Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].N1C=CC=CC=1>C(OCC)(=O)C>[C:9]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][O:1]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1CCC=CO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCC=CO1
Temperature: 0 °C
Yield: 86 %

Procedure:
A mixture of (±)-3,4-dihydro-2H-pyran-2-methanol (514 g, 4.51 mol, 1 eq) and acetic anhydride (621 g, 6.09 mol, 1.35 eq) was cooled to 0° C. To the resultant mixture was added pyridine (35.6 g, 0.45 mol, 0.1 eq) and the resultant reaction mixture was allowed to warm to room temperature with stirring. The resultant reaction mixture was allowed to stir for an additional 8 hours after reaching room temperature and was shown to be complete by thin-layer chromatography (2:1 hexanes:ethyl acetate, 12 staining). The reaction mixture was concentrated in vacuo at 35° C. and the resultant residue was diluted using ethyl acetate (2 L). The resultant mixture was transferred to a separatory funnel and sequentially washed with deionized water (3×1 L), saturated aqueous NaHCO3 (2×10 L), and brine (1.0 L). The organic layer was dried over sodium sulfate and concentrated in vacuo at 35° C. to provide (±)-3,4-dihydro-2H-pyran-2-yl-methyl acetate as a clear liquid (605.9 g, 86% yield). 1H NMR (300 MHz, CDCl3) δ 1.6-2.2 (m, 4 H), 2.1 (s, 3 H), 4.2 (m, 3 H), 4.8 (m, 1 H), 6.4 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:10][CH:9]1[CH3:36])=[O:7].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH2:53]([NH2:56])[CH2:54][CH3:55]>C1COCC1.N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:18]2[C:27]3[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([NH:56][CH2:53][CH2:54][CH3:55])=[O:34])=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:10][CH:9]1[CH3:36])=[O:7]
Reactant: CCCN
Reactant: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(OCCCCC(=O)O)ccc43)CC2C)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCNC(=O)CCCCOc1ccc2c(c1)CCCN2C1CC(C)N(C(=O)c2ccc(OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
5-[[1-[1-(3,4-Dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]-1,2,3,4-tetrahydro-6-quinolinyl]oxy]pentanoic acid (197 mg, 0.35 mmol) prepared in Example 95 was dissolved in THF (10 ml), to which oxalyl chloride (0.079 ml, 1.05 mmol) and DMF (0.1 ml) were then added on ice and stirred at room temperature for 1 hour. After the reaction mixture was concentrated, the residue was dissolved in pyridine (10 ml) on ice and propylamine (62 mg, 1.05 mmol) was added thereto, followed by stirring at room temperature for 16 hours. After the reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated, the residue was applied to silica gel column chromatography (developing solvent: ethyl acetate/hexane=4/1) to give the titled compound (51 mg, yield: 24%) as a colorless oil. (cis:trans=1:2.8)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[C:10](I)=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:11]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2-c1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(-c3ccnc(Cl)c3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 50 %

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.95 g, 0.00256 mol) in dimethoxyethane (30 mL) and water (60 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (1.14 g, 0.00281 mol), sodium carbonate (0.68 g, 0.00640 mol) and tetrakis (triphenylphosphine )palladium (0) (0.30 g, 0.00026 mol) at 80° C. for 3 days. The solid was filtered and washed with water. The solid was triturated with ethyl acetate (75 mL) for 6 hours and filtered, washing with ethyl acetate (20 mL). The solid was then triturated with methanol (75 mL) for 6 hours and filtered, washing with methanol(20 mL). The solid was dried in vacuo to give crude N2-{4-[4-amino-1-(2-chloro-4-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-1-methyl-1H-2-indolecarboxamide (0.672 g, 0.00128 mol) as a tan solid:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[CH3:29][S:30]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][C:12]2[N:13]=[C:9](/[CH:8]=[CH:7]/[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:10][CH:11]=2)=[CH:21][CH:20]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: CS(=O)(=O)OCCCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 97 %

