Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1.[F:15][C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]2[C:17]=1[C:18]([NH:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[N:39][C:40]=1[N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[C:19]([CH3:33])[C:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:21]2.O1CCOCC1>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.O>[NH2:7][C:8]1[N:13]=[C:12]([C:37]2[CH:36]=[C:35]([NH:34][C:18]3[C:17]4[C:22](=[CH:23][C:24]([F:26])=[CH:25][C:16]=4[F:15])[N:21]=[C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:19]=3[CH3:33])[C:40]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)=[N:39][CH:38]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(-c2ccnc(N)n2)cnc1N1CCOCC1
Temperature: 120 °C

Procedure:
A solution of dichlorobis(triphenylphosphine)palladium(ii) (19.5 mg, 0.028 mmol), sodium carbonate (88 mg, 0.83 mmol), 2-amino-4-chloropyrimidine (35.9 mg, 0.28 mmol), 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.28 mmol; described herein), 1,4-dioxane (6 mL), and water (1.5 mL) was heated in a microwave at 120° C. for 60 min. The reaction was then partitioned between EtOAc and water, and the organic layer dried (magnesium sulfate) and concentrated. Chromatography afforded N-(5-(2-amino-4-pyrimidinyl)-2-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.73-8.79 (1H, m), 8.58 (1H, d, J=2.3 Hz), 8.28 (1H, d, J=5.1 Hz), 7.85-7.96 (2H, m), 7.63-7.70 (1H, m), 7.48-7.59 (2H, m), 7.41 (1H, ddd, J=6.8, 4.7, 2.2 Hz), 6.98-7.10 (2H, m), 5.35 (2H, br. s.), 3.95 (4H, d, J=2.3 Hz), 3.10-3.70 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=527.2 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][C:13]=34)=[CH:21][C:20]([CH:24]=C)=[CH:19][CH:18]=5)[C:8]=2[C:26]([F:29])([F:28])[F:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][C:13]=34)=[CH:21][C:20]([CH:24]=[O:34])=[CH:19][CH:18]=5)[C:8]=2[C:26]([F:27])([F:28])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-6-vinyl-4H-indeno[1,2-c]isoxazole (Preparation 87C, 25 mg, 0.063 mmol) in THF (1 mL) were sequentially added NMO (50% in water, 0.016 mL, 0.076 mmol) and osmium tetroxide (4% in water, 0.012 mL, 1.902 μmol) at room temperature. The solution was vigorously stirred at room temperature for 1 hr before more osmium tetroxide (4% in water, 0.02 mL) was added. The mixture was stirred at room temperature overnight. Sodium periodate (17.63 mg, 0.082 mmol) in water (0.1 mL) was added. After the mixture was stirred vigorously at room temperature under nitrogen for 1 hr, water (2 mL) was added. The mixture was concentrated, the solid was filtered, washed with water (1×0.5 mL) and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-indeno[1,2-c]isoxazole-6-carbaldehyde as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=4)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 99.5 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 3-(trifluoromethyl)aniline (191 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (208 mg, 99%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Product: Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(F)(F)F)cc2=O)n1
Yield: 65 %

Procedure:
Using the method described in Example 11, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 21) and 1-methyl-1H-pyrazol-3-ylamine afforded 3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (78.7 mg, 65%); ES+-HRMS m/e calcd for C23H24N5O3F3 [M+H+] 476.1904 found 476.1902. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (m, 1H), 1.26-1.77 (m, 8H), 1.91 (m, 1H), 2.25 (m, 1H), 3.73 (s, 3H), 5.46 (dd, J=4.6, J=10.5 Hz, 1H), 5.92 (d, J=3.0 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.56-7.60 (m, 2H), 7.83 (t, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 8.17 (d, J=3.0 Hz, 1H), 10.75 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CON
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cl
Product: CON=Cc1ccc(C#N)cc1
Yield: 96 %

Procedure:
