Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]>C(OCC)(=O)C>[Br-:9].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N+:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccncc1
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Product: COC(=O)C[n+]1ccc(OC)cc1
Product: [Br-]
Temperature: 25 °C
Yield: 97.1 %

Procedure:
To a solution of 4-methoxypyridine (3.0 g) in ethyl acetate (30 mL) was added methyl bromoacetate (4.6 g), and the mixture was heated under reflux overnight. After cooling to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give 4-methoxy-1-methoxycarbonylmethylpyridinium bromide (7.0 g). To a solution of the obtained compound (6.0 g) in toluene (50 mL) were added acrylonitrile (6.1 g), manganese dioxide (6.0 g) and triethylamine (2.8 g), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give 1-cyano-7-methoxyindolizine-3-carboxylic acid methyl ester (1.0 g). To a mixed solution of the obtained compound (1.0 g) in tetrahydrofuran (20 mL), ethanol (7 mL) and water (7 mL) was added lithium hydroxide monohydrate (0.27 g), and the mixture was stirred at room temperature overnight. To the reaction mixture were added 1 mol/L hydrochloric acid and water, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure at 50° C. to give the 1-cyano-7-methoxyindolizine-3-carboxylic acid (0.80 g). To a suspension of the obtained compound (0.80 g) and quinoline (8 mL) was added copper (0.05 g), and the mixture was stirred at 220° C. for 30 minutes. After cooling to room temperature, to the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.37 g).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28]S([O-])(=O)=O.[Na+]>C(Cl)Cl>[CH3:25][Si:26]([CH3:34])([CH3:33])[CH2:27][CH2:28][S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: C[Si](C)(C)CCS(=O)(=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)CCS(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sulfuryl chloride (43 ml, 539 mmol) was added in 3 min to a clear solution of triphenylphosphine (129 g, 490 mmol) in methylene chloride (200 mL) at 0° C. in a flame-dried three-neck round bottom flask. After stirring at 0° C. for 5 min, the ice-water bath was removed and sodium 2-trimethylsilylethanesulfonate (50 g, 245 mmol) was added in portions over 10 min. The resulting white suspension was stirred at room temperature for 16 h, then it was filtered through a pad of celite. The filtrate was concentrated to ca 50 mL, ethyl acetate/hexanes (1:3, 1000 mL) and celite (40 g) were added. The mixture was stirred at room temperature for 15 min and filtered through a pad of celite. Solvents were removed in vacuo and the residue was loaded onto a pre-wetted column with silica gel (300 mL) using 1:3 ethyl acetate/hexanes as the eluent. Solvents were removed and the title compound was obtained as a light tan liquid (41.9 g, 85%). If not used immediately, the final product should be stored under nitrogen in the freezer or refrigerator to minimize decomposition. 1H-NMR (CDCl3, 500 MHz) δ 3.61-3.57 (m, 2H), 1.32-1.27 (m, 2H), 0.10 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[OH-].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: BrCCCn1nnc2ccccc21
Reaction time: 20 h
Yield: 58.7 %

Procedure:
To a solution of 1,3-dibromopropane (510 μl, 5.0 mmol) in dimethylformamide (10 ml) was added benzotriazole (600 mg, 5.0 mmol) and KOH (430 mg, 7.7 mmol). After stirring for 20 h at room temp., water (15 ml) and ethyl acetate (15 ml) were added. The phases were separated and the aqueous phase was re-extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over MgSO4 and concentrated, giving 1.44 g of the crude product. The crude product was purified by flash chromatography (0–10% methanol in DCM) yielding 705 mg (59%) of the title compound 64. TLC (5% methanol in DCM): Rf=0.4. HPLC-MS (Method A): M+=239.9 (UV/MS(%)=52/58).
Reaction SMILES: [C:1]([C:3]([NH2:8])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].[CH2:9]([O:12][C:13]1[C:21]([O:22][CH3:23])=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[O:24][CH3:25])[C:10]#[CH:11]>>[C:1]([C:3]([NH:8][C:17](=[O:18])[C:16]1[CH:15]=[C:14]([O:24][CH3:25])[C:13]([O:12][CH2:9][C:10]#[CH:11])=[C:21]([O:22][CH3:23])[CH:20]=1)([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2]
Reactant: C#CCOc1c(OC)cc(C(=O)Cl)cc1OC
Reactant: CC(C)C(C)(N)C#N
Product: C#CCOc1c(OC)cc(C(=O)NC(C)(C#N)C(C)C)cc1OC

