Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([NH:72][CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:42])[CH3:41].C(N(C(C)C)CC)(C)C>ClCCl>[C:40]([O:43][CH2:44][CH2:45][CH2:46][NH:47][C:48](=[O:75])[C@H:49]([N:57]([C:59](=[O:74])[C@H:60]([N:72]([C:13](=[O:15])[CH2:12][O:11][CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:17])[CH3:16])[CH3:73])[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[CH3:58])[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)(=[O:42])[CH3:41]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COCC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of (2-t-butoxycarbonylamino-2-methylpropoxy)acetic acid (504 mg, 2.0 mmol) in dichloromethane (10 ml) were added 1-hydroxy-7-azabenzotriazole (278 mg, 2.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (429 mg, 2.3 mmol) and the mixture was stirred for 30 min. 3-((2R)-2-(N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-propyl acetate (500 mg, 1.0 mmol) in dichloromethane (10 mL) was added followed by diisopropylethylamine (0.23 ml, 1.32 mmol) and the mixture was stirred overnight at room temperature. The mixture was washed with water (10 ml), aqueous sodium bicarbonate (10 ml), water (2×10 ml), brine (10 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (60 g) with ethyl acetate/heptane 4:1 to give 623 mg of 3-((2R)-2-(N-((2R)-2-(N-((2-(tert-butoxycarbonylamino)-2-methylpropoxy)acetyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-propyl acetate as an oil. The obtained product was taken up in 50% trifluoroacetic acid in dichloromethane (3 ml) and stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined is organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The product was redissolved in water (30 ml) and the mixture was liophilized to give 434 mg of the title compound as an amorphous powder.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([OH:10])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:5].[CH3:11]OS(OC)(=O)=O>O1CCCC1>[CH3:11][O:10][C:4]([CH3:5])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH3:3]
Reactant: C=CCCC(C)(C)O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCC(C)(C)OC

Procedure:
To a stirred suspension of sodium hydride (46.8 g of a 60% oil dispersion, 1.15 mol) in tetrahydrofuran (240 mL) was added 2-methylhex-5-en-2-ol (120 g, 1.05 mol) in tetrahydrofuran (240 mL). Dimethylsulfate (75 mL, 0.79 mol) in tetrahydrofuran (120 mL) was added to the cooled (0~C) mixture. The mixture was heated at reflux for 6 hours. Workup yielded 2-methoxy-2-methylhex-5-ene, bp40 53-58~C (51.36 g); NMR(CDC13)δ1.1(s,6H), 1.5-1.6(m,2H), 2.0-2.2(m,2H), 3.2(s,3H), 4.8-5.1(m,2H),5.7-6.0(m,1H); IR(neat) 2960, 2925, 1640, 1460, 1360, 1300, 1085 cm-1 ; MS(m/e) 43, 55, 73, 81, 95, 97, 113, 114.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: BrCc1ccccc1
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(C=O)c1OCc1ccccc1
Yield: 93 %

Procedure:
A mixture of 196.0 g (1.30 mole) of o-vanillin (Aldrich), 200 g of benzyl bromide (Aldrich), 500 g of anhydrous potassium carbonate and 1,500 mL of absolute ethanol is heated, with stirring, at reflux for 6 hours. After cooling, the supernatant is decanted and the remainder is filtered. The combined filtrate and supernatant is concentrated at reduced pressure to remove solvent. The remaining oil is extracted into 1 L of ether. The ether solution is washed with 500 mL of water, 600 mL of 1% potassium hydroxide solution, and 500 mL of water and then dried (potassium carbonate) and concentrated to give 263.4 g (84% yield) of product; mp 41-43° C. Reported mp, 43° C. (Chem. Abstr. 62: 16110a).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:15](=[O:16])[NH:14][C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1.[CH2:17](Br)[CH3:18]>CN(C)C=O>[Br:3][C:4]1[C:15](=[O:16])[N:14]([CH2:17][CH3:18])[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: CSc1ncc2cc(Br)c(=O)[nH]c2n1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of NaH (60%, 0.15 g, 3.75 mmol) in anhydrous dimethylformamide (10 mL) was added 6-bromo-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (2, 0.68 g, 2.50 mmol) at room temperature and the reaction was stirred at 50° C. for 0.5 h. The reaction mixture was cooled to room temperature, ethyl bromide (0.22 mL, 0.32 g, 2.93 mmol) was added, and the reaction was stirred at 50° C. for 1.5 h. The mixture was poured into ice water (10 g), and the white precipitate was collected to give 6-bromo-8-ethyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3, 0.57 g, 1.90 mmol, 76%). ESMS m/z 300 (M+H)+. The material was used without any further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:7]2=[O:14].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-amino-6-methoxy-1-oxoisoquinolin-2(1H)-yl)propanamide (98.34 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature overnight. the solvent was removed under reduced pressure and the residue purified by reverse phase preparative HPLC to afford the product as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:26][C:25]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(F)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(F)cc1
Yield: 24.3 %