Procedure:
In substantially the same manner as in Reference Example 12, 6-[4-[2-[(E)-2-phenylethenyl]-4-oxazolyl methoxy]phenyl]hexanol was allowed to react with methanesulfonyl chloride to give 6-[4-[2-[(E)-2-phenyl ethenyl]-4-oxazolylmethoxy]phenyl]hexyl methanesulfonate. The yield was 97%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 88-89° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:34]=[CH:33][C:23]([C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])=[CH:22][CH:21]=2)[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:25])=[CH:22][CH:21]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1ccccc1)c1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(C(=O)Nc4ccccc4)cc3)c3nc[nH]c3n2)CC1

Procedure:
937 mg of trans-1,4-diaminocyclohexane are heated to its melting point (70° C.) and 300 mg of the product obtained in stage 1 above are added. 35 mg of the expected product are thus obtained.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.CI.CC(C)=O.[OH-].[K+]>CO.O>[CH3:3][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1OCc1ccccc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CI
Solvent: CC(C)=O
Product: CNc1ccccc1OCc1ccccc1
Temperature: 59 °C
Reaction time: 0.03 h
Yield: 99.5 %

Procedure:
A well-stirred solution of (25) (0.295 g., 1.0 mM), methyl iodide (0.25 mL, 4.0 mM) and anhydrous acetone (5.0 ml) is set in an oil-bath previously heated to 59° C., and kept for 2 minutes. Powdered anhydrous potassium hydroxide (0.225 g., 4.0 mM) is added all at once, and the bath temperature allowed to rise to 65° C. Clumping-up of some of the KOH is observed. After 15 additional minutes, the reaction mixture is removed from the bath, allowed to cool, and the volatiles removed. Methanol (7 mL) is added with stirring to the residue of N-Methyl-N-trifluoroacetyl-2-benzyloxyaniline (26) obtained, followed by water (1 mL), and methanol (2 mL) (to wash down the sides). After stirring overnight at ambient temperatures, the methanol is removed in vacuo, the residue distributed between ether and water, separated, the organic layer washed with additional water, saturated sodium chloride solution, and dried over sodium sulfate. Concentration of the filtered ether solution gives the title compound (27) (0.212 g.) as an oil. NMR, MS, and TLC indicate little, if any, dimethyl compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:18](Cl)[C:19](=[CH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[C:19](=[CH2:18])[CH3:21]
Reactant: COC(=O)C(c1ccc(O)cc1)C1CCCC1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(C(=O)OC)C2CCCC2)cc1

Procedure:
10 g (0.043 mol) of methyl 2-(4-hydroxyphenyl)-2-cyclopentyl-acetate are dissolved in 200 ml of dimethylformamide and 4.1 g (0.043 mol) of methallyl chloride and 5.9 (0.043 mol) of potassium carbonate are added with stirring. The mixture is allowed to react overnight at 100° C. After cooling, the solvent is evaporated in vacuo, the residue is taken up in 200 ml of dichloromethane, the solution is washed twice with 100 ml of water, the organic phase is dried using sodium sulphate and the product from evaporation in vacuo is purified by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=100:5).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH:11]([NH:17][C:18](=[O:32])[CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([O:14]CC)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[CH:11]([NH:17][C:18](=[O:32])[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C(NC(=O)C(c1ccccc1)c1ccccc1)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC(C(=O)O)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2)C(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 91.5 %

Procedure:
The ester of Example 20 (0.470 g, 0.85 mmol) is dissolved in 100 mL of methanol. The solution is treated with 4.5 mL of 1N aqueous sodium hydroxide and stirred under reflux for 6 hours. Another 4.5 mL of 1N sodium hydroxide is added and reflux is continued for 24 hours. The methanol is evaporated in vacuo and the residue is dissolved in water. The solution is washed with ether, acidified with 3N hydrochloric acid and extracted with ethyl acetate (3×50 mL). The organic phase is dried (magnesium sulfate), filtered, and evaporated to give 0.407 g (91%) of product as a white solid;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1.[C:26]12[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=1)[NH:31]C(=O)O[C:27]2=[O:28]>>[NH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:26]=1[C:27]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:28]
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Nc1ccccc1C(=O)NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 100 %

