diethyl ether added dropwise. After stirring 1 hour at room temperature the amine hydrochloride was removed by filtration and washed with ether. The filtrate was freed of solvent by flash evaporation. The residue weighed 22.4 grams. ##EQU11##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12]C=CC1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:17]CC1.[O:21]1[CH2:25][CH2:24][CH2:23]C1>C(O)(C)(C)C.O.O=[Os](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:23][C@H:24]([OH:17])[C@H:25]([OH:21])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](O)C1

Procedure:
To a solution of N-t-butoxycarbonyl-3-pyrroline (69.3 g) and NMO (72.2 g) in tetrahydrofuran (340 mL), t-butanol (210 mL) and water (100 mL) was added OsO4 (2.5% solution in t-butanol, 4.8 mL), the mixture was heated under reflux for 2.5 hours, and then concentrated in vacuo. After dilution of the residue with brine, the mixture was extracted with ethyl acetate. The organic extracts were concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH:10](O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[N:9][N:8]=[C:4]2[CH:3]=1
Reactant: O=CO
Reactant: NNc1cc(Br)ccn1
Product: Brc1ccn2cnnc2c1
Temperature: 25 °C

Procedure:
A solution of (4-bromo-pyridin-2-yl)-hydrazine (0.50 g) in formic acid (0.50 mL) is stirred at reflux temperature overnight. After cooling to room temperature, the solution was concentrated under reduced pressure. Water was added to the residue and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C1C=C(O[C:19](OC2N=CC=CC=2)=[S:20])N=CC=1>C(Cl)Cl>[N:1]([C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)=[C:19]=[S:20]
Reactant: Cc1c(N)ccc2cc[nH]c12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of 6-amino-7-methylindole (1.0 g, 6.84 mmol) in methylene chloride (50 mL) is added di-2-pyridyl thionocarbonate (1.59 g, 6.84 mmol). The resulting solution is stirred at room temperature for two hours followed by removal of the methylene chloride by rotary evaporation. The crude material is purified via silica gel column chromatography using 10% ethyl acetate/hexane as the eluting solvent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 0.90 g of 6-isothiocyanato-7-methylindole as a white solid (70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH2:32][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: CC(C)Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1-c1ccccc1
Yield: 47.7 %

Procedure:
Compound 79 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].FC(F)(F)C(O)=O.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:40].C(N(CC)CC)C>O1CCCC1>[O:44]1[CH2:43][CH2:42][N:41]([C:39]([CH2:38][CH2:37][N:36]([C:21]([O:1][C@@H:2]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[O:22])[CH3:35])=[O:40])[CH2:46][CH2:45]1
Reactant: O=C(OCc1ccccc1)[C@@H](O)Cc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNCCC(=O)N1CCOCC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl 2(S)-hydroxy-3-phenylpropionate (513 mg) in dry tetrahydrofuran (10 ml) was added trichloromethyl chloroformate (0.244 ml). The mixture was refluxed for 18 hours. The mixture was cooled to 0° C., and a solution of 4-(N-methyl-β-alanyl)morpholine trifluoroacetic acid salt (1.44 g) and triethylamine (701 mg) in dry tetrahydrofuran (10 ml) was added thereto. The mixture was stirred at ambient temperature for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 50% hydrochloric acid, 1 M sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica-gel column chromatography (50% ethyl acetate in n-hexane as eluent) to give benzyl 2(S)-[N-(2-morpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (726 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: Cc1nc(NC(=O)c2ccc(Cl)cc2Cl)sc1C(=O)NCc1ccccc1
Yield: 21 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2,4-dichlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 21% yield; 1H NMR (CDCl3, 300 MHz) δ 7.74 (d, J=8.3 Hz, 1H), 7.45-7.24 (m, 7H), 5.99 (s, 1H), 4.57 (d, J=5.4 Hz, 2H), 2.35 (s, 3H); MS (ES+) m/z 420.0 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(N([CH2:37][CH3:38])CC)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:14][CH:13]=3)[CH:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([C:38]#[C:37][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:21][CH:20]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(C2=CC(c3ccc(Br)cc3)N(c3ccccc3)N2)cc1
Reactant: CCN(CC)CC
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C2=CC(c3ccc(C#C[Si](C)(C)C)cc3)N(c3ccccc3)N2)cc1
Temperature: 66 °C
Reaction time: 8 h

