Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:20]=3)[CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C([O-])(O)=O.[Na+]>CO>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:20]=3)[CH:17]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1-c1nnc2ccc(-c3ccc([N+](=O)[O-])c(OC)c3)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ccc3nnc(-c4ccccc4OC)n3c2)ccc1N
Temperature: 50 °C
Reaction time: 4 h
Yield: 30.5 %

Procedure:
A flask was charged with 6-(3-methoxy-4-nitrophenyl)-3-(2-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.27 mmol), stannous chloride dihydrate (SnCl2, 300 mg, 1.35 mmol) and MeOH (10 mL). The mixture was stirred at 50° C. under Argon for 4 h. The pH of the mixture was adjusted to around 9 by progressively adding solid NaHCO3, and it was evaporated to afford the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give the title compound (28.5 mg, 31.2% yield) as yellow solids. 1H NMR (DMSO-d6): 7.99 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.67-7.61 (m, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=1.8 Hz, 1H), 7.02 (dd, J=8.1 and 1.8 Hz, 1H), 6.71 (d, J=8.1 Hz, 1H), 5.00 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H). MS: m/z 347.2 [M+H+].
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH2:8]O)=[CH:6][CH:7]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C1COCC1>[C:1]([C:3]1[S:4][C:5]([CH2:8][Br:30])=[CH:6][CH:7]=1)#[N:2]
Reactant: N#Cc1ccc(CO)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 2-cyano-5-(hydroxymethyl)thiophene (6.0 g, 43 mmol) in THF (50 mL) was added triphenylphosphine (15.7 g, 47 mmol) and carbon tetrabromide (12.3 g, 47 mmol). After stirring overnight under nitrogen atmosphere at room temperature, the solvent was removed in vacuo and the residue was dissolved in chloroform, then adsorbed onto silica gel and loaded onto a silica gel column. The product was eluted using an ethyl acetate/hexanes gradient. Fractions containing pure product (as judged by TLC) were pooled and concentrated in vacuo to give 6.5 g (75%) of 2-cyano-5-(bromomethyl)thiophene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1)[CH3:2].[H-].[Na+].Br[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.Cl>CN(C)C=O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][N:8]1[C:9](=[O:16])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[N:7]1
Reactant: BrCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1n[nH]c(=O)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nn(Cc2ccc3ccccc3n2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a solution of ethyl-4-oxo-3H-phthalazin-1-ylacetate (1.0 g) and sodium hydride (60% w/w dispersion in mineral oil) in dimethylformamide (30 ml) was added 2-bromomethylquinoline (1.05 g). The resulting solution was stirred at room temperature for 30 minutes, poured onto water (100 ml) containing 1N HCl (5 ml), and extracted with ethyl acetate. The organic extract was washed with water (3×50 ml), dried and evaporated to obtain ethyl 3-(quinolin-2ylmethyl)-4-oxo-phthalazin-1-ylacetate (1.54 g). This substance was dissolved in a water/dioxane mixture (70 ml/70 ml). To the solution was added 5N potassium hydroxide (5 ml). The solution was allowed to stir at room temperature for 15 minutes, concentrated to remove excess dioxane, diluted with water (150 ml) and extracted with ethyl acetate (3×70 ml). The aqueous layer was adjusted to pH 2 with concentrated HCl. The precipitated solid was triturated with hot ethyl acetate and then filtered to obtain the title compound (0.54 g; m.p. 193°-194° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:27])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH2:8][Br:27]
Reactant: CCOc1ccc(C(=O)c2ccc(C)c(Br)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc(C(=O)c2ccc(CBr)c(Br)c2)cc1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
To a stirred solution of (3-bromo-4-methylphenyl)(4-ethoxyphenyl)methanone (0.864 g, 2.71 mmol) in CCl4 (3.5 mL) were added N-bromosuccimide (0.506 g, 2.84 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg, 0.14 mmol). After being vigorously stirred under reflux at an external temperature of 100° C. for 110 min, additional N-bromosuccimide (0.1 g, 0.56 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg, 0.14 mmol) were added. The mixture was stirred for another 30 min, then cooled with ice-water. The resulting precipitates were collected by filtration and washed with ethyl acetate. The filtrate was washed 3× with 5% citric acid, and dried over Na2SO4. Concentration under reduced pressure gave the crude product which was recrystallized from ethyl acetate to yield 0.54 g of the title compound. 1H NMR (CDCl3, 300 MHz: δ 7.96 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 4.64 (s, 2H), 4.13 (q, J=6.8 Hz, 2H), 1.46 (t, J=6.8 Hz, 3H); MS ESI (m/z) 397 (M+1)+, calc. 396.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>C1C=CC=CC=1>[CH:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:1]2[CH2:3][CH2:2]2)=[O:19])=[CH:21][CH:22]=1)([CH3:13])[CH3:12]
Reactant: C1CN1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(=O)N2CC2)cc1
Yield: 93.5 %

