Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]([CH3:28])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:26]3[C:25]4[N:24]=[C:23]([Cl:27])[CH:22]=[CH:21][C:20]=4[N:19]=[CH:18][C:17]=3[N:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[Li+].[OH-]>C1COCC1.CO>[Cl:27][C:23]1[CH:22]=[CH:21][C:20]2[N:19]=[CH:18][C:17]3[N:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C@@H:5]([OH:4])[CH3:28])[CH2:9][CH2:10]4)[C:26]=3[C:25]=2[N:24]=1
Reactant: CC(=O)O[C@@H](C)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-1-oxopropan-2-yl acetate (1.2 g, 2.97 mmol) in a mixture of THF (30 mL) and MeOH (30 mL), was added LiOH (650 mg, 14.9 mmol) drop-wise. The mixture was stirred at room temperature for 3 h. After concentration in vacuo, the residue was diluted with water and the pH was adjusted to 7 with 2N HCl. The resulting mixture was concentrated and the precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford (S)-1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-hydroxypropan-1-one as yellow solid. The crude product was used in next step without further purification. (918 mg, yield 85.4%). MS (m/z): 361 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24]O)([CH3:23])([CH3:22])[CH3:21]>[Mo](=O)(=O)=O.C1(C(C)C)C=CC=CC=1>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:24][C:20]([C:23]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)([CH3:22])[CH3:21])[C:12]([CH3:19])([CH3:18])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: CC(C)c1ccccc1
Product: CC(C)(ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C)c1ccccc1
Temperature: 95 °C
Yield: 76 %

Procedure:
A mixture of 10.1 g (38.6 mmol) of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 15.6 g (155 mmol) of 90% aqueous tert-butyl hydroperoxide, 600 mg of molybdenum trioxide and 60 ml of cumene is heated at 95° C. for two hours. The catalyst is removed by filtration and the filtrate is then evaporated at reduced pressure. The residual red oil is chromatographed on silica gel to afford 5.8 g (38% yield) of a white powder, m.p. 105°-108° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH:12]=[CH2:13])[C:5](=[O:10])[C:6]([O:8]C)=[O:7])[CH:2]=[CH2:3].[OH-].[Na+]>CO>[CH2:11]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:10])[C:6]([OH:8])=[O:7])[CH:12]=[CH2:13]
Reactant: C=CCN(CC=C)C(=O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCN(CC=C)C(=O)C(=O)O
Yield: 83 %

Procedure:
600 mg of methyl N,N-di-allyloxamate was dissolved in 20 ml of methanol. The resulting solution was stirred under ice-cooling, to which 15 ml of 1N aqueous solution of sodium hydroxide was added dropwise. After completion of the dropwise addition, the resultant mixture was stirred for 1 hour at room temperature. The resulting reaction solution was distilled to a volume of about 10 ml at room temperature under reduced pressure. The concentrated solution was adjusted to pH 4 by addition of 1N HCl, followed by extraction with 50 ml of ethyl acetate. The extract solution was washed with saturated saline and dried over anhydrous sodium sulfate added. After filtration, the organic layer (the solution) was concentrated under reduced pressure, to afford 460 mg of the title compound, N,N-di-allyloxamic acid as white solids.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:24].[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[C@H:27]([CH2:25][CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[C:3]([F:24])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1F
Yield: 57.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-3-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 66 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (246 mg) was obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[CH3:26][S:27][C:28]1[N:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][N:29]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH:34]([C:31]3[CH:30]=[N:29][C:28]([S:27][CH3:26])=[N:33][CH:32]=3)[OH:35])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: CSc1ncc(C=O)cn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ncc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 5 °C
Yield: 79.6 %

Procedure:
To a solution of 1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 4.36 g, 10.4 mmol) in tetrahydrofuran (100.0 mL) at −40° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran. 5.06 mL) was added slowly. The reaction was allowed to warm to 5° C. over 60 minutes, then cooled to −40° C., followed by adding 2-methylsulfanyl-pyrimidine-5-carbaldehyde (607, 1.30 g, 8.43 mmol, dissolved in tetrahydrofuran 15.0 mL). The reaction was allowed to warm to 10° C. over 2 hours. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (608, 3.00 g, 79.6%). MS (ESI) [M+H+]+=447.2.
Reaction SMILES: CO.[BH4-].[Na+].[CH2:5]([N:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:13]([C:15](=[O:20])[CH:16]=[C:17]([CH3:19])[CH3:18])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Ce+3].[Cl-].[Cl-]>O>[CH2:5]([N:12]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@H:13]([CH:15]([OH:20])[CH:16]=[C:17]([CH3:18])[CH3:19])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)=CC(=O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C)=CC(O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 7 h
Yield: 82.8 %

