Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:23])/[C:4](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)=[N:5]/[O:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-]>CO>[Cl:22][C:14]1[CH:13]=[C:12](/[C:4](=[N:5]\[O:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)/[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: CNC(N)=O
Reactant: COC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)/C(=N/OC1CCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Yield: 36.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid methyl ester (prepared as in Example 1, 98 mg, 0.27 mmol), methylurea (44 mg, 0.60 mmol) and a 6-10 wt. % solution of magnesium methoxide in methanol (1.33 mL, 0.10 mmol) were combined and warmed in a 70° C. oil bath for 16 h. After cooling, the reaction mixture was diluted with methanol (2 mL) and filtered through celite. The celite was washed with ethyl acetate (100 mL) and the combined filtrates were washed with water (40 mL), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-1-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetyl]-3-methyl-urea (40 mg, 36%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C16H20ClN3O5S [M+] 401.08, found 402 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.65 (m, 4 H, 2×CH2), 1.87 (m, 4 H, 2×CH2), 2.94 (d, J=4.9 Hz, 3 H, NCH3), 3.32 (s, 3 H, SO2CH3), 4.92 (m, 1 H, OCH), 7.50 (brd, Jo=8.2, 1 H, Ar), 7.60 (brs, 1 H, Ar), 8.02 (brm, 1 H, NH), 8.21 (d, Jo=8.2 Hz, 1 H, Ar), 8.82 (s, 1 H, NH).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Solvent: c1ccncc1
Product: Cn1nc(NC(=O)c2ccccc2)c2c(=O)n3c(nc21)SCC3
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
In 14 ml of pyridine was dissolved 1.40 g (6.27 mmol) of Compound 13 prepared in Example 10, and 0.80 ml (6.9 mmol) of benzoyl chloride was added to the solution, followed by stirring at 50° C. for 30 minutes. After evaporation of the solvent, the residue was subjected to partition between chloroform and water. The chloroform layer was washed with a dilute aqueous solution of hydrochloric acid and water, and concentrated to dryness under reduced pressure. The residue was recrystallized from chloroform/ethanol to give 1.81 g (80%) of Compound 21 in pure form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. to a solution of aniline (2.45 mL) and triethylamine (0.73 mL) in methylene chloride (30 mL) a solution of chloroacetyl chloride (2.56 mL) in methylene chloride (10 mL) was added dropwise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 1 hour. A 1M aqueous solution of KHSO4 was added, the phases were separated and the inorganic one was extracted with ethyl acetate (×3). The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated in vacuo to yield crude 2-chloro-N-phenyl-acetamide, which was subjected to the next reaction without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([NH:1][CH:2]2[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]2)=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCN1CC(N)CN1CC
Solvent: Cc1ccccc1
Product: CCN1CC(NC(=O)Nc2cc(Cl)cc(Cl)c2)CN1CC
Reaction time: 8 h

Procedure:
A solution of 4-amino-1,2-diethylpyrazolidine (1.26 g, 8.8 mmol) in anhydrous toluene (5 ml) was added to a solution of 3,5-dichlorophenyl isocyanate (1.71 g, 9.1 mmol) in dry toluene (20 ml) and the mixture stirred overnight. The precipitated solid was collected, washed with toluene and dried to give the title compound, 1.94 g. This was converted to the 1:1 maleate, mp 165°-167° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6]C)=O.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>CO>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:4](=[O:6])[CH2:3][C:2](=[O:1])[CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCCCC
Reactant: CCC(=O)CC(=O)OC
Solvent: CO
Product: CCCCN(CCCC)C(=O)CC(=O)CC
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
0.16 mol (20 ml) of methyl 3-oxovalerate (3-oxo-pentanoic acid methyl ester) and 0.415 mol (70 ml) of dibutylamine were stirred for 3 h at 130° C., where methanol formed was removed via a distillation bridge. Thereafter, excess dibutylamine was distilled on a rotary evaporator, the crude product taken up in 40 ml water and 90 ml of ethanol, with 3 ml 20% HCl adjusted to pH 3 and stirred for 1 h at 50° C. The mixture was again evaporated to dryness, dissolved again in 200 ml ethyl acetate and washed 3 times with 100 ml of water. The organic phase was dried over Na2SO4 and after filtration evaporated in a rotary evaporator to dryness. After drying, 31.8 g of the title compound were obtained.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14](=[O:25])[C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[CH3:4]>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:3][CH3:4])=[C:7]([C:12]2[NH:13][C:14](=[O:25])[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH:8]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Temperature: 100 °C
Reaction time: 6.5 h

