Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3ccc(Cl)cc3)n2)ccc1F
Yield: 80.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 80.8%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2O)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].BrC1C(OC)=C(C(CSC2C=CC=C(O)C=2)=CC=1)C(OC)=[O:30]>>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:30])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CSc2cccc(O)c2)ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(O)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 138, starting from methyl 3-bromo-6-(3-hydroxyphenylthiomethyl)-2-methoxybenzoate (Intermediate 142).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:13][CH2:14]1)=[O:21])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.75 g (5.84 mmol) trans-[4-(5-Hydroxy pentyl)-cyclohexyl)-methyl-carbamic acid tert-butyl ester and 0.5 ml (6.42 mmol) of methanesulfonyl chloride in 20 ml CH2Cl2 was added, under cooling with an ice bath, 1.56 ml (11.7 mmol) of Et3N. The mixture was stirred for 3 h at RT. The reaction-mixture was then partitioned between ether/1N HCl and water. The ether-solution was concentrated in vacuo to yield 2.12 g (96%) of clean trans-Methansulfonic acid 5[-4-(tert-butoxy carbonyl-methyl-amino)-cyclohexyl)-pentylester.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.O=P(Cl)(Cl)[Cl:27]>O1CCOCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([Cl:27])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc2nc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-acetamido-6-chloro-pyrido[3,2-d]pyrimidine (1.19 g, 5 mmol), N,N-diisopropylethylamine (2.6 ml, 15 mmol) and POCl3 (0.7 ml, 7.5 mmol) in dioxane (50 ml), was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was redissolved in dichloromethane (500 ml) and extracted with cold water (200 ml) till pH=6-7. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude title compound which was characterised as follows: MS (m/z): 257, 259 ([M+H]+, 100). This compound was used for further reactions without any purification.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[C:16]2[O:18][C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)=[N:20][C:15]2=[CH:14][CH:13]=1>ClCCl>[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[C:16]2[O:18][C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)=[N:20][C:15]2=[CH:14][CH:13]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 ml of trifluoroacetic acid was added to a solution of 170 mg of tert-butyl {4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}acetate in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 16 h. The reaction was then concentrated under reduced pressure, purified by preparative HPLC and freeze-dried. This gave 85 mg (57%) of the title compound.
Reaction SMILES: O1CCOCC1.[C:7]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[S:13])#[N:8].[OH-].[K+]>[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].O>[C:7]([C:9]1[CH:10]=[C:11]([C:12]2[S:13][C:16]3[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH:28]([CH3:30])[CH3:29])#[N:8]
Reactant: COc1cccc(NC(=S)c2ccc(OCC(C)C)c(C#N)c2)c1
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2nc(-c3ccc(OCC(C)C)c(C#N)c3)sc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 36 %

Procedure:
Dioxane (70 mL) and water (70 mL) were added to a mixture of 3-cyano-4-isobutyloxy-N-(3-methoxyphenyl)thiobenzamide (900 mg, 2.64 mmol), potassium ferricyanide (2.61 g, 7.93 mmol), and potassium hydroxide (892 mg, 15.9 mmol). The resulting mixture was stirred for 20 hours at room temperature. The mixture was then placed under reduced pressure to distill the solvent off, and extracted with ethyl acetate (50 mL). The ethyl acetate portion was washed with water, dried over anhydrous magnesium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica gel column chromatography (ethyl acetate/toluene=1/20-1/10), to give 322 mg (yield 36%) of the desired compound in the form of a pale yellow crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:7]=2)[CH:3]=1.C(NC1C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[N+:37]=[N-:38])[C:12]([O:14][CH3:15])=[O:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[N:7]=2)[CH:3]=1
Reactant: COC(=O)Cc1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=[N+]=[N-])c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetate (1.95 g, 5.49 mmol) and 4-acetamidobenzenesulfonyl azide (1.52 g, 6.32 mmol) in acetonitrile (11 mL) at 0° C. was added 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.04 mL, 6.87 mmol) dropwise over 20 min. The ice bath was removed and stirring continued at room temperature for 1 h. The reaction was partitioned between water and ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (8%→25% ethyl acetate/n-hexane) to give 1.39 g (66%) as a yellow oil. 1H-NMR (CDC13, 500 MHz) δ 8.01 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 5.64 (s, 2H), 3.89 (s, 3H), 3.64 (t, J=8.2 Hz, 2H), 0.93 (t, J=8.4 Hz, 2H), −0.03 (s,9H; 13C NMR (126 MHz, CDCl3) δ ppm 165.9, 143.2, 128.7, 125.3, 123.1, 122.7, 122.5, 116.5, 116.4, 81.8, 67.9, 52.1, 17.8, −1.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([B:14]([OH:19])[OH:15])[CH:3]=1
Reactant: Cc1ccc(C2OCCO2)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: Cc1ccc(C2OCCO2)cc1B(O)O

