Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[NH:9][C:8](=[O:19])[NH:7][C:6]=1[CH2:20][O:21][CH3:22])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1)=[O:35]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=2)[N:9]([C:34]([O:36][C:37]2[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=2)=[O:35])[C:8](=[O:19])[NH:7][C:6]=1[CH2:20][O:21][CH3:22])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)NC(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reaction time: 0.17 h

Procedure:
To a solution of (+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6-(3,4-difluorophenyl)-pyrimidine (1.98 g, 6.34 mmol) in anhydrous THF (20 mL) at −78° C. under argon atmosphere, a solution of lithium hexamethyldisilazide in THF (1M, 18 mL, 18 mmol) was added over 2-3 min. and the mixture was stirred for 10 min. This solution was added over 6 min. via a cannula to a stirred solution of 4-nitrophenyl chloroformate (4.47 g, 22.2 mmol) in THF (20 mL) at −78° C. The stirring was continued for 10 min and the mixture was poured onto ice (50 g) and extracted with chloroform (2×50 mL). The combined extracts were dried (sodium sulfate) and the solvent evaporated. The residue was purified by flash column chromatography using hexanes/ethyl acetate (4:1 to 3.5:1) as eluent. The product was obtained as a yellow syrup which on trituration with hexane became white powder (2.4 g, 79%). 1H NMR (CDC13) δ 3.522 (s, 3H), 3.744 (s, 3H), 4.65-4.80 (q, J=16.5 Hz, 2H), 6.323 (s, 1H), 7.10-7.30 (m, 4H), 7.358 (d, J=9 Hz, 2H), 8.273 (d, J=9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].O=[C:11]([CH2:19][CH2:20][CH3:21])[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:19][CH2:20][CH3:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCC(=O)C(=O)OCC(C)C
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCCC(Nc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and iso-butyl 2-oxopentanoate (prepared by following General Procedure AO above using 2-oxovaleric acid (Fluka) and iso-butanol), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.5 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[Li]CCCC.[O:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:31]4([OH:34])[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: CC(C)[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc3c(cnn3-c3ccc(F)cc3)c2)CCOCC1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
1-(4-Fluorophenyl)-5-iodo-1H-indazole (350 mg, 1.0 mmol) was dissolved in 10 mL dry THF and treated with isopropylmagnesium bromide (1.6 mL of 1 M THF solution) and then BuLi (1.6 M in hexanes, 0.72 mmol, 1.1 mmol) at room temp. After 30 min, tetrahydro-4H-pyran-4-one (270 mg, 2.7 mmol) was added. After 2 h, the reaction was quenched with water, then 1 M HCl, and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated, and the residue was purified using 1:1 EtOAc/hexanes to give 125 mg (39%) of 4-(1-(4-fluorophenyl)-1H-indazol-5-yl)tetrahydro-2H-pyran-4-ol as a clear oil that solidified upon standing. (M+H)+=313.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:35]([O:37][C@H:38]1[CH2:42][CH2:41][O:40][CH2:39]1)=[O:36]>CN(C=O)C>[O:40]1[CH2:41][CH2:42][C@H:38]([O:37][C:35](=[O:36])[NH:1][CH2:2][C@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=4)[N:12]=[C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[OH:26])[N:10]=3)[CH2:4]2)[CH2:39]1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.57 mmol) in DMF under an N2 atmosphere at 0° C. was added triethylamine (115 mg, 1.14 mmol) followed by the dropwise addition of (S)-tetrahydrofuran-3-yl chloroformate (86 mg, 0.57 mmol). The reaction was allowed to warm to room temperature and was stirred for 2 h. The mixture was partitioned between H2O and CH2Cl2 and separated, and the aqueous layer was extracted twice with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 4:1 CH2Cl2:EtOAc afforded (S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate. LC/MS: m/z 463.5 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8](=[O:10])[NH2:9])=[C:6]([CH3:11])[NH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C:19]([CH3:21])=O>C(O)C.CCCCCC>[C:8]([C:7]1[C:3]([N:2]=[C:19]([CH3:21])[CH3:18])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:5][C:6]=1[CH3:11])(=[O:10])[NH2:9]
Reactant: CC(C)=O
Reactant: Cc1[nH]c(-c2ccccc2)c(N)c1C(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)=Nc1c(-c2ccccc2)[nH]c(C)c1C(N)=O
Yield: 82 %

