Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:21])[C:10]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:22](OC(OCC)(OCC)C)[CH3:23].C(O)(=O)C>CO>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]([CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[C:22]([CH3:23])=[N:21][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1cc(Cn2ccnc2)ccc1NCc1cccnc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc2cc(Cn3ccnc3)ccc2n1Cc1cccnc1
Reaction time: 2 h
Yield: 41 %

Procedure:
A mixture of 5.6 parts of 4-(1H-imidazol-1-ylmethyl)-N1 -(3-pyridinylmethyl)-1,2-benzenediamine, 20 parts of triethoxyethane, 2 parts of acetic acid and 200 parts of methanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated. Methanol and methanol, saturated with ammonia, were added. The mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, methanol and methanol, saturated with ammonia, (88:10:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 40 parts of 4-methyl-2-pentanone. The product was filtered off and dried, yielding 2.5 parts (41%) of 5-(1H-imidazol-1-yl-methyl)-2-methyl-1-(3-pyridinylmethyl)-1H-benzimidazole; mp. 174.0° C. (compound 116).
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:6]([N:25]([C:30]3[CH:35]=[C:34]([CH2:36]OCOC)[C:33]([B:41]4[O:45]C(C)(C)C(C)(C)[O:42]4)=[C:32]([F:50])[CH:31]=3)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20]([NH:22][CH3:23])=[O:21])[C:9]=3[CH:24]=2)[CH2:4][CH2:3]1>C1COCC1.CO.C(Cl)Cl>[CH:2]1([C:5]2[C:6]([N:25]([C:30]3[CH:31]=[C:32]([F:50])[C:33]4[B:41]([OH:42])[O:45][CH2:36][C:34]=4[CH:35]=3)[S:26]([CH3:29])(=[O:27])=[O:28])=[CH:7][C:8]3[O:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[C:10]([C:20]([NH:22][CH3:23])=[O:21])[C:9]=3[CH:24]=2)[CH2:4][CH2:3]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(B4OC(C)(C)C(C)(C)O4)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c4c(c3)COB4O)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 7 %

Procedure:
Aqueous hydrochloric acid (4 mL, 1 N) was added to a solution of 5-cyclopropyl-6-(N-(3-fluoro-5-((methoxymethoxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (306 mg) in THF (4.0 mL) and MeOH (0.8 mL). The mixture was heated to 70° C. under N2 overnight. The mixture was cooled to room temperature and the organic solvent was removed under reduced pressure. The crude was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. MeOH (6 mL) was then added to the crude and stirred for 15 min. A white solid was formed which was filtered to give 170 mg crude product (90% purity). 50 mg crude product was purified by silica gel chromatography (0-100% EtOAc in DCM, then 0-10% MeOH in DCM) to give 5-cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (17 mg, 6.24% yield). Another 120 mg crude product was washed with MeOH and dried to give 5-cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (106 mg, 36.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50 (br. s., 1H), 0.81 (br. s., 2H), 0.97 (br. s., 1H), 2.06 (br. s., 1H), 2.84 (d, J=4.3 Hz, 3H), 3.48 (s, 3H), 4.95 (s, 2H), 7.02 (d, J=9.9 Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.41 (t, J=8.8 Hz, 2H), 7.97 (dd, J=8.5, 5.6 Hz, 2H), 8.04 (s, 1H), 8.49 (d, J=4.5 Hz, 1H), 9.28 (s, 1H). LCMS (m/z, ES+)=553 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]3SC)=[O:7])=[CH:4][CH:3]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:16]=2[NH:15][C:14](=[O:17])[CH2:13]3)=[O:7])=[CH:20][CH:21]=1
Reactant: CSC1C(=O)Nc2c(C(=O)c3ccc(Cl)cc3)cccc21
Solvent: C1CCOC1
Product: O=C1Cc2cccc(C(=O)c3ccc(Cl)cc3)c2N1
Yield: 93 %

Procedure:
A stirred solution of 9 g. (0.028 mole) of 7-(4-chlorobenzoyl)-3-methylthioindolin-2-one in 180 ml. of tetrahydrofuran was treated over a two-hour period with 45 g. of a commercial Raney nickel water suspension. After the addition was complete the mixture was filtered. A drop of concentrated hydrochloric acid was added to the filtrate which removed some color and the resulting solution was then stripped under water pump vacuum to yield a cream color material. Recrystallization from toluene gave pink needles, (93% yield); the material sintered at 177°C. and melted at 186°C.
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C(N(CC)C1C=CC=CC=1)C.[C:46]([CH2:48][CH2:49][C:50](Cl)=[S:51])#[N:47]>O1CCCC1>[C:46]([CH2:48][CH2:49][C:50]([NH:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:6]([CH:9]=[CH:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[S:51])#[N:47]
Reactant: N#CCCC(=S)Cl
Reactant: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=S)CCC#N)[C@H]2SC1