Procedure:
Aziridine (4.52 g) and 10.62 g of triethylamine were dissolved in 200 ml of benzene. p-Isopropylbenzoyl chloride (18.26 g) was dropped thereinto with stirring and keeping the inner temperature at 4° to 5° C. After the dropping, the mixture was stirred for 2 hours at the same temperature. After the reaction, the insoluble matters were removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (300 g of silica gel C-200; the eluting solvent was chloroform) to give 17.70 g of the product, yield: 94%.
Reaction SMILES: C([O:5][C:6](=[O:21])/[CH:7]=[CH:8]/[C:9]1[CH:20]=[N:19][C:12]2[NH:13][C:14](=[O:18])[NH:15][C:16](=[O:17])[C:11]=2[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:18]=[C:14]1[NH:13][C:12]2[N:19]=[CH:20][C:9](/[CH:8]=[CH:7]/[C:6]([OH:21])=[O:5])=[CH:10][C:11]=2[C:16](=[O:17])[NH:15]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Reaction time: 6 h
Yield: 116.4 %

Procedure:
To a suspension of (E)-3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid tert-butyl ester (379 mg, 1.19 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (2 mL). After 6 h, the solvent was concentrated, the resulting solid was treated with anhydrous HCl (10 mL of a 4 M solution in dioxane, 40 mmol) and the mixture was sonicated for 10 min. The mixture was diluted with Et2O and the solution was filtered. The olive solid was dried under high vacuum at 45° C. overnight to give the title compound (323 mg, 91%) as the TFA salt: 1H NMR (300 MHz, DMSO-d6) δ 11.89 (s, 1H), 11.56 (s, 1H), 8.94 (d, J=1.8 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.69 (d, J=16.1 Hz, 1H), 6.72 (d, J=16.1 Hz, 1H), 4.40 (bs, 1H); ESI MS m/e 234 (C10H7N3O4+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
To a mixture of methyl 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzoate (510 mg) in methanol (5 ml) and tetrahydrofuran (5 ml) was added 1N aqueous sodium hydroxide solution (4 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and water was added. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from methanol to give the title compound (467 mg, 94%).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([C:6](=[O:15])[C:7](=[O:14])[NH:8]2)=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+].Cl>CO>[CH3:16][O:17][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]2[C:5]([C:6](=[O:15])[C:7](=[O:14])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=C1Nc2c(ccc(Cl)c2[N+](=O)[O-])C1=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1[N+](=O)[O-])NC(=O)C2=O
Temperature: 60 °C
Reaction time: 14 h
Yield: 69 %