Procedure:
According to the same method as that of Production Example 1, 1-cyano-1,2-dimethylpropylamine was used in place of 2,2-dimethylpropylamine, 4-(2-propynyloxy)-3,5-dimethoxybenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-cyano-1,2-dimethylpropyl)-4-(2-propynyloxy)-3,5-dimethoxybenzamide (hereinafter, described as the compound 19 of the present invention) represented by the formula:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11]([NH:14][CH3:15])(=[O:13])=[O:12].C(NCC1C=C(F)C=CC=1S([Cl:31])(=O)=O)(=O)C.CN.Cl.[C:35]([CH:37]([CH:41]1[C:45]([Cl:46])=[C:44](Cl)C(=O)O1)[C:38]([NH2:40])=[O:39])#[N:36]>O1CCCC1.CO.C(N(CC)CC)C>[ClH:31].[Cl:46][C:45]1[CH:41]=[C:37]([C:38]([NH2:40])=[O:39])[C:35](=[NH:36])[N:2]([CH2:3][C:4]2[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=2[S:11](=[O:12])(=[O:13])[NH:14][CH3:15])[CH:44]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CNS(=O)(=O)c1ccc(F)cc1CN
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CNS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
(Step 1) According to the method of Example 29, Steps 2 and 3, 2-(aminomethyl)-4-fluoro-N-methylbenzenesulfonamide hydrochloride was synthesized using 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride, a solution of methylamine in tetrahydrofuran, and hydrochloric acid. 1H NMR (300 MHz, DMSO-d6) 8 ppm 2.46 (3H, d, J=4.9 Hz), 4.41 (2H, q, J=5.7 Hz), 7.48 (1H, td, J=8.3, 2.7 Hz), 7.58-7.68 (1H, m), 7.90-8.04 (2H, m), 8.51 (3H, br. s.). (Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.90 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (1.17 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.74 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:17]([CH3:18])=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[CH3:19])[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+].Cl.O>C(O)C.C(OCC)(=O)C>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([CH3:19])=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][C:17]=2[CH3:18])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(C)c(-n2c(C)ccc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)cc(C)c1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
Methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoate of Step A (1.55 g, 6 mmol) was dissolved in ethanol (100 mL) and treated with 1M sodium hydroxide (9 mL). The solution was refluxed overnight, cooled to room temperature, acidified with 1N hydrochloric acid, and diluted into water and ethyl acetate. The organic layer was washed with water until neutral, dried with anhydrous sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a a cream colored solid (1.36 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[C:12]([OH:21])(=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].C([O-])(=O)C(CCC)CCC.[Ca+2:32].O[C@H](CC(=O)[O-])C[N+](C)(C)C.C([O-])(=O)C(CCC)CCC>O>[OH:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6].[Ca:32].[C:12]([O-:21])(=[O:20])[CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(CCC)C(=O)O
Reactant: [Ca+2]
Agent: CCCC(CCC)C(=O)[O-]
Agent: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Solvent: O
Product: [Ca]

