Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]#[C:12][Si](C)(C)C)=[C:9]([NH:17]C(=O)C)[CH:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[C:22]=2[F:30])[N:6]=1)=[O:4].C(Cl)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]#[CH:12])=[C:9]([NH2:17])[CH:8]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[C:22]=2[F:30])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1C#C[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)Cl
Solvent: CO
Product: C#Cc1c(N)cc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
4-Acetylamino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-trimethylsilanylethynylpyridine-2-carboxylic acid methyl ester (0.196 g, 0.437 mmol) was suspended in methanol (4.36 mL) and acetyl chloride (0.310 mL, 4.37 mmol) was added. The reaction mixture was stirred overnight at ambient temperature then concentrated to dryness. The residue was dissolved in methanol (4.36 mL) and potassium carbonate (0.121 g, 0.873 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h, acidified with 2N HCl, and concentrated but not to dryness. The residue was partitioned between ethyl acetate and sodium bicarbonate; and the organic phase was dried and concentrated. The resulting product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.109 g, 74.6% yield) as a yellow solid, mp 167-169° C.: 1H NMR (CDCl3) δ 7.7 (m, 1H), 7.24 (s, 1H), 7.18 (m, 1H), 5.08 (br s, 2H), 3.99 (s, 3H), 3.97 (d, 3H), 3.84 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:24]([OH:39])[C:25]([N:27]2[CH2:38][CH2:37][CH2:36][C@H:28]2[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[O:52]1[CH2:53][CH2:54][N:49]([CH2:2][C:3]([NH:5][C:6]2[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]([OH:39])[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:50][CH2:51]1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CBr)cc1
Reactant: C1COCCN1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CN2CCOCC2)cc1

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.137 mmol) of 1-[(2S,3S)-3-[N2 -(4-bromoacetamidophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide and 1 ml of morpholine, 70 mg of the title compound were obtained as a colorless powder, melting at 121°-127° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][C:12]1[NH:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:16]=1[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:15]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:12]([CH2:11][CH2:10][CH2:9][OH:8])[NH:13][CH:14]=2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-c2c[nH]c(CCCOCc3ccccc3)c2-c2ccncc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OCCCc1[nH]cc(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 94.5 %

Procedure:
A solution of 2-(3-benzyloxypropyl)-4-(4-fluorophenyl)-3-(4-pyridyl)pyrrole (0.95 g, 0.0025 mol) in ethanol (125 mL) containing concentrated HCl (0.2 mL) was added to Pd on carbon (0.2 g). This mixture was placed in a hydrogen atmosphere for 16 hours on a Parr hydrogenator at 50 PSI. The mixture was filtered through Celite and triethylamine (0.5 mL) was added to the resulting solution, followed by evaporation in vacuo to give a solid. The solid was extracted into ethyl acetate (100 mL) and washed with water (3×50 mL). The organics were dried over Na2SO4 and evaporated in vacuo to give a light yellow solid (0.7 g, 96% yield). 1HNMR (DMSO-d6) δ 11.10 (1H, s, NH), 8.44 (2H, d), 7.05 (6H, m), 6.91 (1H, d), 4.53 (1H, br s, OH), 3.49 (2H, br s), 2.64 (2H, t), 1.72 (2H, m).
Reaction SMILES: [CH2:1]([C:3]1[S:22][C:6]2[NH:7][C:8](=[O:21])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[S:22][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CCc3ccc(F)cc3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CC#N
Product: CCc1cc2c(=O)n(CCc3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
A mixture of 6-ethyl-3-[2-(4-fluorophenyl)ethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.3 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.49 g), potassium carbonate (0.16 g) and acetonitrile (30 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.23 g, 43%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26](O)=[O:27])[N:11]=3)[C:6]=2[CH:29]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])[N:11]=3)[C:6]=2[CH:29]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1)N1CCCCC1
Reaction time: 24 h

Procedure:
To a solution of 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylic acid (25 mg, 0.063 mmol) in THF (2 mL) at 0° C. was added piperidine (8 mg, 0.09 mmol) and triethyl amine (0.052 mL, 0.37 mmol), followed by a solution of triphenylphosphine (0.056 mL, 0.18 mmol) in ethyl acetate. The reaction mixture was allowed to reach room temperature and stirred for 24 h. The solvent was evaporated and a saturated solution of sodium bicarbonate was added to the residue. The solid formed was filtered and dried to give the desired compound as a white solid. Yield: 10 mg, 34%. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 11.89 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.82 (dd, J=4.8, 4.8 Hz, 1H), 7.24 (t, J=6.94 Hz, 1H), 4.58 (m, 1H), 4.03 (t, J=2.2 Hz, 2H), 3.68 (m, 2H), 3.68-3.48 (m, 4H), 2.64-2.55 (m, 2H), 1.79 (d, J=11.6 Hz, 2H), 1.66 (m, 4H), 1.55 (m, 2H); LCMS (EI) m/z 466 (MH)+.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32](=[NH:34])[NH2:33])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:35])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:32]([C:30]1[CH:29]=[CH:28][C:21]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C:18]([CH2:17][N:10]3[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:8]([CH2:7][C:6]([OH:36])=[O:5])[C:9]3=[O:35])=[N:19][C:20]=2[CH:31]=1)(=[NH:33])[NH2:34]
Reactant: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)O)c3ccccc32)nc2cc(C(=N)N)ccc21
Reaction time: 48 h
Yield: 97.8 %