Procedure:
Ethyl 3-(4-fluorophenyl)-2-hydroxyimino-3-oxopropionate (33.5 g) and 4-nitrobenzylamine (23.7 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-fluorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (12.1 g),whichwasdissolvedinethylalcohol. 1MSodiumhydroxidesolution was added and the mixture was reacted and treated in the same manner as in.Starting Material Synthetic Example 2 to give 5-(4-fluorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid (10.3 g), melting point 173-178° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][N:14](C=O)C>C(OCC)(=O)C.O>[C:13]([C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8])#[N:14]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 130 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
2-(3-Bromo-4-fluorophenyl)acetic acid (64 g, 275 mmol) was diluted with DMF (400 mL) followed by the addition of Cu(I)CN (49 g, 549 mmol). The reaction was heated to 130° C. and stirred for 12 hours. The reaction was allowed to cool and diluted with ethyl acetate and water, and the mixture was filtered. The organic layer was washed with water, 1N HCl, water and the brine. The organic layer was dried over MgSO4, filtered and concentrated to yield 2-(3-cyano-4-fluorophenyl)acetic acid (36 g, 73% yield) as light yellow oil that solidified to a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].C(=O)([O-])[O-].[K+].[K+].[CH2:22](I)[CH3:23]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH2:22][CH3:23]
Reactant: CCI
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 5 h
Yield: 56 %

Procedure:
7.9 g (0.03 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 3.0 g (0.022 M) of ground potassium carbonate, 3.0 ml (0.04 M) of ethyliodide and 100 ml of acetone are mixed and then boiled for 5 hours. The acetone then is distilled off. The residue is washed with water and filtered. 6.8 g (80.5 % of the theoretical yield) of N-(2,6-dichlorophenyl)-N'-acetyl-S-ethylisothiourea with a melting point of 97°-100° are obtained. After recrystallization from ethyl alcohol the product has a melting point of 99°-102° C. The yield is 56 % of the theoretical one.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]2[CH2:9][CH2:8]2)=O)[CH2:3][CH2:2]1.O(C)S(C(F)(F)F)(=O)=O.[CH2:19]([C:24]12[CH2:31][CH2:30][C:27]([C:32]([NH:34][NH2:35])=O)([CH2:28][CH2:29]1)[CH2:26][CH2:25]2)[CH2:20][CH2:21][CH2:22][CH3:23].CN(C=O)C.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:7]1([C:5]2[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:32]([C:27]34[CH2:28][CH2:29][C:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:31][CH2:30]3)[CH2:25][CH2:26]4)=[N:34][N:35]=2)[CH2:9][CH2:8]1
Reactant: CCCCCC12CCC(C(=O)NN)(CC1)CC2
Reactant: O=C(NC1CC1)C1CC1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCC12CCC(c3nnc(C4CC4)n3C3CC3)(CC1)CC2
Temperature: 130 °C

