Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH2:14])=[N:11][C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Reactant: O=C(Cl)CCCCBr
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCCCBr)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
9-Fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]-thiazol-2-amine (150 mg, 0.640 mmole) was dissolved in 3 ml of dry THF, mixed with triethylamine (135 μl, 0.970 mmole), cooled in an ice bath and treated with 5-bromovaleryl chloride (90 μl, 0.67 mmole). The mixture was stirred at room temperature for 3 days. TLC analysis of the mixture showed 50% completion. Hence, a catalytic amount of DMAP was added and stirring was continued for 16 hours. There was no change in the TLC of the mixture. 5-Bromovaleryl chloride (90 μl) was added and stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated sodium carbonate and the aqueous phase separated and extracted with 2×3 ml ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, concentrated and chromatographed (silica, Ethyl acetate/hexanes) to give 179 mg of the desired product as a white foam (70%): 397, 399 (ESMS, MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:41][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 563.1 (M+H)+.
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[C:5]([CH3:19])[CH:4]=1.C[O-].[Na+:22]>CO>[CH3:9][C:7]1[C:6](=[C:10]2[C:11]([CH3:18])=[CH:12][N:13]([CH3:17])[CH:14]=[C:15]2[CH3:16])[C:5]([CH3:19])=[CH:4][C:3](=[O:2])[CH:8]=1.[Na+:22].[I-:1]
Reactant: Cc1cc(O)cc(C)c1-c1c(C)c[n+](C)cc1C
Agent: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC(=O)C=C(C)C1=C1C(C)=CN(C)C=C1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the methylpyridinium iodide salt 7 (0.184 g, 0.500 mmol) was added dropwise a solution of sodium methoxide in methanol (1.2 mL, 0.5 M). The color of the mixture immediately changed from yellow to red. After stirring at room temperature for 10 min, the solvent was removed under reduced pressure. The resulting solid was then recrystallized from anhydrous methanol/THF to afford the orange title compound as a complex with NaI (0.382 g, 98%): 1H NMR (400 MHz, DMSO-d6): δ 8.818 (s, 2H), 5.983 (s, 2H), 4.265 (s, 3H), 2.055 (s, 6H), 1.566 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ 161.235, 142.173, 137.851, 132.019, 118.598, 114.039, 46.917, 19.574, 16.754; MS (ESI): m/z 242.4 [(M+H)+, 100]; HRMS (EI): m/z 241.1463 [M+]; calcd, 241.1467. Anal. Calcd. for C16H19NO.NaI: C, 49.12; H, 4.90; N, 3.58. Found; C, 49.04; H, 5.40; N, 3.49.
Reaction SMILES: OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].[P:14]([O:18][CH2:19][C@@H:20]([OH:29])[C@@H:21]([OH:28])[C@H:22]([OH:27])[C:23](=O)[CH2:24][OH:25])([OH:17])([OH:16])=[O:15].[NH2:30][C@H](C(O)=O)CCC(=O)N.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>>[P:14]([O:18][CH2:19][C@H:20]1[O:29][CH:24]([OH:25])[C@H:23]([NH2:30])[C@@H:22]([OH:27])[C@@H:21]1[OH:28])([OH:17])([OH:16])=[O:15]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Product: N[C@H]1C(O)O[C@H](COP(=O)(O)O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
For a calorimetric assay, 1 mL reactions were prepared containing 45 mM KH2PO4/K2HPO4, 20 mM fructose-6-phosphate, 15 mM L-glutamine, 2.5 mM EDTA, pH 7.5, and cell extract. The reactions were incubated at 37° C. for 20 minutes and stopped by boiling for 4 minutes. The resulting precipitate was removed by centrifugation and the supernatant was assayed for glucosamine-6-phosphate by a modification of the method of Elson and Morgan (1933, Biochem. J. 27:1824-1828) essentially as described by Zalkin (1985, Meth. Enzymol. 