Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](Cl)=[O:22].[Na+].C([O-])(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:22]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: O=C([O-])CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 2.75 h

Procedure:
A solution of 46.0 g of (R)-4-phenyl-2-oxazolidinone in 300 g (338 mL) of peroxide-free tetrahydrofuran is cooled to −5 to 0° C. (bath temperature −10 to −5° C.) over a period of 15 minutes. 145.2 g (166.8 mL) of 25% w/w potassium t-amylate/toluene solution is added over a period of 25 minutes while maintaining an internal temperature below 0° C. The reaction mixture is warmed to 20±5° C. within 1 hour and stirred at this temperature for 2.5-3 hours. The mixture is cooled to −15 to −5° C. over a period of 30 minutes, and crude 2-fluorobenzenacetyl chloride (obtained above) is added over a period of 45 minutes while maintaining an internal temperature below −5° C. (bath temperature −15 to −10° C.). After the addition is completed, the mixture is warmed to 20±5° C. over a period of 1 hour, and diluted with 100 mL of toluene. This is added to 500 mL of saturated citric acid monosodium salt solution (100 g in 450 g of water) and the mixture is stirred for 5 minutes. The organic layer is separated, and washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each. The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 450 mL of t-butyl methyl ether and the mixture is heated to reflux (53-58° C.) to obtain a solution; 225 mL of t-butyl methyl ether is then distilled off at atmospheric pressure (bath temperature 60-65° C.). The resulting mixture is cooled to 20-25° C., and stirred at this temperature for 16 hours, then cooled to −5 to 0° C. and stirred at this temperature for additional 2 hours and filtered. The resulting solid is dried under vacuum (66-76 mm Hg) at 45-50° C. for 12 hours to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([O:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:24][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:17][CH:14]([CH3:16])[CH3:15])[N:23]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CC(C)Oc1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(OC(C)C)n1
Temperature: 130 °C
Yield: 13.3 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (1.63 g, 7.36 mmol) in acetonitrile (25 mL) was added 6-isopropoxypyridin-2-amine (1.12 g, 7.36 mmol) and the mixture heated at 130° C. in a sealed tube for 60 h. Upon completion, the mixture was concentrated on to silica gel and purified by chromatography (20% to 66% EtOAc in hexanes) to give ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate (330 mg, 13%). MS (EI/CI) m/z: 337.1 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[N:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1
Reactant: Fc1ccc(C2=NOC(Cn3ccnn3)C2)cc1F
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(C2=NOC(Cn3ccnn3)C2)ccc1N1CCSCC1

