Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C-:7]#[N:8].[K+].F[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30].Cl.C#N>CN(C)C=O.O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=[O:28])=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30])#[N:8]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(F)c([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: C#N
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
Potassium carbonate (16.6 g) and potassium cyanide (7.8 g) were added to a solution of 3-[4-fluoro-3-nitrophenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (31.9 g) in 250 ml of anhydrous N,N-dimethylformamide. The reaction mixture was subsequently stirred for a total of 45 hours at 75-80° C., with two further additions of potassium cyanide (in total 4.6 g) since the reaction had not proceeded completely. For working-up, water (250 ml) was added to the reaction mixture after it had cooled. The pH was subsequently brought to 2-3 by adding 60 ml of 1 N. hydrochloric acid. After nitrogen had been passed through the mixture for 4 hours to expel the hydrocyanic acid which had been liberated, the precipitate formed was separated off, washed with water and petroleum ether and dried. Yield: 17.0 g; m.p.: 135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:27])[CH3:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:27])[CH3:26])=[C:8]2[C:16]([Br:35])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2Cc2ccccc2)c1OC(C)=O
Temperature: 90 °C
Yield: 84.7 %

Procedure:
A mixture of 4-acetoxy-1-benzyl-7-cyano-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (225 mg), NBS (116 mg) in MeCN (3 mL) in a closed vial was heated at 90° C. overnight. Then the solvent was removed, the residue was purified with column to give the desired product (232 mg). The title compound, ESI MS (m/z): 442 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1)C(=O)C.[CH3:18][NH:19][CH3:20].C(O)C.C>>[CH3:18][N:19]([CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CC(=O)N(CCCCCl)c1cc(C)cc(C)n1
Reactant: CNC
Solvent: CCO
Product: Cc1cc(C)nc(NCCCCN(C)C)c1

Procedure:
N-(4-Chlorobutyl)-N-(4,6-dimethyl-2-pyridyl)acetamide (28 g., 0.11 mole) is heated with dimethylamine (25 g., 0.55 mole) in 250 mole of ethanol in the presence of cuprous chloride (0.5 g.) for 6 hours at 100°. On cooling the mixture is treated with charcoal, filtered, and then concentrated under vacuum. The residue is taken up in dilute sodium hydroxide and the mixture extracted with diethyl ether, then methylene chloride. The organic extracts are concentrated after washing with water. The residue, weighing 26 g is then refluxed in 5 N sodium hydroxide (200 ml) overnight. On cooling the mixture is extracted with methylene chloride. The organic extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is distilled to obtain the product oil, b.p. 137-142/1.2 mm.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH:21]=1)[O:8][C:9]1[CH:14]=[CH:13][C:12]([P:15](=[O:18])([OH:17])[OH:16])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].CO.[CH3:32]CN=C=NCCCN(C)C.[OH-].[Na+]>CN(C=O)C.N1C=CC=CC=1.O>[CH3:32][O:18][P:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:19]=[C:20]([C:22](=[O:29])[NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)[CH:21]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[CH:10][CH:11]=1)(=[O:17])[OH:16]
Reactant: CC(C)Oc1cc(Oc2ccc(P(=O)(O)O)cc2)cc(C(=O)Nc2nccs2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COP(=O)(O)c1ccc(Oc2cc(OC(C)C)cc(C(=O)Nc3nccs3)c2)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 24.8 %