Procedure:
The inventors have discovered that simple admixture or combination of L-carnitine, a calcium or magnesium salt, and valproic acid without a suitable solvent is not sufficient to provide an L-carnitine valproate salt of the present invention. After simple admixture or combination without a suitable solvent, L-carnitine retains its objectionable malodor and offensive taste, as well as its hygroscopicity, and valproic acid remains an oil. In contrast, use of the methods of preparing the L-carnitine valproate salt of the present invention as disclosed herein provides a composition of the present invention that is free from objectionable taste and free or nearly free from repugnant odor. Further, an L-carnitine valproate salt of the present invention has different physico-chemical properties from the starting materials. As we discovered and disclose in Example 1, for example, L-carnitine calcium valproate, an embodiment of the present invention, has a melting point of 171.2° C., different from the melting point of L-carnitine (186-190° C.) or valproic acid (an oil at room temperature and above). The 1H-NMR spectrum of L-carnitine calcium valproate (FIG. 2) differs from that of the starting materials (i.e., L-carnitine and valproic acid) and confirms the structure. L-carnitine calcium valproate is soluble in water, and aqueous solutions of this salt provide bioavailable L-carnitine, calcium, and valproate.
Reaction SMILES: CN1CCOCC1.[CH2:8]([NH2:11])[CH:9]=[CH2:10].[I:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(#N)C>[CH2:8]([NH:11][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[I:12])[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: O=C(Cl)c1ccccc1I
Solvent: CN1CCOCC1
Solvent: CC#N
Product: C=CCNC(=O)c1ccccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
470 ml (4.28 mol) of N-methylmorpholine, followed by 224 ml (2.98 mol) of allylamine are added under ice cooling to 750 g (2.81 mol) of 2-iodo-benzoic acid chloride in 7.5 l of acetonitrile, and stirred for 60 min at RT. The precipitate is filtered off and the filtrate concentrated by evaporation on a RE. The residue of evaporation is dissolved in 4 l of EtOAc and 4 l of water, the water phase is separated and extracted twice with EtOAc. The organic phases are washed with water, 0.1 N HCl, water, sat. Na2CO3, water and brine, dried (Na2SO4) and concentrated by evaporation. Stirring of the residue in 2.5 l of hexane and filtering yields 2-iodo-benzoic acid allylamide; m.p. 105-106° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:22])=[CH:6][C:7]([CH3:21])([CH3:20])[NH:8]2.C(N(CC)CC)C.[F:30][C:31]([F:37])([F:36])[S:32](Cl)(=[O:34])=[O:33]>ClCCl.C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][S:32]([C:31]([F:37])([F:36])[F:30])(=[O:34])=[O:33])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:22])=[CH:6][C:7]([CH3:21])([CH3:20])[NH:8]2
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC1=CC(C)(C)Nc2ccc(-c3ccccc3O)c(CO)c21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(C)(C)Nc2ccc(-c3ccccc3OS(=O)(=O)C(F)(F)F)c(CO)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
5-Hydroxymethyl-6-(2-hydroxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 293 mg, 0.992 mmol) was dissolved in anhydrous dichloromethane (5 mL) and then triethylamine (167 μL, 1.20 mmol) and trifluoromethanesulfonyl chloride (106 μL, 0.996 mmol) were added thereto at 0° C. After the reaction mixture was stirred at 0° C. for 1 hour, it was diluted with chloroform (20 mL). The whole was washed with saturated aqueous NaHCO3 solution (20 mL) and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (177 mg) as an orange solid. (Yield 42%)
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>ClCCl.CO.CN(C)C=O>[N:19]([CH2:17][C@@H:13]1[C@@H:14]([OH:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 25 h
Yield: 89.1 %

Procedure:
Process B: (3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (3.00 g), sodium azide (2.32 g), triphenylphosphine (3.43 g) and N,N-dimethylformamide (60 mL) were mixed together. While this mixture was chilled in an ice water bath, carbon tetrabromide (4.34 g) in dichloromethane (14 mL) was added dropwise. The reaction mixture was stirred at room temperature for 25 hours and then at 60° C. for 2 hours. Subsequently, methanol (5 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (200 mL) and the solution was washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate:hexane=2:1) to give (3R,4R)-3-azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine as a pale brown syrup (2.94 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35](F)=[C:34]([F:39])[CH:33]=1)[CH3:29].C(OCC)(=O)C>CC(N(C)C)=O>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[O:7][C:8]1[CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])[CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:31]([O:30][CH2:28][CH3:29])=[O:40]
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)c(F)c1
Temperature: 115 °C
Yield: 31 %

Procedure:
Cesium carbonate (8.3 g, 25.4 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (3.7 g, 12.7 mmol) and ethyl-3,4-difluorobenzoate (2.36 g, 12.7 mmol) in dimethylacetamide (60 mL) and the stirred mixture heated at 115° C. for 3 hours. The mixture was allowed to cool to RT and ethyl acetate (100 mL) added. The mixture was washed with water (5×40 mL), brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (1.8 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH2:16]([CH:18]1[CH2:25][C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH2:19]1)[CH3:17]>O>[CH2:16]([CH:18]1[CH2:25][C:21]2[S:22][C:23]([CH:14]=[O:15])=[CH:24][C:20]=2[CH2:19]1)[CH3:17]
Reactant: CCC1Cc2ccsc2C1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCC1Cc2cc(C=O)sc2C1
Temperature: 30 °C
Reaction time: 6 h