Procedure:
From the compound of Example 33 and acetone, yield 82%, m.p. 221°-223° C. (from ethanol/hexane).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Cl>CN(C)C=O>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: COc1cccc(CCl)c1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 3-methoxybenzyl chloride (17.0 mg, 0.11 mmol), which was stirred for 12 hours at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (34.4 mg, 81%).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:6]2[CH2:5]1.[H][H]>C(O)C.[Pd]>[F:16][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]2[CH2:5]1
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)F)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCN(CC(F)F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of 135a (370 mg, 1.59 mmol) in ethanol (20 mL) was added Pd/C (about 200 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated reduced pressure to afford 135b as a yellow solid (293 mg, 91%), which was used in the next step without further purification. MS-ESI: [M+H]+ 203.2
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42]/[CH:43]=[CH:44]/[C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42]/[CH:43]=[CH:44]/[C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(O)(/C=C/CBr)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/CS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 84.3 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (33.1 mg, 0.0570 mmol), (E)-6-bromo-3-ethyl-4-hexen-3-ol (47.4 mg, 0.229 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate=5:1, developed twice) to give the title compound as a colorless oil (28.2 mg, 84%).
Reaction SMILES: [C:1]([C:4]([CH2:21][C:22]#[C:23][C:24]1([O:30]C(=O)C)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].C(C(CC#CC(OC(=O)C)CCCCC)(CCCCCCC(OCC)=O)C(OCC)=O)(=O)C>>[C:1]([CH:4]([CH2:21][C:22]#[C:23][C:24]1([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CC#CC1(OC(C)=O)CCCCC1)(C(C)=O)C(=O)OCC
Agent: CCCCCC(C#CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Product: CC(=O)C(CC#CC1(O)CCCCC1)CCCCCCC(=O)O

Procedure:
This compound is prepared by the same procedure described in Example 35, Step B, except that diethyl 2-acetyl-2-[3-(1-acetoxycyclohexyl)-2-propyn-1-yl]azelate is substituted for diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate. The chromatographically purified product is a yellowish viscous oil; pmr (CDCl3) δ2.14 (3H,s CH3CO), 6.50 (2H,s OH and COOH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][OH:11].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][OH:11])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20]
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccccc1O
Reactant: CCCCCCCCCCCCCCBr
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccccc1CC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of the alcohol from Step A (218 mg, 0.82 mmol), tetradecyl bromide (170 μL, 0.9 mmol) and CsCO3 (532 mg, 1.63 mmol) in DMF (8 mL) was stirred for 16 hs at room temperature under argon. The mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with water and brine, dried (MgSO4), and concentrated in vacuo to give an oil. Purification by chromatography (SiO2, 20% EtOAc in hexanes) gave the title compound as a solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11].I[CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CCI
Reactant: Cc1ccc(F)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(F)c(OCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
To a solution of sodium hydroxide (3.2 g, 79 mmol) in water (16 mL) was added 2-fluoro-5-methylphenol (5.0 g, 40 mmol) at room temperature. After the solution was stirred for 5 minutes, 3-iodopropionic acid (7.9 g, 40 mmol) was added to the pale yellow solution, and the mixture was refluxed with stirring for 18 hours. The mixture was cooled to room temperature, poured into 2M hydrochloric acid aqueous solution (100 mL) at 0° C., and extracted with ethyl acetate (60 mL×2). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel (gradient elution from hexane/ethyl acetate 3:1 to ethyl acetate only). The resulted pale yellow solid was triturated with hexane, collected by filtration, and dried in vacuum to afford the title compound as a pale yellow solid (2.45 g, 31%).
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:24][O:25][C:26]=2[CH3:27])=[N:16][CH:15]=1.O>O1CCOCC1>[F:35][C:30]1[CH:29]=[C:28]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH3:27])[O:25][N:24]=2)[CH:33]=[CH:32][C:31]=1[F:34]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.1 mL, 2.2 mmol) was added dropwise (exothermic) to a solution of 2,2,2-trifluoroethylamine (250 mg, 2.2 mmol) in dioxane (10 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) in dioxane (10 mL) was added. The resulting mixture was then heated at 85-95° C. for 16 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 1:1) afforded the title compound (150 mg, 63%) which was obtained as a white solid. MS: m/e=482.2 [M+H]′.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10](OCC)(=O)[CH:11]=[O:12].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[C:7]2[N:8]=[CH:10][C:11](=[O:12])[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1ccnc(Cl)c1N
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=c1cnc2c(Cl)nccc2[nH]1
Temperature: -20 °C

