Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:22])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of (R)-4-benzyl-oxazolidin-2-one (3.0 g, 16.9 mmol) in THF (100 mL) at −78° C. was added n-BuLi (2.5 M hexanes, 7.1 mL, 17.8 mmol) in rapid drops via syringe. The solution was stirred for 20 min at −78° C. Propionyl chloride (1.6 mL, 18.4 mmol) was added rapidly via syringe. The reaction solution was allowed to warm slowly to rt overnight then was quenched by the addition of satd. aq. NH4Cl. The mixture was concentrated, diluted with water, and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give the crude product, which was purified by flash chromatography (EtOAc/hexanes) to afford the title compound as a white solid (3.70 g, 94%). 1H NMR (500 MHz, CDCl3): 7.36-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.23-7.19 (m, 2H), 4.71-4.64 (m, 1H), 4.20 (dd, J=9.1, 7.5, 1H), 4.17 (dd, J=9.1, 3.1, 1H), 3.31 (dd, J=13.4, 3.3, 1H), 2.99 (dq, J=17.9, 7.4, 1H), 2.93 (dq, J=17.9, 7.3, 1H), 2.77 (dd, J=13.4, 9.6, 1H), 1.21 (t, J=7.3, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>O1CCCC1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N:7][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)CCC(=O)O)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 18 %

Procedure:
The 6-amino-3-pyridinecarbonitrile (commercially available, 1.0 g, 8.40 mmol) was dissolved in tetrahydrofuran (20 mL) then succinic anhydride (1.04 g, 10.5 mmol) was added, the mixture was stirred at 100° C. for 12 h. The reaction was stopped and the solution was washed with a saturated solution of sodium carbonate. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography eluting with methanol-ethyl acetate (5/95) to give 4-[(5-cyano-2-pyridyl)amino]-4-oxo-butanoic acid A2 (0.325 g, 18%). M.p.=220-221° C., 1H NMR (400 MHz, DMSO-d6) δ 12.18 (bs, 1H), 11.04 (s, 1H), 8.78 (s, 1H), 8.21 (m, 2H), 2.69 (t, 2H), 2.52 (m, 2H) ppm. LC-MS (Method B): RT 1.00, 218 (M−H+) The following compounds from table A were prepared by the same method:
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[C:10]([CH2:13][C@@H:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])(O)=[O:11]>>[CH2:25]([C@H:14]([CH2:13][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6]1)=[O:11])[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: C1CN(C2CC2)CCN1
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCN(C2CC2)CC1)Cc1ccccc1

Procedure:
Using the mixed anhydride coupling procedure of Example with 1-cyclopropylpiperazine and benzyl (2R)-3-carboxy-2-benzylpropionate (Rosenberg et al., EP 307837, 1989) gave the desired product. 1H NMR (CDCl3) 7.10-7.34 (m, 5H), 5.11 (dd, 2H), 3.51 (m, 2H), 3.31 (m, 3H), 3.04 (dd, 1H), 2.74 (m, 2H), 2.52 (m, 3H), 2.35 (dd, 1H), 0.47 (m, 2H), 0.42 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:5]1[C:6]2[C:7]3[CH:15]=[CH:14][S:13][C:8]=3[C:9](=[O:12])[NH:10][C:11]=2[C:2]([F:1])=[CH:3][C:4]=1[O:16][CH3:17]
Reactant: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1Br
Yield: 60.9 %

Procedure:
Following Step 4 from General Procedure A, 6-fluoro-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.0 g, 4.0 mmol) was reacted with N-bromosuccinimide (570 mg, 4.8 mmol) to afford the desired product (800 mg, 61%) as a brown solid: ESI MS m/z 329 [C12H7BrFNO2S+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:17](Cl)(Cl)=[S:18].O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[C:17]=[S:18]
Reactant: COCCN(CCOC)c1ccccc1N
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: COCCN(CCOC)c1ccccc1N=C=S
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of N,N-bis(2-methyoxyethyl)benzene-1,2-diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice water (50 ml) was added and the mixture extracted with ether (3×20 ml). The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to give a residue which was heated at 45° C. under vacuum (100 mm/Hg) to give 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: C1CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCCCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperidine.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#[N:16].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][NH2:16])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cc(-c2ccccc2)co1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: NCc1cc(-c2ccccc2)co1
Reaction time: 12 h
Yield: 21.8 %