Procedure:
Using the method similar to that in Reference Example 1 and using 1-(4-aminobutyl)-4-diphenylmethoxypiperidine instead of 4-methoxybenzylamine and starting from isatoic anhydride (3.18 g), the title compound (9.14 g, about 100%) was synthesized. Recrystallization from ethyl acetate-isopropyl ether yielded a colorless crystal, melting point 74.0 to 75.0° C.
Reaction SMILES: [F:1][CH:2]([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH:2]([F:8])[F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCCOCC(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reaction time: 2 h
Yield: 18.9 %

Procedure:
2-(2,2-difluoroethoxy)ethanol (0.13 g, 1.0 mmol), p-toluenesulfonyl chloride (0.19 g, 1.0 mmol), and DMAP (0.12 g, 1.0 mmol) were dissolved in dichloromethane (2 ml) at 0° C. and stirred for 2 h at this temperature. The reaction mixture was loaded onto a small column, which was eluted with dichloromethane to yield the title compound as a clear oil (53 mg, 19%). It was observed that the size of the column affects reaction yield, with a smaller column giving a better yield. 1H NMR (CDCl3, 300 MHz): δ 7.78 (d, 2H, J=11.2 Hz), 7.34 (d, 2H, J=11.2 Hz), 5.76 (tt, 1H, J1=5.6 Hz, J2=73.6 Hz), 4.17 (t, 2H, J=6.0 Hz), 3.75 (t, 2H, J=6.0 Hz), 3.64 (td, 2H, J1=6.0 Hz, J2=20 Hz), 2.45 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[N:10]#[C:11]Cl.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]#[N:10])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#CNc1ccc(Cl)c(Cl)c1
Yield: 80.2 %

Procedure:
16.2 g (0.1 mole) of 3,4-dichloroaniline were dissolved in 278 g of 64% strength acetic acid; 6.1 ml (0.12 mole) of cyanogen chloride were added at 10° C. and 22 g (0.11 mole) of 20% strength NaOH solution were then added dropwise slowly, with stirring. The mixture was stirred for a further 2 hours at room temperature and filtered with suction, and the filter residue was washed with water and dried. This gave 15 g (≅80% of theory) of 3,4-dichlorophenyl cyanamide which gave a clear solution in 2N NaOH and was homogeneous according to examination by thin layer chromatography.
Reaction SMILES: [N:1]1([C:6](O)=[O:7])C=CN=[CH:2]1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]=1[NH-]>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[N:17]1[C:18]2[C:19](=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:2][NH:1][C:6]1=[O:7]
Reactant: O=C(O)n1ccnc1
Reactant: [NH-]c1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Solvent: C1CCOC1
Product: O=C1NCc2c(Oc3ccccc3)cccc2N1c1c(F)cccc1F
Reaction time: 4 h