Procedure:
To a solution of 6-chloro-7-nitro-1H-indole-2,3-dione (2.0 g, 8.83 mmol) in methanol (20 mL) was added a solution of sodium methoxide in methanol (28%, 3.8 mL) at room temperature. The mixture was stirred at 60° C. for 14 hr. 1N Hydrogen chloride (10 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (×3), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-100% ethyl acetate/n-hexane gradient mixture to give the title compound (1.349 g, 6.07 mmol, 69%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23]CO)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:23])[N:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:28]#[C:27][CH2:26][OH:29])[CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cccc(C#CCO)c2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 7, Example 32) (80 mg, 0.18 mmol), propargyl alcohol (41 mg, 0.74 mmol), triethylamine (87 μl, 0.63 mmol), CuI (3.5 mg, 0.018 mmol), triphenylphosphine (5 mg, 0.018 mmol) and Pd(PPh3)4 (20 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated and dried using a phase separating cartridge then concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 20-30% ethyl acetate/isohexane), yielding Compound 30 as a solid (26 mg).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[C:16]4[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc(-c4ccnc(C#N)n4)c3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(-c4ccnc(C#N)n4)c3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-(3-(2-cyanopyrimidin-4-yl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (17 mg, 0.035 mmol) was treated with TFA (500 μL) and stirred at room temperature for 1 hour. To the resulting mixture was added 1 N sodium hydroxide solution (1 mL) and ethyl acetate (3 mL), then allowed to keep stirring for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were concentrated under reduced pressure and then purified by chromatography on silica eluting with 60-80% ethyl acetatehexane to give ethyl 4-(3-(2-cyanopyrimidin-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C20H15N6O2[M+H]+: 371, found 371. 1H NMR (600 MHz, DMSO-D6) δ 13.04 (bs, 1H), 9.07 (d, J=5.28 Hz, 1H), 8.97 (s, 1H), 8.49 (m, 2H), 8.38 (m, 2H), 7.91 (d, J=7.63 Hz, 1H), 7.72 (t, J 7.63 Hz, 1H), 3.84 (q, J=7.04 Hz, 2H), 0.84 (t, J=7.04 Hz, 3H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5].[CH3:16][Mg]Br>C1COCC1.C(OCC)C>[C:11]([N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH3:16])[CH:7]=[N:8]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)c1cnn(C(C)(C)C)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cnn(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogen, a solution of 5.87 g (27.7 mmol) 1-tert-butyl-1H-pyrazole-4-carboxylic acid methoxy-methyl-amide in 55 ml THF is cooled to 0° C. and 18.5 ml (55.5 mmol) of a 3 M solution of methylmagnesium bromide in diethyl ether is added dropwise at 0° C. The reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is partitioned between brine and ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(1-tert-butyl-1H-pyrazol-4-yl)-ethanone as white solid; HPLC/MS 1.87 min (B), [M+H] 167;
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CN1CCN(c2ccc(N)c(C(=O)O)c2)CC1
Yield: 43.8 %

Procedure:
The mixture of 9 g of 2-nitro-5-(4-methylpiperazino)benzoic acid, 20 mL of cyclohexene and 3.5 g of Pd/C (10%) is heated under reflux conditions in 120 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 3.5 g of the title compound. m.p.: 212° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:59]1([C:65]2[S:66][C:67]([CH2:70]O)=[CH:68][N:69]=2)[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:70][C:67]2[S:66][C:65]([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[N:69][CH:68]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCc1cnc(-c2ccccc2)s1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cnc(-c3ccccc3)s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2-phenyl-1,3-thiazol-5-yl)methanol (0.8 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.93 g, 63%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](C(O)=O)[CH:7]=[CH:6][C:5]=12.C([N:15](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(Cl)Cl>[NH2:15][C:8]1[CH:7]=[CH:6][C:5]2=[N:1][O:2][N:3]=[C:4]2[CH:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ccc2nonc2c1
Temperature: 105 °C
Reaction time: 4 h
Yield: 40.5 %

Procedure:
To a solution of 2,1,3-benzoxadiazole-5-carboxylic acid (102 mg, 0.621 mmol) in THF (3 mL) was added triethylamine (103 mL, 0.739 mmol) followed by DPPA (160 μL, 0.739 mmol) at room temperature. The mixture was stirred for 4 h, diluted with CH2Cl2 and washed with water. The organic layer was dried over MgSO4, concentrated and purified by flash chromatography on silica gel with 0 to 50% EtOAc in CH2Cl2. The resulting material was dissolved in AcOH (2 mL) and water (0.7 mL) was added dropwise yielding a slightly cloudy solution which was heated at 105° C. for 30 min. The mixture was cooled, made basic with sat. Na2CO3 solution and extracted several times with THF. The combined organic layers were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 0 to 15% MeOH in CH2Cl2 to give 34 mg (41%) of compound 480A as a yellow solid. HPLC: 100% at 1.27 min (retention time) (YMC S5 ODS column, 4.6×50 mm Ballistic, 10-90% aqueous methanol over 4 min containing 0.2% H3PO4, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 136.0 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]([NH:29][CH2:30][CH2:31][OH:32])([CH3:28])[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH2:30][CH2:31][OH:32])[CH:26]([CH3:28])[CH3:27])=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCO
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCO)C(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-isopropylamino-ethanol
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CO.[NH4+:12]>>[NH2:12][CH2:3][C@@H:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1]
Reactant: c1cncc([C@@H]2CO2)c1
Reactant: [NH4+]
Solvent: CO
Product: NC[C@H](O)c1cccnc1

