Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][CH:23]=[O:24])[C:4]=1[CH3:25])=O.[OH2:26]>>[CH:23]([NH:22][C:5]1[C:4]([CH3:25])=[C:3](/[CH:7]=[CH:8]/[C:9]([O:10][CH2:11][CH3:3])=[O:26])[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:7]=2[C:6]=1[CH3:21])=[O:24]
Reactant: O
Reactant: Cc1c(C=O)c2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Product: CCOC(=O)/C=C/c1c(C)c(NC=O)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the reaction solution was added (7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 60 (3.0 g, 8.89 mmol), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain the crude product of oily ethyl (2E)-3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-2-propenoate. A mixture of said compound with 10%—palladium carbon (50% hydrous, 300 mg) and ammonium formate (1.26 g, 20 mmol) in ethanol (50 mL), was heated under reflux for 2 hours. The solid material was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and was dried over magnesium sulfate and then concentrated under reduced pressure. The solvent was distilled off under reduced pressure to obtain the crude product of ethyl 3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate. A mixture of said compound with concentrated hydrochloric acid (10 mL)-ethanol (30 mL), was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure and the obtained residue was neutralized with a 12 N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:9].[C:10]1([Li])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[Br:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCCCCBr
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Product: BrCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a stirred solution of 1,7-dibromoheptane (49 g, 0.18 mol) (Aldrich) in THF (300 ml), at -30° C. to -40° C., under N2, was added, dropwise, during 3 h, a solution of phenyllithium (15 g, 0.18 mol) in cyclohexane-ether (2.0 M solution, Aldrich). The reaction was allowed to stir at -10° C. to -20° C. for 3 h and at room temperature overnight. After slow, careful dilution with H2O (50 ml), the aqueous layer was extracted with Et2O (2×150 ml). The extracts and the organic layer were combined, dried (Na2SO4) and concentrated to a yellow oil. Distillation through a Vigreaux column provided 22.5 g of 1-bromo-7-phenylheptane, bp 84°-88° C. (0.2 mm), nD24 1.5220.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:5]=1[C:6]([CH:8](C(=O)C)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.O>C(O)C>[N+:1]([C:4]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:5]=1[C:6](=[O:7])[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: CC(=O)C(C(=O)c1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=C(CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1ccccc1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A solution of 2-(2-nitro-4-trifluoromethylbenzoyl)-1-phenylbutan-1,3-dione (28.5 g) in ethanol (300 ml) was added to a mixture of concentrated sulphuric acid (225 ml) and ethanol (225 ml). The resultant solution was stirred and heated at 100° C. for 1 hour. The cooled solution was poured onto a mixture of ice and water (2 l) and extracted with dichloromethane (3×250 ml). The combined organic layers were washed with water (2×100 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from petroleum spirit (bp 60°-80° C.) to give 1-(2-nitro-4-trifluoromethylphenyl)-3-phenylpropan-1,3-dione (19.6 g) as an off-white solid mp 101°-103° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH:10]2[CH2:12][CH2:11]2)[N:3]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[CH:10]1([NH:9][C:4]2[N:3]=[C:2]([NH:1][C:20](=[O:22])[CH3:21])[N:7]=[C:6]([NH2:8])[N:5]=2)[CH2:12][CH2:11]1
Reactant: Nc1nc(N)nc(NC2CC2)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(N)nc(NC2CC2)n1

Procedure:
To a suspension of 49.8 g of 2,4-diamino-6-cyclopropylamino-1,3,5-triazine and 45.5 g of triethylamine in 1200 ml of tetrahydrofuran are slowly added dropwise, at about 60° C. (in about 6 hours), 31.7 g of acetic acid anhydride dissolved in 100 ml of tetrahydrofuran. The reaction mixture is subsequently refluxed for 18 hours, filtered hot and then concentrated by evaporation until crystallisation commences. After the addition of about 300 ml of diethyl ether, the product if filtered off as white crystalline powder. It has a melting point of 190°-195° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C(O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[O:29])=[CH:23][CH:22]=1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCO
Product: COc1ccc(NC(=O)NCCCOc2cccc(CN3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.3 %

