Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (32 mg, 0.064 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (5.38 mg, 0.128 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) and then Prep HPLC to give 5-(4-chlorobenzyl)-6-((5-fluoropyridin-3-yl)oxy)-3-(3-hydroxypropyl)-1-methyl pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4 mg, 13.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.47-8.35 (m, 2H), 8.03 (s, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 4.24 (t, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.73 (s, 3H), 3.57 (t, J=5.6 Hz, 2H), 2.01-1.88 (m, 2H). LCMS: MH+ 471 and TR=2.246 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:15]1[C:27]2[NH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]([CH3:45])[CH3:44])[CH:38]=1)(C)C>[Cu].C1(C)C=CC=CC=1>[CH:3]1[C:4]2[N:26]([C:25]3[CH:20]=[CH:44][C:43]([C:39]4[CH:38]=[CH:37][C:42]([N:26]5[C:25]6[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=6[C:19]6[C:27]5=[CH:15][CH:16]=[CH:17][CH:18]=6)=[CH:41][CH:40]=4)=[CH:45][CH:24]=3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:6]=[CH:7][CH:2]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc(-c2ccc(-n3c4ccccc4c4ccccc43)cc2)cc1
Yield: 68.6 %

Procedure:
A 2-L Kolben equipped with a stirrer and a drain device was charged under a nitrogen stream with 150 g (369.5 mmol) of 4,4′-diiodobiphenyl, 123.5 g (738.6 mmol) of carbazole, 23 g of copper powder, 100 g of potassium carbonate, and 500 ml of 1,3-diisopropylbenzene. The mixture was heated under reflux for 30 hr and was allowed to cool. Toluene was then added, and the mixture was filtered. The solvent in the filtrate was distilled off under reduced pressure. Methanol (500 ml) was added to the residue to precipitate crystals. The crystals were collected by filtration to give CBP (4,4′-bis(carbazol-9-yl)-biphenyl) (122.8 g, yield 68.6%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: C1COCCN1
Product: O=c1[nH]c2cc(CN3CCOCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and morpholine to give a yellow solid. MS m/z: 405.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:27][OH:28]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][O:28][CH3:27])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CO
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Product: COCc1c(C)n(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c1=O
Temperature: 60 °C

Procedure:
1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate are dissolved in 10 ml of methanol and the solution is heated at 60° C. for 45 minutes. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in ethyl acetate and shaken with aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure, and the residue is purified by chromatography on a silica gel column using diethyl ether/ethyl acetate (15:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-methoxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 4.40 ppm (d, 1H), 4.33 ppm (d, 1H), 3.49 ppm (s, 3H), 3.39 ppm (s, 3H), 2.43 ppm (s, 3H), 1.35 ppm (d, 6H).
Reaction SMILES: BrB(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16]2)[CH:9]=[C:10]([F:14])[C:11]=1[O:12]C.CO>ClCCl>[F:5][C:6]1[CH:7]=[C:8]([C:15]2([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]2)[CH:9]=[C:10]([F:14])[C:11]=1[OH:12]
Reactant: COC(=O)C1(c2cc(F)c(OC)c(F)c2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(c2cc(F)c(O)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Tribromoborane (0.666 ml, 7.04 mmol) was added dropwise to methyl 1-(3,5-difluoro-4-methoxyphenyl)cyclopropanecarboxylate (Intermediate 28-4; 1.4216 g, 5.87 mmol) in dichloromethane (46.2 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to methanol (11.87 mL, 293.45 mmol) (care reaction is vigorous and exothermic—MeOH kept in ice bath) and the mixture was stirred for a further 20 minutes. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed sequentially with saturated NaHCO3 (50 mL) and water (50 mL). The organic layer was dried with MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluted at 25% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(3,5-difluoro-4-hydroxyphenyl)cyclopropanecarboxylate (0.657 g, 49.1%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([OH:13])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]([NH2:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(Cl)Cl.C(N(CC)CC)C>[C:25]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:11]([C:4]1[C:5]([C:7]([F:10])([F:9])[F:8])=[CH:6][N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Reactant: Nc1ccccc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccccc2-c2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-methyl-4-trifluoromethylpyrrol-3-carboxylic acid (1.9 g) and oxalyl chloride (0.9 ml) in methylene chloride (20 ml) is stirred at room temperature in the presence of a catalytic amount of DMF. The solvent is evaporated under reduced pressure to give a crystalline solid. This solid is dissolved in methylene chloride (1 ml) and added to a solution of 2-biphenylamine (1.7 g) and triethylamine ( 4.2 ml) in methylene chloride (20 ml) at 0° C. The reaction mixture is stirred at room temperature for 2 hours. Evaporation of the solvent under reduced pressure, addition of water and filtering gives the N-(2-biphenylyl)-1-methyl-4-trifluoromethylpyrrol-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:23]([O-])([OH:25])=[O:24].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)nc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a suspension of 2,6-dichloro-4-methylpyridine (1 g, 6.17 mmol) in trifluoroacetic acid anhydride (5 mL, 35.4 mmol) cooled down to 0° C. was added dropwise nitric acid (0.579 mL, 12.96 mmol) into it. The resulting solution was stirred at RT for 18 hr. The reaction mixture was added slowly to a chilled solution of sodium metabisulfite (1.183 g, 6.17 mmol) in water (8 mL) and stirred at RT for 2 hr. The reaction mixture was neutralized to pH 7 using 8N NaOH solution and extracted twice with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title product (1.187 g, 5.73 mmol, 93% yield) as white solid. tR: 1.07 min (LC-MS 2); ESI-MS: 208 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3H) 7.90 (s, 1H).
Reaction SMILES: C([S:5][C:6]([CH3:22])([CH3:21])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1NCC(S)(C)C)CCC>[Tc]([O-])(=O)(=O)=O.[Na+]>[SH:5][C:6]([CH3:22])([CH3:21])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Agent: O=[Tc](=O)(=O)[O-]
Agent: [Na+]
Product: CC(C)(S)CNc1ccccc1

