Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.[C:5]([O:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[CH3:6].[C:12](OCC=C)(=O)[CH:13]=[CH2:14].C(O)(=O)C=C.[OH2:25]>>[C:5]([O:8][CH2:9][CH:10]=[CH2:11])(=[O:7])[CH3:6].[O:25]=[O:3].[CH2:12]=[CH:13][CH3:14]
Reactant: CC(=O)O
Reactant: C=CCOC(=O)C=C
Reactant: O
Agent: C=CC(=O)O
Agent: C=CCOC(C)=O
Product: C=CC
Product: O=O

Procedure:
The acetic acid-containing liquid (a bottom liquid 18 of the first distillation column in this example) contains, in addition to the unreacted acetic acid, water as a reaction product and a trace amount of allyl acetate, components such as impurities (unsaturated compounds such as allyl acrylate and acrylic acid) by-produced in the reaction in the oxidation reactor 5, and raw materials. With respect to a standard boiling point of these components, while acetic acid has a standard boiling point of 118° C., water has a standard boiling point of 100° C., allyl acetate has a standard boiling point of 103° C., allyl acrylate has a standard boiling point of 122° C., and acrylic acid has a standard boiling point of 139° C. The standard boiling points of these components are close to each other and it is difficult to separate these components from the acetic acid-containing liquid by simple distillation. On the other hand, there are circumstances, when allyl acetate is produced from oxygen, acetic acid and propylene, it is desirable to recycle the unreacted acetic acid in the production of allyl acetate from the viewpoint of effective utilization of raw materials, energy saving and cost. Conventionally, the acetic acid-containing liquid was recycled to the acetic acid-water evaporator 4 without sufficiently removing impurities such as unsaturated compounds, and then mixed with other raw materials and fed to the oxidation reactor 5. According to such a conventional process, components other than acetic acid contained in the acetic acid-containing liquid, such as water, allyl acetate, allyl acrylate and acrylic acid are also evaporated in the acetic acid-water evaporator 4 and then fed to the oxidation reactor 5. The present inventors have found that unsaturated compounds such as allyl acrylate and acrylic acid serve as a catalyst poison of the catalyst in the production of allyl acetate, and shorten the lifetime or the like, and investigated a process which could prevent these unsaturated compounds from being recycled to the oxidation reactor 5 as much as possible.
Reaction SMILES: I[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][O:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1)#[CH:51]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][C:6]1[O:5][N:4]=[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]=1[C:51]#[C:50][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: C#Cc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
A mixture of 4-iodo-5-methyl-3-phenylisoxazole (285 mg, 1.00 mmol), palladium(II) acetate (7 mg, 0.03 mmol), 1,3-bis(diphenylphosphino)propane (12 mg, 0.03 mmol), triethylamine (348 μL, 2.50 mmol) and 2-ethynylpyridine (131 μL, 1.30 mmol) in N,N-dimethylformamide (2 mL) was evaporated and flushed with argon. Cuprous iodide (4 mg, 0.02 mmol) was added and the reaction mixture was stirred for 3 h at 90° C. before cooling to ambient temperature and separated between aqueous sodium hydroxide (1 M, 30 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and washed with aqueous sodium hydroxide (1 M, 30 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (60 mg, 23%) as a light brown solid. MS: m/e=261.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(F)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 56 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), 6-mercaptopurine monohydrate (116 mg, 0.681 mmol), K2CO3 (94 mg, 0.681 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 152 mg of a white solid (56%), mp 222.7-223.8° C. (discolors). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 7.89 (dt, J=5.6, 8.1 Hz, 1H); 7.76 (dd, J=1.6, 7.3 Hz, 1H); 7.67 (d, J=7.4 Hz, 1H); 7.56 (d, J=8.1 Hz, 1H); 7.47 (t, J=7.1 Hz, 1H), 7.41-7.53 (m, 2H); 7.37 (dd, J=8.7, 11 Hz, 1H); 4.38-4.52 (m, 2H). 13C NMR (DMSO-d6) ppm: 160.9 (d, J=264 Hz), 157.6, 156.8, 154.1, 151.5, 149.6, 149.0, 143.6, 136.4 (d, J=11 Hz), 133.9, 132.2, 131.7, 131.6, 130.5, 130.2, 128.8, 123.6, 114.4 (d, J=20 Hz), 110.2, 32.0. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.5C2H6O: C, 54.61; H, 3.27; Cl, 7.68; N, 18.19; S, 6.94. Found: C, 54.37; H, 3.26; Cl, 7.89; N, 18.26; S, 6.55.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][CH:9]=2)[CH:7]=1.C([Li])CCC.N1(C=O)CC[O:21][CH2:20]C1.O>CCOCC>[C:8]1([C:6]2[CH:7]=[C:2]([CH:20]=[O:21])[CH:3]=[N:4][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=CN1CCOCC1