Procedure:
To the mixture of 3-(3-piperidinomethylphenoxy)propylamine (3.1 g) in ethanol (31 ml) was added 4-methoxyphenylisocyanate (1.9 g) dropwise slowly under cooling on an ice-water bath. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane (50 ml), washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the crude product (3.3 g) was obtained (yield 66.0%). This crude product was recrystallized from ethanol to give the title compound (2.1 g), mp 111-112° C.
Reaction SMILES: [NH2:1]CC(O)=O.[CH3:6][O:7][C:8](=[O:19])[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][F:18])[CH:12]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[F:18][CH2:17][C:13]1[CH:12]=[C:11]([N:10]([CH2:9][C:8]([O:7][CH3:6])=[O:19])[NH2:1])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CNc1cccc(CF)c1
Reactant: NCC(=O)O
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1cccc(CF)c1
Reaction time: 1 h

Procedure:
The glycine (Intermediate 54, 1 g, 5.1 mmol) was dissolved in acetic acid (10 ml) and water (1 ml) and cooled to ~5° C. Sodium nitrite (0.37 g, 5.4 mmol) in water (1.3 ml) was added to the glycine solution dropwise, maintaining the temperature at or below 5° C. The reaction was stirred at this temperature for 1 h. Zinc (1.33 g, 20.3 mmol) was then added slowly to the reaction keeping the temperature below 4° C., and the reaction was stirred for 1 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 ml) followed by saturated aqueous sodium bicarbonate (1×100 ml) then water (100 ml), dried (Na2SO4) and concentrated in vacuo to give an orange oil (1.06 g). The crude material was purified by chromatography on silica (Merck 9385, 28 g) eluted with ether-hexane 1:4 to give the title compound (Intermediate 55, 453 mg, 40%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][S:13][CH3:14])[N:8]=1)[CH3:6].I([O-])(=O)(=O)=[O:25].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]([C:7]1[O:11][N:10]=[C:9]([CH2:12][S:13]([CH3:14])=[O:25])[N:8]=1)[CH3:6]
Reactant: CSCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CS(C)=O)no1
Yield: 100.4 %

Procedure:
To a solution of 0.95 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylthiomethyl-1,2,4-oxadiazole in 150 ml of ethanol was added a solution of 1.36 g of sodium metaperiodate in 50 ml of water. After stirring with reflux for 9 hours, the reaction mixture was cooled, diluted with water and extracted with chloroform. The extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform to yield 1.0 g of 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-methylsulfinylmethyl- 1,2,4-oxadiazole. It was recrystallized from ethyl acetate-diisopropyl ether to give colorless needles, m.p. 71°-72° C. (decomp.).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:14][O:15][CH2:16]Cl>C(Cl)Cl>[CH3:14][O:15][CH2:16][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CO
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOCC(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of methyl glycolate (18.02 g) and triethylamine (20.24 g) in anhydrous methylene chloride (100 ml.) is added dropwise over 40 minutes to an ice-cold, stirring solution of chloromethyl methyl ether (17.7 g) in methylene chloride (200 ml.). The resulting mixture is allowed to stand overnight in a flask protected from moisture by a drying tube. The mixture is washed with water, 5% aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Distillation of the residue yields methyl methoxymethyloxyacetate.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[NH2:2].[C:13]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([CH:27]=O)[CH:23]=[CH:22]2)([CH3:16])([CH3:15])[CH3:14]>C(O)C>[C:13]([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24](/[CH:27]=[N:2]/[NH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1)[CH:23]=[CH:22]2)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(NN)nc1
Reactant: CC(C)(C)c1cccc2ccc(C=O)nc12
Solvent: CCO
Product: COC(=O)c1ccc(N/N=C/c2ccc3cccc(C(C)(C)C)c3n2)nc1
Yield: 82.1 %