Procedure:
Bromine (0.93 g, 0.0058 mol) was added dropwise to a stirred solution of 5-(2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (Preparation 7, 1.1 g, 0.00352 mol) in glacial acetic acid (20 ml). The mixture was stirred at 100° C. for 6.5 hours and the solvent was then removed by evaporation under vacuum. The residue was dissolved in a 9:1 mixture of methanol in dichloromethane (50 ml), and the solution washed with saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml) and saturated brine (50 ml), then dried (MgSO4) and evaported under vacuum. The residue was chromatographed in silica gel (15 g) eluting with a mixture of methanol and dichloromethane (1:99) to give, after crystallisation from acetonitrile, the title compound (0.62 g, 45%), m.p. 157°-159° C. Found C,52,41; H,5.25; N,14.01. C17H19BrN4O2 requires C,52.18; H,4.89; N,14.32%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1.[NH3:23]>CO.C(Cl)Cl>[NH2:23][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)C1CCC(Cc2cc(Cl)n3nccc3n2)CC1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CCC(Cc2cc(N)n3nccc3n2)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a 10-20 mL microwave vessel was charged ethyl 4-((7-chloropyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4g, 2.29 g, 7.12 mmol). To this was added ˜7N NH3 in methanol (15 mL). The resulting solution was stirred at 90° C. for 4 hours. After 4 hours, the reaction was cooled to room temperature and diluted with DCM (100 mL). This solution was washed with H2O and the organic layer was extracted. The aqueous phase was again extracted with DCM. The combined organics were dried over Na2SO4 and then the solvent was removed in vacuo. The resulting solid was taken on without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:34][C:35]1[CH:44]=[C:43]2[C:38]([CH2:39][CH2:40][C:41](=[O:45])[NH:42]2)=[CH:37][CH:36]=1.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56](O)[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1>[O:45]=[C:41]1[CH2:40][CH2:39][C:38]2[C:43](=[CH:44][C:35]([O:34][CH:56]3[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:54][CH2:55]3)=[CH:36][CH:37]=2)[NH:42]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.9 %

Procedure:
Triphenylphosphine (0.577 g, 2.2 mmol) was dissolved in dry tetrahydrofuran (20 mL) under argon and the solution cooled to 0–5° C. Diisopropyl azodicarboxylate (0.404 g, 2 mmol) was added dropwise and the mixture stirred at 0–5° C. for 20 min. before addition of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (0.326 g, 2 mmol) and 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.402 g, 2 mmol). The resulting mixture was stirred at ambient temperature for 18 h then evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with a gradient of ethyl acetate in 60–80° C. petroleum ether, gave the title compound (0.2 g, 29%) as a white solid.
Reaction SMILES: O[CH:2]([C:6]1([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]2=[N:8][CH2:7]1)[C:3]([OH:5])=[O:4]>C(O)=O.[Pd]>[CH3:18][O:17][C:15]([C:12]1[CH:13]=[CH:14][C:9]2[N:10]([C:6]([CH2:2][C:3]([OH:5])=[O:4])([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)[CH2:7][N:8]=2)[CH:11]=1)=[O:16]
Reactant: COC(=O)C1=CN2C(=NCC2(c2ccc(C)cc2)C(O)C(=O)O)C=C1
Agent: [Pd]
Solvent: O=CO
Product: COC(=O)C1=CN2C(=NCC2(CC(=O)O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a solution of 4 (8.5 g, 25 mmol) in formic acid (100 ml) under nitrogen was added 10% palladium/carbon catalyst (600 mg) and the mixture heated at reflux overnight. The mixture was cooled to room temperature, filtered and evaporated to dryness. Water (100 ml) was added and the mixture stirred for 2 h. The white precipitate was filtered, washed with water (2×50 ml) and dried to give the light brown/yellow solid 2-[6-methoxycarbonyl-3-(4-tolyl)imidazo[1,2-a]pyridine-3-yl]acetic acid 5 (7.9 g, 97%).
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH2:4][CH2:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH3:3].[CH:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:12]([CH:15]1[O:10][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:7])[O:8]1)([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(O)CCC(C)(C)O
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)OC(C(C)(C)C)O1
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 730 g (5 mol) of 2,5-dimethylhexane-2,5-diol, 3 g of p-toluenesulfonic acid, 430 g (5 mol) of pivalaldehyde and 1 l of toluene was refluxed for 4 hours (h) during which the water of reaction produced (90 ml) was removed. The reaction mixture was then cooled down to room temperature (RT) and stirred up with 10 ml of 25% strength aqueous sodium hydroxide solution, the phases were separated, the organic phase was washed with a little water until neutral, and the toluene was then removed at 50°-60° C. The residue obtained was fractionated under reduced pressure affording 909 g (4.25 mol) of 2-tert.-butyl-4,4,7,7,-tetramethyl-1,3-dioxacycloheptane (boiling point 54° C./0.2 mbar). This corresponds to a yield of 85% of theory.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[CH:12]=[CH:11][N:10]=1.O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[OH:16][CH2:15][C:14]1[C:9]([CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[N:10][CH:11]=[CH:12][C:13]=1[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccnc(CN)c1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccnc(CNC(=O)C(C)C)c1CO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of isobutyryl chloride (29 μL, 0.276 mmol) in DCM (0.20 mL) was added to a vigorously stirred mixture of (2-aminomethyl-4-methyl-pyridin-3-yl)-methanol (30 mg, 0.20 mmol) in DCM (1.0 mL) and aqueous Na2CO3 (1 M, 1 mL) at 0° C. After stirring for 30 min at 0° C., DCM (10 mL) and water (1 mL) was added, and the aqueous layer was extracted with DCM (1×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with MeOH/DCM 1:20) to give the title compound. MS (m/z): 223.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:30](=[O:32])[CH3:31]>O1CCCC1>[CH3:17][CH:16]([CH3:18])[CH2:15][N:3]1[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=[C:2]1[CH2:1][C:30](=[O:32])[CH3:31]
Reactant: CON(C)C(C)=O
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Cc1nc2cnc3ccccc3c2n1CC(C)C
Temperature: -78 °C