Reactant: Brc1cncc(C2=CCCC2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: O=Cc1cncc(C2=CCCC2)c1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-5-cyclopenten-1-ylpyridine (9) (1 g, 4.5 mmol) in 25 ml of ether is added to a solution of n-butyllithium (1.6M in hexane, 4.2 ml, 6.7 mmol) in 25 ml of ether kept at −60° C. The reaction mixture is stirred for 2 h 30 min at −60° C. and then 1.4 ml of 4-morpholinecarboxaldehyde (13.4 mmol) are added. The reaction is stirred for 1 hour at −60° C. and then poured into water, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 80/20). The title product is obtained in the form of a beige solid (0.38 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].[OH-].[Na+].[Br:12][CH2:13][CH2:14]Br>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:14][CH2:13][Br:12]
Reactant: BrCCBr
Reactant: Oc1cc(Cl)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(Br)c(OCCBr)c1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
To a suspension of 2-bromo-5-chloro-phenol (2.58 g, 12.44 mmol) in water (8 mL) was added sodium hydroxide (995 mg, 24.88 mmol) and the solution heated to reflux for 1 h and then allowed to cool to room temperature. 1,2-dibromoethane (4.67 g, 24.88 mmol) was added and the mixture heated at reflux for 25 h. The solution was allowed to cool to room temperature and partitioned between EtAOc and water. The aqueous was washed with saturated sodium hydrogen carbonate, water and brine and then dried (MgSO4) and concentrated. Material was purified using an ISCO (0-5% EtOAc/hexanes) to afford 1-bromo-2-(2-bromoethoxy)-4-chlorobenzene as a white solid (1.30 g, 33%). 1H NMR (500 MHz, d6-DMSO) δ 7.62 (1H, d), 7.26 (1H, s), 7.02 (1H, d), 4.46 (2H, t), 3.83 (2H, t).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[CH:7]=[N:8]2)=[CH:4][N:3]=1
Reactant: C1=COCCC1
Reactant: Clc1ncc2[nH]cnc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ncc2c(ncn2C2CCCCO2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A 100-mL, round-bottom flask was charged with 2-chloro-7H-purine (0.200 g, 1.29 mmol), toluene (20 mL), p-toluene sulfonic acid (0.011 g, 0.06 mmol), 3,4-dihydro-2H-pyran (0.328 g, 3.90 mmol), and the resulting solution stirred for 2 h at 80° C. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting 1:5, with ethyl acetate/petroleum ether) to afford 2-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-purine (0.245 g, 79%) as brown oil. MS (ESI, pos. ion) m/z 239 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10][N:9]=1.[H-].[Na+].Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl.O>CN(C)C=O>[CH3:23][N:24]([CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:11]=[CH:10][N:9]=1)[CH3:28]
Reactant: Oc1ccccc1-c1cc(-c2ccccc2)ncn1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccccc1-c1cc(-c2ccccc2)ncn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.8 %

Procedure:
A solution of 4-(2-hydroxyphenyl)-6-phenyl-pyrimidine (0.5 g, example 1) and sodium hydride (0.12 g, 80% in oil) in anhydrous dimethylformamide (5 ml) was stirred 20 minutes at room temperature. Then 2-dimethylaminoethyl chloride hydrochloride (0.29 g) was added and the solution was heated at 100° C. under stirring for 6 hours. The reaction mixture was cooled, then poured into water, and the separated oil was extracted with ethyl acetate. The organic layer was dried, then evaporated to dryness to give 500 mg of the title compound as a crude residue, which was purified through its hydrochloride salt. This was obtained by dissolving the free base in acetone, adding a hydrochloric acid ethereal solution and filtering off the crystallized salt.
