Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24](=[O:35])[NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[CH2:26][NH:25][C:24]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[N:12]([CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[C:11]=1[CH:21]([CH3:23])[CH3:22])=[O:35]
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ncco1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 47, 197 mg, 0.414 mmol) in EtOH (12 ml) was added NaOH (82 mg, 2.07 mmol) and H2O (1 ml). The reaction was stirred at 25° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7](O)[CH:6]=[CH:5][C:4]1=[O:9])[CH3:2].[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:4](=[O:9])[CH2:5][CH:6]([NH:13][CH2:10][CH:11]=[CH2:12])[CH:7]=1)[CH3:2]
Reactant: CCC1C(=O)C=CC1O
Reactant: C=CCN
Solvent: Cc1ccccc1
Product: C=CCNC1C=C(CC)C(=O)C1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
2-Ethyl-3-hydroxy-4-cyclopentenone (12.6 g) was dropwise added to a mixture of allylamine (25 g) and toluene (25 g) in the same flask as used in Example 1 at a temperature of 10° to 20° C. for 1 hour. The reaction mixture was kept at a temperature of 20° to 30° C. for 3 hours. After completion of the reaction, the mixture was treated and purified in the same manner as in Example 1 to obtain 2-ethyl-4-allylamino-2-cyclopentenone (15.7 g). Yield, 95%. nD20 1.4924.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[CH2:8][CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:2]
Reactant: CCCO
Reactant: N#CCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCOC(=O)CC#N
Temperature: 105 °C

Procedure:
Cyanoacetic acid (85.5 g; 1.0 mol), 1-propanol (120 g; 2.0 mol) and p-toluenesulfonic acid monohydrate (1.00 g; 0.005 mol) were introduced into a 500 ml flask. The mixture was slowly heated to a maximum of 105° C. while collecting distillates at 88-90° C. The pressure was reduced so that the flask was maintained at 105-110° C. and the distillates were collected continuously, and the propanol was returned to the flask. After distilling off the unreacted propanol, the n-propyl cyanoacetate (bp 100° C./23 mm Hg) was collected as a clear liquid. The yield was 122 g (96% of theoretical) and its purity was >99% (GC assay).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N+:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.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>[CH3:18][C:17]([C:15]1[CH:14]=[CH:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:28]([O-:30])=[O:29])[CH:36]=4)[N:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1)([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:27]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
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: C1CCOC1
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4cccc([N+](=O)[O-])c4)n3)cnc2n1
Temperature: 25 °C