Procedure:
Prepare a solution of 4-phenyl-2-formylfuran (1.5 g, 8.7 mmol) and MeOH (35 mL). Add NH4OAc (6.7 g, 87.1 mmol) and NaCNBH3 (380 mg, 6.1 mmol). Stir the reaction mixture under nitrogen for 12 hours. Upon completion of the reaction, concentrate the resulting mixture, dilute with water (10 mL), basify with 1 N sodium hydroxide, and extract with diethyl ether (2×10 mL). Dry the organic phase (Na2SO4), filter, and concentrate. Perform flash chromatography on silica gel eluting with 9:1 ethyl acetate/MeOH to afford the title compound (230 mg) as a white solid. 1H NMR (CDCl3) δ 7.65 (s, 1H), 7.46 (d, J=7 Hz, 1H), 7.36 (t, J=7 Hz, 1H), 7.26 (m, 1H), 6.49 (s, 1H), 3.89 (s, 2H), 2.10 (s, 2H).
Reaction SMILES: [CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[CH:12][C:11]=3[N:20]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:26].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH:1]([C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N+:13]([O-:26])=[CH:12][C:11]=3[N:20]=[C:8]2[CH2:7][O:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COCc2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 1.25 h
Yield: 100.1 %

Procedure:
(11S)-11-Isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (1.13 g, 4.23 mmol) was dissolved in 40 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (MCPBA) (1.13 g, 77% max). After stirring for 75 minutes, the reaction was treated with 20 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 10 mL of brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give (11S)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (1.20 g) as a crusty, off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:22])[C:3]([O:5][CH2:6]C)=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1.ClC(Cl)(Cl)C([N:39]=C=O)=O>C[O-].[Na+]>[NH2:39][C:13]1[C:12]2[N:11]=[C:10]([CH3:22])[N:9]([CH2:8][C:2]([CH3:1])([CH3:23])[C:3]([O:5][CH3:6])=[O:4])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C)(C)Cn1c(C)nc2cnc3ccccc3c21
Agent: C[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Product: COC(=O)C(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21
Yield: 33.5 %

Procedure:
The methods described in Part B of Example 60 were used to treat ethyl 2,2-dimethyl-3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (7.2 g, 22 mmol) with mCPBA (9.6 g of 77% pure material), followed by trichloroacetyl isocyanate (3.1 mL, 26 mmol), followed by sodium methoxide (20 mL of 25% in methanol). After the collection of the precipitate, the filtrate was concentrated under reduced pressure, and the residue was mixed with methanol (50 mL). The resulting solid was isolated by filtration, and the isolated solids were combined to provide 2.3 g of methyl 3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([NH:7][CH2:8][C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])([CH3:11])[CH3:10])=[CH:5][C:4]=1[C:25]([F:28])([F:27])[F:26])#[N:2].[CH2:29]=O>C(O)(=O)C>[C:1]([C:3]1[CH:24]=[CH:23][C:6]([N:7]2[CH2:8][C:9]([CH3:11])([CH3:10])[N:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[O:14])[CH2:29]2)=[CH:5][C:4]=1[C:25]([F:26])([F:27])[F:28])#[N:2]
Reactant: CC(C)(CNc1ccc(C#N)c(C(F)(F)F)c1)NC(=O)Nc1ccc(F)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: CC1(C)CN(c2ccc(C#N)c(C(F)(F)F)c2)CN1C(=O)Nc1ccc(F)cc1
Temperature: 50 °C

