Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24](C5C=CC=CC=5)N(C)[C:26]=4[CH3:27])=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].CS([O:42][CH2:43][CH2:44][CH2:45][N:46]1[CH2:52][CH:51]([OH:53])[C:48]2([CH2:50][CH2:49]2)[CH2:47]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:53][CH:51]1[C:48]2([CH2:50][CH2:49]2)[CH2:47][N:46]([CH2:45][CH2:44][CH2:43][O:42][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:2]5[CH:11]=[CH:10][CH:5]=[CH:4][CH:3]=5)[C:20]([C:22]5([C:23]([NH2:24])=[O:35])[CH2:27][CH2:26]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:36][CH3:37])[CH2:52]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)nc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(N(C(=O)C4(C(N)=O)CC4)c4ccccc4)nc3)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 120.3 %

Procedure:
To a solution of N-(5-(7-hydroxy-6-methoxyquinolin-4-yloxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.640 mmol) in DMA (4 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (239 mg, 0.960 mmol) and Cs2CO3 (416 mg, 1.280 mmol). The reaction was then stirred at rt for 48 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (5 mL) and CHCl3 (25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (100:15:1 (v/v/v)EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (240 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].O>O1CCOCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)c(F)cc2s1
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Temperature: 80 °C
Yield: 65 %

Procedure:
To a solution of 5-bromo-6-fluoro-benzothiazol-2-ylamine (0.36 g, 1.45 mmol) in 1,4-dioxane (25.0 mL) was added ethyl isocyanate (0.69 mL, 8.74 mmol) and the resulting reaction mixture was heated at 80° C. for 15 h. After the completion of the reaction (TLC monitoring) the solvent was evaporated. The residue thus obtained was stirred with water at 60° C. for 5 h. The solution was then filtered and washed with ether to get the title compound (0.30 g, 69%). 1H-NMR (400 MHz, DMSO-d6): δ 1.08 (t, J=6.80 Hz, 3H), 3.17 (m, 2H), 6.69 (br s, 1H), 7.92 (d, J=6.40 Hz, 1H), 8.0 (d, J=8.40 Hz, 1H) and 10.86 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A mixture of 4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenol (6.00 g, 17 mmol), methyl bromoacetate (2.96 g, 1.83 mL, 19 mmol), potassium carbonate (2.91 g, 21 mmol), potassium iodide (catalyic amount) and acetonitrile (80 mL) was stirred at reflux. After 1 hour, the mixture was cooled, filtered and the solvent removed to leave a crystalline solid that was tritrated with hexanes and filtered to give methyl 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate (7.27 g, 100%). An analytical sample was obtained by recrystallizing a 2.25 g batch from methanol to give 1.70 g of pure material which had m.p. 122°-125° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)=[N:8][C:9]3[N:10](N=CC=3)[CH:11]=2)=[CH:2]1.NC1[NH:25][CH:26]=[CH:27]N=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([C:15]3[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[CH:21][CH:22]=3)=[N:8][C:9]3[N:10]([CH:27]=[CH:26][N:25]=3)[CH:11]=2)=[CH:2]1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccsc2)cc1
Reactant: Nc1ncc[nH]1
Product: O=Cc1ccc(-c2nc3nccn3cc2-c2ccsc2)cc1