Procedure:
A mixture of (5RS)-3-(3,4-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-4,5-dihydroisoxazole (528 mg, 2 mM), potassium carbonate (414 mg, 3 mM), and thiomorpholine (7.5 ml) was heated under nitrogen at 130° for 40 hours. After cooling, the mixture was partitioned between water (150 ml) and ethyl acetate (150 ml). The organic extract was washed with aqueous sodium dihydrogen phosphate (75 ml), sodium bicarbonate (75 ml), and brine (75 ml). After drying (magnesium sulfate) and evaporation, the crude product was then purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient from 50–100% ethyl acetate in isohexane. Relevant fractions were combined to give the desired product (305 mg).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48](O)[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3].C(N(S(F)(F)[F:63])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([F:63])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH2:7][CH2:6][C:5]1=[O:56])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-allyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 62 yields 17-Allyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [Al](Cl)([CH2:4][CH3:5])CC.[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:32])/[CH:21]=[CH:22]/[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C=CC=C.Cl.[C:38](OCC)(=[O:40])[CH3:39]>C(Cl)Cl.O.C1COCC1>[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20]([C@@H:21]1[CH2:5][CH2:4][C:38](=[O:40])[CH2:39][C@H:22]1[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:32])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: CC[Al](Cl)CC
Reactant: O=C(/C=C/COCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C=CC=C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=C1CC[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](COCc2ccccc2)C1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
A solution of Et2AlCl (1.8 M in toluene, 158 mL, 284 mmol) was added slowly down the flask wall to a −78° C. solution of (4R)-4-benzyl-3-[(2E)-4-(benzyloxy)but-2-enoyl]-1,3-oxazolidin-2-one (70.9 g, 202 mmol) in CH2Cl2 (200 mL). After 10 min, a solution of 2-(trimethylsilyl)oxy-1,3,-butadiene (100 g, 700 mmol) in CH2Cl2 (120 mL) was introduced in the same manner over a period of 15 min. Stirring was continued at −78° C. overnight (18 h). The reaction flask contents were then warmed to −50° C. and a solution composed of THF (150 mL) and 6M HCl (150 mL) was CAREFULLY added dropwise over 45 min followed by stirring at rt for 1 h. Water, ethyl acetate and Celite® were then added and the mixture was filtered through a Celite® pad. The filtrate was transferred to a separatory funnel and the layers were separated. The organic phase was washed with saturated NaCl aqueous solution, dried over a mixture of Na2SO4 and MgSO4 and concentrated in vacuo. Flash chromatography of the residue on silica gel eluting with 13/87 ethyl acetate/benzene gave (4R)-4-benzyl-3-({(1R,2R)-2-[(benzyloxy)methyl]-4-oxocyclohexyl}carbonyl)-1,3-oxazolidin-2-one as a colorless solid. 1H NMR (400 MHz, d6-acetone) δ 7.38-7.32 (6H, m), 7.31-7.25 (4H, m), 4.59-4.53 (1H, m), 4.47 (2H, q, J= 8.5 Hz), 4.19 (1H, dd, J= 3.0, 9.0 Hz), 4.15-4.09 (1H, m), 4.03 (1H, t, J= 8.6 Hz), 3.53-3.47 (2H, m), 3.13 (1H, dd, J= 3.4, 13.6 Hz), 2.97 (1H, dd, J= 8.2, 13.5 Hz), 2.70-2.60 (1H, m), 2.54-2.46 (1H, m), 2.44 (2H, d, J= 9.3 Hz), 2.41-2.29 (2H, m), 1.92-1.82 (1H, m).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[K+].C(O)(=O)C.Br[CH2:13][C:14](=[O:36])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C:30](=[O:34])[CH2:31]2)[C@:27]2([CH3:28])[C@H:22]([CH2:23][C@@H:24]([OH:35])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][CH2:16]1>CC(C)=O.O>[C:1]([O:4][CH2:13][C:14](=[O:36])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([C:30](=[O:34])[CH2:31]2)[C@:27]2([CH3:28])[C@H:22]([CH2:23][C@@H:24]([OH:35])[CH2:25][CH2:26]2)[CH2:21][CH2:20]3)[CH2:17][CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 22.8 %

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].Cl.Cl.Cl.[N:32]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33]1>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:20]([N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][N:32]3[CH2:33][CH2:34][CH2:35]3)[CH2:43][CH2:42]2)=[O:21])[CH:6]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1CN(CCN2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCN(CCN2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then triethylamine (0.100 ml) and phenyl chloroformate (0.0903 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 20 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (3 ml). 1-[2-(Azetidin-1-yl)ethyl]piperazine trihydrochloride (214 mg) and triethylamine (0.234 ml) were added thereto, followed by stirring for 6 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml), and brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=9:1). Fractions containing the target compound were concentrated under reduced pressure to provide a crude product of the titled compound (110 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH2:23])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][S:34]([C:26]2[O:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)(=[O:35])=[O:36])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1cc(CSc2ccc(Cl)cc2N)ccn1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)ccn1
Yield: 55.6 %

