Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:9]=1[CH:28]=[C:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH3:7].C(OCC)C.O1CCCC1>C(OCC)C.[Cu]I>[CH2:6]([C:8]1[N:13]=[C:12]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:11]2=[C:10]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[C:9]=1[CH:28]([CH:29]1[S:33][C:32](=[O:34])[NH:31][C:30]1=[O:35])[CH2:1][CH2:2][CH3:3])[CH3:7]
Reactant: CCC[Mg]Cl
Reactant: CCc1nc2sc3c(c2c(-c2ccc(C)cc2)c1C=C1SC(=O)NC1=O)CCCC3
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)C1SC(=O)NC1=O
Reaction time: 0.33 h
Yield: 9 %

Procedure:
To a cold (−15° C.) solution of copper(I)iodide (0.200 g; 1.05 mmol) in anhydrous diethyl ether (5 mL) was added a 2M solution of n-propylmagnesium chloride in diethyl ether (1.0 mL; 2.0 mmol). The mixture was stirred for 20 min and a solution of 5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylene]thiazolidine-2,4-dione (0.083 g; 0.197 mmol) in a mixture diethyl ether-tetrahydrofurane (2/1, 3 mL) was added dropwise and stirring was carried on for 2 h at −15° C. and 18 h at room temperature. The reaction was quenched with a saturated solution of ammonium chloride (50 mL) and diluted with diethyl ether (20 mL). Both phases were separated, the aqueous layer was extracted with diethyl ether, the combined organic phases were washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by preparative HPLC (HPLC method 1) furnished 0.008 g (9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH3:26])=[CH:4][CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:34][CH2:26][C:9]1[C:10]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13](=[O:23])[N:12]([CH3:24])[C:11]=2[S:25][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCn1c(=O)c2c(CBr)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of methyl 3-(6-(4-chlorophenyl)-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (25 mg, 0.0636 mmol) in CCl4 (1 mL) was added NBS (11.3 mg, 0.0636 mmol) followed by benzoyl peroxide (2 mg). The reaction was heated at reflux for 4 h, cooled to RT then diluted with DCM (10 mL). The mixture was washed with aq. NaHCO3 (5 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated to give methyl 3-(5-(bromomethyl)-6-(4-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (30 mg, 100% yield). LCMS: MH+ 473 and TR=1.907 min. Used without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:22])[Cl:23])[CH:15]=[C:14]([Cl:24])[C:13]=1[O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CO)cc1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(COc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Yield: 46.8 %

Procedure:
To a mixture of 3.40 g of p-(hydroxymethyl)benzaldehyde obtained in the same manner as described above, 7.2 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 6.56 g of triphenylphosphine, and 50 ml of tetrahydrofuran was slowly added dropwise 5.05 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 4.75 g (yield, 46%) of 4-((2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)methyl)benzaldehyde, m.p., 93.9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-chloro-phenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[O:11][C:12](=[N:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:13]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:9])(C)(C)C>N1CCCCC1.Cl.O1CCOCC1>[NH2:7][CH:8]([C:10]1[N:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:12](=[O:11])[C:13]2[C:14](=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[N:15]=1)[CH3:9]
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=Nc2cc(F)cc(F)c2)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: CC(N)c1nc2cccc(Cl)c2c(=O)n1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98 %