Procedure:
This compound was prepared in a manner according to 4-(6-thiophen-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl)-benzaldehyde by using 2-aminoimidazole in the first step.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[C:6]3[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[C:6]3[C:12]([CH2:13][CH3:14])=[N:11][N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:7]3=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2ccc(OC)cc2)c2ncc(C3CC3)c(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-3-ethyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.21 g, 0.43 mmol) was placed in DCM (5 mL). TFA (1.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The crude product was then azeotroped with toluene (3×) and dried to give the crude 5-cyclopropyl-3-ethyl-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine (0.16 g, 96% yield).
Reaction SMILES: [F:1][C@:2]1([CH3:17])[C@H:6]([OH:7])[C:5](=[CH2:8])[O:4][C@H:3]1[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]1=[O:16].[C:18](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C1COCC1>[O:16]=[C:10]1[NH:11][C:12](=[O:15])[CH:13]=[CH:14][N:9]1[C@@H:3]1[O:4][C:5](=[CH2:8])[C@@H:6]([O:7][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@:2]1([F:1])[CH3:17]
Reactant: C=C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a mixture of chiral 1-((2R,3R,4R)-3-fluoro-4-hydroxy-3-methyl-5-methylene-tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (18.3 g, 75.6 mmol) and DMAP (27.7 g, 227 mmol) in anhydrous THF (900 mL) at 0° C. was added BzCl (15.9 g, 113.4 mmol) dropwise. The reaction mixture was stirred at 0° C. for 0.5 h, then sat. NaHCO3 was added to quench the reaction. The mixture was extracted with EA (300 mL×3). The combined organic extract was washed with H2O, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography column (DCM:MeOH=160:1 to 120:1) to give the title compound as a white solid (17 g, 65%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][CH3:13])[CH:7]=1)=[O:4].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]([F:14])([F:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]([CH3:13])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=2)[CH:7]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNc1cccc(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1cccc(NC(=O)C(F)(F)F)c1)c1ccc([N+](=O)[O-])cn1
Temperature: 120 °C
Reaction time: 23 h
Yield: 96.3 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[3-(methylamino)phenyl]acetamide (10.0 g, 45.8 mmol) in N,N-dimethylformamide (40 mL) was added 2-chloro-5-nitropyridine (7.99 g, 50.4 mmol), and the mixture was stirred at 120° C. for 23 hr. The reaction mixture was cooled to room temperature, aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with water (70 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was purified by silica gel column chromatography (150 g, ethyl acetate) to give the title compound (15.0 g, 96%) as a yellow powder.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]3[CH:17]=[N:18][C:19](S(C4C=CC=CC=4)(=O)=O)=[CH:20][CH:21]=3)=[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O-:32].[Na+]>CO.O1CCOCC1>[CH3:31][O:32][C:19]1[N:18]=[CH:17][C:16]([C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=23)=[CH:21][CH:20]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine (3.93 g) and sodium methoxide (5.2M MeOH solution, 10 mL) in MeOH (60 mL) and 1,4-dioxane (60 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated in vacuo, and ice water was added, extracted, with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 2:3) to give 3-(6-methoxy-3-pyridinyl)-2-phenylpyrazolo[1,5-a]pyrazine (2.37 g) as an oil.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[C:34]5=[CH:35][C:36]([C:38]6[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=6)=[CH:37][N:33]5[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=O)=[CH:11][CH:10]=1.O>C1COCC1>[F:8][C:9]1[CH:10]=[CH:11][C:12](/[C:15](/[C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[C:34]5=[CH:35][C:36]([C:38]6[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=6)=[CH:37][N:33]5[N:32]=[CH:31][N:30]=4)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[N:7]/[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])=[CH:13][CH:14]=1
Reactant: Cn1cc(-c2cc3c(N4CCN(c5ncc(C(=O)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1
Reactant: CC(C)(C)[S@@](N)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc3c(N4CCN(c5ncc(/C(=N\[S@@](=O)C(C)(C)C)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1
Yield: 100 %

Procedure:
(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70° C. for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (S,Z)—N-((4-fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100% yield) as an orange solid. MS (ES+) C29H31FN10OS requires: 586. found: 587 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.[CH3:29][N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36](O)=[O:37])[C:31]1=[O:39]>>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:36]([C:32]2[C:31](=[O:39])[N:30]([CH3:29])[CH:35]=[CH:34][CH:33]=2)=[O:37])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH3:26])[C:11]=12
Reactant: Cn1cccc(C(=O)O)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Product: Cc1n[nH]c2nccc(Oc3ccc(NC(=O)c4cccn(C)c4=O)cc3F)c12
Yield: 99 %

Procedure:
Prepared by a 2-step process from 3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (prepared according to Example 5, Step D) and 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid according to the procedure described for Example 21 (Steps A and B). The crude was purified by silica gel flash column chromatography (3% MeOH in CH2Cl2) to afford 16 mg (99%) of the desired product. LRMS (ESI pos) m/e 394.2 (M+1). 1H NMR (400 MHz, CD3OD) δ 8.56 (dd, 1H), 8.26 (d, 1H), 8.02 (m, 2H), 7.47 (m, 1H), 7.39 (t, 1H), 6.62 (t, 1H), 6.29 (d, 1H), 3.72 (s, 3H), 2.72 (s, 3H); 19F-NMR (376 MHz, CD3OD) δ −130.0.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1)[CH2:3]O.C(N(CC)CC)C.C1(C)C=CC(S([Cl:41])(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:41][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(CO)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCl)CN1CCN(c2ccccc2OCC(F)(F)F)CC1
Reaction time: 8 h
Yield: 19705.9 %

