Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O([C:8]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][N+:10]([O-:12])=[O:11])C1C=CC=CC=1.[NH2:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[N:26]=[C:27]([CH2:30][N:31]([CH3:33])[CH3:32])[S:28][CH:29]=1>O1CCCC1.C(O)(C)C>[CH3:33][N:31]([CH2:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][S:23][CH2:22][CH2:21][NH:20][C:8]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][N+:10]([O-:12])=[O:11])[N:26]=1)[CH3:32]
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.07 g (27.5 mmol) of 1,1-diphenoxy-2-nitroethene in 70 ml of tetrahydrofuran was stirred at 25° C. To this solution was added a mixture of 6.83 g (27.5 mmol) of 93% pure 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine in 100 ml of isopropyl alcohol. The reaction mixture was stirred for approximately one hour at 25° C. and the progress of the reaction was followed by thin-layer chromatography to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine. The product was not isolated but rather used directly in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][NH:32][CH:33]=2)O1>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[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:29]4[CH:30]=[N:31][NH:32][CH:33]=4)=[CH:16][CH:15]=3)[O:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1ccc(C2(c3ccc(I)cc3)CNCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Clc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CNCCO2)cc1

Procedure:
2-(4-chloro-phenyl)-2-(4-Iodo-phenyl)morpholine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst to give the title compound. LCMS (PS-A3) Rt 6.88 min [M+H+] 340. 1H NMR (Me-d3-OD) δ 2.84-2.88 (2H, m), 3.32-3.36 (1H, m), 3.45-3.49 (1H, m), 3.69-3.72 (2H, m), 7.31 (2H, d), 7.40 (4H, apparent d), 7.56 (2H, d), 7.92 (2H, br.s).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:16]1([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCN1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=C1CCCN1c1ccccc1
Yield: 49.6 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), 2-pyrrolidinone (91 μL, 1.20 mmol), Iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL) at 90° C. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded N-(phenyl)-2-pyrrolidinone (80 mg, 50% isolated yield) as white solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104; and Kang, S. -K.; Lee, S. -H.; Lee, D. Synlett 2000, 1022-1024.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)C>N1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Oc3cc(F)cc(F)c3)cc2)cc1
Temperature: -20 °C
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (2.66 g, 10.0 mmol) in pyridine (2.8 g), p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was gradually added with stirring while cooling at -20° C. and the resultant mixture was allowed to stand in a refrigerator overnight. Diethyl ether was added to the reaction mixture, which was washed with dilute hydrochloric acid until the aqueous layer became acidic, followed by washing with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The obtained ether layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl p-toluenesulfonate (3.90 g).
Reaction SMILES: [CH3:1][C:2]([N+:14]([O-:16])=[O:15])([CH3:13])[CH2:3][CH2:4][CH:5]=[C:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].CO.[H][H]>[C].[Pd].O>[CH3:13][C:2]([N+:14]([O-:16])=[O:15])([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]1[NH:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: CC(C)(CCC=C1NC(=O)NC1=O)[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(CCCC1NC(=O)NC1=O)[N+](=O)[O-]
Yield: 34.5 %

Procedure:
To 5-(4-methyl-4-nitropentylidene)hydantoin (3.15 g, 13.9 mmol) were added methanol (60 ml) and water (10 ml), and the mixture was reduced by the addition of palladium-carbon (2.2 g) and hydrogen. After the reaction, palladium-carbon was filtered off and the residue was concentrated to dryness. Decantation with water and dichloromethane gave 5-(4-methyl-4-nitropentyl)hydantoin (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5](/[CH:6]=[N:7]/[OH:8])=[C:4]([O:11][CH2:12][C:13]#[C:14][C:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:17][N:16]=2)[CH:3]=1.BrN1C(=O)CCC1=O.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6]3=[N:7][O:8][C:14]([C:15]4[C:19]([C:20]([F:23])([F:21])[F:22])=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:17][N:16]=4)=[C:13]3[CH2:12][O:11][C:4]=2[CH:3]=1