Procedure:
A solution of compound 169 (1.68 mmol) in piperidine (2 mL) was stirred for 3 h at ambient temperature. Evaporation of the reaction mixture to dryness under high vacuum gave a yellow foam. This foam was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (4 mL) and stirred for 17 h at ambient temperature. The reaction mixture was then concentrated to dryness, basified with 10% aqueous potassium carbonate (40 mL) and extracted with MTBE (3×20 mL). Combining the organic extracts, drying over sodium sulfate and concentrating to dryness afforded a solid residue. This residue was dissolved in d-chloroform (5 mL), and warmed for 15 h at 50° C. After cooling to ambient temperature, the reaction mixture was washed with water (3×10 mL), dried over sodium sulfate and evaporated to dryness, affording a 98% yield of compound 170 as a white solid. m.p. 200-202° C.; 1H NMR (CDCl3) δ (ppm) 7.65 (m, 2H), 7.49 (m, 1H), 7.01 (t, 1H, J=6.6 Hz), 6.89 (m, 2H), 3.68 (m, 1H), 1.33 (d, 3H, J=6.6 Hz), 1.25 (s, 2H); m/z=336 (M+H). The reaction described above and compound 170 are shown below.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[N:27]=1.C(=O)([O-])[O-].[K+].[K+].ClCCl>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:31]4[C:26]([O:25][CH3:24])=[N:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)c(OC)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(OC)n1
Temperature: 160 °C
Yield: 29.2 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 2,6-dimethoxy-pyridin-3-ol (Aagile Labs Division of Tyger Scientific, Ewing, N.J., USA; 30 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Dichloromethane and water were added, and the aqueous layer was extracted twice with dichloromethane. The dichloromethane layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water to give 4-[4-(2,6-dimethoxy-pyridin-3-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 29%) as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.96-2.04 (m, 2H), 2.18-2.30 (m, 2H), 2.90-3.05 (m, 2H), 3.90 (s, 3H), 3.95 (s, 3H), 4.25-4.38 (m, 2H), 4.90-5.00 (m, 1H), 6.37 (d, 1H, J=8.2 Hz), 7.41 (d, 1H, J=8.2 Hz), 8.03 (s, 1H), 8.50 (s, 1H). Mass spectrum MH+=457. HRMS Calcd. For C22H29N6O5 (MH+): 457.2194. Found: 457.2193.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH3:25])[C:17](=[O:26])[C:16]2[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[N:30][C:15]1=2)CC1C=CC=CC=1)[CH3:2]>CO.[Pd]>[CH2:1]([NH:3][CH2:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]([CH3:25])[C:17](=[O:26])[C:16]2[C:27]([CH3:32])=[CH:28][C:29]([CH3:31])=[N:30][C:15]1=2)[CH3:2]
Reactant: CCN(CCCN1c2ccccc2N(C)C(=O)c2c(C)cc(C)nc21)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCNCCCN1c2ccccc2N(C)C(=O)c2c(C)cc(C)nc21

Procedure:
14 gm of the end product of step (a) were hydrogenated in 400 ml of methanol in the presence of 5 gm of 10% palladium-on-charcoal at 50° C. and 50 atmospheres. After separating the catalyst, the reaction mixture was evaporated in vacuo, and the residue was purified on a silica gel column. Then, the product was recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 42% of theory of 11-(3-ethylamino-propyl)-6,11-dihydro-2,4,6-trimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one which had a m.p. of 101°-103° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22]([OH:24])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH2:19][CH:20]([C:22]([NH:33][CH2:32][CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1ncc(C2=NC(C(=O)O)CS2)c1-c1ccc(F)cc1
Reactant: NCCC1CCOCC1
Product: CC(C)(C)n1ncc(C2=NC(C(=O)NCCC3CCOCC3)CS2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-(tert-butyl)-5-(4-fluorophenyl)-1H-pyrazol-4-yl)-4,5-dihydrothiazole-4-carboxylic acid and 2-(tetrahydro-pyran-4-yl)-ethylamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: CB1N2CCC[C@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[C:22]1([Si:28]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:50]([CH3:53])([CH3:52])[CH3:51])[O:29][C:30]2[CH:31]=[C:32]([C:36](=[O:49])[CH2:37][CH2:38][C:39]3[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=3[C:41]([O:43][CH3:44])=[O:42])[CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B.C1COCC1>C1COCC1>[C:54]1([Si:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:50]([CH3:51])([CH3:52])[CH3:53])[O:29][C:30]2[CH:31]=[C:32]([C@H:36]([OH:49])[CH2:37][CH2:38][C:39]3[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=3[C:41]([O:43][CH3:44])=[O:42])[CH:33]=[CH:34][CH:35]=2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: COC(=O)c1ccccc1CCC(=O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CC[C@@H](O)c1cccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
At -20° C., (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c)(1,3,2)oxazaborole (J. Am. Chem. Soc., 104, 5551-5553 (1987), 3.82 g, 0.014 mol) was added to a solution of the ketone of Step 2 in THF (556 mL). To this mixture, 1.0M BH3.THF (111 mL) was slowly added within 10 min. After 15 min, the reaction was quenched with 2M HCl (250 mL). After extraction with EtOAc, the organic phase was washed with 25% aq NH4OAc followed by saturated NaCl. The solvent was removed at reduced pressure to afford an oil which was purified by flash chromatography (20% EtOAc in hexane) to give 70 g (95%) of the title compound.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]1([C:11]2[CH:19]=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[N:1]([C:19]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)=[O:3]
Reactant: O=N[O-]
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Nc1c(-c2ccccc2)nn2ccccc12
Reaction time: 0.33 h
Yield: 71.3 %