Procedure:
{3-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester (1.0 g, 2.0 mmol) was dissolved in CH2Cl2 (50 ml) treated with TFA (3 ml) and stirred for 48 h. The solvent was removed and the residue triturated with EtOAc to give 850 mg (98%) of {3-[5-Carbamimidoyl-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid as a with solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9]O.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12>>[O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[CH2:11][N:35]1[C:31](=[O:41])[C:32]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]2[C:34]1=[O:36]
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C1NC(=O)c2ccccc21
Product: C[C@H](CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CN1C(=O)c2ccccc2C1=O

Procedure:
Thereafter, (25R)-16-oxo-26-hydroxycholesterol (9) is converted to (25R)-16-oxo-26-hydroxycholesterol-26-tosylate (8) directly or indirectly by solvolysis of a (25R)-16-oxo-26-hydroxycholesterol-3β,26--ditosylate (7). Intermediate (8) is then subjected to displacement reaction with a phthalimide salt to form (25R)-16-oxo-26-phthalimidocholesterol (5). The reaction conditions and reagents for effecting all these conversions are the same as described above.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:42]=[CH:41][C:17]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])[CH:20]=2)=[C:16]([F:43])[CH:15]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:43][C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:12])[CH:42]=[CH:41][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]([N:28]2[CH2:29][CH2:30][CH:31]([N:34]3[CH2:35][CH2:36][CH:37]([OH:40])[CH2:38][CH2:39]3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Reaction time: 1 h
Yield: 57 %

Procedure:
After adding a solution of 2-phenylacetyl isothiocyanate in toluene (0.2 M, 4.0 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (164 mg) and (+)-10-camphorsulfonic acid (85 mg) in ethanol (4.0 ml) at room temperature, the mixture was stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=98:2 to 95:5) to provide the title compound (127 mg, 57%) as white powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:33])=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28])C>CO>[OH:33][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)O)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)O)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Reaction time: 168 h
Yield: 44.2 %

Procedure:
453 mg (2.5 mmol, 1.5 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added to 471 mg (1.7 mmol, 1 eq) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxybenzoic acid dissolved under hot conditions in 50 ml of methanol. The reaction medium was heated at 50° C. for 18 hours and then at 60° C. for 7 days. The methanol was evaporated off and the residue was chromatographed on silica gel (column puriFlash IR50SI-120G, Spot II) eluted with dichloromethane/methanol (gradient). The solid was taken up with a little ethyl acetate, filtered and dried under vacuum at 55° C. 310 mg of 2-hydroxy-3-(2-{[(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}-3,4-dioxocyclobut-1-enylamino)benzoic acid were obtained in the form of a brown solid. (Mp=180-185° C.). Yield=44%. LC/MS: 97.08% [412].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-])=[CH:4][CH:3]=1.C[Si]([C:20]#[N:21])(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(Cl)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]#[N:21])[CH:11]=[CH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc[n+]([O-])c1-c1ccc(F)cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)nc1-c1ccc(F)cc1
Yield: 66.7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-3-methylpyridine 1-oxide (24 g, 0.118 mol) in tetrahydrofuran (200 mL) were added trimethylsilyl cyanide (19.2 mL, 0.153 mol) and dimethylcarbamoyl chloride (14.1 mL, 0.153 mmol), and the mixture was heated under reflux for 2 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to give the title compound (16.7 g, 67%) as a white solid. Under reduced pressure, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9) to give the title compound (3.0 g, 12%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10].[CH3:20][NH:21][CH2:22][C:23]([OH:25])=[O:24].C([O-])([O-])=O.[Na+].[Na+].O>N#N>[C:23]([CH2:22][N:21]([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[NH:12][C:13]([CH:15]1[CH2:17][C:16]1([CH3:19])[CH3:18])=[O:14])/[C:9]([OH:11])=[O:10])([OH:25])=[O:24]
Reactant: CC1(C)CC1C(=O)N/C(=C\CCCCCBr)C(=O)O
Reactant: CNCC(=O)O
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(CCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O)CC(=O)O