113:278-281), both publications of which are incorporated herein by reference in their entireties. To 100 μL of the above supernatant was added 12.5 μL of saturated NaHCO3 and 12.5 μL of cold, freshly prepared 5% aqueous acetic anhydride. After incubating for 3 minutes at room temperature, the mixture was boiled for 3 minutes to drive off excess acetic anhydride. After cooling to room temperature, 150 μL of 0.8 M potassium borate, pH 9.2 (0.8 M H3BO3 adjusted to pH 9.2 with KOH) was added and the mixture was boiled for 3 minutes. After cooling to room temperature, 1.25 mL Ehrlich's reagent (1% p-dimethylaminobenzaldehyde in glacial acetic acid containing 0.125 N HCl) was added to each tube. After incubating at 37° C. for 30 minutes, the absorbance at 585 nm was measured and the amount of glucosamine-6-phosphate formed was determined using a standard curve. In the absence of the substrate, fructose-6-phosphate, or when boiled extract was used in the assay, no significant absorbance at 585 nm was observed.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[C:6]([O:21][CH:22]([CH3:24])[CH3:23])[CH:5]=1.CCO.O.[OH-].[Na+]>C1COCC1>[CH:22]([O:21][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=1)[C:3]([OH:25])=[O:2])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.6 %

Procedure:
To a solution of 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester (prepared as in Example 6 Step A) (6.50 g, 17.8 mmol) in THF (120 mL) was added EtOH (80 mL) and water (40 mL) at room temperature. Sodium hydroxide solution (1.0 M, 36.0 mL) was added slowly with some external cooling, if needed. The mixture was stirred at room temperature overnight. On the second day organic solvents were removed by evaporation. The residue was partitioned between ether and water. After the ether layer was discarded, the aqueous layer was acidified with HCl (6.0 M, ˜6.0 mL) to pH<2, and extracted with EtOAc three times. Combined EtOAc layers were washed with brine, dried with anhydrous MgSO4, filtered, and concentrated to give 3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzoic acid (6.40 g, 100%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1H), 7.93 (d, J=9 Hz, 2H), 7.23 (m, 1H), 7.14 (d, J=9 Hz, 2H), 7.10 (m, 1H), 6.85 (m, 1H), 4.57-4.65 (m, 1H), 3.01 (s, 3H), 1.37 (d, J=6 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)=[CH:8][CH:7]=1)(=[O:5])=[O:4].S(=O)(=O)(O)O>>[F:23][C:2]([F:1])([F:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:12][C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:17])[C:10]=2[CH:11]=1)(=[O:5])=[O:4]
Reactant: O=C(O)c1ccccc1Sc1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2sc2ccc(S(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
A solution of 7.6 g. (0.021 mol) of 2-(4-trifluoromethylsulfonylphenylthio)benzoic acid in 40 ml. of concentrated sulfuric acid is stirred and heated on a steam bath for 1.5 hours. After cooling to room temperature, the solution is slowly poured onto 400 g. of crushed ice. The oil that precipitates is extracted with three 150 ml. portions of an ether-benzene mixture. The combined organic extracts are washed four times with water and three times with dilute sodium bicarbonate solution. The ether-benzene layer is dried over magnesium sulfate, filtered, and evaporated to dryness on a rotary evaporator. The pale yellow solid obtained is recrystallized from acetonitrile to give 2-(trifluoromethylsulfonyl)thioxanthen-9-one, m.p. 163°-164.5°.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:41]([O:48][C:49](=[O:55])[C@H:50]1[CH2:54][CH2:53][CH2:52][NH:51]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:41]([O:48][C:49](=[O:55])[C@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), HOBt (476 mg, 3.5 m mole) and oily D-proline benzylester hydrochloride (968 mg, 4 m mole) were dissolved in DMF (5 ml) and WSC (0.64 ml, 3.5 m mole) were added thereto while cooling to -15° C. The reaction was carried out for 3 hours under cooling and then overnight at room temperature, and ethyl acetate (100 ml) was added to the reaction solution. The mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order, and then dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving an oily dibenzylphosphoryl-L-alanyl-L-prolyl-D-proline benzylester material.