Reaction SMILES: [NH2:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].CCOCC.[OH-].[Na+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.O1CCCC1>[C:21]([NH:1][C@H:2]([CH2:10][OH:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
N-benzoylphenylalaninol is synthesized by following steps of: i) suspending 1 mole (163 g) of L-phenylalaninol to 1 L of tetrahydrofuran, ii) adding 2.5 mole (100 g) of NaBH4 to the solution, iii) dropping 1.25 mole of ether-diluted sulfuric acid (66 ml, total volume 200 ml) to the solution at 0° C., iv) after reacting the solution for 12 hours at room temperature, adding 200 ml of methanol slowly, v) after adding 1 L of 5N-NaOH, evaporating organic solvent and refluxing for 3 hours, vi) after cooling to room temperature, adding 1 L of methylenechloride to the solution, vii) adding 1 mole of benzoylchloride to the solution slowly at 0° C., viii) after finishing the reaction, filtering the reaction mixture, ix) washing the product with hot water three times, and x) obtaining 207 g (81%) of N-benzoylphenylalaninol after drying the product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[S:14][CH:15]=[C:16]([CH3:17])[C:10]=2[CH2:9]1)=O)(C)(C)C.CO.Cl.Cl>C(Cl)(Cl)Cl>[CH3:17][C:16]1[C:10]2[CH2:9][NH:8][CH2:13][CH2:12][C:11]=2[S:14][CH:15]=1
Reactant: Cc1csc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1csc2c1CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-t-Butoxycarbonyl-3-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (150 mg, 0.49 mmol) was dissolved in chloroform (1 ml), and the solution was mixed with hydrochloric acid methanol solution (2 ml), stirred at room temperature for 8 hours, further mixed with concentrated hydrochloric acid (1 ml) and stirred for 16 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the thus obtained residue was mixed with 47% hydrobromic acid (6 ml) and stirred at 140° C. for 4 hours. The reaction solution was returned to room temperature and alkalified by adding sodium hydroxide aqueous solution and then the reaction product was extracted there from with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure to obtain 68 mg (0. 44 mmol, 90% in yield) of the title compound. MW 153.24 (C8H11NS); Mass spectrum EI-MS m/z 153 (M)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[C:5]2[NH:19][CH3:20].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.[ClH:31]>O1CCOCC1.O.C(O)C.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>[ClH:31].[ClH:31].[F:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([CH3:12])[CH:11]=2)[N:8]=[C:7]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:6]=[C:5]3[NH:19][CH3:20])[CH:25]=[CH:24][CH:23]=1
Reactant: CNc1nc(-c2cccnc2)nc2c(C)cc(Br)cc12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2cccnc2)nc2c(C)cc(-c3cccc(F)c3)cc12
Temperature: 90 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
6-Bromo-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (340 mg, 1.03 mmol), 3-fluorobenzeneboronic acid (217 mg, 1.55 mmol), K2PO4 (658 mg, 3.10 mmol) and Pd(PPh3)4 (59.7 mg, 0.052 mmol) were dissolved in the mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 90° C. for 6 hours under a nitrogen atmosphere. After the reaction was completed, water was added to the mixture and stirred for 30 minutes. The resulting precipitate was collected by filtration and purified by column chromatography on NH-silica gel (eluted with THF) to give a yellow powder. The solid was suspended in ethanol and 5N HCl (1 mL) was added to the mixture. The mixture was sonicated for 10 min and the resulting precipitate was collected by filtration and dried to give 304 mg of 6-(3-fluorophenyl)-N,8-dimethyl-2-(pyridin-3-yl)quinazolin-4 amine dihydrochloride as a yellow powder in 71% yield.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])[CH3:3].[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]Cl>C(O)C>[CH2:2]([O:4][C:5]([C:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:33][CH2:32][CH2:31][N:30]([CH3:35])[CH3:29])=[C:15]([O:20][CH3:21])[CH:14]=2)[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:10]([CH3:27])[NH:9][C:8]=1[CH3:28])=[O:6])[CH3:3]
Reactant: CN(C)CCCCl
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(O)c(OC)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc(OCCCN(C)C)c(OC)c1
Yield: 75 %

Procedure:
A solution of 2.3 g of sodium in 100 ml of ethanol is added to a warm solution of 37.5 g of 2,6-dimethyl-4-(3-methoxy-4-hydroxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (melting point 172°C) in 300 ml of ethanol. The mixture is heated at reflux and 15 g of 3-dimethylaminopropyl chloride are added dropwise. After refluxing for several hours, the mixture is filtered hot, the residue being washed with alcohol, and the filtrate is evaporated in vacuo to yield yellow crystals of melting point 62°C after recrystallization from ligroin-petroleum ether. Yield: 75% of theory.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](=O)[CH3:33])[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:32]([CH3:33])[CH2:31][C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: CC(=O)Cc1cc(F)cc(F)c1