Procedure:
A methanol solution (10 ml) containing sodium borohydride (1.5 g) and (S)-2-(dibenzylamino)-5-methyl-4-hexen-3-one (4.2 g) obtained in the 3rd step were added to an MeOH (30 ml) solution containing cerium chloride (10 g), followed by stirring for 7 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:0.2). A yellow liquid of (2S)-2-(dibenzylamino)-5-methyl-4-hexen-3-ol (3.5 g) was thus obtained.
Reaction SMILES: [C:1]12([C:11]3[CH:23]=[CH:22][C:14]([O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:20])([CH3:21])[C:17]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:18])=[CH:22][CH:23]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CN(C)CCN
Reactant: CC(C)(Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)C(=O)O
Product: CN(C)CCNC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 94.1 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid (0.2 g, 0.63 mmol), prepared from the step 2 of example 23, and N,N-dimethylethane-1,2-diamine (0.056 g, 0.63 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide as a white solid (0.228 g, 93.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1.[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:31]([C:36](O)=[O:37])[C@H:32]([CH2:34][CH3:35])[CH3:33].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:42]([O:41][C:39]([NH:30][C@@H:31]([C@@H:32]([CH3:33])[CH2:34][CH3:35])[C:36]([O:18][CH2:17][C@@H:10]1[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]3[S:21][C:22]([C:25]4[O:26][CH:27]=[CH:28][CH:29]=4)=[CH:23][N:24]=3)[CH:4]=2)[O:9]1)=[O:37])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.1 %

Procedure:
A mixture of parent compound 89 (438 mg, 1.0 mmol), N-Boc-Ile (463 mg, 2.0 mmol), EDCI (384 mg, 2.0 mmol) and DMAP (162 mg, 1.3 mmol) in DMF (0.9 mL) was stirred at room temperature for 15 h. The reaction mixture was poured into 1.0 M HCl solution, and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled intermediate (157 mg, 24%). MH+651.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].C(O)C.C(O)(=O)C>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:14]2[CH:13]=[C:12]([N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccccc23)CC1
Yield: 100.4 %

Procedure:
A mixture of 1.5 g (3.8 mmol) of 1-[2-(4-chlorophenyl)-4-quinolinyl]-4-piperidinecarboxylic acid ethyl ester, 2.7 ml of 3N aqueous sodium hydroxide, and 50 ml of ethanol was heated on a steam bath for 0.5 hr. It was then cooled, acidified with acetic acid, and diluted with water to give 1.4 g of product, mp 245°-247°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(CCNCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CCNCc2ccccc2)cc1

Procedure:
The mixture containing [(4-nitrophenyl)ethyl]benzylamine in methanol with catalytic amount of 10% Pd/C was hydrogenated until disappearance of yellow color to yield [(4-aminophenyl)ethyl]benzylamine. MS: MH+=226.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][CH:5]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl.O>CCOCC>[OH:1][CH2:2][CH2:3][N:4]([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:17][CH3:16])[CH:19]=1)[CH2:8][CH2:7][OH:6]
Reactant: COc1cccc(CCl)c1
Reactant: OCCN1CCOC1c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(CC(c2ccccc2)N(CCO)CCO)c1
Yield: 70.7 %

Procedure:
A solution of 3-(2-hydroxyethyl)-2-phenyloxazolidine (11.0 g) in anhydrous ether (30 ml) is added dropwise with stirring to Grignard reagent which is prepared from magnesium turnings (3.3 g) and m-methoxybenzyl chloride (20.7 g) in anhydrous ether (150 ml), and the mixture is refluxed for 3 hours. After the reaction, the reaction mixture is decomposed by adding water thereto. The ether layer is separated and extracted with 10% hydrochloric acid (100 ml). The hydrochloric acid layer is made alkaline with ammonia and extracted with ether. The ether layer is dried over anhydrous sodium sulfate, and the solvent is distilled off to give crude dl-N,N-bis(2-hydroxyethyl)-2-(3-methoxyphenyl)-1-phenylethylamine (12.7 g) as an oily substance. When this substance is recrystallized from ethanol, it shows a melting point of 67°-69° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10](C)([O-])C.[Na+].C(I)C>CO>[CH2:9]([O:8][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH3:10]
Reactant: Oc1cccnc1O
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCI
Solvent: CO
Product: CCOc1cccnc1O
Temperature: 100 °C
Yield: 47.9 %