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[Cl:9])[OH:2].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1C=CC=CC=1>[C:10]([OH:17])(=[O:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:9][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1=[N:1][OH:2]
Reactant: O=C(Cl)c1ccccc1
Agent: ON=C1CCCCC1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1

Procedure:
The procedure of Example II is repeated except that 7.4 grams (0.05M) of 1-oximino-2-chlorocyclohexane, 7.0 gm. (0.05M) of benzoyl chloride, 5.1 grams (0.051M) of triethylamine, and 130 ml. of benzene are employed.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[NH:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5])[CH3:16]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1ccc(Br)cc1C#N
Yield: 67.9 %

Procedure:
A suspension of 2-amino-5-bromobenzonitrile (58.5 g, 297 mmol) in ethyl chloroformate (141 mL, 1.48 mol) was heated at reflux for 5 h. The excess ethyl chloroformate (99 mL) was distilled off and toluene (96 mL) was added. Slow addition of cyclohexane (228 mL) induced crystallization. The resulting solid was collected by filtration and rinsed with cyclohexane. Drying in vacuo afforded the title compound (54.3 g, 68%) as an orange solid. MS: m/e=267.1/269.2 [M—H−].
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11](OCC)=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].CCOC(C)=O>O1CCCC1.C(O)C.C(Cl)Cl>[OH:12][CH2:11][C:6]1[CH:5]=[C:4]([CH3:16])[C:3]([C:1]#[N:2])=[C:8]([O:9][CH3:10])[N:7]=1
Reactant: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc(CO)cc(C)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred suspension of ethyl 5-cyano-6-methoxy-4-methylpicolinate (5.0 g, 22.70 mmol) and calcium chloride (10 g, 90 mmol) in tetrahydrofuran (50 mL) and ethanol (50.0 mL) at 0° C. in an ice bath was added sodium borohydride (2.5 g, 66.1 mmol). The reaction was slowly allowed to warm to RT and stirred for 18 hr. A large amount of ppt. formed and LCMS showed that the reaction was complete. An equal volume of EtOAc was added and the reaction stirred for 1 hr. The suspension was filtered through a pad of Celite and washed with EtOAc. The filtrate was transferred to a reparatory funnel, washed with aq. NH4Cl, brine, dried (Na2SO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF40-120 g, 0 to 30% EtOAc in CH2Cl2) gave the product 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (3.75 g, 21.05 mmol, 93% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1 H), 5.61 (t, J=5.8 Hz, 1 H), 4.51 (d, J=5.8 Hz, 2 H), 3.94 (s, 3 H), 2.47 (s, 3 H). MS(ES)+m/e 179.1 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C@@H:15]([OH:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.CCOCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:7][CH2:8][C@H:9]([C@@H:11]1[C@:19]2([CH3:20])[C@H:14]([C:15](=[O:21])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: C[C@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Temperature: 0 °C
Yield: 91.8 %

Procedure:
The compound of Example 1C (1.1 g, 3.7 mmol) was dissolved in 5 mL of dichloromethane and cooled to 0° C.; 4.1 g of pyridinium dichromate was added, followed by 30 mg of pyridinium p-toluenesulfonate. The resultant mixture was stirred for 8 hours at 0° C.; an additional 1.8 g of pyridinium dichromate and 20 mg of pyridinium p-toluenesulfonate were added, and the mixture was allowed to warm to ambient temperature overnight. The mixture was diluted with ether and filtered through a pad of diatomaceous earth with an ether wash. The filtrate was washed with 1 N aqueous HCl, and then filtered through a plug of silica gel. The crude product was purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 10% to 15% ethyl acetate in hexanes to furnish the titled compound (1.0 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(O)(C(F)(F)F)=O.