Procedure:
To 244 mg of benzhydryl 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate in 20 ml of anhydrous tetrahydrofuran were added dropwise at -7° C. with stirring 115 mg of N,N-diethylaniline and, subsequently, 115 mg of cyanomethylthioacetyl chloride in 5 ml of anhydrous tetrahydrofuran. After completion of the reaction, the reaction mixture was then treated in the same manner as in Example 1--(a) to give a crude product. The crude product was purified by developing it with ethyl acetate by the use of silica gel thin layer chromatography (20×20×0.2 cm) to yield 50 mg of benzhydryl 7-cyanomethylthioacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24]#[N:25].[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].O>CN(C)C=O>[C:26]([O:29][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[C:24]#[N:25])(=[O:28])[CH3:27]
Reactant: N#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(C#N)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-cyanoquinoline (238 mg) and sodium acetate (94 mg) in dimethylformamide (1 ml) was stirred at ambient temperature overnight. To the residue was added water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane-dichloromethane) to give 4-acetoxymethyl-3-cyano-8-(2,6-dichlorobenzoylamino)quinoline (54 mg).
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([NH:41][C:20](=[O:22])[C@H:16]([CH:17]([CH3:18])[CH3:19])[NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH3:40])=[CH:35][CH:34]=1
Reactant: COc1ccc(C(C)N)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C(C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 217.1 %

Procedure:
2.3 g (0.023 mol) of N-methylpiperidine are added to 5.0 g of t-butoxycarbonyl-L-valine (0.023 mol), dissolved in 50 ml of CH2Cl2, at -20° C. 3.2 g (0.023 mol) of isobutyl chloroformate are then rapidly added dropwise at -20° C., the mixture is subsequently stirred at the same temperature for 10 minutes and cooled to -60° C. and 3.5 g (0.023 mol) of 4-methoxy-1-phenylethylamine are allowed to run in, the temperature being kept below -15° C. After 2 hours at -15° C., the mixture is subsequently stirred at room temperature for 15 hours, the solid is filtered off and rinsed with CH2Cl2, the filtrate is concentrated, the residue is introduced into water, the mixture is extracted twice with ethyl acetate and the combined ethyl acetate phases are washed with NaHCO3 solution and water, dried and concentrated. 17.5 g (85% of theory) of N-(t-butoxycarbonyl)-L-valine 4-methoxy-1-phenylethylamide of melting point 126°-127° C. are obtained.
Reaction SMILES: [O:1](C(OC(C)(C)C)=O)[C:2]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=O.[F:16][C:17]([F:33])([F:32])[C:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][CH:25]=1)([OH:23])[C:19]([F:22])([F:21])[F:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:2](=[O:1])([O:23][C:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[CH2:31])=[CH:26][CH:25]=1)([C:19]([F:21])([F:20])[F:22])[C:17]([F:32])([F:33])[F:16])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(OC(=O)OC(C)(C)C)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The title compound was prepared by a modification of the procedure of Przybilla, described in German Patent No. DE42072261A1 (Sep. 9, 1993), herein incorporated by reference. 9.35 mL of (t-BOC)2O (40.70 mmol) in THF (10 mL) was added to a mixture of 1,1,1,3,3,3-Hexafluoro-2-(4-vinylphenyl)-2-propanol (10.00 g, 37.01 mmol) and K2CO3 (10.00 g, 72.35 mmol) in THF (90 mL) was added. The reaction mixture was allowed to stir at room temperature for 4 days, concentrated, then partitioned between hexane/H2O. The aqueous solution was extracted with hexane, and the combined extracts were washed with brine, dried (Na2SO4), and concentrated to provide 15.17 g of a pale yellow oil. This material was purified by column chromatography on silica gel using 50:1 hexane/ethyl acetate to provide 5.16 g (38%) of a white solid, plus 4.68 g of a 90:10 mixture of protected/unprotected material; 1H NMR (CDCl3) δ 7.49 (d, 2ArH), 7.42 (d, 2ArH), 6.74 (dd, CH═), 5.83 (dd, ═CHH), 5.36 (dd, ═CHH), 1.49 (s, t-Bu).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[CH2:11]([O:13][C:14](=[O:27])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:27])[CH:15]([O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:12]
Reactant: CCCCCCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(Oc1ccc2c(c1)OCO2)C(=O)OCC
Yield: 79.9 %