Reaction of 4-cyanobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a white solid (96% yield), (Gordon, M. S. et al., J. Org. Chem., 49, 1984, 97–100). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.07 (4H, m, aromatics), 8.06 (1H, s, CH).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.N.[N:13]#[C:14][NH2:15]>O>[NH:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)[C:14]([NH2:15])=[NH:13]
Reactant: N#CN
Reactant: NCc1ccc(C(=O)O)cc1
Agent: N
Solvent: O
Product: N=C(N)NCc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.51 g (10.0 mmol) of 4-aminomethylbenzoic acid, 20 ml of water, 2.0 ml of 28% aqueous ammonia and 1.00 g (23.8 mmol) of cyanamide was stirred at 60° C. overnight. The white precipitate thus formed was taken by the filtration, washed with water and dried to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:10](=[O:12])[CH3:11].[OH:19]O.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:19][C:9]1([C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)C(=Cc1ccccc1C)c1ccncc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C1(c2ccncc2)OC1c1ccccc1C
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3-butene-2-one (step 1) (1.0 g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H2O2 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4 ml) was added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2SO4, filtered and concentrated to give an oil. 4-(2-Methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone was isolated from the oil residue by chromatography.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1.[CH3:13][O-].[Na+].IC>C(O)C>[NH2:1][C:2]1[N:7]([CH3:13])[C:6](=[O:8])[C:5]([CH2:9][CH2:10][OH:11])=[C:4]([CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: Cc1nc(N)[nH]c(=O)c1CCO
Agent: [Na+]
Solvent: CCO
Solvent: CI
Product: Cc1nc(N)n(C)c(=O)c1CCO
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a stirred mixture of 67.7 parts of 2-amino-5-(2-hydroxyethyl)-6-methyl-4(3H)-pyrimidinone and 800 parts of ethanol were added 80 parts of a sodium methoxide solution 30%. The reaction mixture was heated to reflux temperature and 62.5 parts of iodomethane were added dropwise. Upon complete addition, stirring was continued for 4 hours at reflux temperature. The reaction mixture was evaporated and the residue was suspended in 400 parts of water. The precipitated product was filtered off, washed with 40 parts of ethanol and dried, yielding 58.3 parts (79.6%) of 2-amino-5-(2-hydroxy-ethyl)-3,6-dimethyl-4(3H)-pyrimidinone (interm. 12).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12].[C:13]([O-:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na+]>CN(C=O)C>[C:13]([O:21][CH2:2][C:3]1[C:8]([Cl:9])=[C:7]([F:10])[N:6]=[C:5]([F:11])[C:4]=1[Cl:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Fc1nc(F)c(Cl)c(CBr)c1Cl
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1c(Cl)c(F)nc(F)c1Cl)c1ccccc1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
To a stirred DMF (90 ml) in an ice bath, 4-(bromomethyl)-3,5-dichloro-2,6-difluoropyridine (20 g, 72 mmol) and sodium benzoate (15 g, 104 mmol) were added. After 1 hr., the mixture was stirred in a water bath for ca. 20 hr. The product was then extracted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The light brown oil was purified by silica gel column chromatography (eluent, ether:hexane (1:15) to afford 18.6 g (81%) of (3,5-dichloro-2,6-difluoropyridin-4-yl)methyl benzoate as a colorless oil. 1H NMR (200 MHz, CDCl3) δ 5.61 (2H, s), 7.40-7.64 (3H, m), 8.00-8.05 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH3:28])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC1CCCCC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN(C)C3CCCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (400 mg, 1.03 mmol, Example 56, Step D) in dioxane (10 mL) was added N-methylcyclohexylamine (1.3 mL, 10.3 mmol). The mixture was stirred at 80° C. overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (5%-15% methanol in methylene chloride) to give 250 mg (60%) of the desired product as a white solid: mp 122-124° C.; MS(APCI+): m/z 405.2 (MH+); Anal. Calcd for C26H32N2O2.0.5H2O: C, 75.51; H, 8.04; N, 6.77. Found: C, 75.25; H, 8.04; N, 6.78.