Procedure:
Following General Procedure B, the title compound (555 mg, 56%) was prepared from tert-butyl(4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate (667 mg, 1.827 mmol) and benzofuran-2-sulfonyl chloride (396 mg, 1.827 mmol) in pyridine (10 ml).
Reaction SMILES: Br[CH:2]([C:4]1([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)OCCO1)C.ClC1C=CC=CC=1.[OH-:26].[Na+].[CH3:28][OH:29]>[O-2].[Zn+2]>[CH2:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:4]([CH3:2])[C:28]([OH:29])=[O:26])=[CH:14][CH:13]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)Cc1ccc(C2(C(C)Br)OCCO2)cc1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Agent: [O-2]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 99 %

Procedure:
In a reactor, 32 g (0.10 mol) of 2-(1'-bromoethyl)-2-(4'-isobutylphenyl)-1,3-dioxolane, 0,81 g (0.01 mol) of zinc oxide, and 40 ml of monochlorobenzene were heated at 140° C. for two hours. The resultant reaction mixture was filtered to recover the catalyst (93%) and then distilled to expel the monochlorobenzene. Then, the residue was subjected to hydrolysis by following the procedure of Example 10 (150 ml of methanol and 400 ml of 50% NaOH aqueous solution). Consequently, there was obtained 2-(4'-isobutylphenyl)-propionic acid in a yield of 99%. When the same reaction was repeated by using the recovered zinc oxide as the catalyst, there was obtained 2-(4'-isobutylphenyl)-propionic acid in a yield of 95%.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18](Cl)=[N:19][CH:20]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[C:18]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a suspension of sodium hydride (5.08 g, 127 mmol) in dimethylformamide (75 mL) was added diethyl malonate (1926 mL, 127 mmol) at 0° C. The solution was then stirred at ambient temperature for 30 minutes and a solution of 5-bromo-2-chloro-3-nitropyridine (30 g, 127 mmol) in dimethylformamide (75 mL) was added dropwise. The dark brown mixture was then stirred at 100° C. for 2 hours before being cooled to ambient temperature and quenched with a saturated solution of ammonium chloride (500 mL) at 0° C. The mixture was extracted with ethyl acetate (3×500 mL) and the combined organics were dried over magnesium sulfate. The solvent was removed in vacuo to give a dark brown oil which was purified by flash column chromatography (10% ethyl acetate/hexane) to afford diethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate as a brown solid (31.8 g, 88 mmol, 69%). 1HNMR (400 MHz, CDCl3): 8 ppm 8.86 (s, 1H), 8.61 (s, 1H), 5.44 (1H, s), 4.29 (q, 4H), 127 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-:20])[C:7]=1[CH3:8]
Reactant: Cc1nc2[nH]cnc2cc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c(Br)cc2nc[nH]c2[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) (Graboyes et al J. Am. Chem. Soc. 1957, 79, 6421-6426) in CH2Cl2 is added m-CPBA (1.50 equivalents). The resulting solution is stirred at room temperature for 16 hours. The precipitate is filtered off, washed with ether, and dried in vacuo to afford the desired product. The product is purified by re-crystallization if further purification is necessary.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:29])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH2:27][CH3:28])[N:6]=2.[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH2:31]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:27]([C:19]1[N:18]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[C:3]([CH2:2][N:30]4[CH2:33][CH:32]([N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[CH2:31]4)[N:4]3[CH3:29])=[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=1)[CH3:28]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCl)n(C)c2n1
Reactant: C1CN(C2CNC2)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.4 %

Procedure:
To a solution of 8-chloromethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (107 mg, 0.26 mmol) and 4-azetidin-3-ylmorpholine (44 mg, 0.31 mmol) in DMF (3 mL) was added K2CO3 (106 mg, 0.77 mmol). The resulting mixture was allowed to stir at room temperature for 16 h. The reaction mixture was dissolved in EtOAc, washed with H2O (×4) then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-5%). The resulting residue was further purified by Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH, followed by reverse phase HPLC (Phenomenex Luna C18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 95:5 to 2:98) to afford 309 as a white solid (14 mg, 11%). LCMS (Method G): RT 5.74 min, [M+H]+ 518.3. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.27-7.23 (m, 2 H); 4.35 (m, 4 H); 3.89-3.82 (m, 6 H); 3.83 (s, 3 H); 3.72 (m, 4 H); 3.56 (m, 2H); 3.34 (q, J=7.5 Hz, 2 H); 3.15-3.03 (m, 3 H); 2.34 (m, 4 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14](=[O:22])[CH2:15][C:16](=[O:21])[CH2:17][C:18]([OH:20])=[O:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>O.C(Cl)Cl.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14](=[O:22])[CH2:15][C:16](=[O:21])[CH2:17][C:18]([O:20][CH3:3])=[O:19])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C(=O)CC(=O)CC(=O)O)cc1OC
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COC(=O)CC(=O)CC(=O)c1ccc(OC)c(OC)c1
Yield: 56 %