[H-].[Na+]>>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][O:7]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn(C2CCCCO2)n1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 3-methylpyrazole (3.0 g, 35.4 mmol), 3,4-dihydro-2H-pyrane (4.97 mL, 53.2 mmol) and TFA (0.02 mL, 0.260 mmol) was stirred at 85° C. for 6 h under an argon atmosphere. The RM was cooled to RT and NaH 60% in mineral oil (0.061 g, 1.524 mmol) was and the RM was stirred for 10 min. The RM was purified by bulb-to-bulb distillation to give 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (b.p. 150-170° C./12 mbar). A solution of n-BuLi in n-hexane (3.38 mL of 1.6 M, 5.41 mmol) was added dropwise over 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.0 g, 5.41 mmol) in THF (12 mL) at −70° C. under a nitrogen atmosphere and The RM was stirred for 10 min and then treated dropwise with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.898 g, 5.69 mmol) and stirred at −70° C. for 1 h. The RM was allowed to warm to RT, treated with n-hexane and the product was filtered, dissolved in water (10 mL) and acidified to pH 6 with aqueous citric acid (10%). The water was evaporated off under reduced pressure and the aqueous residue extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=0.56 min, m/z=211.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][OH:19])[CH:9]([CH3:17])[C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH3:17])=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:19][N:18]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)C(C)C(=NO)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1onc(-c2ccc(F)cc2)c1C
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Ethyl 4-(4-fluorophenyl)-4-(hydroxyimino)-3-methyl-2-oxobutanoate (10.1 g, 37.8 mmol) and concentrated sulfuric acid (10 mL) were added to 150 mL of absolute ethanol and the mixture was refluxed for 20 hours. After the mixture cooled to room temperature, saturated sodium bicarbonate solution was added to neutralize the mixture. The product was extracted with EtOAc and the combined organic layer was dried over MgSO4 and concentrated to give 8.6 g of the title compound. MS: (+) m/z 250.41 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24]N5CCCCC5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.IC.C(=O)([O-])[O-].[K+].[K+].C(O[CH2:44][CH3:45])(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH:45]5[CH2:44][CH2:14][N:13]([CH3:22])[CH2:8][CH2:7]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(ON3CCCCC3)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC3CCN(C)CC3)cc2c1=O
Reaction time: 19 h

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-(piperidin-yloxy)quinazolin-3(4H)-yl]benzamide (0.3 g), iodomethane (0.044 ml) and potassium carbonate (0.397 g) were stirred in DMF (2 ml) for 18 hours at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with water (5×), brine (2×), dried (magnesium sulfate) and concentrated. The residue was dissolved in methylene chloride (2 ml) and stirred with PS-isocyanate resin (1.25 mmol/g) (0.28 g) and MP-carbonate (2.89 mmol/g) (0.488 g) for 19 hours and then filtered and concentrated to yield the title compound (0.129 g) as a cream solid; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.69 (m, 2H), 1.70 (m, 2H), 1.97 (m, 2H), 2.13 (s, 3H), 2.19 (s, 3H), 2.22 (m, 2H), 2.60 (m, 2H), 2.85 (m, 1H), 4.55 (m, 1H), 7.51 (d, 1H), 7.52 (d, 1H), 7.59 (s, 1H), 7.72 (d, 1H), 7.82 (s, 1H), 7.90 (d, 1H), 8.17 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=1.[C:21](=[O:23])=[O:22]>O1CCCC1.CCCCCC>[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[C:19]=1[C:21]([OH:23])=[O:22]