Procedure:
After charging 4.6 parts of 1-phenyl-3,5-di(4-bromophenyl)pyrazoline synthesized by a known method, 2.4 parts of trimethylsilylacetylene, 0.46 parts of tetrakis(triphenylphosphine)palladium(0), 0.038 parts of copper iodide and 20 ml of triethylamine in 40 ml of THF, the mixture was stirred at 66° C. for 8 hours and then the reaction mixture was filtered and washed with THF. The obtained filtrate was concentrated, and the precipitate was filtered, washed, recrystallized from methanol and dried at 60° C. to obtain 4.4 parts of 1-phenyl-3,5-di(4-trimethylsilylethynylphenyl)pyrazoline having a melting point of 108-110° C.
Reaction SMILES: BrCC1[CH:4]=[C:5]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:6]#[N:7].C(=O)(O)[O-].[Na+].Cl.[C:18]([O:22][C:23](=[O:32])[C@@H:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:25][CH2:26][CH3:27])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.O>[C:6]([C:5]1[CH:4]=[C:27]([CH:10]=[C:9]([F:11])[CH:8]=1)[CH2:26][NH:25][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:32])#[N:7]
Reactant: CCN[C@H](CC(C)C)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)cc(CBr)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(bromomethyl)-5-fluorobenzonitrile (4.0 g, 0.02 mol) in dry DMF (40 mL) were added sodium bicarbonate (3.9 g, 0.046 mol) and ethyl D-leucine tert-butyl ester hydrochloride (4.2 g, 0.019 mol). The reaction mixture was stirred at RT for 16 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a colorless liquid. 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (d, J=9.5 Hz, 1H), 7.63 (s, 1H), 7.53 (d, J=9.8 Hz, 1H), 3.78 (d, 1H), 3.64 (d, 1H), 2.97 (d, 1H), 2.60 (brs, 1H), 1.97-1.71 (m, 1H), 1.36 (m, 11H), 0.86 (d, 3H), 0.80 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C(Cl)Cl.CN(C=O)C>[C:12]([C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([NH:36][CH2:35][C:34]1[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=1)=[O:7])(=[O:14])[CH3:13]
Reactant: COc1ccc(C(C)=O)cc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(C)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-Methoxy-5-acetylbenzoic acid (Step B, 2.5 g, 12.8 mmol), HOBt.H20 (2.08 g, 15.4 mmol), and EDC (3.70 g, 19.3 mmol) in CH2Cl2 (20 ml) and DMF (5 ml) was added 4-(Trifluoromethyl)benzylamine (2.48 g, 14.1 mmol), and the mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then redissolved in ethyl acetate. The organic layer was washed with 3% K2CO3, 1 N HCl, and brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on silica gel column (chloroform:methanol 95:5) to provide the title compound as white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:28])[C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:14]=3[F:27])[CH:9]=2)[NH:4][N:3]=1.[CH3:29][N:30]([CH3:49])[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][N:30]([CH3:49])[CH2:31][CH2:32][O:33][C:34]1[CH:35]=[C:36]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([NH:11][C:12](=[O:28])[C:13]4[C:18]([F:19])=[CH:17][CH:16]=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[C:14]=4[F:27])[CH:9]=3)[NH:4][N:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(Br)c3c2)c1F
Reactant: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-c4cccc(OCCN(C)C)c4)c3c2)c1F
Temperature: 160 °C
Yield: 27.5 %

Procedure:
Pd(PPh3)4 (0.0075 g, 0.0065 mmol) was added to a suspension of N-(3-bromo-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.031 g, 0.065 mmol), N,N-dimethyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethanamine (0.029 g, 0.098 mmol) and K2CO3 (0.072 g, 0.52 mmol) in MeCN/H2O (4:1, 1 mL). The reaction mixture was heated to 160° C. in a microwave reactor for 30 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through GF/F paper. The filter cake was rinsed with ethyl acetate (50 mL). The filtrate was transferred to a separation funnel, and the organic layers were washed with water (3×20 mL). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with DCM/MeOH (10:1), DCM/MeOH (10:1) containing 1% triethylamine to give N-(3-(3-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.010 g, 27%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.0 (s, 1H), 8.7 (s, 1H), 7.7 (m, 1H), 7.6 (m, 2H), 7.5 (m, 1H), 7.2 (m, 1H), 7.1 (d, J=7.0 Hz, 1H), 4.3 (t, J=5.2 Hz, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 2.5 (s, 6H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-pos) M+1=559.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[C:21]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.ClCCl.[Pd]>[CH:1]1([C:7]2[CH:8]=[C:9]([CH:30]=[CH:31][N:32]=2)[C:10]([NH:12][C:13]2[S:14][C:15]3[C:21]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=[C:18]([O:28][CH3:29])[C:16]=3[N:17]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C4=CCCCC4)c3)nc12
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(C4CCCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
To a stirred solution of 585 mg (theoretically max 1.30 mmol) crude 2-cyclohex-1-enyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in 5 ml methanol and 10 ml dichloromethane was added 500 mg 10% palladium on charcoal and the mixture was then stirred for 16 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered, washing with dichloromethane, and the filtrate concentrated in vacuo. Flash chromatography (1/19 methanol/dichloromethane) followed by trituration in ether and pentane afforded 125 mg (21%) 2-cyclohexyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide as an off-white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CC[N:12](C(C)C)C(C)C>>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([NH2:12])=[O:9])[N:6]=1
Reactant: O=C(O)c1c[nH]c(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Product: NC(=O)c1c[nH]c(Cl)n1