Procedure:
A mixture of 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (prepared according to Example 34) (250 mg, 0.62 mmol), 3-nitrobenzeneboronic acid (207 mg, 1.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (71 mg, 10 mol %) in THF (3 ml) and 2N Na2CO3 solution (1.24 ml, 2.48 mnmol) was heated at reflux for 2.5 h. The mixture was cooled to room temperature, diluted with CH2Cl2 (30 ml), separated and concentrated to approximately 2 ml under reduced pressure. Purification by column chromatography on silica using 3% MeOH/CH2Cl2 afforded 7-(1-methyl-1-triethylsilanyloxyethyl)-3-[2-(3-nitrophenyl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine: m/z (ES+) 491 (M+H+).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>ClCCl>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:14](=[O:16])[CH3:15])[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
Tert-Butyl piperazine-1-carboxylate (4.00 g, 21.4 mmol) is dissolved in dichloromethane (40 mL), cooled to 0° C. and treated with acetic anhydride (2.23 mL, 23.6 mmol) over a period of 2 min. The reaction mixture is stirred at 0° C. for 30 min, LCMS analysis used to indicate completion of the reaction and the volatiles evacuated in vacuo. The residue is treated carefully with NaHCO3 (sat. aq., 50 mL), stirred vigorously for 30 min and the resulting mixture extracted with diethyl ether (4×20 mL). The combined organic extracts are dried (MgSO4), filtered and concentrated in vacuo to afford tert-Butyl-4-acetylpiperazine-1-carboxylate as a white solid (4.53 g, 93%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.39 (s, 9H), 1.99 (s, 3H), 3.22-3.29 (m, 2H), 3.30-3.34 (m, 2H), 3.36-3.41 (m, 4H); ESI-MS: m/z 229.3 (M+H)+.
Reaction SMILES: B(Cl)(Cl)Cl.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].Cl>ClCCl.C1C=CC=CC=1>[OH:25][C:19]1[CH:18]=[C:17]([O:16][CH3:15])[C:22]([O:23][CH3:24])=[CH:21][C:20]=1[C:10]([C:9]1[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=1)=[O:11]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(O)cc1OC
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cc(O)c(C(=O)c2ccc(F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1.0M solution of boron trichloride(142 ml) in dichioromethane was added to 4-fluorobenzoyl chloride(16.8 ml) in benzene (200 ml). Next, 3,4-dimethoxyphenol(20.0 g) in benzene (100 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then poured onto ice water and allowed to stir for 15 minutes, then 1N HCl (500 ml) was added and stirred at room temperature for 17 hours. The reaction mixture was extracted with EtOAc, the EtOAc was separated, concentrated and dried to give the title product(41.7 g) as an orange solid. 1H NMR consistent with desired structures.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:3]=[CH:2]1.[H-].[Na+].I[CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][N:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:3]=[CH:2]1
Reactant: CC(C)(C)CCI
Reactant: CCOC(=O)Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(CCC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
Ethyl 1H-imidazol-4-ylacetate (3.74 g) obtained in Step 1 was dissolved in N,N-dimethylformamide (30 mL). To this solution, sodium hydride (63%, 1.02 g) and 1-iodo-3,3-dimethylbutane (5.66 g) were added under ice cooling. The mixture was stirred overnight at room temperature and then separated into aqueous and organic layers by the addition of ethyl acetate and a saturated aqueous solution of ammonium chloride. The obtained aqueous solution was washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluting solvent: methylene chloride/methanol=95/5) to obtain the title compound (2.32 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:12][C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[N:10]=[CH:11][C:3]=12>CO.[Pd]>[C:18]1([N:17]2[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=[C:13]2[CH2:12][N:9]2[C:4]3=[N:5][C:6]([NH2:8])=[N:7][CH:2]=[C:3]3[CH:11]=[N:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc(Cl)c2cnn(Cc3nc4ccccc4n3-c3ccccc3)c2n1
Agent: [Pd]
Solvent: CO
Product: Nc1ncc2cnn(Cc3nc4ccccc4n3-c3ccccc3)c2n1
Yield: 14.6 %

Procedure:
A solution of 4-chloro-1-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-1H-Pyrazolo[3,4-d]pyrimidin-6-ylamine (1.5 g, 4 mmol) and Pd/C (0.3 g) in MeOH was stirred with H2 40 psi at 50° C. overnight. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by P-TLC to give 157 (200 mg, yield 15%) as white solid. LCMS (ESI), M+H+=340.14. 1HNMR (400 MHz, DMSO) δ 5.0374 (s, 2H), 5.597 (s, 2H), 7.015 (s, 1H), 7.152-7.211 (m, 5H), 7.309-7.327 (m, 3H), 7.746 (s, 2H), 8.567 (s, 1H)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CCOC(=O)CC(NC(=O)OCc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CC(NC(=O)OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(1-(benzyloxycarbonylamino)-3-ethoxy-3-oxopropyl)piperidine-1-carboxylate (660 mg, 1.52 mmol) in CH2Cl2 (5 mL), TFA (5 mL) was added. The mixture was stirred at room temperature for 3 h. It was concentrated in vacuo. The residue was purified by HPLC to give ethyl 3-(benzyloxycarbonylamino)-3-(piperidin-4-yl)propanoate as TFA salt. The salt was dissolved in EtOAc (50 mL), which was washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 3-(benzyloxycarbonylamino)-3-(piperidin-4-yl)propanoate as free base (102 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1c(Cl)cncc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)cncc1Cl
Temperature: 25 °C
Yield: 63.1 %