Procedure:
Sesamol (42.7 grams) was dissolved in 300 ml of DMF, 100 grams of 2-bromolauric acid ethyl ester was added and the mixture was stirred. Potassium carbonate (50 grams) was added and the mixture was reacted at 80° C. for 10 hours. The end of the reaction was verified using TLC, after which 1 liter of water and 500 ml of ethyl acetate were added and the mixture was extracted. The organic layer was washed twice with water and then dried over magnesium sulfate and, on removing the solvent by distillation, 90 grams of 2-(3,4-methylenedioxy-phenoxy)lauric acid ethyl ester was obtained as an oily material for a yield of 79.9%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([C:34]3[CH:35]=[N:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)[N:24]=2)=[O:22])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:41][O:40][C:37]1[N:36]=[CH:35][C:34]([N:25]2[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:23]([C:21]([N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[O:22])=[N:24]2)=[CH:39][CH:38]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)N3CCNCC3)cc2-c2ccccc2)cn1
Reaction time: 0.7 h

Procedure:
At room temperature, trifluoroacetic acid (2.4 mL) was added to a solution of the above-mentioned 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]piperazine-4-carboxylic acid tert-butyl ester (0.639 g) in methylene chloride (15 mL), followed by stirring of the mixture for 0.7 hours. The reaction solvent was removed under reduced pressure, and the residue was partitioned between chloroform and saturated aqueous sodium hydrogencarbonate. The aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. After filtration, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (0.446 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3)C2=O)cn1
Yield: 40 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and benzyl bromide. Yield: 40%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.42 (s, 3H), 3.84 (s, 2H), 4.61 (s, 2 H), 5.06 (s, 2H), 7.40-7.27 (m, 5H), 7.92 (s, 1 H), 8.08 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.09 μM.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:24][CH:25]([Si:27](Cl)([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH3:26].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:7]=3[N:8]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:26])[CH3:24])[C:9]=2[CH:10]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Br)ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 60.7 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (300 mg, 0.85 mmol) was dissolved in DMF (3 mL), and NaH (60% weight dispersion in mineral oil, 40 mg, 1.02 mmol) and TIPSCl (164 mg, 1.02 mmol) were added. After stirring for 1 h, the mixture was poured into water and extracted with EtOAc. Concentration of the organic extracts and purification of the residue by flash column chromatography (silica gel, EtOAc/hexanes) provided the title compound (262 mg, 61%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.4 Hz, 1H), 4.59 (s, 2H), 3.76-3.71 (br m, 2H), 2.96-2.90 (br m, 2H), 1.81-1.71 (m, 3H), 1.51 (s, 9H), 1.15 (d, J=7.5 Hz, 18H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1.[OH:12]OS([O-])=O.[K+].[OH2:18]>CN(C=O)C>[CH3:1][S:2]([C:3]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)(=[O:12])=[O:18]
Reactant: O=S([O-])OO
Reactant: CSc1n[nH]c2cnccc12
Reactant: O
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1n[nH]c2cnccc12
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3-(methylthio)-1H-pyrazolo[3,4-c]pyridine (10 g, 60.6 mmol) in DMF (100 mL) was added oxone (37 g, 121.2 mmol.) in portions. The reaction mixture was stirred at RT. After the reaction completed, water (100 mL) was added. The reaction was quenched carefully by addition of Na2SO3 and Na2CO3. The solid was filtered off and washed with MeOH (300 mL). The filtrate was concentrated under vacuum and the residue was purified by chromatography on silica gel column (DCM/MeOH=20/1) to give 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (10.7 g, yield: 90%) as a yellow solid. MS obsd. (ESI+) [(M+H)+] 198.0.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18]O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl.CN(C=O)C>[Cl:33][CH2:18][C:13]1[N:14]([CH3:17])[C:15]2[C:11]([N:12]=1)=[C:10]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:9]=[C:8]([N:7]1[C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[N:4]=[C:3]1[CH2:1][CH3:2])[N:16]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CO)n(C)c2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a suspension of [2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]methanol (200 mg, 0.51 mmol) in DCM (6 mL) and DMF (100 μL) was added oxalyl chloride (129 μL, 1.52 mmol) and the resulting solution was stirred at room temperature for 19 h. The reaction mixture was concentrated in vacuo to an oil which was purified by column chromatography (Si—PCC, MeOH:DCM, 0-10%) affording 8-Chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine as an impure mixture which was used directly in subsequent reactions.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:5]C(C1C(C)=CC=CC=1Cl)=O.[N+]([C:27]1C=C(C=CC=1)C(O)=O)([O-])=O>>[CH3:27][C:21]1[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH2:16][C@@H:4]([C:3]([OH:2])=[O:23])[NH2:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1c(C)cccc1Cl
Product: Cc1cccc(C[C@H](N)C(=O)O)c1