Procedure:
2-(2-(Butylthio)2-methylpropylamino]-1-(2-mercapto-2-methylpropylamino)benzene was reacted with Tc-99m sodium pertechnetate by the method of Example 7 to produce Tc-99m complex of 2-(2-butylthio)2-methylpropylamino)-1-(2-mercapto-2-methylpropylamino)benzene. The complex was purified by filtration through Millex GS and Jelco 5 micron fitlers. HPLC (90% ethanol/H 2 O, 1.5 ml/min, C18 5 micron Radial Pak) Rt 4.4 min (99%). TLC (50% diethyl ether/chloroform) Rf 0.89, radiochemical purity 92%. Electrophoresis (0.05 M NaH2PO4, buffer pH 4.5 constant 300 volts, 30 min) neutral.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:18])=[C:6]([C:8]([C:10]2[C:15](F)=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1.C[C:20]([O:23]C)(C)C.C[O-].[Na+].CO>C(O)C(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:18])=[C:6]([C:8]([C:10]2[C:15]([O:23][CH3:20])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1
Reactant: COC(C)(C)C
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)CO
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1I
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Into a reactor at room temperature was added 2 (67.6 kg, 179 mol) and MTBE (344 L). The mixture was warmed to 40° C. and stirred for 30 min until solids fully dissolved. The mixture was then cooled to 25 to 30° C. Sodium methoxide as a 25% w/w solution in methanol (45.2 kg, 209 mol) was added over a minimum of 90 min at 25 to 30° C. The reaction mixture was stirred for at least 2 h until >99.0% conversion was obtained by HPLC analysis. Water (483 L) was added slowly over 30 min while maintaining the temperature between 20 and 25° C. The layers were separated and the aqueous phase was extracted with MTBE (77 L). The combined organic extracts were washed with a dilute brine solution (38 kg NaCl in 342 L water). The organic layer was filtered, washed with water (242 L) and the organic phase was filtered. The resulting organic phase was concentrated until 360 L of solvent were removed while maintaining the internal temperature below 70° C. Isobutanol (302 L) was added and the mixture was concentrated while maintaining the internal temperature below 70° C. until 307 L of solvent were removed. A second portion of isobutanol (330 L) was added and the mixture was concentrated while maintaining the internal temperature below 70° C. until 210 L of solvent were removed. The mixture was heated to 60 to 85° C. until a clear solution was obtained and cooled to 50° C. A slurry of seed crystals (50 g in 150 mL isobutanol) was added and the mixture was cooled to 40° C. A second slurry of seed crystals (30 g in 60 mL isobutanol) was added and the mixture was cooled to 20 to 25° C. over a minimum of 3 h. The resulting mixture was stirred an additional 2 h. The mixture was filtered and washed with isobutanol (2×65 L). The resulting wet cake was dried at 20 to 35° C. under vacuum to provide 50.9 kg of crude 3. Into a separate reactor was charged crude 3 and isobutanol (69 L). The mixture was heated to 75 to 80° C. until a clear solution was obtained. The reaction mixture was cooled to 55° C. and a slurry of seed crystals (50 g in 500 mL isobutanol) was added. The mixture was stirred for 30 min at 55° C., cooled to 20 to 25° C. over a minimum of 3 h and stirred an additional 2 h. The mixture was filtered and washed with isobutanol (2×31 L). The wet cake was dried under vacuum at 40° C. to provide 46.0 kg (66% yield) of purified 3. 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.2 Hz, 1H), 7.42 (m, 2H), 7.13 (dd, J=2.3, 8.2 Hz), 6.76 (m, 2H), 3.73 (s, 3H); MS (ESI) m/z 391.2 (M+H+, 30%).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1(CO)CC[CH:16]([CH2:19][OH:20])CC1.[CH2:23](O)[CH2:24][OH:25]>>[OH:20][CH2:19][CH2:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:23][CH2:24][OH:25])=[O:11])=[CH:3][CH:4]=1
Reactant: OCCO
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: OCC1CCC(CO)CC1
Product: O=C(OCCO)c1ccc(C(=O)OCCO)cc1