Procedure:
A suspension 2-chloropyridine-3,4-diamine (2.5 g, 17.41 mmol) and a 50% solution of ethyl glyoxalate in toluene (3.45 mL, 17.41 mmol) in ethanol (34.8 mL) was stirred at reflux for 24 hours. The solution was cooled to −20° C. for 16 hours, and the resulting precipitate was collected by vacuum filtration and rinsed with ethanol. The crude product was purified via reverse-phase HPLC, eluting with 5-50% acetonitrile/0.1% trifluoroacetic acid in water/0.1% TFA, to afford the title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[C:6]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20].[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:12]([C:6]1[C:7]([CH3:11])=[N:8][N:9]([CH3:10])[C:5]=1[O:4][CH2:3][CH2:2][N:23]([CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CNc1ccccc1
Reactant: Cc1nn(C)c(OCCBr)c1C(=O)c1ccc(Cl)cc1Cl
Product: Cc1nn(C)c(OCCN(C)c2ccccc2)c1C(=O)c1ccc(Cl)cc1Cl

Procedure:
A mixture of 1.1 g of 5-(2-bromoethoxy)-4-(2,4-dichlorobenzoyl)-1,3-dimethylpyrazole and 6 ml of N-methylaniline was heated at 110° to 120° C. for 3 hours with stirring. Excess N-methylaniline was distilled off under reduced pressure. The residue was then purified by silica gel chromatography (eluent, benzene:ethyl acetate at 10:1) to give 0.71 g of the desired product, Compound 2, having a refractive index nD24 1.5975 (yield 60.5%).
Reaction SMILES: CN(C)C=O.[C:6]([O:25][CH2:26][CH:27]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[OH:28])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH2:50]([N:52]([CH2:58][CH3:59])[CH2:53][CH2:54][C:55](O)=[O:56])[CH3:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:50]([N:52]([CH2:58][CH3:59])[CH2:53][CH2:54][C:55]([O:28][CH:27]([CH2:29][O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:26][O:25][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:56])[CH3:51]
Reactant: CCN(CC)CCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCN(CC)CC
Reaction time: 8 h
Yield: 62.2 %

Procedure:
In a solvent mixture of 3 ml N,N-dimethylformamide and 6 ml methylene chloride was dissolved 172 mg (0.277 mmol) of 1,3-dioleoylglycerol followed by addition of 101 mg (0.556 mmol) of N,N-diethyl-β-alanine (hydrochloride), 114 mg (0.553 mmol) of N,N-dicyclohexylcarbodiimide, and 7 mg (0.057 mmol) of 4-dimethylaminopyridine and the mixture was stirred overnight. This reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and washed with water. The washed solution was dried and concentrated and the residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 129 mg (62%) of the title compound.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=C.C(OCC)C>C(C(C)=O)C>[CH2:8]=[CH:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:2]1[C:1](=[O:7])[O:6][C:4](=[O:5])[CH:3]=1
Reactant: C=C(C)c1ccccc1
Agent: O=C1C=CC(=O)O1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: C=Cc1ccccc1
Temperature: 60 °C