Procedure:
In a manner similar to that of Example 2(k), by reacting 11.1 g (46 mmol) of 2-(3-bromo-4-methylphenyl)[1,3]dioxolane with 12.3 ml (55 mmol) of triisopropyl borate, 6 g (88%) of product are obtained in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9](N)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[ClH:16]>O.O.O.[Cu](Cl)Cl>[Br:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:16])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1nc2c(Br)cccn2n1
Reaction time: 18 h

Procedure:
To a cooled, stirred suspension of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.961 g, 4.51 mmol) and copper(II)chloride dihydrate (0.20 g, 1.2 mmol) in 12 M of hydrochloric acid (10.0 mL) at 5° C. was added dropwise a solution of sodium nitrite (0.37 g, 5.4 mmol) in water (2 mL). Gentle gas evolution was noted. The mixture was stirred for 30 minutes at 5° C. then at room temperature for 18 hours. The yellow mixture was diluted with water (80 mL) and the resulting precipitate was filtered, rinsed with water and dried in-the-air. 8-Bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine was isolated as a pale yellow solid (0.947 g, 90%) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.98 (d, J=6.9 Hz, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.22 (t, J=7.0 Hz, 1H). MS=232, 234, 236 (MH)+. 68b) (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (234.0 mg, 1.007 mmol) and 2-methanesulfonyl-phenylamine; hydrochloride (220.0 mg, 1.059 mmol) with 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (105.0 mg, 0.1815 mmol) as the ligand in a manner analogous to Step 2d. The reaction product was isolated as a pale yellow solid (0.115 g, 35%). MP=180-182° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.2, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.2 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 3.12 (s, 3H). MS=323, 325 (MH)+. 68c) N(8)-(2-Methanesulfonyl-phenyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-phenyl)-amine (95.0 mg, 0.294 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (32.0 mg, 0.0585 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a light brown foam (0.077 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (s, 1H), 8.11 (d, J=6.5, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.58-7.51 (m, 2H), 7.43 (s, 1H), 7.30-7.25 (m, 1H), 7.20 (t, J=8.1 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.84-6.78 (m, 2H), 6.57 (d, J=8.1 Hz, 1H), 3.33-3.25 (m, 4H), 3.13 (s, 3H), 2.70-2.57 (m, 4H), 2.39 (s, 3H). MS=478 (MH)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[C:11]([NH:15][C:16]([CH:18]1[CH2:20][C:19]1([CH3:22])[CH3:21])=[O:17])[C:12]([OH:14])=[O:13]>CO>[CH3:21][C:19]1([CH3:22])[CH2:20][CH:18]1[C:16]([NH:15]/[C:11](=[CH:10]\[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:2][CH3:1])/[C:12]([OH:14])=[O:13])=[O:17]
Reactant: C[O-]
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Agent: [Na+]
Solvent: CO
Product: COCCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Yield: 49.4 %