Procedure:
To a solution of N-cyclopropylcyclopropanecarboxamide (2-A) (26 mg, 0.210 mmol) in 0.50 ml toluene was added methyl triflate (1.45 mg, 1 eq) and the reaction was heated at 100° C. for 5-7 min until all of the amide went into solution. To this crude solution was added 0.740 mL of a 0.3 M solution of 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide in DMF (1.1 eq, crude, prepared as described in Step A of Example 1) followed by triethylamine (0.059 mL, 2 eq) and the mixture was heated at 130° C. for 4 h. After this time the solvent was removed under reduced pressure, and the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TPA). The fractions containing the compound were determined by LCMS, added to 200 mL of methylene chloride, and extracted with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under diminished. The residue was lyophilized from benzene to afford 3,4-dicyclopropyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (2-B); MS (ESI+)=328.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[H-].C([Na])#N.[NH2:26][C:27]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:28]=1[CH:29]([OH:45])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:31]=1>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:26][C:27]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:28]=2[CH:29]([OH:45])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:44])[CH3:42])=[O:39])[CH:31]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [H-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCCc2ccc(OCc3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example 1-(2) (0.5 g) and 4-benzyloxyphenylacetaldehyde (0.4 g). To the solution were added acetic acid (0.1 g) and, subsequently, cyano sodium hydride (0.11 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was diluted with ethyl acetate (60 ml), which was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 2-[2-(4-benzyloxyphenyl)ethyl]amino-α-(3-tert-butoxycarbonylaminomethylphenyl)-5-chloro-benzyl alcohol (0.45 g) as a colorless oily product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(#N)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([Cl:31])[CH:33]=3)=[CH:16][CH:15]=[C:14]([C:19]([F:21])([F:22])[F:20])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2N)CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.1 %

Procedure:
To a mixture of 0.150 g (0.453 mmol) of (3′-amino-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (3 mL) is added 0.19 mL (1.4 mmol) of triethylamine followed by 0.069 mL (0.54 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred overnight at room temperature then an additional 0.21 mL (1.6 mmol) of 3-chlorobenzoyl chloride is added and the mixture is stirred for an additional two days. The mixture is concentrated under reduced pressure and purified by flash silica gel chromatography to provide 0.23 g (quant.) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].O1CCCC1.[C:10]12[CH2:16][C:13](=[CH:14][CH:15]=1)[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]2=1.[OH-].[Na+]>O.[BH4-].[Na+]>[NH2:1][C:15]1[CH:14]=[C:13]2[CH2:16][C:10]=1[C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]2=1
Reactant: [N-]=[N+]=[N-]
Reactant: C1=C2CC(=C1)c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC1=C2CC(=C1)c1ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium azide (2 g) was combined with water (40 ml) and tetrahydrofuran (40 ml) and cooled to 0° C. Mercuric acetate (4g) was added to the cold solution and the mixture was stirred for 20 minutes. Benzobicyclo[2.2.1]heptadiene (2 g) was added to the stirred mixture and the resulting mixture was heated to 75° C. for 24 hours. The solution was cooled to room temperature, treated with 10% sodium hydroxide in water (10 ml) and sodium borohydride (0.4 g), and stirred for 1 hour. The two layers were separated and the organic layer was dried over magnesium sulfate and the solvent removed on a rotary evaporator. The residue was combined with tetrahydrofuran (20 ml) and added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 3 hours, treated with water (1 ml) and filtered. The solvent was removed on a rotary evaporator to provide the product as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][OH:9])[CH:2]=1.[CH2:10]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18])[C:11]#[CH:12]>C(Cl)(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[C:11]([CH2:10][N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[O:9][N:8]=2)[CH:2]=1
Reactant: ON=Cc1cccnc1
Reactant: C#CCN1CCCC1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1CCCN1Cc1cc(-c2cccnc2)no1
Yield: 35.4 %

Procedure:
The desired compound was prepared by the method of Example 8 from 500 mg (4.09 mmol) of 3-pyridine aldoxime and 1.0 g (2 equivalents) of 1-propargyl pyrrolidin-2-one prepared in Example 7, and purified by separation with silica gel column chromatography using ethyl acetate and then chloroform/methanol (30:1) to obtain 352.2 mg (35.4% yield) of 1-(3-pyridin-3-yl-isoxazol-5-yl-methyl)-pyrrolidin-2-one.
Reaction SMILES: [Na].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].Cl[CH2:12][C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=2[O:16][C:17]=1[CH3:18].Cl>C(O)C.O>[CH2:9]([O:8][C:2]([CH:3]([C:4](=[O:5])[CH3:6])[CH2:12][C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:15]=2[O:16][C:17]=1[CH3:18])=[O:7])[CH3:10]
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cc1c(C)oc2c([N+](=O)[O-])cccc12)C(C)=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a solution of sodium (52 mg) in ethanol (5 ml) was added ethyl acetoacetate (293 mg) and 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (339 mg). The mixture was stirred at 60° C. for 3 hours, cooled and poured into cold water. The pH of the aqueous solution was adjusted to 3 with 1N-hydrochloric acid and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from n-hexane to give 3-(2-ethoxycarbonyl-3-oxobutyl)-2-methyl-7-nitrobenzo[b]furan (205 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][N:6]=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1([C:44]([O:46][CH3:47])=[O:45])[CH2:43][CH2:42][CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:47][O:46][C:44]([C:40]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:2]#[C:1][C:3]2[C:8]([C:9]([F:10])([F:12])[F:11])=[CH:7][N:6]=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:4]=2)[CH2:43][CH2:42][CH2:41]1)=[O:45]
Reactant: COC(=O)C1(c2ccccc2I)CCC1
Reactant: C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1