Reactant: O/N=C/c1ccc(Br)cc1OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1c(-c2onc3c2COc2cc(Br)ccc2-3)noc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
To a solution of (E)-4-bromo-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-ynyloxy)benzaldehyde oxime (Preparation 62E, 0.142 g, 0.305 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. was added N-bromosuccinimide (0.081 g, 0.458 mmol) followed by triethylamine (0.085 mL, 0.610 mmol). The resulting homogeneous reaction mixture was stirred at 0° C. for 10 min. and then at room temperature for 50 min. HPLC and LCMS analysis indicated that ˜65% of the starting material remained. The reaction mixture was then stirred at 75° C. for 60 min. HPLC analysis indicated that the reaction had progressed to ˜1:1 starting material to product. Additional N-bromosuccinimide (0.081 g, 0.458 mmol) and triethylamine (0.085 mL, 0.610 mmol) were added, and the reaction was heated for an additional 60 min. Very little change was noted upon HPLC analysis. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with a 10% aqueous solution of lithium chloride (2×), and washed with brine. The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The solid residue was triturated with methanol with sonication to afford 7-bromo-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-chromeno[4,3-c]isoxazole (0.063 g, 0.136 mmol, 45% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:18][CH:17]=[CH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of the phenol from step 2 (16.5 g, 75 mmol), allyl bromide (10.8 g, 90 mmol) and cesium carbonate (48.7 g, 150 mmol) in DMF(300 mL) was stirred at 25° C. for 6 h. The mixture was poured into water (1.0 L) and extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water (3×100 mL), dried over magnesium sulfate and concentrated. The crude product was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][N:15](C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[OH:13][CH2:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:14]#[N:15]
Reactant: CN(C)C=O
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(CO)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.4 g, 5.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.64, 0.55 mmol) and zinc cyanide (388 mg, 3.31 mmol) were combined in dimethylformamide (6 mL). The reaction mixture degassed repeatedly using the freeze-thaw method. After warming to room temperature, the reaction was heated at 90° C. for 1 h, cooled to room temperature and concentrated. The crude product was dissolved in ethyl acetate, washed with water (2×), 1 N hydrochloric acid (2×), brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel gave 0.37 g (33%). LC/MS (HPLC method 3): tR=2.06 min, 202.02 (MH)+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:4]([O:3][C:1]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:17]1[CH:23]=[CH:22][CH:21]=[C:19]([NH2:20])[CH:18]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
1-N-Boc-pyrrole-2-boronic acid (0.184 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (5-60% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.037 g in 25% yield.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:15][C:16](=O)[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)C>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:16](=[O:15])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)COc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)COc1cccc(Cl)c1)OC
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To 20.6 g (166 mmol, 238 mol %) of dimethyl methylphosphonate in 110 mL of THF at -78° C. was added dropwise 65 mL (162 mmol, 232 mol %) of a 2.5M solution of n-BuLi in hexanes. After addition was complete, the mixture was stirred for an additional 1 h, after which 15.0 g (69.9 mmol) of aryloxyester 10 in 40 mL of THF was added dropwise. The reaction was stirred for 1 h and then quenched by the addition of 100 mL of saturated NH4Cl. The mixture was poured into 200 mL of a 1/1 mixture of saturated NaCl/ethyl acetate, layers were separated, and the aqueous layer was further extracted with ethyl acetate (2×100 mL). Combined organic layers were dried over MgSO4, filtered, and concentrated, to afford 20.5 g (100%) of 11 as a viscous oil. 1H NMR δ 7.22 (t, J=8.1 Hz, 1H), 7.05-6.90 (m, 2H), 6.85-6.78 (m, 1H), 4.72 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.27 (d, J=22.8 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9](Cl)=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:7]2.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCC1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCCC1>[CH2:16]([O:15][C:13]([C:6]1[O:7][C:8]2[C:3]([C:4](=[O:18])[CH:5]=1)=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cc(=O)c2c(C)ccc(Cl)c2o1