Procedure:
2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1 g, 4.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) then cooled to −78° C. A portion of lithium diisopropyl amide (2.8 mL, 4.2 mmol) was added dropwise to the cooled solution. At 10 minutes post addition, N-methoxy-N-methylacetamide (0.45 g, 4.4 mmol), prepared according to the method of T. A. Oster and T. M. Harris, Tetrahedron Letters, 24, 1851 (1983) was added. After 15 minutes the reaction was quenched with water and the resulting precipitate was collected and dried to provide the desired product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[C:6](=[O:17])[CH:7]2[CH:12]([C:13](=[O:15])[CH:14]=1)[CH:11]1[CH2:16][CH:8]2[CH:9]=[CH:10]1.C([O-])([O-])=O.[Na+].[Na+].Cl>C(Cl)(Cl)Cl>[CH3:3][O:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[CH:11]3[CH2:16][CH:8]([CH:9]=[CH:10]3)[C:7]=2[C:6]=1[OH:17]
Reactant: COC1=CC(=O)C2C3C=CC(C3)C2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(O)c2c(c1O)C1C=CC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
To stirred MeOH (65 mL), which had been purged with N2 for 5 min, there was added 1,4,4a,8a-tetrahydro-6-methoxy-1,4-methanonaphthalene-5,8-dione (47, 1.50 g, 7.30 mmol) to give a solution. Solid Na2CO3 (2.02 g, 14.6 mmol) was then added under N2. The resulting light green suspension was allowed to stir under N2 for 15 min at rt. TLC analysis (10% MeOH, 90% CHCl3) indicated total consumption of the organic starting material. While still under N2, the reaction was diluted with H2O (20 mL). The pH was adjusted to slightly acidic by the slow and careful addition of concd HCl, after which the solution was light pink. The methanol was then removed in vacuo (vacuum relieved with N2) to give a light green solution. The pH was approximately 8. The pH was then adjusted to 2 with 10% HCl at which point the product crystallized. The crystals were collected, washed with 10% HCl (4×3 mL) and dried in vacuo to yield 48 as a near colorless crystalline solid (1.32 g, 88%, pure by TLC and 1H NMR); mp 151°-153° C.; 1H NMR (vide infra).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:13]1([CH3:19])[CH:18]=CC=C[CH:14]=1>C(OCC)(=O)C>[C:13]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[C:3]([CH3:12])=[CH:4][C:5]=1[CH3:11])([CH3:19])([CH3:18])[CH3:14]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(=O)OC(C)(C)C)cc1I
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Iodo-2,4-dimethylbenzoic acid (4.5 g, 16.3 mmol) obtained in Step 1 above was placed in a reaction vessel, and then anhydrous toluene (10 ml) and N,N-dimethylformamide/di-tert-butyl acetal (25 ml) were added thereto. The resulting mixture was stirred at 80° C. for 2 hours. The reaction solution was diluted with ethyl acetate (300 ml), and washed three times with a saturated aqueous sodium bicarbonate solution (100 ml), twice with water (100 ml), and once with a saturated aqueous sodium chloride solution (100 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (50 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=10:1) to yield 5-iodo-2,4-dimethylbenzoic acid tert-butyl ester (3.8 g) as a white solid material.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1>CCOCC>[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([O:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: OC(CCCCCCCCCCCCOCc1ccccc1)CCCCCCCCCCCCOCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC(CCCCCCCCCCCCOCc2ccccc2)CCCCCCCCCCCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
First, 3 g of bis(12-benzyloxydodecyl)methanol and 20 ml of pyridine were placed in a 100 ml flask. Then, 1.15 g of p-toluenesulfonylchloride was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ether. The diluted mixture was washed with diluted hydrochloric acid, aqueous sodium bicarbonate, and water in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from acetone to obtain 1.6 g of bis(12-benzyloxydodecyl)methyl p-toluenesulfonate (Y: 42%). The compound thus obtained had a purity of 98.5% by HPLC.
Reaction SMILES: [CH:1]([C:3](=[C:8]([CH3:10])[CH3:9])[CH2:4][C:5]([OH:7])=[O:6])=[O:2].CCOCC.[Cl-:16].[Li+].Cl>O>[Cl:16][C:8]([C@H:3]1[C@H:1]([OH:2])[O:6][C:5](=[O:7])[CH2:4]1)([CH3:10])[CH3:9]
Reactant: [Cl-]
Reactant: CC(C)=C(C=O)CC(=O)O
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(Cl)[C@@H]1CC(=O)O[C@H]1O
Temperature: 25 °C
Reaction time: 54 h
Yield: 43.4 %