Procedure:
In 200 ml of methyl ethyl ketone were dissolved 18.14 g of maleic anhydride and 21.86 g of α-methylstyrene, and to the solution was added 1.82 g of azobisisobutylnitrile (AIBN). The resulting mixture was heated at 60° C. for 7 hours under nitrogen atmosphere for performing polymerization. The reaction solution was then dropwise added to 500 ml of ethyl ether under stirring to precipitate a polymer. Thus precipitated polymer was collected by filtration and purified by repeating twice the THF dissolution-ethyl ether precipitation procedure described in Example 1. Thus purified polymer was dried under vacuum at 100° C. for 24 hours to give 17.0 g of a maleic anhydride-styrene copolymer. It was confiremed by elementary analysis that the copolymerization ratio was approximately 1:1. Mn was 11,730.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28]OC(=O)C(C)(C)C)[C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:42])(=[O:41])[CH2:39][OH:40].Cl.C(O)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:28][O:40][CH2:39][C:38]([OH:42])=[O:41])[C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)=[CH:17][CH:16]=2)[C:10](=[O:36])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CO
Reactant: CC(C)(C)C(=O)OCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)COCN(c1ccc(CN2CCN(Cc3ccccc3)C(=O)C2=O)cc1)c1ncccn1
Yield: 52.7 %

Procedure:
In 30 ml of ethyl acetate was dissolved 1 g of 1-benzyl-4-{4-[N-pivaloyloxymethyl-N-(2-pyrimidinyl)-amino]benzyl}-2,3-dioxopiperazine, and 1 g of glycolic acid and 0.02 ml of N hydrogen chloride-ethanol solution were added, after which the resulting mixture was subjected to reaction at room temperature for 3 hours with stirring. After the completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was extracted with 100 ml of methylene chloride. The methylene chloride layer was washed with 30 ml of water and then 30 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (Wakogel C-200, eluted with chloroformethanol), and recrystallized from ethyl acetate-diisopropyl ether, to obtain 0.5 g (52.8% yield) of 1-benzyl-4-{4-[N-carboxymethoxymethyl-N-(2-pyrimidinyl)amino]benzyl}-2,3-dioxopiperazine having a melting point of 85° to 90° C.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1)[CH:3]=O.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][C:2]1[CH:3]=[N:13][NH:14][C:5]=1[CH:6]1[CH2:10][CH2:9][O:8][CH2:7]1
Reactant: CC(C=O)C(=O)C1CCOC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cn[nH]c1C1CCOC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 119.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 2-methyl-3-oxo-3-(tetrahydrofuran-3-yl)propanal (compound 263.3, 3.00 g, 19.2 mmol) in ethanol (25 mL). Hydrazine hydrate (1.16 mL, 24 mmol) was added and the resulting solution was stirred for 3 h at 80° C. The resulting mixture was concentrated under reduced pressure to obtain the title compound as a colorless oil (3.5 g, crude).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:12]#[C:13][C:14]([OH:17])([CH3:16])[CH3:15]>C(N)(C)C.CO.[Cu]Cl>[OH:17][C:14]([CH3:16])([CH3:15])[C:13]#[C:12][C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: CC(C)(O)C#CBr
Reactant: C#Cc1cccc(OC)c1
Agent: Cl[Cu]
Solvent: CC(C)N
Solvent: CO
Product: COc1cccc(C#CC#CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
50 mg of copper (I) chloride were dissolved in a mixture of 10 ml of isopropylamine and 15 ml of methanol in an atmosphere of argon, and 660 mg of 3-ethynylanisole were then added to the reaction mixture, followed by stirring at room temperature for 10 minutes. 1300 mg of 1-bromo-3-hydroxy-3-methyl-1-butyne were then dropwisely added to the solution over a time of about 2 hours, followed by stirring at room temperature for 2 hours. The solvent was then evaporated from the reaction mixture, and the residue was then neutralized and diluted by 1N hydrochloric acid, and subjected to extraction with dichloromethane three times. The organic layer was then dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel column chromatography using benzene as an eluent to obtain 800 mg of 5-hydroxy-5-methyl-1-(3-methoxyphenyl)hexane-1,3-diyne.