Procedure:
To a cold (−20° C.) solution of 8.9 mL (63.7 mmol) of diisopropylamine in 100 mL of diethyl ether under argon was added 28.1 mL (63.7 mmol; 2.27 M solution in hexanes) of n-BuLi via syringe and the solution was stirred at 0° C. for 45 min. In a separated flask, 3.315 g (25.5 mmol) of freshly distilled ethyl acetoacetate and 50 mL of diethyl ether were added and the solution was cooled to −78° C. To it, the above LDA solution was added via cannula, then 3.84 mL (25.5 mmol) of N,N,N′,N′-tetramethylethylenediamine (TMEDA) (distilled from LiAlH4) was added via syringe, and the solution was stirred at 0° C. for 3 h. To this dianion solution, a solution of 5.0 g (25.5 mmol) of methyl 3,4-dimethoxybenzoate in 50 mL of diethyl ether was added via cannula and the reaction solution was warmed to room temperature and stirred for 40 h. The reaction mixture was filtered through fritted funnel, and the solid (desired product) was saved. The organic filtrate from the above filtration was washed with a solution of 50 mL of 1 N HCl and 50 mL of distilled water, and then with 80 mL of brine, dried (MgSO4), and concentrated to give the desired product, 5-(3,4-dimethoxy-phenyl)-3,5-dioxopentanoic acid. The solid obtained above was dissolved in 80 mL of distilled water and 10 mL of 1 N HCl solution, and washed twice with methylene chloride (100 mL each). The water layer was further acidified with 100 mL of 1 N HCl, extracted twice with methylene chloride (50 mL each). The combined methylene chloride extract was washed with 80 mL of brine, dried (MgSO4), concentrated to give the desired carboxylic acid [5-(3,4-dimethoxyphenyl)-3,5-dioxopentanoic acid]. This acid and the above acid from the filtrate were combined and dissolved in 50 mL of CH2Cl2, cooled over ice-water bath, and a solution of diazomethane in diethyl ether was added dropwise until the carboxylic acid was no longer present. The solution was concentrated on a rotary evaporator and dried under vacuum, and column chromatographed on silica gel using a gradient mixture of hexane and ethyl acetate as eluant to give 3.798 g (56% yield) of pure 13B. 1H NMR δ7.51 (dd, J=8.5 Hz, 2 Hz, 1 H, C5′ H, Ar), 7.45 (d, J=2 Hz, 1 H, C2′ H), 6.9 (d, J=8.5 Hz, 1 H, C6′ H), 6.24 (s, 1 H, ═CH of enol at C4&5), 3.95 (s, 6 H, 2 OMe on Ar ring), 3.77 (s, 3 H, MeO), 3.47 (s, 2 H, CH2); 13C NMR δ186.18 (s, C3 C═O), 184.05 (s, C5═C—O), 168.21 (s, C═O ester), 153.16 (s, C4′Ar), 149.07 (s, C3′Ar), 127.04 (s, Cl′Ar), 121.49 (d, C2′), 110.56 (d, C5′), 109.66 (d, C6′), 96.17 (d, C4═CH), 56.06 (q, OMe), 56.0 (q, OMe), 52.32 (q, OMe of ester), 44.89 (t, CH2); MS.FAB, m/z 281 (M+1), 280 (M+).