Procedure:
The product from Example 1A (2.1 g, 11 mmol) in POCl3 (25 mL) was stirred at reflux overnight, allowed to cool to room temperature, poured onto ice, and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to give 1.2 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 8.96 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[C:13]([NH2:14])=[N:12][N:11]([CH3:15])[C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[C:16]([NH:14][C:13]1[C:9]2[S:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:10]=2[N:11]([CH3:15])[N:12]=1)=[O:20]
Reactant: CC(C)C(=O)Cl
Reactant: Cn1nc(N)c2sc3c(Cl)cccc3c21
Product: CC(C)C(=O)Nc1nn(C)c2c1sc1c(Cl)cccc12

Procedure:
By substituting this amide for the amide employed in Example 1, the corresponding 3,7-dichlorobenzo[b]thiophene-2-carbonitrile, m.p. 124°-128° C., was obtained. Treatment of this nitrile was methylhydrazine in dimethyl sulfoxide gave 5-chloro-1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-amine, m.p. 239°-241° C. Reaction of this amine with isobutyryl chloride followed by work up as described in Example 1 gave 2-methyl-N-(5-chloro-1-methyl-1H-(1)benzothieno[3,2-c]pyrazol-3-yl)-propanamide, m.p. 218°-219° C.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([C:20](O)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:23]([C:20]([C:16]1[C:13]2[N:14]([CH3:15])[C:10]([CH2:9][C:2]3[C:1]([CH3:26])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=3[CH3:8])=[N:11][C:12]=2[CH:19]=[CH:18][CH:17]=1)=[CH:21][CH3:22])[CH3:24]
Reactant: CCC(O)(CC)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: CC=C(CC)c1cccc2nc(Cc3c(C)cc(C)cc3C)n(C)c12

Procedure:
A solution of 3-[2-(mesitylmethyl)-1-methyl-1H-benzimidazol-7-yl]pentan-3-ol (200 mg, 0.571 mmol) and p-toluenesulfonic acid monohydrate (326 mg, 1.71 mmol) in xylene (10 mL) was refluxed for 3 hr. After cooling, the mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10-20% ethyl acetate/n-hexane gradient mixture to give the title compound (180 mg, 0.542 mmol, 95%, as a mixture of geometric isomers) as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:31]([OH:33])=O)[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:34][NH:35]C(C1CCNCC1)=O>>[OH:34][NH:35][C:31]([C:15]1([S:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][CH2:16]1)=[O:33]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1
Reactant: O=C(NO)C1CCNCC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
Starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid (700 mg, 1.4 mmol) and following the procedure as outlined in example 83, 300 mg of 4-(4-n-butoxy-benzenesulfonyl)-1-3-phenoxy-propyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as an off white solid. Yield 43%; mp 84° C.; MS: 491.5 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ0.9 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 2.18 (m, 2H), 2,3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.2 (m, 2H), 3.40 (m 6H), 3.97 (t, 2H), 6.9-7.7 (m, 9H), 10.7 (bs, 1H), 11.28 (bs, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25]OS(C)(=O)=O)[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1)[CH3:16]
Reactant: CCOc1ccccc1CCOS(C)(=O)=O
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1CCn1cnc(-c2cc(C(N)=O)ccn2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (200 mg, 1.06 mmol, PREPARATION 7), methanesulfonic acid 2-(2-ethoxy-phenyl)-ethyl ester (311 mg, 1.28 mmol) and K2CO3 (294 mg, 2.13 mmol) in DMF (10 mL) was stirred overnight at 70° C., LC/MS showed the reaction was completed, purified by FCC (DCM/MeOH=20/1) to give the title compound (189 mg, 53%) as a yellow solid. [M+H] Calc'd for C19H20N4O2, 337. Found, 337.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[CH2:12]([O:19][C:20]1[CH:45]=[CH:44][CH:43]=[CH:42][C:21]=1[CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N12CCCN=C1CCCCC2.CCCCCC>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:19][C:20]1[CH:45]=[CH:44][CH:43]=[CH:42][C:21]=1[CH:22]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=CC=Cc1ccccc1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C(C=Cc1ccccc1OCc1ccccc1)=Cc1ccccc1
Yield: 97.7 %