Procedure:
To a solution of 2.43 mmoles of sodium methoxide in 5 ml of methanol was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid. The solution was heated under reflux in a nitrogen atmosphere for 1 hr. The reaction mixture was evaporated under reduced pressure, the residue dissolved in water and acidified with 2.5 N hydrochloric acid. The oil which precipitated was extracted with ether (3X). The ether extracts were washed with water, and saturated brine and dried over MgSO4. Removal of the ether under reduced pressure gave a colorless oil that crystallized upon standing. It was recrystallized from ether-hexane to give 140 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-methoxy-2-octenoic acid, m.p. 71°-72° C. Homogeneous by TLC (toluene-HOAc, 4:1). The NMR spectrum was in accord with the desired structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1.S(Cl)([Cl:29])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([Cl:29])=[O:26])[CH2:20][CH2:19]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Solvent: ClCCl
Product: O=C(Cl)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
A mixture of 4 g of 1-[6-fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarboxylic acid, 12 ml of thionyl chloride, and 100 ml of methylene chloride were stirred and heated under reflux for 1 hr. The reaction mixture was cooled and concentrated in vacuo to leave 4.2 g of product as a yellow solid, mp 243°-5°.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].CN1C=CC=C1C(N1CCOCC1)C#N.[C:24]([O:28]CC)(=[O:27])[CH:25]=[CH2:26].Cl>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:26][CH2:25][C:24]([OH:28])=[O:27])=[O:8]
Reactant: Cn1cccc1C=O
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: Cn1cccc1C(C#N)N1CCOCC1
Product: Cn1cccc1C(=O)CCC(=O)O

Procedure:
As for Example 6, 1-methyl-2-pyrrolecarboxaldehyde is converted to α-(1-methyl-2-pyrrolyl)-4-morpholineacetonitrile. The preceding compound is reacted with ethyl acrylate and the resulting 1,4-addition product is heated at 100° C. with 6 N hydrochloric acid to give 3-(1-methyl-2-pyrrolylcarbonyl)propionic acid.
Reaction SMILES: [CH:1]([C:4]1([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])SCCCS1)([CH3:3])[CH3:2].C[OH:16]>C(#N)C>[OH:14][CH:10]([CH2:11][CH2:12][CH3:13])[C:4](=[O:16])[CH:1]([CH3:3])[CH3:2]
Reactant: CCCC(O)C1(C(C)C)SCCCS1
Reactant: CO
Solvent: CC#N
Product: CCCC(O)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of (101) (5.0 g, 21.4 mmol) in acetonitrile (270 mL) was added under vigorous stirring a solution of Hg(ClO4)2 in methanol (30 mL). The resulting mixture was stirred at room temperature for 2 h. After filtration, the filtrate was carefully concentrated under reduced pressure without heating. Purification of the residue using silica gel flash column chromatography (10% ethyl acetate/hexane) provided 2.8 g (91%) of the title compound as colorless liquid. 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.2 Hz, 3H), 1.35-1.46 (m, 4H), 1.75 (m, 1H), 2.80 (m, 1H), 3.45 (d, J=5.2 Hz, 1H), 4.29 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:14]1(=[O:23])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 17.8 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 15.52 g (55 mmol) of N-(4bromobutyl)phthalimide in 80 ml of DMF was added 8.23 ml (5 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture was stirred at room temperature for 7 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.63 g of the desired compound (yield: 17.2%, colorless crystals).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=1
Reactant: Nc1cncc(F)c1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Br)c1Nc1cncc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-bromo-2-fluoro-3-nitrobenzene (5.69 g, 25.9 mmol) and 3-amino-5-fluoropyridine (2.6373 g, 23.53 mmol) in DMF (39.2 mL) was added potassium tert-butoxide (5.28 g, 47.1 mmol) and the solution was stirred under nitrogen at rt overnight. After 5 additional h, the mixture was poured into water (150 mL) and extracted with EtOAc (2×100 mL). The organic extract was dried over MgSO4. The solution was filtered and concentrated in vacuo to provide the crude material as a orange solid. The orange solid was purified by chromatography through a Redi-Sep™ pre-packed silica gel column (120 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide N-(2-bromo-6-nitrophenyl)-5-fluoropyridin-3-amine as orange syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, s), 8.09 (1H, dd, J=8.1, 1.5 Hz), 8.03 (1H, dd, J=8.2, 1.4 Hz), 7.97 (1H, d, J=2.5 Hz), 7.88 (1H, t, J=1.9 Hz), 7.44 (1H, t, J=8.1 Hz), 6.77 (1H, dt, J=11.2, 2.3 Hz); LC-MS (ESI) m/z 312.0 [M+H (79Br)]+ and 313.9 [M+H (81Br)]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([NH2:8])=[O:7])[CH2:4][OH:5].[C:9]([O:20][C@H:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][C:23](O)=[O:24])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(Cl)Cl>[C:9]([O:20][C@H:21]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][C:23]([NH:8][C:6](=[O:7])[C@H:3]([CH2:4][OH:5])[NH2:2])=[O:24])(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCC
Reactant: NC(=O)[C@@H](N)CO
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)NC(=O)[C@@H](N)CO)OC(=O)CCCCCCCCC
Yield: 73.6 %