Procedure:
The title compound was prepared from 3-[(2R)-oxiranyl]pyridine (which was obtained in Example 134) and saturated ammonium methanol in substantially the same manner, as described in Example 124. The product was obtained as a brown oil; 1H NMR (300 MHz, DMSO-d6) δ 1.70 (brs, 2 H), 2.62–2.74 (m, 2 H), 4.46–4.50 (m, 1 H), 5.20 (brs, 1 H), 7.30–7.34 (m, 1 H), 7.68–7.71 (m, 1 H), 8.42–8.50 (m, 2 H); MS (ES) m/z: 139 (MH+).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([CH3:32])=[N:28][O:29][C:30]=4[CH3:31])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:40]1([NH2:44])[CH2:43][CH2:42]C1>C1COCC1>[N:44]1([C:22]2[N:21]=[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:37])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])[C:25]([C:26]3[C:27]([CH3:32])=[N:28][O:29][C:30]=3[CH3:31])=[CH:24][N:23]=2)[CH2:40][CH2:43][CH2:42]1
Reactant: Cc1noc(C)c1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: NC1CCC1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cnc(N2CCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 150 °C

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(3,5-dimethylisoxazol-4-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one was dissolved in an excess amount of cyclobutylamine in THF, then heated to 150° C. for 2 hours in a microwave reactor. The reaction mixture was evaporated, then reconstituted in methanol and purified by preparative reverse phase HPLC to give the title compound. LCMS (M+H)+: 556.1. 1H NMR (CDCl3, 500 MHz): δ 8.15 (s, 1H), 7.91 (s, 1H), 7.74 (s, 2H), 5.77 (d, 1H), 4.50-4.30 (m, 6H), 3.92 (t, 1H), 2.53 (m, 2H), 2.32 (d, 3H), 2.16 (d, 3H), 0.77 (d, 3H). RTA IC50: 271 nM.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5](Br)=[C:6]([OH:8])[CH:7]=1.Cl.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].NC1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:15][C:14]1[CH:13]=[CH:12][C:7]2[C:6]([OH:8])=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: C/C=C/C=O
Reactant: Nc1cc(O)c(Br)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Nc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc2c(O)cccc2n1

Procedure:
To a stirred mixture of the 5-amino-2,4-dibromophenol prepared in example 3 (13 g, 49 mmol), acetic acid (65 mL) and HCl (65 mL) was added crotonaldehyde and the resultant mixture was heated at reflux for 1.5 h under argon. HBr (65 mL) and aniline (13 mL) were added and the mixture was refluxed for 5 h. After cooling, the reaction mixture was neutralized by adding of NaHCO3 (˜180 g) and then extracted with EtOAc. The organic extract was dried (MgSO4) and concentrated in vacuo to give a black solid (22 g). The crude product was purified by column chromatography (eluents: CH2Cl2-MeOH 98:2). Yield 5 g (49%) brown-white solid. Rf=0.43 (CH2Cl2-MeOH 9:1).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:11](=O)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]1([CH2:7][N:8]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)/[C:11](=[N:30]/[NH:29][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(c1)N(CC1CCCCC1)C(=O)C2=O
Reactant: NNC(=O)c1ccccc1
Product: COc1ccc2c(c1)N(CC1CCCCC1)C(=O)/C2=N\NC(=O)c1ccccc1

Procedure:
The title compound was prepared as a yellow solid, using 1-cyclohexylmethyl-6-methoxy-isatin and benzhydrazide according to the synthetic method E. NMR (CDCl3-d6): δ 1.01-1.09 (m, 2H), 1.16 to 1.26 (m, 3H), 1.68-1.86 (m, 6H), 3.56 (d, 2H), 6.44 (d, 1H), 6.64 (dd, 1H), 7.51 (t, 2H), 7.58 (t, 1H), 7.80 (d, 1H), 8.01 (d, 2H), 13.98 (br s, 1H).