Procedure:
A solution of sodium nitrite (533 mg) in water (2.5 ml) was added dropwise to a solution of 2-phenylpyrazolo[1,5-a]pyridine (1.0 g) in acetic acid (5 ml) at 13° to 15° C. After being stirred at the same temperature for 20 minutes, the reaction mixture was poured onto ice-water. Resultant precipitates were collected by filtration, washed with water and recrystallized from acetone to give crystals of 3-nitroso-2-phenylpyrazolo[1,5-a]pyridine (0.82 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[F:11][C:12]1[CH:27]=[CH:26][C:15]2[C:16](=O)[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=[CH:20][C:14]=2[CH:13]=1.O>O1CCCC1.C(Cl)Cl>[F:11][C:12]1[CH:27]=[CH:26][C:15]2[CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=[CH:20][C:14]=2[CH:13]=1
Reactant: O=c1c2ccccc2ccc2cc(F)ccc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C=Cc1ccccc1C2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
LiAlH4 (0.0686 mol) was added dropwise to a suspension of AlCl3 (0.0718 mol) in tetrahydrofuran (75 ml), cooled on an ice-bath and under N2 atmosphere. The mixture was stirred for 10 minutes at 0° C. A solution of 2-fluoro-5H-dibenzo[a,d]cyclohepten-5-one (0.0653 mol and prepared as described in DE 3,644,462) in tetrahydrofuran (75 ml) was added dropwise and the resulting reaction mixture was allowed to warm to room temperature. Then, the reaction mixture was stirred and refluxed for 2 hours. The mixture was cooled on an ice-bath. Water and CH2Cl2 was added. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried, filtered and the solvent was evaporated, yielding 13.16 g (96%) of 2-fluoro-5H-dibenzo[a,d]cycloheptene (intermediate 1)
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:31]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:31].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[C:4]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (110 mg, 0.230 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes, and the TFA was removed in vacuo. The oily residue obtained was dissolved in CH2Cl2 (1 mL), and 2M HCl in Et2O was added. The mixture was stirred at ambient temperature for 30 minutes. The solid formed was filtered and triturated with CH3CN to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (70 mg, 67% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.82 (s, 1H), 9.65 (s, 1H), 8.26 (br s, 3H), 8.22 (s, 1H), 7.47 (s, 1H), 3.46-3.40 (m, 3H), 3.31-3.23 (m, 1H), 3.12-3.06 (m, 1H), 2.15-2.09 (m, 1H), 1.87-1.80 (m, 2H), 1.76-1.69 (m, 1H), 1.53-1.43 (m, 1H), 0.83-0.81 (m, 4H); LCMS (APCI+) m/z 378.8, 379.9 (M+H)+, Retention time=2.18 minutes (Method 2).
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12])(=O)C>N>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12]
Reactant: CCCC(CCCCCSC(C)=O)C(=O)O
Agent: N
Product: CCCC(CCCCCS)C(=O)O
Yield: 60.3 %