Procedure:
To a solution of {4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-phenyl}-phosphonic acid (Example 3) (100 mg, 0.225 mmol) in DMF (2 mL) and pyridine (300 μL) was added methanol (91 μL, 2.25 mmol) and EDCI (47 mg, 0.247 mmol). The resulting mixture was subjected to microwave heating at 130° C. for 5 min. Then NaOH (2 mL) was added and the resulting mixture was stirred at rt for 10 min. The residue was partitioned between EtOAc and H2O. The aqueous layer was acidified with HCl (6N) to pH 2 and extracted into EtOAc. The organic layer was washed with brine (2×), dried and concentrated to give an oil. Water was added (10 mL) until a precipitate formed which was filtered and dried to afford 25 mg (25%) of {4-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)phenoxy]phenyl}phosphonic acid monomethyl ester. 1H NMR (500 MHz, DMSO-d6): δ 7.71 (dd, J=12, 9 Hz, 2H), 7.53 (m, 2H), 7.32 (m, 2H), 7.15 (dd, J=9, 3 Hz, 2H), 6.89 (t, J=3 Hz, 1H), 4.76 (m, 1H), 3.52 (d, J=11 Hz, 3H), 1.30 (d, J=6 Hz, 6H); LCMS m/z=449.6 [C20H21N2O6PS+H]+; Anal. Calcd. for (C20H21N2O6PS+0.5H2O): C, 52.51; H, 4.85; N, 6.12. Found: C, 52.54; H, 4.93; N, 6.15.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(CCCC)CCCC)CCC.COCCO>C1(O)CCCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccnc1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCCCN(CCCC)CCCC
Solvent: COCCO
Solvent: OC1CCCCC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccc2F)CC1

Procedure:
A mixture of 2 mmol of 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester, 1 mmol of 2-chloro-3-fluoropyridine, and 1 mmol of tributylamine were heated to reflux in 2 mL of cyclohexanol for 3 days (or 2-methoxyethanol for 14 days) under nitrogen. Preparative TLC eluting with 75:25 ether:hexane gave 4-[(3-fluoro-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester:
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([F:23])[CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][Mg+].[Br-]>C1COCC1.CCOCC>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:13]([C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:12]=2)([OH:14])[CH3:36])=[CH:16][C:17]=1[F:23])#[N:22]
Reactant: C[Mg+]
Reactant: N#Cc1ccc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1F
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(c1ccc(C#N)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-3-fluorophenyl 1-(triphenylmethyl)imidazol-4-yl ketone, as described above in Step B, (7.0 g, 15.3 mmol) in dry THF (280 mL), under argon, at −78° C., was added MeMgBr (5.3 mL of a 3.0M solution in Et2O, 15.9 mmol), dropwise. After 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane—30% to 50% EtOAc, to yield the titled product as pale solid.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].N1C=CC=CC=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1>[C:11]([N:3]([CH3:2])[OH:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CNO
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(O)C(=O)c1ccccc1
Reaction time: 8 h
Yield: 47 %

Procedure:
10.0 g of N-methylhydroxylamine hydrochloride was added to 100 ml of tetrahydrofuran and 19.8 g of pyridine was added to the mixture. To the resulting mixture, there was dropwise added a solution of 16.8 g of benzoyl chloride in 100 ml of tetrahydrofuran at room temperature over one hour with stirring. The stirring was continued for additional 8 hours to proceed the reaction. After addition of 50 ml of dilute hydrochloric acid, the tetrahydrofuran was removed in vacuo and the remaining solution was extracted with ethyl acetate. The resultant extract was dried over anhydrous magnesium sulfate and then the ethyl acetate was removed under reduced pressure. The crude product obtained was purified by column chromatography (packed material: silica gel; eluent: ethyl acetate/hexane) to give 8.5 g of N-benzoyl-N-methylhydroxylamine as an oil having a melting point of not more than 20° C.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C1COCC1.CN(C=O)C.CCOC(C)=O>[N:1]1([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of benzimidazole (5 mmol, 0.97 g) in THF/DMF (5:1, 20 mL) is treated with sodium hydride (0.5 g), stirred for 10 minutes at room temperature, treated with methyl 4-(bromomethyl)benzoate (1.4 g, 6 mmol) and stirred at room temperature overnight. The reaction mixture is diluted with EtOAc, washed with saturated NaHCO3, dried over MgSO4 and concentrated in vacuo to give methyl 4-[(1H-benzoimidazol-1-yl)methyl]benzoate as a solid residue. The residue is dissolved in MeOH/water (2:1), treated with lithium hydroxide (0.42 g, 10 mmol), stirred at room temperature overnight, evaporated to remove the MeOH. The resultant concentrate is diluted with 1N sodium hydroxide (50 mL), washed with EtOAc, acidified with concentrated HCl and extracted with EtOAc. The extracts were combined, dried over MgSO4 and concentrated to dryness to give the title product in 75% yield, identified by NMR and mass spectral analyses. 1H NMR (400 MHz, DMSO-d6): 8.08 (s, 1H); 7.99 (d, J=8 Hz, 2H); 7.78 (d, J=8 Hz, 1H); 7.24-7.27 (m, 5H); 5.49 (s, 2H). LCMS (ESI+) 253 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=O)[NH:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:21])=O>[Cl-].C[N+](C)(C)C>[Cl:21][C:14]1[NH:15][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=[CH:17][C:12]=2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: COc1cccc(-c2ccc3nc(Cl)[nH]c3c2)c1