Procedure:
5.28 g of cinnamaldehyde and 19.8 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) were dissolved, with heating, in 200 ml of acetonitrile, and then 6 g of 1,8-diazabicyclo[5,4,0]undec-7-ene were added dropwise to the solution. The resulting mixture was then heated under reflux for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was again dissolved in 200 ml of ethyl acetate, with heating, and 50 ml of hexane was added to the solution, after which deposited insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 12.2 g (yield 97.7%) of 1-(2-benzyloxyphenyl)-4-phenylbutadiene as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (53.4 g) in dichloromethane (500 ml) were added triethylamine (36 ml) and methanesulfonyl chloride (19.8 ml) under ice bath cooling and the mixture was stirred at the same temperature for 3 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (56.2 g) as colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.I[C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=1.O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[C:33]#[N:34])=[CH:28][CH:27]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccc(I)cc1
Reactant: OB(O)c1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)c1ccc(-c2ccc(N(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc2)cc1
Temperature: 75 °C

Procedure:
A 2 L flat bottomed flask fitted with an argon inlet and condenser was charged with (4-(bis(4-chlorophenyl)amino)phenyl)boronic acid (39.3 g), 2-(4-iodophenyl)-2-methylpropanenitrile, compound from Example 5 (c) (27.1 g) and tetrahydrofuran (591 mL). Sodium carbonate (33.9 g) was dissolved in water (393 mL) and this was added to the tetrahydrofuran mixture. The reaction mixture was then heated to 75° C. for 16 hours. Ethyl acetate (200 mL) and water (200 mL) were added and the mixture filtered through a celite pad. The layers were split, the organic layers washed with brine (600 mL), dried over MgSO4 and concentrated. The resulting material was purified by flash column chromatography eluting with ethyl acetate/heptane mixtures. The fractions were concentrated to a thick slurry and the solid filtered off, washed with heptane and dried under vacuum to give an off-white solid. Yield: 27 g. 1H NMR (400 MHz, CDCl3): δ 7.56-7.42 (6H, m, Ar—H), 7.21 (4H, m, Ar—H), 7.15-7.02 (6H, m, Ar—H), 1.77 (6H, s, CH3).
Reaction SMILES: [O:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>>[C:13]12([C:23]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9][N:10]([C:23]([C:13]45[CH2:22][CH:17]6[CH2:16][CH:15]([CH2:21][CH:19]([CH2:18]6)[CH2:20]4)[CH2:14]5)=[O:24])[CH2:11][CH2:12][O:1][CH2:2][CH2:3]3)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: C1COCCNCCOCCN1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Product: O=C(N1CCOCCN(C(=O)C23CC4CC(CC(C4)C2)C3)CCOCC1)C12CC3CC(CC(C3)C1)C2

Procedure:
Analogously to Example 2 from 1,7-dioxa-4,10-diazacyclododecane and 1-adamantylcarbonyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[N:23]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O=[Pt]=O.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]2[C:30]3[CH2:29][CH2:28][CH2:27][NH:26][C:25]=3[N:24]=[N:23]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3c2CCCN3)cc1
Reaction time: 8 h

Procedure:
A 250 mL pressure vessel was charged with 4-tert-butyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridine-1-yl-phenyl)-benzenesulfonamide (synthesized according to general procedure G, 100 mg, 0.23 mmol), PtO2 (50 mg, 0.22 mmol), and MeOH (20 mL). The pressure vessel was placed under 60 p.s.i. of H2 and agitated for 8 hours. The reaction mixture was subsequently filtered through celite, concentrated in vacuo, and purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 446.1, found 446.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[N:24]=[CH:23][CH:22]=[CH:21][C:18]=2[CH:19]=O)=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([CH2:19][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:21][CH:22]=[CH:23][N:24]=2)=[CH:25][CH:26]=1
Reactant: C1COCCN1
Reactant: Cn1c(Nc2ccc(Oc3ncccc3C=O)cc2)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(Nc2ccc(Oc3ncccc3CN3CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-(4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenoxy)nicotinaldehyde (0.2 g, 0.6 mmol) in DCM (2 mL) was added morpholine (0.05 mL, 0.6 mmol). Sodium triacetoxyborohydride (0.1 g, 0.6 mmol) was added and the resulting mixture was stirred for 3 h at RT. LC/MS showed complete conversion. The reaction mixture was purified by silica gel chromatography (0-10% MeOH/DCM) to afford product 1-methyl-N-(4-(3-(morpholinomethyl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine as solid. MS (ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.