Procedure:
N-[1-(2-Chloro-6-methylphenyl)carbonyl]-4-[[2-(3-nitrophenyl))-1-oxoethyl]amino]-3-methyl-L-phenylalanine was prepared from 4-amino-3-methyl-N-[[(2-chloro-6-methylphenyl)carbonyl]-L-phenylalanine methyl ester (52 mg) and 3-nitrobenzoic acid (32 mg, 0.19 mmol) using the procedure described in example 120 to give 15 mg of a white powder. HR MS (C25H22N3O6Cl): Obs. Mass 496.1288. Calcd. Mass 496.1288 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:22][C:23]1([CH3:31])[C:25]([CH3:27])([CH3:26])[CH:24]1[C:28](Cl)=[O:29]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[C:28]([CH:24]1[C:25]([CH3:27])([CH3:26])[C:23]1([CH3:31])[CH3:22])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3c(OCc4ccccc4)cccc23)C1(C)C
Yield: 40 %

Procedure:
A mixture of 7-benzyloxyindole (Matrix Scientific, 2.0 g, 9.0 mmol), ethylmagnesium bromide (1.0 M solution in THF, 11 mL, 11 mmol), zinc chloride (1.0 M solution in Et2O, 11 mL, 11 mmol) and the product of Example 1A (13.4 mmol) in 30 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.3 g, 3.6 mmol, 40% yield). MS (DCI/NH3) m/z 348 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:24])([F:23])[O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[N:19]O)[NH2:18])=[CH:15][CH:14]=1.N1C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][N:19]=[C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]([F:10])([F:23])[F:24])=[CH:22][CH:21]=2)[N:18]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: FC(F)(F)Oc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 3-chloro-thiophene-2-carbonyl chloride (72.4 mg, 0.4 mmol) and 4-trifluoromethoxybenzamidoxime (88 mg, 0.4 mmol) in dioxane:pyridine (11 mL, 10:1) was refluxed for 10 h and cooled to room temperature. To the stirred solution was added 20 mL of water to produce precipitates. The solid was collected by filtration and washed with dioxane:water (1:3), and dried to yield 103 mg (75%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:20])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]1([C:19](=[O:20])[C:18]#[C:17][C:14]2[CH:13]=[CH:12][N:11]=[CH:16][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC(C#Cc1ccncc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(C#Cc1ccncc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 32.6 %

Procedure:
Place oxalyl chloride (0.5 mL of a 2 M solution in methylene chloride, 1 mmol) under argon atmosphere and cool with a dry ice/acetone bath. Add dimethylsulfoxide (0.14 mL, 2 mmol) and stir for 10 minutes at -70° C. Add α-[(4-pyridinyl)ethynyl]-benzenemethanol (0.18 g, 0.86 mmol) in methylene chloride (1 mL). Stir for 20 minutes at -78° C. Add triethylamine (0.56 mL, 4 mmol), remove the cooling bath and stir for 45 minutes. Pour onto silica gel and elute with 60% ethyl acetate/hexane. Evaporate the solvent in vacuo and recrystallize (hexane/chloroform) to yield 58.1 mg of the title compound; mp 74°-75° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[NH2:13][C:14]1[C:22]2[O:21][C:20]([CH3:24])([CH3:23])[CH2:19][C:18]=2[CH:17]=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH2:32])[CH:26]=1>>[CH3:23][C:20]1([CH3:24])[CH2:19][C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:13][C:6]3[CH:5]=[CH:4][C:3]4[C:2]([NH:32][CH2:31][C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=3)[C:22]=2[O:21]1
Reactant: NCc1cccnc1
Reactant: CC1(C)Cc2cccc(N)c2O1
Reactant: Clc1ccc2c(I)cccc2n1
Product: CC1(C)Cc2cccc(Nc3ccc4c(NCc5cccnc5)cccc4n3)c2O1

Procedure:
The title compound, MS: m/e=397.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, 7-amino-2,3-dihydro-2,2-dimethylbenzofuran (CAS 68298-46-4) and 3-picolylamine.