Procedure:
A mixture of 2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-1-propanol (991 mg, 2.9 mol), triethylamine (0.4 mL, 2.9 mmol), p-toluenesulfonyl chloride (678 mg, 3.4 mmol), 4-dimethylaminopyridine (35 mg, 0.29 mmol) and methylene chloride (15 mL) was stirred 8 hours at 20° to 25° C. The reaction mixture then was filtered and concentrated and the residue was purified by chromatography on silica gel eluting with hexanes/ethyl acetate (95:5) to give 1-chloro-2,2-dimethyl-3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propane (238 mg, 0.67 mol).
Reaction SMILES: Cl[C:2]([C:5]1[C:6]([Cl:11])=[N:7][CH:8]=[CH:9][CH:10]=1)=[N:3][OH:4].[CH3:12][O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17].C(N(CC)CC)C>C(OCC)C>[CH3:12][O:13][C:14]([C:15]1[C:2]([C:5]2[C:6]([Cl:11])=[N:7][CH:8]=[CH:9][CH:10]=2)=[N:3][O:4][C:16]=1[CH3:17])=[O:18]
Reactant: ON=C(Cl)c1cccnc1Cl
Reactant: CC#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1c(-c2cccnc2Cl)noc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine chloro(2-chloro(3-pyridyl))(hydroxyimino)methane (2.90 g, 0.015 mol) with methyl-2-butynoate (1.19 mL, 0.012 mol) in diethyl ether (75 mL). Cool the mixture in an ice bath under a nitrogen atmosphere. Add a solution of triethylamine (1.77 mL, 0.013 mol) in diethyl ether (10 mL) in a dropwise manner. Stir the mixture overnight while warming to ambient temperature. Quench the mixture with water and extract with diethyl ether. Concentrate the combined extracts and elute over silica gel with 10% methanol/dichloromethane to give the desired isoxazole along with a co-eluting impurity (2.30 g, 60%). MS(ES): (M+1)+ 253.0, 255.0 m/z.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: OC1CCNC1
Product: OC1CCN(c2ccc(Cl)c(C(F)(F)F)c2)C1
Yield: 90 %

Procedure:
The title compound (8.56 g, yield 90%) was obtained from bromo-4-chloro-3-(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH:1][C:2]3[CH:17]=[CH:16][C:5]4[N:6]([C:9]5[CH:10]=[CH:11][C:12]([NH:15][C:27]([C:24]6[CH:25]=[C:26]7[C:21]([CH:20]=[CH:19][NH:18]7)=[CH:22][CH:23]=6)=[O:29])=[CH:13][CH:14]=5)[CH:7]=[N:8][C:4]=4[CH:3]=3)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: Nc1ccc(-n2cnc3cc(N)ccc32)cc1
Product: O=C(Nc1ccc(-n2cnc3cc(NC(=O)c4ccc5cc[nH]c5c4)ccc32)cc1)c1ccc2cc[nH]c2c1