Procedure:
To a solution of 2,3-dihydroxypyridine (5.0 g, 45.0 mmol, 1.0 equiv) and sodium tert-butoxide (4.33 g, 45.0 mmol, 1.0 equiv) in methanol (25 mL) was added ethyl iodide (5.21 mL, 7.72 g, 49.5 mmol, 1.1 equiv) and the reaction mixture heated to 100° C. under microwave irradiation for 20 min. The solvent was removed and the reaction product dissolved in dichloromethane (50 mL), the obtained suspension filtered and the organic phase concentrated by evaporation under reduced pressure. The crude material was purified by column chromatography on silica eluting with dichloromethane/methanol (9:1) yielding 3.0 g (41%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.50 (t, J=7.0 Hz, 3H), 4.05 (q, J=7.0 Hz, 2H), 6.20 (t, J=7.1 Hz, 1H), 6.76 (dd, J=7.4 Hz, J=1.3 Hz, 1H), 7.05 (dd, J=6.5 Hz, J=1.3 Hz, 1H), 13.36 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23](OCC)=[O:24])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH:23]=[O:24])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c(C)c2-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of (10 mL) ethyl 4-methyl-1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (420 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/l solution (2.1 mL) of diisobutylaluminum hydride in toluene was added dropwise, and the mixture was further stirred at −78° C. for 30 min. 1 mol/l Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (15 mL) of the residue in acetonitrile was cooled to −78° C., tetra-n-propylammonium perruthenate (37 mg), N-methylmorpholine N-oxide (185 mg) and molecular sieves 4A powder (1.0 g) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→1:1) to give the title compound as a brown oil (yield 320 mg, 90%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([N:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])=[O:23].O>CN(C=O)C.C(Cl)Cl.CCCCCCC>[CH2:25]([N:24]([CH2:28][CH2:29][CH3:30])[C:22]([CH2:21][O:5][C:4](=[O:6])[CH2:3][CH2:2][NH:1][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:23])[CH2:26][CH3:27]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of Boc-Beta-Ala-OH (40.0 g, 211 mmol) in DMF (200 ml) at 60° C. under N2 was added potassium carbonate (40.0 g, 289 mmol). To this mixture was added 2-chloro-N,N-dipropyl-acetamide (36.7 g, 207 mmol) in DMF (75 ml). The reaction mixture was allowed to stir at 60° C. overnight. The reaction was allowed to cool to RT and diluted with DCM (400 ml) followed by water (500 ml). The organic layer was separated and washed with brine (200 ml), dried over MgSO4 and concentrated in vacuo to yield a pale yellow oil. To the oil was added n-heptane (500 ml) (azeotrope for DMF) which was concentrated in vacuo to afford the title compound; LC-MS Rt 1.14 mins; 331.3 [M+H]+, Method 2minLC_v003.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:33])([F:32])[O:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1>>[CH3:14][C@@:11]1([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([C:22]([C:21]3[CH:30]=[CH:31][C:18]([O:17][C:16]([F:15])([F:32])[F:33])=[CH:19][CH:20]=3)=[O:23])[CH2:25][CH2:26]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Product: C[C@]1(CN2CCC(C(=O)c3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 36.9 %

Procedure:
Using (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (1.0 g, 4.6 mmol) and 4-(4-trifluoromethoxybenzoyl)piperidine (1.3 g, 4.8 mmol) gave (S)-[l-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-(4-trifluoromethoxyphenyl)methanone (771 mg, yield 37%) as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.CCOCC>C1(C)C=CC=CC=1.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.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:31]1[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 4-chlorophenylboronic acid (0.20 g) in ethanol (1 ml). The mixture was heated under reflux for 3 hours, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:2). Combination and evaporation of suitable fractions followed by recrystallisation from ether/hexane gave the title compound as an off-white solid, m.p. 235-7° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@@H:4]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][C:21]([NH:3][C@@H:4]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 1M solution of NaOH (135 ml, 135 mmol) was added 2(S)-amino-4,4-dimethylpentanoic acid (commercially available) (9.8 g, 67.5 mmol), followed by benzyloxycarbonyl chloride (11.6 ml, 80.99 mmol) in acetonitrile (20 ml) and the reaction mixture was stirred for 12 h at room temperature. The solvent was evaporated using rotavap and the slurry was washed with hexane and then adjusted the pH to 6 using 6N HCl. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to get 2(S)-benzyloxycarbonylamino-4,4-dimethylpentanoic acid (18.6 g) as a sticky gum which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:6][CH2:5]2.[CH3:19][O:20][C:21](=[O:27])[CH2:22][CH2:23][S:24]([O-:26])=[O:25].[Na+]>[Cu]I>[Si:12]([O:11][CH:7]1[C:8]2[C:4](=[CH:3][C:2]([S:24]([CH2:23][CH2:22][C:21]([O:20][CH3:19])=[O:27])(=[O:26])=[O:25])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COC(=O)CCS(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Agent: [Cu]I
Agent: [Na+]
Product: COC(=O)CCS(=O)(=O)c1ccc2c(c1)CCC2O[Si](C)(C)C(C)(C)C
Temperature: 110 °C

Procedure:
[(5-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (1.62 g, 4.95 mmol), sodium 3-methoxy-3-oxopropane-1-sulfinate (3.45 g, 19.8 mmol) and CuI (3.77 g, 19.8 mmol) were charged in a sealable microwave flask. The flask was closed and degassed twice, after which dry DMSO (10 mL) was added and the reaction mixture was degassed before being heated at 110° C. in an oil bath overnight. The reaction mixture was cooled and diluted with ethyl acetate (40 mL), filtered on a silica gel pad, and eluted with ethyl acetate. The organic solvents were concentrated under reduced pressure. The crude concentrate was purified on silica gel eluting with hexanes and ethyl acetate, then with DCM and methanol to afford the title compound.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]2[NH:27][N:28]=[C:29]([NH2:30])[C:21]=12>O1CCCC1>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]2[NH:27][N:28]=[C:29]([NH:30][CH:8]=[C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[C:21]=12
Reactant: Cc1cc(C)c2c(N)n[nH]c2n1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(NC=C3C(=O)Nc4ccccc43)n[nH]c2n1

Procedure:
The named compound is prepared by substituting 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2118 gms. of 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).