Procedure:
A 1.0 g portion of 1-[2-(4-cyano-3-trifluoromethylanilino)-1,1-dimethylethyl]-3-(4-fluorophenyl)urea synthesized in Reference Example 9-1 was dissolved in 10 ml of acetic acid, and the solution was mixed with 0.4 ml of formalin and heated at 50° C. for 2 hours. The solvent was evaporated, the resulting residue was purified by a silica gel column chromatography, and the compound obtained from chloroform-methanol (30:1, v/v) eluate was washed with diisopropyl ether to obtain 751 mg of the title compound.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:10]([C:12]2[C:13]3[CH:22]=[CH:21][NH:20][C:14]=3[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(N2CCCC2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 35.5 %

Procedure:
A mixture of Example 330a (90 mg, 0.27 mmol) and pyrrolidine (668 μL, 8.08 mmol) in 1 mL DMSO was heated at 160° C. under microwave conditions for 30 minutes. The product was purified by preparative HPLC (C18, 10-80% CH3CN/water (0.1% TFA)) to give the title compound (37 mg, 35.7% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.07 (s, 1H), 7.61 (dd, J=8.8, 2.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.26 (t, J=2.8 Hz, 1H), 7.20 (s, 1H), 6.95 (d, J=8.9 Hz, 1H), 5.99-5.94 (m, 1H), 3.56 (s, 3H), 3.16 (q, J=7.3 Hz, 2H), 3.06 (s, 4H), 1.69 (t, J=6.3 Hz, 4H), 1.10 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 386.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][C:18]1([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][C:18]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1(CO)CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCC1(Nc2nc(Cl)ncc2Br)CCCC1
Temperature: 0 °C

Procedure:
An ice-cooled solution of 2.28 g (10.0 mmol) of 5-Bromo-2,4-dichloropyrimidine and 1.7 ml (12.0 mmol) of triethylamine in 10 ml of acetonitrile is mixed with 1.38 g (12.0 mmol) (1-amino-cyclopentyl)-methanol. After 16 hours at room temperature the batch is filtrated to remove the solid precipitate. The precipitate is dried. 1.48 g (4.8 mmol, corresponding to 48% of theory) of the product is obtained.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH3:9][O:10][C:11](=[O:16])[C:12](Br)([CH3:14])[CH3:13]>>[CH3:9][O:10][C:11](=[O:16])[C:12]([CH3:14])([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH3:13]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COC(=O)C(C)(C)Br
Product: COC(=O)C(C)(C)n1cnc([N+](=O)[O-])c1

Procedure:
4-nitroimidazole was alkylated with 2-Bromo-2-methyl-propionic acid methyl ester to provide the title compound: 1H NMR (400 MHz, CDCl3) 1.89 (s, 6H), 3.78 (s, 3H), 7.59 (d, 1H, J=1.7 Hz), 7.89 (s, 1H, J=1.7 Hz); MS 214.1 m/z (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3Cl)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[C:31]1([CH2:41][NH2:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:24]#[N:25])=[N:18][C:19]=3[NH:42][CH2:41][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33][CH:32]=2)[O:7][C@@H:6]1[CH2:26][O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCc1cccc2ccccc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of (2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (3.0 g, 6.86 mmol) (Preparation 10), 1-naphthalenemethylamine (1.2 g, 7.63 mmol), and triethylamine (2.8 g, 27.72 mmol) in acetonitrile (30 ml) was left to stand at room temperature for 2 hours during which time a fine precipitate slowly formed. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (150 ml) and water (50 ml). The organic phase was separated and the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (4:1 by volume) to give a product which was azeotroped with dichloromethane to afford the title compound as a foam (3.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]O)=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][Cl:33])=[C:12]2[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(CCl)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 98.9 %