Procedure:
In the same manner as described in Example 25-(1), L-serinamide hydrochloride (169 mg, 1.2 mmol) was acylated with (R)-3-decanoyloxytetradecanoic acid (478 mg, 1.2 mmol) in the presence of EEDQ (371 mg, 1.5 mmol) in CH2Cl2 to afford 428 mg (74%) of N-[(R)-3-decanoyloxytetradecanoyl]-L-serinamide as a white solid: 1H NMR (CDCl3) δ 0.88 (t, 6H), 1.1-1.7 (m, 34H), 2.33 (t, 2H, J=7.5 Hz), 2.54 (d, 2H, J=6.6 Hz), 3.35 (s, 2H), 3.72 (dd, 1H, J=11.0, 5.2 Hz), 3.84 (dd, 11H, J=11.3, 5.0 Hz), 4.20 (t, 1H, J=5.1 Hz), 5.26 (t, 1H, J=6.4 Hz).
Reaction SMILES: O[CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].C(Br)(Br)(Br)[Br:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[Br:26][CH:2]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCC#CC(O)CCCCC(=O)OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC#CC(Br)CCCCC(=O)OC

Procedure:
This compound was prepared by reaction of methyl 6-(±)-hydroxy-7-eicosynoate (preparative example V) with CBr4 /Ph3P reagent in exactly the same manner as described in preparative example VIII.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([N:30]2[C:34](=[O:35])[CH:33]=[CH:32][C:31]2=[O:36])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29]>>[CH2:10]([N:8]([O:9][CH:25]1[CH2:26][C:27](=[O:28])[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:30]2[C:34](=[O:35])[CH2:33][CH:32]([O:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:31]2=[O:36])[C:24]1=[O:29])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1N1C(=O)C=CC1=O
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1c1ccccc1N1C(=O)CC(ON(Cc2ccccc2)Cc2ccccc2)C1=O
Yield: 67.9 %

Procedure:
The procedure of Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 3.35 g (12.5 mmole) of N,N'-ortho-phenylenedimaleimide. The residue is purified by preparative HPLC (Silica gel: 7:3 heptane:ethyl acetate eluent) to give 5.9 g (34%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[N:4]=1.[C:10]([NH:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)(=[O:12])[CH3:11].N1C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][N:6]([C:18]2[CH:19]=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[CH:15]=[CH:16][CH:17]=2)[C:5](=[O:9])[N:4]=1
Reactant: COc1cn[nH]c(=O)n1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cnn(-c2cccc(NC(C)=O)c2)c(=O)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
According to Scheme 6 Step 1: To a stirred solution of 5-methoxy-1,2,4-triazin-3(2H)-one (1 g, 7.9 mmol) in DMF (5 mL) were successively added the 3-acetamidophenylboronic acid (1.4 g, 7.9 mmol), copper(II) acetate (1.4 g, 7.9 mmol) and pyridine (1.2 g, 7.9 mmol). The mixture was stirred overnight at 60° C. The reaction mixture was quenched with a saturated sodium bicarbonate solution and extracted with ethyl acetate (×3). The combined organic layers were washed successively with water, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 70 g column, CH2Cl2/MeOH 98/2 to afford(0.493 g, 24%) of N-(3-(5-methoxy-3-oxo-1,2,4-triazin-2(3H)-yl)phenyl)acetamide