Procedure:
The product of example 1c above, 2-phenoxy-6-(2,6-difluorophenylamino)benzylamine, (0.159 g 0.49 mmol) was dissolved in dry tetrahydrofuran (6 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.102 g, 0.63 mmol) dissolved in dry tetrahydrofuran (4 mL) was added and the mixture stirred at room temperature, and then heated to reflux The solvent was evaporated in vacuo, to give a crude product which was flash chromatographed on silica gel eluted with 0–3% methanol in methylene chloride to give an intermediate imidazole-1-carboxylic acid[2-(2,6-difluorophenylamino)-6-phenoxyphenylamide. The imidazole-1-carboxylic acid[2-(2,6-difluorophenylamino)-6-phenoxyphenylamide was dissolved in tetrahydrofuran (5 mL) and sodium hydride hydride, dry, 95% (0.025 g, 1 mmol) was added. The resulting mixture was stirred for four hours under argon. The solvent was evaporated and the residue was partioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–20% ethyl acetate in CH2Cl2 to give the title compound as a white amorphous solid. mp 199–201° C.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])(=[O:3])[CH3:2].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]=O.[OH-].[Na+].Cl>C(O)C.O>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:7]([O:6][C:5]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:24]=[CH:25][C:4]=1[C:1](=[O:3])/[CH:2]=[CH:39]/[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=1)[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2ccsc2)ccc1C(=O)/C=C/c1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
A solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)-butanoate (0.5 g) in ethanol (5 mL) is treated with pyridine-2-carboxaldehyde (0.12 g) and aqueous sodium hydroxide solution (0.95 g; 33% w/w) and stirred at 25° C. for 90 minutes. The solution is diluted with water and then brought to pH 7 by treatment with hydrochloric acid (2 M), forming a yellow gum. This gum is extracted with ethyl acetate, and the extract is washed with water, dried and evaporated. The resulting residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (65:35 v/v), followed by trituration with pentane, to give (E)-(RS)-4-(2-methylphenyl)-4-[2-{3-(2-pyridyl) prop-2-enoyl}-5-(3-thienylmethoxy)phenoxy]butanoic acid (0.22 g) in the form of a yellow solid, m.p. 65-70° C. [NMR(CDCl3):- 2.1-2.9 (4H,m),2.4(3H,s),4.9(2H,q),5.6(1H,q), 6.2-7.6(12H),7.7(1H,d,J=16 Hz),7.8(1H,t), 8.0(1H,d,J=16 Hz),8.6(1H,d)].
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(N(CC)CC)C.[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1.O.CCOC(C)=O>[CH2:12]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:3]([OH:4])[CH3:2])=[O:24])=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CNO
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCc1ccc(C(=O)N(C)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of N-methylhydroxylamine hydrochloride (701 mg, 2 eq.) in 20 ml of THF:H2O (1:1) with triethylamine (1.75 ml, 3.0 eq.) was added 4-n-heptyl benzoic acid chloride (1.0 g, 4.2 mmol). The solution was stirred for 1/2 hour at 0° C. then allowed to warm to room temperature and stir overnight. The reaction mixture was diluted with EtOAc and the organic layer washed with H2O, 1N HCl (2×), and brine, then dried over anhydrous MgSO4. Concentration in vacuo gave an oil which was flash chromatographed on LPS-1 silica gel eluting with (1:1) hexane:EtOAc. Product containing fractions were concentrated in vacuo to yield title product, 448 mg (43%) as a light yellow oil which solidified upon standing. TLC (1:1) Hexane:EtOAc Rf =0.18, UV+PMA. Product streaks to baseline.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)COc1ncccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A mixture of 0.1 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine, 31 mg of potassium carbonate, and 1 ml of methanol was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 73 mg of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([NH:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1)=[O:15])[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nncs1
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)Nc1nncs1
Reaction time: 2 h
Yield: 79.1 %

Procedure:
Dissolved in tetrahyrofuran were 6.6 g of t-butyoxycarbonyl-DL-threonine and 3.1 g of triethylamine, to which was added dropwise 3.3 g of ethyl chlorocarbonate at 0° C. After stirring for two hours, 3.1 g of 2-amino-1,3,4-thiadiazole was added, and stirred at room temperature for further 20 hours. The reaction solution was concentrated under a reduced pressure, water was added to the residue, and the precipitates were collected by filtration to obtain 7.2 g (Yield 80%) of 2-(t-butoxycarbonyl-DL-threonyl)amino-1,3,4-thiadiazole as white crystals having a melting point of from 165° to 172° C. (dec.).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:26][CH2:25][CH2:24][O:23]1>>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][C:22]3([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:23][CH2:24][CH2:25][O:26]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1(c2ccccc2)OCCO1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: c1ccc(Oc2ccc(C3CCN(CC4(c5ccccc5)OCCO4)CC3)cc2)cc1

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and 2-bromomethyl-2-phenyl-1,3-dioxolane to produce the above.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[H-].[Na+].[CH2:14](I)[CH3:15]>CN1CCCC1=O>[CH2:14]([N:4]([CH2:1][C:2]#[CH:3])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[CH3:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C#CCN(CC)C(=O)OC(C)(C)C

Procedure:
The sub-titled compound was prepared from tert-butyl prop-2-ynylcarbamate (0.6g), 60% sodium hydride (0.186 g), ethyl iodide (1.55 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). The crude product was purified by chromatography on silica gel eluting with iso-hexane:ethyl acetate (19:1) to afford (0.34 g) of a colourless oil.