Procedure:
A solution of methyl 6-hydrazinylnicotinate (1.00 g, 5.98 mmol) and 8-tert-butylquinoline-2-carbaldehyde (1.28 g, 5.98 mmol) in absolute ethanol (20 mL) was stirred at ambient temperature for 4 hours. The solid that formed was collected by filtration, washed with ethanol (10 mL), ether (100 mL) and dried to give (E)-methyl 6-(2-((8-tert-butylquinolin-2-yl)methylene)hydrazinyl)nicotinate (1.78 g, 82.1%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N+:3]=1[O-].O.P(Cl)(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[C:4]([Cl:22])[N:3]=1
Reactant: O=S(=O)(c1ccc(Cl)[n+]([O-])c1)c1ccccc1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=S(=O)(c1ccccc1F)c1ccc(Cl)nc1Cl
Temperature: 120 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine 1-oxide from Step 1 (0.27 g, 0.938 mmol) was suspended in phosphorus oxychloride (10 mL) and stirred at 120° C. overnight. The cooled solution was poured into water and extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10–20% ethyl acetate/isohexane gave the product 2,6-dichloro-5-[(2-fluorophenyl)sulfonyl]pyridine (115 mg) and impure product (100 mg). The latter material was recrystallised from ethanol to give further clean product (42 mg, total yield 55%). δH (400 z, d6 DMSO): 8.68 (1H, dd, J=1.1, 8.3 Hz), 8.15 (1H, td, J=7.6, 1.7 Hz), 7.93 (1H, d, J=8.2 Hz), 7.89–7.85 (1H, m), 7.55 (1H, td, J=7.6, 0.9 Hz), 7.48–7.44 (1H, m); m/z (ES+) 306, 308 [MH+].
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=2)=[O:14])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][C@H:12]([CH2:11][OH:10])[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(=O)c1ccc(OC(=O)[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1ccc(OC(=O)[C@H](N)CO)cc1
Reaction time: 1 h

Procedure:
Under nitrogen, 4-acetylphenyl 3-tert-butoxycarbonyl-2,2-dimethyloxazolidine-4-(R)-carboxylate (440 mg) is dissolved in dichloromethane (15 ml), and trifluoroacetic acid (TFA; 8 ml) is added. After being subjected to agitation for 1 hour, the reaction mixture is concentrated and ether is added. The formed precipitate is filtered, then vacuum dried to obtain the desired product as a white powder (280 mg). Melting point: 115-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[O:13].[H-].[Na+].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[CH:18][CH:17]=1.O>CN(C=O)C>[CH2:22]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6](=[O:13])[C:7]1=[O:12])[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Reaction time: 0.33 h
Yield: 81.5 %

Procedure:
A stirred solution of 5-methoxyisatin (5.0 g, 28 mmol) in dry DMF (40 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 1.7 g, 42 mmol) slowly, the dark red solution turning quickly black. After stirring for 20 min, BnBr (3.7 mL, 31 mmol) was added to the reaction mixture by syringe and the resulting mixture was stirred for 1 h. Water (150 mL) was added with stirring, and the resulting dark red precipitate collected by filtration and washed with water to give 1-benzyl-5-methoxyindoline-2,3-dione as a dark red solid (6.1 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 7.17 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 4.92 (s, 2H), 3.79 (s, 3H). MS ESI 268.1 [M+H]+, calcd for [C16H13NO3+H]+ 268.09. A solution of 1-benzyl-5-methoxyindoline-2,3-dione (6.1 g, 23 mmol) and hydrazine hydrate (50-60% grade, 2.9 mL, ca. 2 eq) in DMSO (15 mL) is heated to 140° C. in an oil bath. After 3 h, the mixture was cooled, diluted with water and EtOAc, the layers separated and the aqueous extracted with EtOAc three times (30 mL). The combined organic portions were washed with 2M H2SO4, brine, and dried over MgSO4, filtered and concentrated to afford the crude product as a viscous brown oil. The crude product was purified by silica gel chromatography (20-50% EtOAc in hexane) to yield the title compound as a brown oil (5.0 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 6.89 (s, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.62 (s, 2H). MS ESI 254.0 [M+H]+, calcd for [C16H15NO2+H]+ 254.1.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH2:22][C:23]([OH:25])=O)=[CH:14]1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]1>ClCCl>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([CH2:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH2:27]2)=[O:25])=[CH:14]1
Reactant: O=C(O)Cc1coc2ccccc12
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)Cc2coc3ccccc23)CC1
Reaction time: 1 h