Product: CCCC(NC(C)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 1-(3,5-difluoro-phenyl)-propan-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.0, 14.1, 19.2, 19.5, 20.1, 21.1, 24.3, 26.6, 36.1, 36.6, 43.6, 44.1, 54.4, 54.9, 56.0, 59.1, 59.1, 60.9, 61.1, 67.3, 101.8, 101.9, 102.0, 102.2, 102.3, 102.4, 104.7, 104.7, 112.0, 112.1, 112.2, 112.3, 112.3, 112.4, 112.5, 131.1, 137.2, 137.3, 143.1, 143.1, 161.8, 162.0, 164.3, 164.4, 172.1, 172.4; MS m/z 462.4 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([OH:10])=[O:9]>N1C=CC=CC=1>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)=[O:16])[CH2:3][O:4][C:15]([C:14]1[CH:18]=[CH:19][C:11]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)=[O:16]
Reactant: CC(C)(CO)CO
Reactant: O=C(O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(COC(=O)c1ccc(C(=O)O)cc1)COC(=O)c1ccc(C(=O)O)cc1
Yield: 80.4 %

Procedure:
A mechanically stirred mixture of 15.6 g (0.15 M) of 2,2-dimethyl-1,3-propanediol, 92.25 g (0.5 M) of 4-carboxybenzoyl chloride and 500 ml of pyridine was refluxed under a nitrogen atmosphere. The resulting mixture was concentrated to dryness under reduced pressure, dispersed in 500 ml of distilled water, and acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered off, washed three times with distilled water, and dried overnight at 100° C in a vacuum oven. The product was extracted for 5 days with 2 liters of hot benzene. The extract, on cooling, yielded 48.2 g of 4,4'-[(2,2-dimethyl-1,3-propanediyl)bis(oxycarbonyl)]bis(benzoic acid) melting at 287°-288° C. The infrared spectrum was consistent with the proposed structure and the compound was found to contain 5.13 meq of CO2H/g which corresponded to a molecular weight of 390 for the diacid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10](O)=O>C(OC(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=CO
Reactant: Nc1cc(Br)cnc1N
Solvent: CCOC(OCC)OCC
Product: Brc1cnc2[nH]cnc2c1
Yield: 86.7 %

Procedure:
A solution of 5-bromo-pyridine-2,3-diamine (3.0 g, 15.96 mmol) and HCOOH (1.1 mL) in triethoxymethane (48 mL) was stirred at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 6-bromo-3H-imidazo[4,5-b]pyridine as a light brown solid (2.74 g, 86.7%). 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.44 (s, 1H), 8.30 (br s, 1H). LCMS (ESI) m/z 198 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C([Li])CCC.[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O1CCCC1.C(OCC)C>[CH2:26]([Sn:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[C:5]1[S:4][C:3]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)=[C:2]([CH3:1])[CH:6]=1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccsc1C1OCCO1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)c(C2OCCO2)s1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(3-methylthien-2-yl)-1,3-dioxolane (intermediate 75, 1.5 g) in tetrahydrofuran (50 ml), stirred at −60° C. under a nitrogen atmosphere, was treated drop-wise with 1.6M n-butyl lithium in hexanes (6.1 ml). The reaction mixture was stirred at this temperature for 1 hour and tributyltin chloride (2.6 ml) was added; stirring was continued at −60° C. for 1 hour and then the reaction allowed to warm to ambient temperature. After 18 hours the reaction mixture was diluted with diethylether and this mixture was extracted with water and the ether layer dried with brine and over magnesium sulfate. The product isolated after evaporation of the solvent was further purified by flash column chromatography using cyclohexane:ethyl acetate (50:1) as eluent to give the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19].[O-]CC.[Na+]>C1COCC1.ClCCl>[O:23]=[C:17]([CH2:2][C:1](=[O:3])[C:4]1[S:5][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(=O)c1ccc(C#Cc2ccccc2)s1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-acetyl-5-(phenylethynyl)thiophene (1.81 g, 8.02 mmol), diethyl oxalate (2.17 mL, 16 mmol), and sodium ethoxide (1.09 g, 16 mmol) in anhydrous THF (25 mL) was stirred at rt under an atmosphere of argon for 5 hr. The resultant mixture was diluted with dichloromethane, and washed successively with dilute HCl, and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide yellow solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([O:37][CH3:38])[C:27]=1[C:28](Cl)=[O:29]>C1COCC1>[F:25][C:26]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([O:37][CH3:38])[C:27]=1[C:28](=[O:29])[CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1cccc(OC)c1
Reactant: COc1ccc(OC)c(C(=O)Cl)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)c1c(OC)ccc(OC)c1F)c1cccc(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
To a mixture of 2-fluoro-3,6-dimethoxybenzoic acid (4.8 g, 24 mmol) in anhydrous dichloromethane (75 mL) at 0° C., SOCl2 (14.2 g, 120 mmol) was slowly added followed by DMF (0.1 mL). The resulting mixture was stirred at room temperature for 2 h and concentrated in vacuo to give 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g). To a solution of ethyl 2-(3-methoxyphenyl)acetate (4.7 g, 24 mmol) in anhydrous THF (40 mL) at −78° C., LiHMDS (1.0 M in THF, 36 mL) was added dropwise. The resulting solution was stirred at −78° C. for 30 min and a solution of 2-fluoro-3,6-dimethoxybenzoyl chloride (5.2 g, 24 mmol) in anhydrous THF (60 ml) was added dropwise. The reaction mixture was stirred for additional 2 h at −78° C. and quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (7.8 g).