Procedure:
A mixture of 1 g of the product of Example 2, 25 ml of ether and 1 g of dry lithium chloride was stirred under a current of gaseous hydrogen chloride at -30° C. for 2 hours and then at 0° C. hours after which the current of gaseous hydrogen chloride was stopped. The mixture was stirred at room temperature for 48 hours and after 54 hours of contact, the mixture was poured into iced water. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The 1.1 g of residue was chromatographed over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to obtain 545 mg of dl trans 4-(2-chloro-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one in the form of crystals melting at 80° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:8]=1[C:9](OCC)=[O:10]>>[CH2:1]([NH:5][C:9](=[O:10])[C:8]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[N:17][C:7]=1[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C
Product: CCCCNC(=O)c1cc([N+](=O)[O-])cnc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To n-butylamine (5 ml.) was added ethyl 2-methyl-5-nitronicotinate (1 g.) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by a silica gel dry column chromatography to give 0.9 g. of the desired pale orange crystals. mp 98° - 99° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][OH:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:18][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: OCc1ncco1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc(OCc2ncco2)cn1
Temperature: 40 °C
Reaction time: 24 h
Yield: 26.4 %

Procedure:
To a flask was added methyl 5-chloropyrazine-2-carboxylate (1.5179 g, 8.80 mmol), oxazol-2-ylmethanol (0.697 ml, 8.80 mmol), and cesium carbonate (0.845 ml, 10.56 mmol) in DMF (25.1 mL) to stir at 40° C. for 24 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, brine, and dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (100 g), eluting with a gradient of 10-100% EtOAc/hexane, to provide methyl 5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylate (0.547 g, 2.327 mmol, 26.5% yield). MS m/z=236.0 [M+H]+. Calculated for C10H9N3O4: 235.059
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.Cl.[NH:12]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:12]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1Cc1ccc(OC)cc1
Temperature: 62 °C
Reaction time: 72 h
Yield: 51.3 %

Procedure:
4-Methoxy benzyl chloride (55 mmol, 8.61 g) was add ed t o a mixture of K2C3 (56 mmol, 7.7 4 g) and ethyl pipecolinate hydrochloride (50 mmol, 9.68 g) in DMF (55 mL). The mixture was stirred for 3 days at 62° C., and was filtered. Ice-cold HCl solution (1.5 N, 50 mL) was added to the filtrate and it was extracted with ether (3×100 mL). The aqueous phase was basified with NaOH solution (40%) and extracted with ether (5×100 mL). The combined extracts were washed with brine, dried with Na2SO4 and MgSO4 and concentrated in vacuo to give ethyl N-(4-methoxyphenylmethyl)-pipecolinate as a yellow oil (7.12 g): 1H NMR (300 MHz) δ 7.23 (d, J=8.6 Hz, 2 H), 6.84 (d, J=8.6 Hz, 2 H), 4.22 (q, J=7.1 Hz, 2 H), 3.70 (s, Me), 3.73 (d, J=13.1 Hz, 1 H), 3.34 (d, J=13.6 Hz, 1 H), 3.08 (dd, J=8.2, 4.3 Hz, 1 H), 2.93 (m, 1 H), 2.10 (m, 2 H), 1.80 (m, 2 H), 1.56 (m, 3 H), 1.30 (t, J=7.1 Hz, 3 H); 13C NMR δ 174.00, 158.68, 130.43, 130.01, 113.46, 64.55, 60.30, 59.87, 55.20, 50.15, 29.64, 25.24, 22.67, 14.33; MS (E) 277 (2, M), 204 (90), 121 (100); HRMS (EI) m/e calcd for C16H23NO3 277.1678, found 277.1682.