Procedure:
Heat a mixture of 5-(3-methoxyphenyl)benzimidazolidin-2-one (1.4 g) and tetramethylammonium chloride (ca. 2 g) in phosphorous oxychloride at 100° C. for 8 hours. After cooling, concentrate the mixture in vacuo, triturate with water, and neutralize with ammonium hydroxide. Collect the precipitate and air-dry to obtain 2-chloro-5-(3-methoxyphenyl)benzimidazole.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([CH:9]1[O:13][N:12]=[C:11]([C:14]([O:16]CC)=[O:15])[CH2:10]1)([OH:8])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+]>C(O)C>[F:7][C:4]([F:5])([F:6])[C:3]([CH:9]1[O:13][N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH2:10]1)([OH:8])[C:2]([F:20])([F:19])[F:1]
Reactant: CCOC(=O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1=NOC(C(O)(C(F)(F)F)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of ethyl 5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-4,5-dihydroisoxazole-3-carboxylate from example 8-1 (2.58 g, 8.34 mmol) in ethanol (5 ml) was added 1 N NaOH (16.7 mL). The mixture was stirred at r.t. for 1 h. Ethanol was removed under reduced pressure, and to the aqueous solution was added concentrated HCl (1.5 mL). The product was extracted 3 times with EtOAc and 2 times with isopropyl ether, and the combined organic layers were dried over MgSO4. Solvents were removed under reduced pressure to afford the carboxylic acid intermediate as an off-white solid (2.30 g, 98%). 1H NMR (DMSO-d6) δ 3.2-3.4 (m, 2H), 5.12 (t, 3H), 8.6 (br, 1H); ESIMS: m/z 280 (M−H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1])=[O:15]
Reactant: CN=C=O
Reactant: Cc1[nH]cnc1CNCCN
Product: CNC(=O)NCCNCc1nc[nH]c1C