Procedure:
The poly(ethylene terephthalate) and poly(ethylene terephthalate-co-1,4-cyclohexanedimethylene terephthalate) polyesters described in Tables 1 and 2 were prepared by standard melt polymerization techniques known to the art. Terephthalic acid, ethylene glycol and 1,4-cyclohexanedimethanol (CHDM) were first pre-esterified to form the bis(2-hydroxyethyl)terephthalate or the equivalent CHDM co-terephthalate monomers in a pressurized vessel. This was required due to the high temperature necessary to dissolve terephthalic acid in the polyhydric alcohols. However, this should not be limited to such a procedure, as a continuous process, or any other polyester synthesis based on TPA (terephthalic acid) known the art, could also be used. Once formed, the monomers were added to a 4-necked 500 mL round bottom glass flask which was equipped with a nitrogen inlet, an additive inlet, a condensate outlet and a stirrer. Catalysts, stabilizers and toner dyes, as indicated in Table 1, were also added to this same reaction vessel. The reaction flask was then purged with nitrogen and then immersed in a metal bath which was preheated to 225° C. The mixture was stirred and held at this temperature for 15 minutes to form a homogeneous melt. The temperature was then raised to 280° C. and vacuum was applied incrementally until a vacuum of <1 mm Hg was obtained. The reaction mixture was stirred and maintained under these conditions for 45 minutes. The formed polyester was then isolated, and analyzed for color, molecular weight, and thermal stability.
Reaction SMILES: C([N:9]([C:18]1[C:19]2[N:26]=[C:25]([C:27]3[N:31]([CH3:32])[CH:30]=[N:29][C:28]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:24][C:20]=2[N:21]=[CH:22][N:23]=1)C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42].[CH:45](=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CCN(C(C)C)C(C)C>CC#N.CO.N>[CH3:39][N:40]([CH3:44])[C:41](=[O:42])[O:52][CH:45]([C:30]1[N:31]([CH3:32])[C:27]([C:25]2[S:24][C:20]3[N:21]=[CH:22][N:23]=[C:18]([NH2:9])[C:19]=3[N:26]=2)=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:29]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1nc2c(N(C(=O)c3ccccc3)C(=O)c3ccccc3)ncnc2s1
Reactant: O=Cc1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: N
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)OC(c1ccccc1)c1nc(-c2ccccc2)c(-c2nc3c(N)ncnc3s2)n1C
Temperature: 55 °C
Yield: 68 %