Reactant: CN1CCNCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCC1)C1CCCC1
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(=O)c2c(C)ccc(N3CCN(C)CC3)c2o1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
Ethyl 5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylate (1.0 g, 3.6 mmol) as prepared in Reference Example 6c above, was azeotroped with anhydrous toluene then the white solid was dissolved in 100 ml anhydrous toluene in a 250 mL single-neck round bottom flask. The mixture was degassed by alternating argon sparge and vacuum (3×), and the following were added in order: N-methylpiperazine (0.6 ml, 5.37 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (JACS 1998, 120, p9722) (40 mg, 0.1 mmol,), tris(dibenzylideneacetone) dipalladium (0) (66 mg, 0.072 mmol) then cesium carbonate (1.6 g, 5.37 mmol). The mixture was again degassed via alternating argon sparge and vacuum and was heated at 80° C. for 17 h. Additional tris(dibenzylideneacetone) dipalladium (0) (66 mg, 0.072 mmol) and (2′-dicyclopentylphosphanyl-biphenyl-2-yl)dimethyl-amine (40 g, 0.1 mmol,) were added and the reaction was stirred at 80° C. for another four days at which time the conversion was still only about 50% complete by HPLC. Tetrahydrofuran (100 mL) was added, and the combined mixture was filtered, concentrated under vacuum and purified by chromatography on silica eluted with 2.5% methanol in chloroform. The desired fractions were concentrated under vacuum to yield a yellow powder (250 mg=21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1.[K].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:13](=[O:18])[N:12]=[C:11]3[CH:19]2[CH2:21][CH2:20]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1nc(C2CC2)c2cc(-c3cccc(Cl)c3)ccc2[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(-c4cccc(Cl)c4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-(3-chlorophenyl)-4-cyclopropyl-1H-quinazolin-2-one (0.5 g, 1.68 mmol) in anhydrous DMF was added potassium hexmethylsilyl amide (0.45 g, 2.1 mmol) at ambient temperature under nitrogen. The reaction mixture was stirred at ambient temperature for 30 minutes, treated with p-methoxy benzyl chloride (0.35 mL, 2.5 mmol), and heated at 55° C. for 5 hours. The mixture was then cooled to room temperature and quenched with a saturated aqueous ammoniun chloride solution (10 mL). Methylene chloride (50 mL) was added and organic layer was separated. The aqueous layer was extracted with methylene chloride (2×20 mL) and the combined organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was separated on a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-1-(4-methoxybenzyl)-1H-quinazolin-2-one as an off-white solid: mp 173-174° C.; 1H-NMR (DMSO-d6) δ 8.65 (d, 1H, J=1.8 Hz), 8.10 (dd, 1H, J=8.9, 1.8 Hz), 7.93 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=7.6 Hz), 7.53 (d, 2H, J=8.4 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.21 (d, 2H, J=8.6 Hz), 6.88 (d, 2H, J=8.6 Hz), 5.41 (s, 2H), 3.73 (s, 3H), 3.18 (m, 1H), 1.18-1.27 (m, 4H); MS (CI) m/z 417([M+H]+, 100%); Anal. Calc. For C25H21ClN2O2; C, 72.02, H, 5.08, N, 6.72. Found: C, 71.88, H, 4.91, N, 6.70.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](Cl)(C)C.C[Si](C)(C)N[Si](C)(C)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.CO.C(N(CC)CC)C>[C:22]([NH:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C(O)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 37.5 °C
Reaction time: 8 h

Procedure:
To dichloromethane (400 ml), D-serine (50 g) was added at ambient temperature under nitrogen atmosphere to form a suspension and then trimethylsilyl chloride (61.92 g) and hexamethyldisilazane (107.5 ml) was added to the suspension in 10-15 minutes at ambient temperature. The reaction mixture was refluxed at 35-40° C. for 3 hours and then it was cooled to 0° C. To this mixture, a solution of anhydrous methanol (22.83 g) in dichloromethane (50 ml) was added at 0° C. and the mixture was allowed to reach at room temperature. Triethylamine (48.14 g) was slowly added to it at 25-30° C. and then trityl chloride (132.63 g) was added in 3 lots to the mixture at an interval of 10 minutes. The reaction mixture was then stirred for overnight under nitrogen at ambient temperature. After completion of the reaction, methanol (76.12 g) was added at ambient temperature in 10-15 minutes and the solvent was recovered under vacuum at 40-45° C. Hexane (400 ml) and 5% citric acid solution (750 ml) was added to the recovered solid and filtered. The solid product obtained was washed with water (750 ml) and hexanes (200 ml) and then filtered. The filtered solid was washed with hexanes (200 ml) and dried to obtain the titled product. Yield=125 gm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1>C(O)(=O)C.[Fe]>[NH2:10][C:4]1[C:5]([C:8]#[N:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ncc(Br)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
Iron powder (5.0 g, 90 mmol) was added to a solution 5-bromo-3-nitropyridine-2-carbonitrile (4.56 g, 20 mmol) in glacial acetic acid (125 ml). The suspension was stirred for 2 h at 80° C. The cooled mixture was filtered through a short plug of Celite and washed with EtOAc. Solvents were evaporated, the residue was dissolved in EtOAc and neutralised with 20% aqueous K2CO3. Phases were separated and organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and evaporated. Crude product was purified by CombiFlash (DCM-MeOH, gradient elution). Product fractions were combined and evaporated to produce 1.67 g of product. 1H-NMR (400 MHz; d6-DMSO): δ 6.55 (s, 2H), 7.46 (d, 1H, J=2.0 Hz), 7.94 (d, 1H, J=1.9 Hz).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C1C=CC=CN=1)C.N1C=CN=C1.[Si:52](Cl)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]>N1C=CC=CC=1>[Si:52]([O:10][C@@H:9]1[C@@H:11]([CH2:12][OH:13])[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: CN(C)c1ccccn1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a solution of 5-fluoro-2'-deoxyuridine (14, 1.00 g, 4.06 mmol) in pyridine (7 ml) was added triphenylmethyl chloride (1.25 g, 4.47 mmol) and dimethylaminopyridine (0.4 g, 3.05 mmol). The mixture was allowed to stir at 80° C. for 30 min. The pyridine was removed under reduced pressure and the residue dissolved in DMF (4 ml). Imidazole (0.67 g, 9.77 mmol) and t-butyldimethylsilyl chloride (0.74 g, 4.88 mmol) were added, and the mixture was allowed to stir overnight at room temperature. The DMF was removed under pressure, and the residue was dissolved in 80% aqueous acetic acid (5 ml). The mixture was allowed to reflux for 30 min, cooled, and neutralized with NaOH. The mixture was lyophilized, and the residue was purified by chromatography (1:1 EtOAc:hexanes) to give 15 as a white solid (709 mg, 48%): mp 138°-142° C.; Rf 0.65 (1:9 MeOH:CH2Cl2); 1H NMR (CDCl3) 7.98(d, 1H, J=6.39 Hz), 6.23(t, 1H, J=6.78 Hz), 4.49(dt, 1H, J=5.56 Hz), 3.98(m, 2H), 3.84(m, 1H), 2.26(m, 2H), 0.90(s, 9H), 0.10(s, 6H); IR (KBr) 3460, 3190, 3080, 3050, 2930, 2860, 1720, 1655, 1490, 1475, 1445, 1400, 1335, 1250, 1190, 1120, 1095, 1030, 1005, 950, 910, 835, 760, 700, 670, 640 cm-1 .
Reaction SMILES: C1C([N+]([O-])=O)=CC=C([O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])C=1>CS(C)=O.C([O-])(=O)C.[Na+].C1C([N+]([O-])=O)=CC=C(O[C@@H]2O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]2O)C=1>[O:10]=[CH:11][C@@H:12]([C@H:13]([C@@H:14]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:19])[OH:20])[OH:21]
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.33 h

Procedure:
Specific activity. 4-Nitrophenyl-beta-D-glucopyranoside (pNPG) was dissolved in DMSO to produce a 100 mM stock solution. Right before assay, the 100 mM pNPG stock solution was diluted 100-fold in 50 mM sodium acetate pH 5 with 0.01% TWEEN® 20 to 1 mM pNPG. Enzyme was diluted to a wide range of concentrations in the same buffer. To 20 μl of the enzyme dilutions (a range of concentration), 100 μl of the 1 mM pNPG solution were quickly added. The reaction was incubated at 40° C. for 20 minutes before the reaction was stopped with 50 μl of 1 M sodium carbonate pH 10, and the absorbance at 405 nm was measured for 4-nitrophenolate production. The specific activity of the Penicillium oxalicum GH3 beta-glucosidase on pNPG was determined to be 72.3±1.7 IU/mg, where one mg of enzyme produce 1 μmole of glucose per minute at 40° C., pH 5.