Procedure:
By the procedure of Example 24, N-(5-methyl-4-imidazolylmethyl)ethylenediamine is reacted with methyl isocyanate to give, after concentrating and separating the residue by column chromatography, the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9](O)(=O)C.S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][C:7]=1[CH3:9]
Reactant: CC(=O)O
Reactant: Cc1ccc(Cl)nn1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: Cc1cc(C)c(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To a mixture of 3-chloro-6-methylpyridazine (0.2 g, 1.55 mmol), acetic acid (0.2 mL, 3.49 mmol), sulphuric acid (0.124 mL, 2.33 mmol) and silver nitrate (0.026 g, 0.16 mmol) in water (4.5 mL) was added dropwise a solution of ammonium persulfate in water (1.5 mL). The mixture was held at 75° C. for 30 minutes, allowed to cool to r.t. and poured onto ice. The mixture was basified to pH 9-10 with ammonium hydroxide and extracted with DCM (50 mL). The organic fraction was washed with aqueous sodium hydroxide (1.0N, 2×15 mL), dried (MgSO4), concentrated in vacuo and purified by preparative HPLC (Method 6). The product was dissolved in DCM (15 mL), washed with aqueous potassium carbonate solution (0.7M) and concentrated in vacuo to give the title compound (0.111 g, 50%) as a pink solid. δH (DMSO-d6) 7.62 (1H, s), 2.57-2.54 (3H, m), 2.33 (3H, s). LCMS (ES+) 142.97 (M+H)+, RT 1.93 minutes (Method 1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19](O)=[O:20].[Si:22]([O:29][CH2:30][CH2:31][N:32]1[C:40]2[CH2:39][CH2:38][CH2:37][CH:36]([NH2:41])[C:35]=2[CH:34]=[N:33]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Si:22]([O:29][CH2:30][CH2:31][N:32]1[C:40]2[CH2:39][CH2:38][CH2:37][CH:36]([NH:41][C:19](=[O:20])[CH2:18][C@@H:3]3[C:2](=[O:1])[NH:7][CH2:6][CH2:5][N:4]3[S:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:15])=[CH:16][CH:17]=3)(=[O:10])=[O:9])[C:35]=2[CH:34]=[N:33]1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2CC(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ncc2c1CCCC2N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCNC(=O)[C@H]2CC(=O)NC2CCCc3c2cnn3CCO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (R)-2-(3-oxo-1-tosylpiperazin-2-yl)acetic acid (624 mg, 2.0 mmol), 1-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-amine (649 mg, 2.2 mmol), HOBt (297 mg, 2.2 mmol) and EDCI (422 mg, 2.2 mmol) in 1.2 mL of DMF was stirred overnight at room temperature. After quenching with Sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vaco. Flash chromatography (SiO2, EtOAc/MeOH=100:4 to 100:8 to 100:10 to 100:15) gave the title compound as a white solid. MS: 590.2 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:16]=2)=[O:9])[CH:3]=1.[CH3:24][OH:25]>Cl>[CH3:24][O:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:16]=2)=[O:9])[CH:3]=1
Reactant: O=C(Nc1cncc(Oc2cncnc2)c1)c1cc(F)ccn1
Reactant: CO
Agent: Cl
Product: COc1ccnc(C(=O)Nc2cncc(Oc3cncnc3)c2)c1
Yield: 19 %