Procedure:
N-Benzoyl-N-[2-(1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]benzamide (Intermediate 96) (0.05 g) was dissolved/suspended in MeCN (5 mL), dimethylcarbamyl chloride (0.015 mL) added, then benzaldehyde (16 mg) and DIPEA (0.05 mL). The reaction mixture was heated at reflux for 24 hours then additional dimethylcarbamyl chloride (0.015 mL), benzaldehyde (16 mg) and DIPEA (0.05 mL) added. After heating for 5 days, the reaction mixture was concentrated in vacuo, diluted with saturated NaHCO3 solution (5 mL) then extracted with DCM (2×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give a brown residue which was dissolved in MeOH (2 mL)/concentrated aqueous NH3 (2 mL). The reaction mixture was heated at 55° C. for 1 hours then concentrated in vacuo, diluted with 2M NaOH (8 mL) and extracted with DCM (1×20 mL). The organic layer was dried (MgSO4), filtered, concentrated in vacuo giving a residue which was purified by flash chromatography on silica (2% MeOH/DCM) to give the title compound as a colourless solid (0.033 g, 68%);
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.O1CCOCCOCCOCCOCCOCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: O=Cc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccccn2)cc1
Temperature: 120 °C
Yield: 45.2 %

Procedure:
A stirred mixture of 36.7 grams (0.30 mole) of 4-hydroxybenzaldehyde, 12.9 mL (0.15 mole) of 2-fluoropyridine, and 41.0 grams (0.30 mole) of potassium carbonate, and 1.05 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 200 mL of dimethyl sulfoxide was heated at 120° C. for four days. The reaction mixture was cooled to ambient temperature, and 500 mL of water was added. The organic and aqueous layers were separated. The aqueous layer was basified with aqueous 10% sodium hydroxide and extracted with two 400 mL portions of diethyl ether. The ether extracts were combined and washed with one 100 mL portion of aqueous 5% sodium hydroxide, followed by one 100 mL portion of aqueous 10% lithium chloride. The organic layer and extracts were combined, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield a residue, which was subjected to column chromatography on silica gel. Elution was accomplished with 15-20% acetone in petroleum ether mixtures. The product-containing fractions were combined and concentrated under reduced pressure, yielding 13.5 grams of 4-(pyrid-2-yloxy)benzaldehyde. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOCOc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 40 h
Yield: 79.7 %

Procedure:
2-Methoxyethoxymethyl chloride (5.10 mL, 45.0 mmol) was slowly added to a mixture of 4-hydroxybenzaldehyde (5.00 g, 40.9 mmol) and K2CO3 (6.20 g, 45.0 mmol) in acetone (70 mL) cooled at 0° C. The mixture was allowed to reach room temperature and stirred for 40 h. After removal of the solvent, the crude residue was dissolved in EtOAc (50 mL) and consecutively washed with water (50 mL) and NaOH (10% aqueous solution, 2×20 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, 6.85 g of 4-((2-methoxyethoxy)methoxy)benzaldehyde were obtained [Rf=0.6 (50% AcOEt/Hexanes), colorless oil, 80% yield], that were used without further purification.
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([O-:3])=[O:2].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH:4][N+:1]([O-:3])=[O:2])[CH3:14]
Reactant: CCOC(CN)OCC
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(CNC(=C[N+](=O)[O-])c1ccccc1)OCC
Yield: 86.4 %

Procedure:
Alpha-nitro acetophenone (5.7 g, 0.0345 mol) is taken up in 100 mL toluene and 4.6 g (0.0345 mol) of amino acetaldehyde diethyl acetal is added. The reactants are put into a 250 mL RB flask fitted with a Dean-Stark trap. The trap is filled with 4A molecular sieves and the mixture is heated at reflux for 18 hours. The toluene is removed in vacuo to give 8.36 g of α-(2,2-diethoxyethylamino)-β-nitrostyrene as a brown oil. To this oil is added 50 mL of concentrated HCl. As the flask is swirled the oil turns to a yellow suspension. After 10 minutes the solid is filtered to give 2.48 g of a yellow solid. Recrystallization from ether/ethylacetate/hexane gives the product as two fractions, 2.08 g of mp 190°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1

Procedure:
Compound 10 (12.3 g) was dissolved in 100 mL acetone and 7.6 g of potassium carbonate was added. 8.6 g of benzyl bromide was added with stirring. The solid was removed by suction filtration and the liquid was evaporated to product 11.