Procedure:
Scheme 2 illustrates the synthesis of compounds 9 and 10. Lithiation of compound 6 with n-BuLi followed by the addition of carbon dioxide affords 2-chloro-imidazole-4-carboxylic acid 7. Reaction of acid 7 with amine 2 in the presence of DMC and DIEA furnishes 2-chloro-imidazole-4-carboxamide 8, which undergoes Suzuki coupling reaction with arylboronic acid to give 2-aryl-imidazole-4-carboxamide 9. Reduction of amide 9 with Alane-N,N-dimethylethylamine complex gives compound 10. Alternatively, compound 10 is prepared from hydroxymethylimidazoles 12 via SOCl2 treatment and subsequent alkylation reaction with amine 2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>ClCCl>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([C:13](=[O:15])[CH3:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 124d (672 mg, 4.0 mmol) in dichloromethane (20 mL) was added acetyl chloride (936 mg, 12.0 mmol) and K2CO3 (1104 mg, 8.0 mmol). The mixture was stirred overnight. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 124e as white solid (500 mg, 60%). MS: [M+H]+ 211.2
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([C@@H:31]([NH:33][CH2:34][C:35]([C:37]2([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38]2)=[O:36])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([N:33]([CH2:34][C:35]([C:37]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH2:39]1)=[O:36])[C@H:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:32])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)CN[C@@H](C)c2ccccc2)CC1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Diethylphosphonoacetic acid (15.1 g, 76.8 mmol) was dissolved in anhydrous tetrahydrofuran (120 ml), and after adding 1,1′-carbonyldiimidazole (13.7 g, 84.5 mmol) while cooling with ice, it was stirred at room temperature for 1 hour. After adding an anhydrous tetrahydrofuran (30 ml) solution of ethyl 1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (17.6 g, 64.0 mmol) to the reaction solution while cooling with ice, it was stirred at room temperature for 1 hour. After adding 1 mol/l hydrochloric acid (100 ml) and ethyl acetate (100 ml) to the reaction solution and performing an extraction operation, the organic layer was separated. The aqueous layer was then subjected to extraction with ethyl acetate (100 ml) and the combined organic layer was washed with saturated sodium bicarbonate water (100 ml) and saturated saline solution (100 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering and then concentrating the filtrate under a reduced pressure, 28.7 g (99%) of the title compound was obtained as a yellow syrup.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CN=C1>CN(C=O)C.ClCCl>[Si:16]([O:1][CH:2]1[CH2:5][CH:4]([C:6]([N:8]([O:10][CH3:11])[CH3:9])=[O:7])[CH2:3]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)C1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)C1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Yield: 50 %

Procedure:
Into a solution of 3-hydroxy-N-methoxy-N-methylcyclobutanecarboxamide (0.6 g, 0.004 mol in DMF (10 mL) was added tert-butylchlorodiphenylsilane (3 mL, 0.01 mol), followed by 1H-imidazole (1 g, 0.02 mol). The mixture was stirred at rt over night. The reaction was diluted with dichloromethane and washed with sat. NaHCO3, water and brine. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-30% EtOAc/Hex) to give the desired product (0.7 g, 50%) as cis- and trans-isomer mixtures. LCMS calculated for C23H32NO3Si(M+H)+: 398.2; Found: 398.1.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([S:10][C:11]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=2[CH2:13]Cl)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CS(C)=O>[C:4]1([S:10][C:11]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:12]=2[CH2:13][C:1]#[N:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccc(Sc2ccccc2)c(CCl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Temperature: 40 °C
Reaction time: 9 h

Procedure:
11.2 g of sodium cyanide in 135 ml of dimethyl sulphoxide are warmed to 40° c and treated dropwise over a period of 10 minutes with a solution of 87 g of 2-(phenylthio)-5-trifluoromethyl-benzyl chloride in 72 ml of dimethyl sulphoxide. The mixture is stirred at 40° C for 9 hours, cooled to room temperature, treated with 200 ml of water and extracted with 200 ml of ether. The aqueous phase is then extracted twice with 100 ml of ether each time. The combined organic phases are now washed twice with 200 ml of water each time, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 2-(phenylthio)-5-trifluoromethyl-phenylacetonitrile as a dark-red oil.