Procedure:
A solution of 7-acetylthio-2-propylheptanoic acid (0.8 g) in 5 N methanolic ammonia (50 ml) was stirred for 2 hours at ambient temperature in an argon atmosphere and concentrated to dryness under reduced pressure. The residue was dissolved in a small amount of a mixture of water and methanol and passed through a column of ion-exchange resin (Dowex 50W, H+ type). The eluate with a mixture of water and methanol was concentrated to dryness under reduced pressure to give semisolid of 7-mercapto-2-propylheptanoic acid (0.4 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:23][CH2:22]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2ccc(-c3noc(C(F)(F)F)c3C)s2)CC1
Yield: 81 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-methoxypiperidine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (151 mg, 81%). 1H NMR (CDCl3) 1.64-1.72 (m, 2H), 1.86-1.93 (m, 2H), 2.33 (d, J=1.3, 3H), 3.36 (s, 3H), 3.47-3.58 (m, 3H), 3.87-3.95 (m, 2H), 7.29 (d, J=3.5, 1H), 7.42 (d, J=4.0, 1H). 13C NMR 7.9, 30.9, 42 (br), 56.1, 75.2, 114.7, 118.7 (q, J=271), 128.0, 129.1, 131.1, 140.3, 155.2 (q, J=40), 158.0, 162.7. 19F NMR −63.2. LC/MS 6.31 min, [M+1]+ 375.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](O)(=O)C.O1CCCOO1.O>CS(O)(=O)=O.FC(F)(F)C(O)=O>[CH2:13]1[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[CH2:7][CH2:8][S:9](=[O:10])(=[O:11])[NH:12]1
Reactant: NS(=O)(=O)CCc1ccccc1
Reactant: CC(=O)O
Agent: C1COOOC1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCc2ccccc2CN1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenylethanesulfonamide (3.62 g) in methanesulfonic acid (20 ml)-acetic acid (5 ml) was added a solution of trioxane (582 mg) in trifluoroacetic acid (3 ml)and the mixture was stirred for 3 hours at 35° C. To the reaction mixture was added water and was extracted with chloroform. The organic layer was washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and was concentrated. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give the title compound (1.78 g) having the following physical data.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(=O)(O)[O-].[Na+].C([O:19][C:20](=O)/[CH:21]=[C:22](/[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])\[CH2:23]Br)C>C(O)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:21][C:20]1=[O:19])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)/C=C(\CBr)Oc1ccccc1Cl
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 147.2 %

Procedure:
To a solution of (L)-leucine methyl ester hydrochloride salt (152.6 g, 0.840 mol) in ethanol (200 proof denatured, 2500 mL) was added sodium bicarbonate (115.3 g, 1.37 mol) at room temperature and the resulting mixture stirred for 15 min. To this mixture was added (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (87.7% pure by HPLC, 200 g, 0.549 mol). The resulting cloudy solution was heated to reflux and approx. 500 mL of solvent was removed via a Dean Stark trap before reflux was continued overnight. To this solution was added glacial acetic acid (200 mL) and the solution was heated to reflux for an additional 2 h. The reaction mixture was cooled to room temperature and methyl t-butyl ether (2.7 L) and water (2 L) were added. The mixture was separated and the organic phase washed with a 20% sodium chloride solution (2 L). The solution was evaporated, the residue treated with toluene (2 L) and evaporated again to give (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (83.3% pure by HPLC, 273 g) as a dark orange oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]1[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]1)[C@@H:9]([OH:11])[CH3:10].[S:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[S:23]1[C:24]([C:2]2[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=2)[O:5][CH2:6][CH2:7][C@@H:8]([N:12]2[CH:16]=[C:15]([C:17]([NH2:19])=[O:18])[N:14]=[CH:13]2)[C@@H:9]([OH:11])[CH3:10])=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=2
Reactant: C[C@H](O)[C@@H](CCOc1cccc(Br)c1)n1cnc(C(N)=O)c1
Reactant: OB(O)c1cc2ccccc2s1
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: COCCOC
Solvent: O
Product: C[C@H](O)[C@@H](CCOc1cccc(-c2cc3ccccc3s2)c1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
To a solution of 1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide in DME (5 ml) was added Pd(PPh3)4 (29.3 mg, 0.025 mmol)at ambient temperature under N2. After stirring for 20 min., benzothiophene-2-boronic acid (54.2 mg, 0.304 mmol) and a solution of Na2CO3 (40.3 mg, 0.38 mmol) in H2O (1 ml) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and partitioned between ethyl acetate (20 ml) and H2O. The organic layer was washed successively with saturated NaHCO3 aqueous solution, H2O and then brine, dried (sodium sulfate) and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with chloroform/methanol (100:1 to 20:1) to give 1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide (41) (66.9 mg, 62.6%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13].[C:14]([S:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([S:18][C:19](=[O:24])[CH:20]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[Cl:13])[C:21](=[O:23])[CH3:22])([CH3:17])([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-methanesulfonylbenzene and 3-oxothiobutyric acid S-tert-butyl ester