Procedure:
Compound 561 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)benzimidazole and indole-6-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.19; found: 511.01.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[Li]CCCC.CON(C)[C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>C1COCC1>[OH:6][C:2]([CH3:3])([CH3:1])[C:4]#[C:5][C:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:24]
Reactant: C#CC(C)(C)O
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#CC(C)(C)O)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a stirred solution of 2-methylbut-3-yn-2-ol (2.15 g, 25.6 mmol) in dry THF (80 mL) was added n-BuLi (24.0 mL, 38.7 mmol, 1.6 M in hexane) drop wise at −20° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −20° C., a solution of N,4-dimethoxy-N-methylbenzamide (2.5 g, 12.8 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −20° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (100 mL), brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 4-hydroxy-1-(4-methoxyphenyl)-4-methylpent-2-yn-1-one (2.25 g, 81%) as a colorless liquid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([NH:10][CH3:11])=[N:8][CH:9]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([N+:12]([O-:14])=[O:13])[C:7]([N:10]([CH3:11])[S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(C)c2ncc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in 2.0 ml of DMF, 5-chloro-2-methylamino-3-nitropyridine (0.20 g (1.07 mmol)) was added under cooling with ice and with stirring. To the resulting mixture, after 15 minutes' stirring under cooling with ice, p-toluenesulfonyl chloride (0.23 g (1.21 mmol)) was added. The reaction mixture was stirred under cooling with ice for 30 minutes and then at room temperature for 30 minutes, poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.16 g (44%) of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][CH:19]2[S:23][CH2:22][CH2:21][S:20]2)[CH2:8][C:7]1=[O:24])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:26]([O:29][NH3+:30])[CH:27]=[CH2:28]>C(O)C.C([O-])(=O)C.[Na+]>[CH2:26]([O:29][NH:30][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]([CH2:17][CH2:18][CH:19]2[S:23][CH2:22][CH2:21][S:20]2)[CH2:8][C:7]1=[O:24])[CH2:2][CH2:3][CH3:4])[CH:27]=[CH2:28]
Reactant: C=CCO[NH3+]
Reactant: CCCC(=O)C1C(=O)CC(CCC2SCCS2)C(C(=O)OC)C1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(CCC2SCCS2)C(C(=O)OC)C1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
12.0 parts by weight of 2-butyryl-4-methoxycarbonyl-5-[2-(1,3-dithiolan-2-yl)-ethyl]-cyclohexane-1,3-dione were dissolved in 150 parts by volume of ethanol, and 3.29 parts by weight of allyloxyammonium chloride and 3.28 parts by weight of anhydrous sodium acetate were added. The mixture was stirred at 20° C. for 20 hours, poured onto ice-water and extracted with methylene chloride. The organic phase was concentrated to give 13.1 parts by weight of 2-(1-allyloxyaminobutylidene)-4-methoxycarbonyl-5-[2-(1,3-dithiolan-2-yl)-ethyl]-cyclohexane-1,3-dione (compound No. 3) as a viscous oil having the following structure: ##STR9## C20H29O5NS2, molecular weight=427. Calculated: C 56.2, H 6.8, N 2.3, S 15.0. Found: C 57.0, H 6.7, N 2.8, S 14.7.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][C@@H:4]([C:18]([OH:20])=[O:19])[CH2:3]1.CCN(CC)CC.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)(Cl)Cl>[CH3:32][C:31]([Si:28]([CH3:30])([CH3:29])[O:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:5][C@@H:4]([C:18]([OH:20])=[O:19])[CH2:3]1)([CH3:34])[CH3:33]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.6 %

Procedure:
To cis-(3RS,5RS)-5-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinecarboxylic acid (0.78 g; 2.8 mmol) in CHCl3 was added Et3N (2.0 ml; 15 mmol), and tert-butyldimethylsilyl chloride (1.06 g; 7.0 mmol). The reaction was allowed to stir for 14 hours under N2 at room temperature. The reaction was diluted with 200 ml of CHCl3 and washed with saturated aqueous NaHCO3, 0.1 N aqueous HCl, saturated aqueous NH4Cl, and brine. The organic layer was dried with Na2SO4, and the solvents were removed to provide the desired compound (0.80 g; 73%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH:5]=[C:4]([NH2:16])[N:3]=1.[N:17]([O-])=[O:18].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[C:5]([N:17]=[O:18])=[C:4]([NH2:16])[N:3]=1
Reactant: Nc1cc(OCC2CC=CCC2)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=O)c(OCC2CC=CCC2)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-diamino-4-cyclohex-3-enylmethyloxypyrimidine (0.5 g, 2.27 mmol) in 30% acetic acid solution was heated to 80° C., and sodium nitrite solution (0.22 g, 3.19 mmol, in 10 ml H2O) was added dropwise over 1 h until excess oxidant was in evidence (starch-iodide paper). The reaction mixture was cooled to room temperature and the resultant violet crystals were collected, washed thoroughly with water and dried (0.52 g, 92%), m.p. 237° C.; δH (200 MHz, d6-DMSO) 1.51-2.19 (7H, m, C6H7), 4.51 (2H, d, OCH2, J=5.66 Hz), 5.82 (2H, br s, C2H2), 7.95 (2H, br s, NH2), 8.15 (1H, br s, NH), 10.21 (1H, br s, NH); m/z (+EI) 249 (M+, 22%), 155 (M+-C7H11, 60), 138 (M+-C7H11O, 100), 69 (24).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[N:9]2)=[CH:4][C:3]=1[F:18].[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1ccn(-c2ccc(Cl)c(F)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2ccc(Cl)c(F)c2)n1
Yield: 95.6 %

Procedure:
To a solution of ethyl 1-(4-chloro-3-fluorophenyl)pyrazole-3-carboxylate (268 mg, 1 mmol) in THF was added 3.0 mL of 1.0M of LiOH (3.0 mmol). The resulting mixture was stirred at room temperature for 3 h at which time 1.0 M of HCl was added to adjust pH to 1.0. The organics were extracted with EtOAc (2×100 mL), followed by drying over MgSO4 and concentrated under reduced pressure to give a white solid (230 mg, 96%), which was used for next step without further purification.