Procedure:
115 cm3 of phosphorus oxychloride and 155 cm3 of N-methylformanilide are stirred for 30 minutes at ambient temperature. 228 g of 5-ethyl-4,5-dihydro-6H-cyclopenta[b]thiophene, prepared as in Example 5, are added dropwise to this complex whilst the temperature is maintained at 30° C., if necessary by cooling with iced water. After the end of the addition, the reaction mixture is stirred for a further 6 hours at ambient temperature and is then poured carefully on to a mixture of water and ice. The organic products are extracted with ether. The extract is washed with water until neutral and then dried over sodium sulphate. The ether is evaporated and the residue obtained (290 g) is distilled in vacuo. This gives 205 g of 5-ethyl-4,5-dihydro-6H-cyclopenta[b]thiophene-2-carboxaldehyde as a liquid, b.p. 112°-115° C./0.6 mm Hg.
Reaction SMILES: [CH:1]([S:4][C:5]1[C:6]([C@H:11]2[C@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[OH:28]OS([O-])=O.[K+].[OH2:34]>CCO.CCOC(C)=O>[CH:1]([S:4]([C:5]1[C:6]([C@H:11]2[C@H:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]2[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:28])=[O:34])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1SC(C)C
Reactant: O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ncccc1S(=O)(=O)C(C)C
Reaction time: 18 h
Yield: 90 %

Procedure:
To 65D (1.51 g, 3.83 mmol) in EtOH (25 mL) at 0° C. was added Oxone® (3.53 g, 1.5 eq.) in water (25 mL). The mixture was stirred from 0° C. to rt over 18 h. It was quenched with sat. NaHCO3 and Na2S2O3. The precipitate was removed by filtration and the filtrate was condensed, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. After removal of solvent, the crude was purified by silica column chromatography using gradient EtOAc in hexanes to give 65F (1.51 g, 90% yield). 1H NMR (400 MHz, 90° C., DMSO-d6) δ ppm 1.19 and 1.32 (br s, 18H) 2.10 (br s 1H) 2.34 (br s, 1H) 2.95 (br s, 1H) 3.49 and 3.70 (br 3H), 4.12 (br s, 2H), 5.79 (br s, 1H), 7.57 (br s, 1H), 8.20 (br s, 1H), 8.81 (br s, 1 H). LS-MS 427 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:21][C:22]1[C:27]([NH2:28])=[CH:26][N:25]=[C:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1.CN(C)CCCN>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:21][C:22]1[C:27]([NH:28][S:42]([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:26][N:25]=[C:24]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[N:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:20])[N:17]([CH3:18])[CH3:19])=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)c1ncc(N)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN(C)CCCN
Solvent: c1ccncc1
Product: CCN(CC)c1ncc(NS(=O)(=O)c2ccc(F)cc2)c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
A pyridine (120 mL) solution of 2-(2-diethylamino-5-aminopyrimidin-4-ylamino)-3-(4-dimethylcarbamoyloxy-phenyl)propionic acid t-butyl ester (32.0 g, 0.067 mol) was cooled to −20° C. with a dry ice/CH3CN bath. The mixture stirred for 30 minutes, and then p-fluorobenzenesulfonyl chloride (13.18 g, 0.067 mol) was added slowly. The reaction was stirred at −20° C. for 4.5 hrs, and then 3-dimethylaminopropyl amine (8.52 mL, 0.067 mol) was added, and then the mixture was allowed to warm to room temperature overnight. The reaction was concentrated in vacuo. The residue was taken up in EtOAc (1 L), and the organic phase was washed with 0.5 M citric acid (3×900 mL), water (1×900 mL), sat. NaHCO3 (3×900 mL), brine (1×900 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a brown residue. The residue was purified by flash chromatography (50% EtOAc/hexanes on silica gel) to yield 33.04 g (77%) the title compound as a yellow foam. Rf=0.54 (3:2 EtOAc/hexanes on silica gel).
Reaction SMILES: BrCCCCCC(C)C(OCC)=[O:9].CC(C)(CCCCCI)C(OC)=O.C([O:30][CH:31]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:32][CH2:33][CH2:34][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](C)(C)[C:44]([O:46]C)=[O:45])[C:36]#[N:37])(=O)C>>[OH:30][C@H:31]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:32]#[C:33][CH2:34][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:36]#[N:37].[OH:30][C@H:31]([CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:32]#[C:33][CH2:34][N:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([OH:46])=[O:45])[C:36]([NH2:37])=[O:9]
Reactant: CCOC(=O)C(C)CCCCCBr
Reactant: CCCCCC(CCCN(C#N)CCCCCC(C)(C)C(=O)OC)OC(C)=O
Agent: COC(=O)C(C)(C)CCCCCI
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 7 except that, in Step A, the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 2,2-dimethyl-7-iodoheptanoate. The product of Step A is thus methyl 7-[N-(4-acetoxynonyl)cyanamido]-2,2-dimethylheptanoate. The subsequent steps yield 7-[N-(4-hydroxynonyl)cyanamido]-2,2-dimethylheptanoic acid (B) and 7-[1-(4-hydroxynonyl)ureido]-2,2-dimethylheptanoic acid (C).