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[O:10][CH2:11][C:12]1[S:16][C:15](=[S:17])[NH:14][N:13]=1)([CH3:6])[CH3:5].I[CH3:27]>CO>[CH3:23][C:22]([C:19]1[CH:18]=[C:9]([O:10][CH2:11][C:12]2[S:16][C:15]([S:17][CH3:27])=[N:14][N:13]=2)[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:20]=1[OH:21])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(OCc2n[nH]c(=S)s2)cc(C(C)(C)C)c1O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(COc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reaction time: 0.5 h

Procedure:
A solution of 1N sodium hydroxide (1.05 mL, 1.05 mmol) is added over 5 minutes to a solution of 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]-methyl]-1,3,4-thiadiazole-2(3H)-thione (0.37 g, 1.05 mmol) and iodomethane (0.26 mL, 4.20 mmol) in methanol (10 mL). The reaction is stirred for 30 minutes, then the pink precipitate is filtered and washed with methanol/water. A second crop is collected, and the combined precipitate is (71%) of pink platelets which are 2,6-bis(1,1-dimethylethyl)-4-[(5-methylthio-1,3,4-thiadiazol-2-yl)methoxy]phenol; mp 128.0°-129.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC2=CC(O)=CCC2CC1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-(t-Butyloxycarbonyl)-7-hydroxy-tetrahydro-isoquinoline-3-carboxylic acid (0.5 g, 1.71 mmol) was dissolved in 10% MeOH/CHCl3 (70 mL). The solution was cooled to 0° C. and trimethylsilyldiazomethane (2 M in hexane) (1.88 mL, 3.76 mmol) was added dropwise via syringe. A yellow color persisted after addittion of 1.2 mL of this reagent. The cooling bath was removed and the solution was stirred at 25° C. for 0.75 hr. The reaction was cooled to 0° C. and acetic acid was added dropwise until the yellow color disappeared. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and evaporation in the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:38]>CO>[ClH:38].[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:37])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])[S:15][C:8]=12
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetyl isocyanate (83 mg, 0.62 mmoL) [J. Hill et al. JACS, 62: 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc. A white solid was obtained, which was suspended in MeOH and treated with HCl (1 mL, 1.0M in Et2O) to form a clear solution. The solution was concentrated to form a precipitate which was collected by filtration, to afford the title compound 305a (48 mg, 33% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.05(s, 1H), 10.62(s, 1H), 8.57(d, 1H), 8.02(s, 1H), 7.81(d, 1H), 7.48-7.43(m, 2H), 7.33-7.25(m, 5H), 6.74(d, 1H), 3.85(t, 2H), 3.78(s, 2H), 3.51(t, 2H), 1.98-1.86(m, 2H). MS (m/z): 519.2(M+H) (found).
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([CH2:12]I)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Si:1]([N:8]1[C@@H:11]([CH2:12][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CI
Reactant: C1CCNCC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CN1CCCCC1
Yield: 71 %

Procedure:
1-(tert-butyldimethylsilyl)-4(R)-(iodomethyl)-azetidin-2-one (202 mg, 0.62 mmol) was heated at reflux in piperidine (5 mL) for 2 h. The solution was concentrated, dissolved in CH2Cl2 and washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to give 1-(tert-butyldimethylsilyl)-4(R)-(piperidin-1-ylmethyl)azetidin-2-one (116 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 3.70-3.63 (m, 1H), 3.16 (dd, J=15.3, 5.4 Hz, 1H), 2.70-2.61 (m, 2H), 2.45-2.26 (m, 5H), 1.60-1.53 (m, 4H), 1.46-1.38 (m, 2H), 0.96 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[N+:12]([C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18])([O-:14])=[O:13].Cl>O.O1CCOCC1>[N+:12]([C:15]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:16]=1[C:17]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:18])([O-:14])=[O:13]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