Reactant: Clc1cncc(Cl)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Cl)cncc1Cl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.96 ml (0.036 mole) of diisopropylamine in 200 ml of tetrahydrofuran at -65° C. under a nitrogen blanket was added dropwise 14.9 ml of 2.5M n-butyllithium in hexane while maintaining the above temperature. Twenty minutes subsequent to that addition, a solution 5.0 g (0.034 mole) of 3,5-dichloropyridine in 30 ml tetrahydrofuran at -60° to -70° C. was added. The reaction mixture was stirred at -70° C. for 1/2 hr, poured onto a large excess of dry ice and allowed to evaporate overnight at room temperature. The residue was taken up in 100 ml of dilute aqueous sodium hydroxide, washed with 3×30 ml of methylenechloride and filtered. The filtrate was acidified to ~pH 2 with dilute hydrochloric acid to precipitate out the product. After cooling, the precipitate was collected and recystallized from ethyl acetate/hexane giving 1.9 g (29%) of white analytically pure crystals, m.p. 231°-35° C. (decomp.).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH:28]([C:36]1([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]1)[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)(C(C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([CH:28]([C:36]2([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH2:37][CH2:38]2)[CH2:27][OH:26])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1(C(CO[Si](C)(C)C(C)(C)C)c2ccc(Cl)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(CO)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
TBAF (2.8 g, 8.9 mmol) was added to a stirred solution of tert-butyl 1-(2-(tert-butyldimethylsilyloxy)-1-(4-chlorophenyl)ethyl)cyclopropylcarbamate (1.9 g, 4.5 mmol) in THF (80 mL). The mixture was stirred at room temperature for 2 hours. Saturated NH4Cl solution was added to the reaction. The mixture was extracted with ether. The combined organic layer was washed with brine, dried and concentrated. The residue was purified by column (hexane:EtOAc, 20:1 to 4:1) to give tert-butyl 1-(1-(4-chlorophenyl)-2-hydroxyethyl)cyclopropylcarbamate (1.1 g, 79%) as a white solid. LCMS: 311.8 [M+H+] (APCI+); Rf: 3.47 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[O:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[C:7]([OH:13])[CH:6]=2.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)=[O:25])[CH2:17][CH2:16]1>C(OC(O)C)C.O.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[OH:13][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([CH3:12])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH2:22][CH2:21][N:18]4[CH2:19][CH2:20][O:15][CH2:16][CH2:17]4)=[O:25])=[CH:27][CH:28]=3)[C:3](=[O:14])[O:4]2)=[CH:9][CH:8]=1
Reactant: Cc1c(Br)c(=O)oc2cc(O)ccc12
Reactant: O=C(NCCN1CCOCC1)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOC(C)O
Solvent: O
Product: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2cc(O)ccc12
Temperature: 150 °C
Yield: 182.2 %

Procedure:
A mixture of 3-bromo-7-hydroxy-4-methyl-2H-chromen-2-one (1) (7.66 g, 30 mmol), 4-(2-morpholmoethylcarbamoyl)phenylboronic acid (2) (10.02 g, 36 mmol), Na3PO4 (17.21 g, 105 mmol) in a mixture of ethoxyethanol (0.140 g) and water (14 g) was purged with Argon for five minutes in a 250 mL pressure vessel. Ligand Sphos (738 mg, 1.8 mmol) and Pd(OAc)2 (206 mg, 0.90 mmol) were added under an Argon atmosphere then the vessel was sealed and heated for 60 min in a 150° C. oil bath with strong stirring. This process was repeated once. Upon cooling, the reaction mixtures were filtered through a silica plug using CH2Cl2 and MeOH wash. The unified solutions were evaporated to 100 mL slowly diluted with water (100 mL) and crystallized at 0° C. The product was filtered, washed with 50% MeOH (2×50 mL) and dried to afford 22.33 g (9.1%) of the title compound. MS (ESI): 409 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.57 (s, br, 1H), 8.46 (t, 1H), 7.88 (d, 2H), 7.69 (d, 1H), 7.39 (d, 2H), 6.84 (dd, 1H), 6.76 (d, 1H), 3.57 (m, 4H), 3.40 and 2.48 (2q, 2×2H), 2.43 (m, 4H), 2.22 (s, 3H).