Procedure:
22 g of carbonyldiimidazole are added in portions to 23.9 g of benzofuran-3-ylacetic acid in 250 ml of dichloromethane. When the evolution of gas has stopped, the reaction mixture is stirred for 1 hour and then 21 ml of ethyl piperid-4-ylcarboxylate are added dropwise. After 12 hours' stirring at room temperature, the reaction mixture is washed with 1N sodium hydroxide solution and then with 1N hydrochloric acid. After decanting and drying, concentration under reduced pressure enables the expected product to be isolated.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][C:41]([OH:43])=[O:42]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][C:41]([OH:43])=[O:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)O
Yield: 58.8 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (400 mg) prepared by the method described in Preparation 2 and glycine (300 mg), N-(3-hexadecanoyloxyoctadecanoyl)glycine (260 mg) was obtained as powders according to a similar manner to that of Preparation B-1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:4][C@H:3]1[OH:17].ClC(Cl)Cl.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>C(N(CC)CC)C>[OH:17][C@H:3]1[C@H:2]([NH:1][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:4]1
Reactant: N[C@@H]1CCN(CCNc2ncccn2)C[C@H]1O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(N[C@@H]1CCN(CCNc2ncccn2)C[C@H]1O)c1cccc(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
To a stirred solution of 2.37 parts of trans-4-amino-1-[2-(2-pyrimidinylamino)ethyl]-3-piperidinol in 120 parts of trichloromethane were added 2.08 parts of 3-(trifluoromethyl)benzoyl chloride. The whole was stirred for 15 minutes in an ice bath. After the addition of 1.26 parts of N,N-diethylethanamine, stirring was continued for 18 hours and the temperature was allowed to reach room temperature. The reaction mixture was washed with a sodium carbonate solution and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.07 parts (50.5%) of trans-N-[3-hydroxy-1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-3-(trifluoromethyl)benzamide; mp. 148.3° C. (compound 65).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.CN1CCOCC1.Cl.[NH2:55][C@H:56]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>CN1CCCC1=O>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:29])[C:11]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:55][C@H:56]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:25])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(CCc3ccc(C(=O)O)cc3)cnc2n1
Agent: Cl
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.19 g (1.0 eq) of 4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoic acid 0.19 g (1.5 eq) of phenyl N-phenylphosphoramidochloridate, 0.24 g (5.0 eq) of N-methylmorpholine, and 20 mL of N-methylpyrrolidone is stirred under nitrogen and at room temperature for one hour and 0.23 g (2.0 eq) of diethyl L-glutamate hydrochloride is added. The mixture is stirred for an additional 24 hours under nitrogen and the solvents then removed by evaporation. Chloroform is added and this mixture is then washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed, eluting with 2% methanol/chloroform to yield diethyl N-(4-[2-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate. m.p. >250° C.; 1H NMR (CDCl3) delta 8.63 (s, 1H), 8.33 (s, 1H), 7.74 (d, J=8.11 Hz, 2H, Ar), 7.21 (d, J=8.11 Hz, 2H, Ar), 7.19 (d, J=6.9 Hz, 1H, NH), 4.77-4.84 (m, 1H-CH--), 4.24 (q, J=7.4 Hz, 2H, CO2CH2), 4.12 (q, J=7.4 Hz, 2H, COOCH), 3.05 (s, 4H, 2° aliphatic), 1.97-2.61 (m, 4H, 2° aliphatic), 1.34 (s, 9H, t-butyl), 1.29 (t, J=8.4 Hz, 3H, --CH3), 1.22 (t, J=8.4 Hz, 3H, --CH3).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>CCOCC>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 2,5-dichloronicotinic acid (20.2 g, 0.105 mol, Aldrich) in methanol (500 mL) was cooled to 0° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ˜30 min. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to room temperature, and the reaction was allowed to stir for an additional 2 days at room temperature. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in ether (˜500 mL) and the resulting solution was washed successively with saturated aqueous sodium bicarbonate solution (˜300 mL), water (˜300 mL), and brine (˜300 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,5-dichloronicotinate (21.0 g, 97% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[S:8][C:9]=1[CH3:10].[NH3:15]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:15])(=[O:13])=[O:12])[S:8][C:9]=1[CH3:10]
Reactant: COCCc1cc(S(=O)(=O)Cl)sc1C
Reactant: N
Solvent: ClCCl
Product: COCCc1cc(S(N)(=O)=O)sc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
To a solution of the above prepared 4-(2-methoxy-ethyl)-5-methyl-thiophene-2-sulfonyl chloride (4.59 g, 18 mmol) in DCM (18 mL) were added 25% aqueous NH3 (9 mL, ˜120 mmol) and the biphasic reaction mixture was vigorously stirred at rt for 3 h. After the addition of DCM (120 mL) the reaction mixture was washed with H2O (2×120 mL) and the aqueous layers were extracted with DCM (50 mL). The combined organic layers were dried (Na2SO4) and evaporated affording 5.0 g crude product as a yellow viscous oil which was purified by chromatography over silica with hexane-ethyl acetate 2:1 providing 3.62 g (85% GC 96.3%) yellow viscous oil. ESI-MS (m/z) 253 (M+NH4+, 100).