To an ice cold suspension of glycine (1.01 g, 13.56 mmol) in water (20 mL) was added Na2CO3 (1.437 g, 13.56 mmol) and stirred for 10 min. A solution of 2,4-dinitrobenzoyl chloride (prepared from 2,4-dinitrobenzoic acid, 2.3 g with SOCl2, 20 mL) in dioxane (20 mL) was added to the above solution and stirred at rt for 4 h. The reaction mixture was diluted with ice cold water and acidified with cold dil. HCl (pH: 6.0). The solution was extracted with EtOAc (5×100 mL) and the combined organic layer was dried over anhyd Na2SO4 and filtered. The solution was evaporated and the residue was chromatographed over silica gel column using chloroform:methanol (95:5) as eluents to give the product as a white color solid (2.5 g, 85%), mp 188-190° C. 1H NMR (400 MHz, DMSO-d6): δ 12.79 (1H, br s), 9.29 (1H, t, J=5.4 Hz), 8.77 (1H, d, J=2.0 Hz), 8.64 (1H, dd, J=8.4, 2.0 Hz), 7.89 (1H, d, J=8.4 Hz), 3.99 (2H, d, J=6.0 Hz); LC-MS (negative ion mode): m/z 268 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)[CH:25]=2)[C:20](=[O:32])[NH:19][C:18]1=[O:33]>CN(C)C=O>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:32])[NH:19][C:18](=[O:33])[C:17]2=[CH:16][NH:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-c3ccco3)cc21
Reactant: CCCOc1cnc(CN)cc1O
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(-c4ccco4)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (73 mg, 0.40 mmole), 5 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-(furan-2-yl)-4H-isoquinoline-1,3-dione (108 mg, 0.40 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a pale yellow solid, 139 mg, (83%); m.p. 288-90° C. dec; MS (ES+): m/z 420.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[OH:15][NH:16][C:17](=N)[CH2:18][O:19][CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:20][O:19][CH2:18][C:17]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C@H:5]3[CH2:6][C@H:4]3[CH2:3][CH2:2][OH:1])[CH2:12][CH2:11]2)[O:15][N:16]=1
Reactant: COCC(=N)NO
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml RBF was added a solution of 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carbonitrile (from Step B, Intermediate 7; 7.5 g, 40 mmol) in 1:1 THF:EtOAc (150 ml). To this solution was added N-hydroxy-2-methoxyethanimidamide (5 g, 45 mmol) as a solid and the resulting mixture was stirred to yield a clear solution. An addition funnel was added to the flask and the whole set up was set under nitrogen atmosphere. The solution was placed in an oil bath heated to 70° C. A 0.5M solution of zinc chloride (100 ml, 50 mmol) in THF was placed in the addition funnel and added over a 5 minute period to the reaction mixture. Upon complete addition, the resulting mixture was stirred at 70° C. for 2 hours. After 30 minutes the clear solution became cloudy. After 1 hour at 70° C., a thick white precipitate formed. TLC indicates consumption of the all starting material. The mixture was cooled to RT and the white solid was filtered off and washed with 1:1 THF:EtOAc (200 mL) and dried. The white solid in the fritted funnel was dissolved in 50 mL of DMF and drawn through by vacuum into a 250 ml RBF. To this solution was then added Tosic Acid (4 g, 20 mmol) and the resulting mixture stirred at 80° C. overnight. The mixture was allow to cool to room temperature and then was diluted with 150 mL of ethyl acetate. The mixture was placed in a separatory funnel and washed with sat'd sodium bicarbonate solution (150 mL). The aqueous was extracted once with ethyl acetate (100 mL) and the organics were combined. The organics were washed with 1M Na2CO3 (50 mL), followed by water (2×100 mL), and then brine (100 mL). The organics were dried over sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was taken up in 50 mL DCM and loaded onto a Flash 75 system (silica gel column). Biotage Flash 75 purification was done eluting with 40-80% ethyl acetate/hexane for 4 column volumes followed by 80% ethyl acetate for 4 column volumes (total solvent 16 L). The fractions containing the product were collected and concentrated under reduced pressure to afford the pure product. LC/MS (m/z): 282 (M+H)+.