Procedure:
3.32 g of Z-8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid, 1.0 g of CH3NHCH2CO2H, 3.5 g of Na2CO3 and 30 ml of water were heated at 80° C. in N2 for 1.5 hours. After purification, 1.01 g of product was prepared, calc for C17H28N2O5.2H2O: C, 54.24; H, 8.57; N, 7.44; found: C, 54.40; H, 8.34; N, 7.16.
Reaction SMILES: [CH3:1][C:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[C:5](=O)[CH2:4][C:3]2=[O:11].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C(Cl)(Cl)Cl>[Cl:13][C:5]1[CH:6]2[O:9][C:2]([CH3:1])([CH2:8][CH2:7]2)[C:3](=[O:11])[CH:4]=1
Reactant: CC12CCC(O1)C(=O)CC2=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC12CCC(O1)C(Cl)=CC2=O
Yield: 82.9 %

Procedure:
To a solution of 1-methyl-8-oxa-bicyclo[3.2.1]octane-2,4-dione (175 mg, 1.14 mmol) in chloroform (2 ml) is added, under N2, in one portion, the phosphorous pentachloride (135 mg, 0.65 mmol). The reaction mixture is stirred for reflux for 5 hours. Silica gel is added to the cooled crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-chloro-1-methyl-8-oxa-bicyclo[3.2.1]oct-3-en-2-one (93 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:26])([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.300 g, 0.763 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.316 g, 0.839 mmol) according to the general procedure VI. Obtained as an off-white solid (0.040 g, 10%). MS (ISP) 532.1 [(M+H)+]; mp 227° C.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:20]=3)[C:6](=[O:30])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][CH3:40].N1CCOCC1>CN(C=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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:20]=3)[C:6](=[O:30])[N:5]([CH2:38][CH2:39][CH3:40])[C:4]=2[N:3]=1
Reactant: CCCI
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(CCCCc3nc(-c4ccccn4)no3)c(=O)c21
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: CN(C)C=O
Solvent: C1COCCN1
Product: CCCn1c(=O)n(CCCCc2nc(-c3ccccn3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (40 mg, 0.09 mmol) in DMF (3 ml) was treated with potassium carbonate (15 mg, 0.11 mmol) and 1-iodopropane (19 mg, 0.11 mmol). The mixture was heated at 40° C. for 3 h then at 70° C. for a further 3 h. The mixture was cooled and degassed by the successive application of vacuum and nitrogen gas. The mixture was then treated with a solution of tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and morpholine (0.1 ml, 1.2 mmol) and then stirred overnight. The mixture was evaporated and partitioned between chloroform (2 ml) and water (2 ml). The aqueous phase was extracted with further chloroform (2 ml) and the combined organics evaporated and the residue dissolved in methanol (2 ml). The solution was applied to a 1 g aminopropyl SPE and eluted with methanol and then with 5% acetic acid in methanol. Product-containing fractions were pooled and evaporated and the product further purified by MDAP to reveal 8-chloro-3-propyl-1-{4-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]butyl}-3,7-dihydro-1H-purine-2,6-dione (1.4 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)nc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)cn1

Procedure:
5-Aminopyridine-2-carboxylic acid (1.60 g, 11.6 mmol) was dissolved in MeOH (100 mL) and concentrated sulfuric acid (1.7 mL, 12.8 mmol) was added and the mixture was heated to 80 C for 5 hours. The reaction mixture was concentrated under vacuum, neutralised by adding 1M aq. sodium bicarbonate and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title compound as a pale yellow solid (1.813 g, quant.). Method B HPLC-MS: MH+ requires m/z=153 Found: m/z=153, Rt=0.35 min (by MS).
Reaction SMILES: [CH:1]1[C:6]2[S:7][CH2:8][CH2:9]CO[C:5]=2[C:4]([C:12]([OH:14])=O)=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH3:37].CN([CH:41]=[O:42])C>C(OCC)(=O)C>[CH:1]1[C:6]2[S:7][CH2:8][CH2:9][O:42][CH2:41][C:5]=2[C:4]([C:12]([NH2:37])=[O:14])=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1OCCCS2
Reactant: CN(C)C=O
Reactant: N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: NC(=O)c1cccc2c1COCCS2
Reaction time: 48 h
Yield: 64 %

Procedure:
To 7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid (16.5 g, 78.4 mmol) in 100 mL DMF was added in succession solid HOBT (213 g, 1573 mmol), solid EDC hydrochloride (30.1 g, 157.0 mmol), and 25% aqueous ammonia (18 ml, 128.4 mmol). After stirring for 48 h, the reaction mixture was diluted with 200 mL ethyl acetate and washed with water, 1N HCl, saturated NaHCO3, sated NH4Cl, and brine. Drying over Na2SO4 and concentration yielded the amide as a tan solid (10.5 g, 64%).