Procedure:
Compound 8 (30 mg, 0.096 mmol, 1.0 eq) stirred in 1N HCl in MeOH (0.75 mL) at rt overnight. The reaction was concentrated in vacuo and purified by reverse-phase preparatory HPLC to afford 6 mg (19%) of the title compound as a mono-TFA salt: 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.09 (s, 1H), 9.03 (d, J=2.0 Hz, 1H), 8.79 (s, 2H), 8.55 (d, J=5.7 Hz, 1H), 8.29 (d, J=2.5 Hz, 1H), 8.14 (t, J=2.3 Hz, 1H), 7.66 (d, J=2.5 Hz, 1H), 7.25 (dd, J=5.7, 2.6 Hz, 1H), 3.93 (s, 3H); ES-MS [M+1]+: 324.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH2:21][C:17]4([CH2:20][CH2:19][CH2:18]4)[O:16][N:15]=3)[CH:11]=[C:10]([C:22]([O:24]C(C)(C)C)=[O:23])[CH:9]=2)=[CH:4][CH:3]=1.Cl>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH2:21][C:17]4([CH2:18][CH2:19][CH2:20]4)[O:16][N:15]=3)[CH:11]=[C:10]([C:22]([OH:24])=[O:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C3=NOC4(CCC4)C3)c2)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)cc(C3=NOC4(CCC4)C3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 4′-methyl-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)biphenyl-3-carboxylate (1.26 g, 3.34 mmol) in dichloromethane (12 mL) was added hydrogen chloride (4.0 M in dioxane; 4.17 mL, 16.7 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was concentrated. Dichloromethane was added and the suspension was filtered. The solid cake was washed with dihchloromethane and dried under reduced pressure gave the title compound (1.0 g). MS 322.2 (M+1).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][N:12]=[C:13]=[O:14]>CN(C=O)C>[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[CH2:11][NH:12][C:13](=[O:14])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4]
Reactant: O=C=NCc1ccccc1Cl
Reactant: OCCNCCO
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1Cl)N(CCO)CCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of 2,2′-azanediyldiethanol (1.58 g, 15 mmol) in DMF (5 mL) was added 2-chlorobenzylisocyanate (1.26 g, 7.5 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 3-(2-chlorobenzyl)-1,1-bis(2-hydroxyethyl)urea (1.3 g, 65%). LRMS (M+H+) m/z 272.1.
Reaction SMILES: [CH:1]([Mg]Cl)(C)C.[O:6]1[CH2:11][CH2:10][CH:9]([C:12]([O:14]C)=O)[CH2:8][CH2:7]1.Cl.CNOC.[Cl-].[NH4+].C[Mg]Cl>O1CCCC1>[O:6]1[CH2:7][CH2:8][CH:9]([C:12](=[O:14])[CH3:1])[CH2:10][CH2:11]1
Reactant: COC(=O)C1CCOCC1
Reactant: CC(C)[Mg]Cl
Agent: CNOC
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1CCOCC1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Add 2 M isopropylmagnesium chloride in tetrahydrofuran (520.22 mL, 3.0 eq) to a mixture of methyl tetrahydro-2H-pyran-4-carboxylate (46.30 mL, 346.81 mmol) and N,O-dimethylhydroxylamine hydrochloride (52.44 g, 1.6 eq) in tetrahydrofuran (2.43 L) during 15 minutes at −20° C. under nitrogen. After 30 min, add saturated aqueous ammonium chloride (400 mL) to the reaction at −20° C. Extract the aqueous solution with methyl tert-butyl ether (250 mL×3). Wash the combined organics with saturated aqueous sodium chloride. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Add dichloromethane (500 mL), filter through Celite® and concentrate in vacuo. Add tetrahydrofuran (700 mL), then add 3 M methyl magnesium chloride in tetrahydrofuran (231.21 mL, 2.0 eq) dropwise over 15 minutes at 7° C. After 40 minutes, add saturated aqueous ammonium chloride (250 mL) to the reaction. Extract the aqueous solution with methyl tert-butyl ether (250 mL×2). Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 2:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate, to give 1-(tetrahydro-pyran-4-yl)-ethanone (33.18 g, 75%). 1H NMR (300 MHz, DMSO-d6) δ 3.98 (m, 2H), 3.42 (m, 2H), 2.52 (m, 1H), 2.15 (s, 3H), 1.74 (m, 4H).
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](Cl)(=[O:29])[CH:27]=[CH2:28].Cl>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: C=CC(=O)Cl
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a 500-ml four-necked flask equipped with a thermometer, stirring apparatus, condenser and dropping funnel were added 82.0 g (0.241 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 200 g of toluene and 23.9 g (0.290 mole) of triethylamine. After replacing the air in the container with nitrogen, 25 g (0.276 mole) of acryloyl chloride was added dropwise with stirring. After completion of the dropwise addition, stirring was continued for 1 hour, excess triethylamine was neutralized with a dilute hydrochloric acid and the formed triethylamine hydrochloride was then removed by washing with water. Toluene was then removed by evaporation from the toluene layer after completion of the washing, and the residue obtained was recrystallized from 20 g of n-hexane to obtain 90.0 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate as a white crystal. Melting point, 132°-134° C. Yield, 95%.
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([CH3:40])[CH:32]=2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33](/[CH:40]=[CH:6]/[N:7]([CH3:9])[CH3:8])[CH:32]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 100.7 %

Procedure:
tert-butoxybis(dimethylamino)methane (0.47 mL, 2.30 mmol) was added to a solution of 3-(4-chlorophenyl)-2-(3-methyl-4-nitrophenyl)quinazolin-4(3H)-one (0.300 g, 0.76 mmol) in DMF (30 mL). After heating at 40° C. for 3.5 hours, concentration in vacuo afforded (E)-3-(4-Chlorophenyl)-2-(3-(2-(dimethylamino)vinyl)-4-nitrophenyl)quinazolin-4(3H)-one (0.342 g, 100%).