Procedure:
To a suspension of 6-(benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.26 g, 3 mmol) in toluene (20 ml) was added thionyl chloride (0.44 ml, 6 mmol). The resulting mixture was refluxed for 2 h. The reaction mixture was added to a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-(benzyloxy)-3-(chloromethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.30 g, 100%) as an oil.
Reaction SMILES: CC(C1C=C(SC(SC2C=C(C(C)(C)C)C([O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35]Br)=C(C(C)(C)C)C=2)(C)C)C=C(C(C)(C)C)C=1O)(C)C.[N+:42]([O-:45])([O-:44])=[O:43].[Ag+]>C(#N)C.C1COCC1>[N+:42]([O:45][CH2:35][CH2:34][CH2:33][C:32]([OH:31])=[O:37])([O-:44])=[O:43]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OC(=O)CCCBr)c(C(C)(C)C)c1
Agent: [Ag+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)CCCO[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 4-bromobutanoic acid [4-[[1-[[3, 5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]ester (150 mg, 0.22 mmol) in acetonitrile/THF (15 ml 2/1 v/v), AgNO3 was added (80 mg, 0.47 mmol) and the solution was heated in the dark at 60° C. for 6 hours. The silver salt was then filtered off (AgBr) and the solvent was evaporated at reduced pressure. The product thus obtained was purified by chromatography on silica gel with a mixture of ethyl acetate/hexane as eluent (4/6 v/v) to give 4-nitrooxybutanoic acid, [4-[[1-[[3,5-bis(1,1-dimethyletihyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis (1,1-dimethylethyl)-phenyl] ester (100 mg).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)[CH3:28]
Reactant: CCOC(=O)COc1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
Benzyl bromide (0.23 mL) was added to a mixture of ethyl (4′-hydroxybiphenyl-4-yloxy)acetate (0.50 g) and potassium carbonate (0.38 g) in N,N-dimethylformamide (5 mL) at room temperature with stirring, and the mixture was stirred at that temperature for 1 hr. Benzyl bromide (0.021 mL) was added to the reaction mixture. After being stirred for 30 minutes, benzyl bromide (0.044 mL) was added, and the mixture was stirred for 30 minutes. The reaction mixture was partitioned between methylene chloride and water, and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3-1/2-2/1) to afford the title compound (0.64 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][O:12][C:13]4[C:22]5[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=5)[N:16]=[CH:15][CH:14]=4)=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][C:27]=1[CH:41]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH3:42]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(C)NC(=O)OC(C)(C)C)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A suspension of 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (180 mg, 527 μmol), tert-butyl 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate (302 mg, 790 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (77.1 mg, 105 μmol), cesium carbonate (686 mg, 2107 μmol) in DMF (2 mL) and water (0.4 mL) was first sparged with argon for 5 min then heated to 100° C. with stirring. 2:20 pm After 10 min, LCMS suggests >95% conversion. Reaction then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (5 mL). Organic then dried over MgSO4, concentrated, and purified on silica (40 g) eluting with isocratic 4% of 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 561 (MH+). Calc'd exact mass for C29H29ClN6O4: 560.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[F:12][C:13]1[CH:14]=[CH:15][C:16](B2OC(C)(C)C(C)(C)O2)=[C:17]([CH:20]=1)[C:18]#[N:19]>>[F:12][C:13]1[CH:20]=[C:17]([C:18]#[N:19])[C:16]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[CH3:11])=[CH:15][CH:14]=1
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(F)cc2C#N)OC1(C)C
Product: Cc1c(-c2ccc(F)cc2C#N)cccc1[N+](=O)[O-]

Procedure:
2-Bromo-6-nitrotoluene and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile were coupled using the procedure described in Example 1 to afford crude 4-fluoro-2′-methyl-3′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 2.32 (3H, s), 7.34-7.46 (5H, m), 7.95 (1H, m).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)C(C)C)C.Cl[CH2:17][C:18](=[O:20])[CH3:19].[N:21]1([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[O:20]=[C:18]([CH3:19])[CH2:17][N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC(=O)CCl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Yield: 58.6 %

Procedure:
Potassium carbonate (1.27 g, 9.22 mmol), N-ethyldiisopropylamine (0.80 ml, 4.61 mmol), and chloroacetone (1.22 ml, 13.83 mmol) were added to a solution of benzyl piperazine-1-carboxylate (2.03 g, 90.22 mmol) in acetonitrile(20 ml), and the mixture was heated under reflux for 2 hours. The insoluble substances were removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(methylene chloride/methanol=100/1) to afford benzyl 4-(2-oxopropyl)piperazine-1-carboxylate (2.24 g, yield 88%) as a pale yellow oil.