Procedure:
A suspension of tert-butyl 4-(4-((4-ethynyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A51 (169 mg, 0.380 mmol), methyl 1-(2-iodophenyl)cyclobutanecarboxylate A53 (100 mg, 0.316 mmol), PPh3 (8 mg, 0.03 mmol) and CuI (3 mg, 0.02 mmol) in DMF (3 mL) and Et3N (0.5 mL) was sonicated for 10 minutes before PdCl2(PPh3)2 (22 mg, 0.032 mmol) was added. The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes, adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C. (column run twice)) to give the title compound A54 as a yellow oil (33 mg, 16%). LCMS-A: rt 7.919 min; m/z 635 [M+H]+.
Reaction SMILES: CS(C)=O.[CH:5]1([CH2:11][CH2:12][OH:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH:5]1([CH2:11][CH:12]=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OCCC1CCCCC1
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC1CCCCC1
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Dimethyl sulfoxide (DMSO) (3.3 ml, 58.5 mmol) was added dropwise at -78° C. to a solution of oxazolyl dichloride (3.6 ml, 46.8 mmol) in methylene chloride and the mixture was stirred for 15 minutes. To the resulting mixture, a solution of 2-cyclohexylethanol (5.5 ml, 39.0 mmol) in methylene chloride was added dropwise and the mixture was stirred at -78° C. for 1 hour. The reaction was stopped by adding triethylamine (20 ml) and water (100 ml). The reaction mixture was extracted 3 times with diethyl ether. The organic layer was washed 3 times each with saturated aqueous solutions of ammonium chloride and NaCl and dried over anhydrous sodium sulfate. After the solvent was distilled off, the obtained oil was applied to a silica gel column (2.5×40 cm) and eluted with a mixed solution (chloroform:methanol=10:1). The desired fractions were collected and the solvents were distilled off to yield cyclohexylacetaldehyde (2.88 g, 58.4%) as an oil. The same procedure as in Example 2-(2) was performed with ethyl isobutyrate (2.14 ml, 17.8 mmol) and the obtained cyclohexylacetaldehyde (2.25 g, 17.8 mmol) to yield a crystal of 4-cyclohexylmethyl-3,3-dimethyl-2-azetidinone (0.46 g, 13.3%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH2:21][CH3:22])=[N:18][N:17](C(OC(C)(C)C)=O)[C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:30])[C:5]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:19]([O:20][CH2:21][CH3:22])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[O:9])=[C:6]([F:30])[C:5]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OCC)nn3C(=O)OC(C)(C)C)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]nc(OCC)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
A mixture of tert-butyl 5-(6-chloro-2-fluoro-3-(propylsulfonamido)benzamido)-3-ethoxy-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.090 g, 0.162 mmol) and TFA (3.12 mL, 40.5 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using toluene to azeotrope. The crude material was purified by silica gel flash column chromatography (5% 7N NH3-MeOH in CH2Cl2) to afford 6-chloro-N-(3-ethoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-fluoro-3-(propylsulfonamido)benzamide (40 mg, 54% yield). LRMS (ACPI pos) m/e 456.1 (M+1). 1H NMR (400 MHz, d6-DMSO) δ 12.57 (s, 1H), 11.08 (s, 1H), 9.98 (br s, 1H), 8.55 (d, 1H), 8.50 (d, 1H), 7.55 (t, 1H), 7.46 (d, 1H), 4.40 (q, 2H), 3.16 (t, 2H), 1.75 (m, 2H), 1.42 (t, 3H), 0.99 (t, 3H); 19F NMR (376 MHz, DMSO) δ−124.0.