Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@H:11]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a stirred solution of tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (1.37 g, 3.4 mmol, J. Antibiotics, 1997, 50, 567-585) in ethanol (30 mL) was added 10 wt. % palladium on carbon (140 mg). The resulting mixture was stirred under hydrogen (4 atom) at room temperature for 3 h. The mixture was filtered through a pad of Celite and the filter cake was washed with ethanol. The combined filtrate was concentrated to give 1.34 g (97%) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[CH2:12]Br.[OH-].[Na+]>[Cu].C(O)C>[CH2:11]1[CH2:12][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[O:1]1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc2c(c1)OCCO2

Procedure:
(i)(a) A mixture of 3,4-dihydroxybenzaldehyde (10.0 g), ethylene dibromide (13.61 g), copper powder (trace), sodium hydroxide (5.80 g) and ethanol (500 ml) was heated at reflux for 2 days. Subsequently, the solvent was evaporated and the residue was dissolved in dichloromethane. The organic phase was shaken with a little water and then dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluant dichloromethane) giving 3,4-ethylenedioxybenzaldehyde as an oil. The product was characterized by proton nuclear magnetic resonance spectroscopy. Pmr spectrum (CDCl3 ; δ in ppm): 4.35 (4H, s); 6.98 (1H, d); 7.40 (2H, m); 9.70 (1H, s).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>C(#N)C>[CH3:15][C:2]1[N:18]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]2=[N:16][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC(Br)C(=O)c1ccc2oc(=O)[nH]c2c1
Solvent: CC#N
Product: Cc1ccn2c(C)c(-c3ccc4oc(=O)[nH]c4c3)nc2c1
Yield: 25.1 %

Procedure:
A solution of 5-(2-bromopropionyl)-2-benzoxazolinone (5.4 g) and 2-amino-4-picoline (6.5 g) in acetonitrile (100 ml) was refluxed for an hour. The reaction mixture was evaporated in vacuo and the residue was poured into a suspension of water and ethyl acetate with stirring. The resultant mixture was acidified to pH 0.8 with 10% hydrochloric acid and stirred for 20 minutes at ambient temperature. The resultant precipitate was collected by filtration. The product was suspended in a mixture of water and ethyl acetate and the resultant mixture was adjusted to pH 8.0 with 20% potassium carbonate. The precipitate was collected by filtration and washed with water and ethyl acetate. The precipitate was recrystallized from an aqueous tetrahydrofuran to afford 5-(3,7-dimethylimidazo[1,2-a]pyridin-2-yl)-2-benzoxazolinone (1.4 g). mp. 276°-280° C. (dec.).
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/[N:21](C)C)=[N:12]3)[C:4]=2[O:3]1.[NH:26]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32])N>C(O)C>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:26]([C:28]5[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=5)[C:31]#[N:32])[N:21]=[CH:20][CH:19]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Reactant: N#Cc1cccc(NN)c1
Solvent: CCO
Product: N#Cc1cccc(-n2nccc2-c2nn(-c3cccc4c3OC(F)(F)O4)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 3-hydrazino-benzonitrile in ethanol as solvent according to the method described for example 91. MS: M=420.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].C(O)(=O)C>[Zn].O>[CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reaction time: 1 h
Yield: 96.7 %

Procedure:
5.9 g of zinc powder were introduced int a solution of 6.5 g of the product of Step D, 23.4 ml of acetic acid and 2.6 ml of water and the mixture was stirred for 1 hour and filtered. The filtrate was decanted and the organic phase was washed with water. The aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness to obtain 4.7 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(3-hydroxy-3-oxo-propynyl)-cyclopropane-carboxylate which was used as is for the next step.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][N:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][N:22]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cc(CCO)ccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (3.18 g, 12.12 mmol) and diisopropylazodicarbocylate (2.39 μL, 12.12 mmol) in 10 mL of THF was stirred at 0° C. for 30 min and combined with a solution of 2-(2-methyl-pyridin-4-yl)-ethanol and phthalimide (1.33 g, 9.7 mmol) in 10 mL of THF. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions. The organic layer was dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica using a dichloromethane/methanol gradient (2–10%) gave 2.5 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:35]=[N+:36]=[N-].[Na+]>Cl.O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:35]=[N-:36]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc(-c2ccc([N+](=O)[O-])cc2)c1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 25 %

Procedure:
A mixture of methyl 3-amino-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)isonicotinate (1 g, 2 4 mmol) in concentrated hydrochloric acid (20 mL, 37%) was cooled in an ice bath and a solution of sodium nitrite (0.99 g, 14.4 mmol) in water (0.5 ml) was added in small portions. The orange-red solution was stirred for 20 min and then a solution of sodium azide (0.94 g, 14.4 mmol) in water (0.5 mL) was added in portions. A precipitate formed and, after 30 min, the reaction was partitioned between DCM and water. The organic phase was washed with brine (2×50 mL), sat. aq. Na2CO3 solution, water, brine and then dried with sodium sulfate. Removal of the solvent followed by silica gel chromatography (elution with 40% EtOAc in hexane) afforded methyl 3-azido-2-(4-nitrophenyl)-6-(3-(trifluoromethyl)phenyl)-isonicotinate (1.0 g, 2 1 mmol, 89% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.40 (2H, d, J=9.2), 8.33 (s, 1H), 8.29 (d, 1H, J=8.3), 8.22 (s, 1H), 8.07 (d, 2H, J=8.9), 7.74 (d, 1H, J=7.3), 7.66 (t, 1H, J=7.6), 4.12 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[OH:16])[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[C:17]1([C:23]2[S:24][CH:25]=[C:26]([CH:28]=O)[N:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[O:11]=[C:9]1[NH:8][C:7](=[O:12])[CH:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([OH:16])=[C:2]([N:1]=[CH:28][C:26]3[N:27]=[C:23]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:24][CH:25]=3)[CH:3]=2)[S:10]1
Reactant: Nc1cc(CC2SC(=O)NC2=O)ccc1O
Reactant: O=Cc1csc(-c2ccccc2)n1
Solvent: CCO
Product: O=C1NC(=O)C(Cc2ccc(O)c(N=Cc3csc(-c4ccccc4)n3)c2)S1
Yield: 97.8 %

Procedure:
A mixture of 500 mg of 5-(3-amino-4-hydroxybenzyl)-2,4-dioxothiazolidine, 405 mg of 2-phenyl-4-formylthiazole and 30 ml of ethanol is refluxed for 20 minutes, and the solvent is distilled off. 840 mg of 4-(2,4-dioxothiazolidin-5-yl)methyl-2-[(phenylthiazol-4-yl)methylidene]aminophenol obtained as a crude product are dissolved in 40 ml of benzene, and 1.26 g of lead tetraacetate are added thereto. After the mixture is stirred at room temperature for 15 minutes, the solvent is distilled off. Ethyl acetate and water are added to the residue, and the ethyl acetate layer is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1), whereby 400 mg of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(2-phenyl-1,3-thiazol-4-yl)benzoxazole are obtained. The Mass and IR data of this product are identical with those of the product obtained in Example 8.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH2:19][O:20][CH3:21])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:47]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[N:5]=[C:6]([CH2:19][O:20][CH3:21])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=3)[CH2:49][CH2:48]2)=[O:13])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: COCc1nc(C2CC2)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
Into a round-bottom flask, was placed a solution of 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 4.10, 30 mg, 0.10 mmol) in dichloromethane (5 mL). HBTU (76 mg, 0.20 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 35 mg, 0.15 mmol, 1.50 equiv) and triethylamine (28 μL, 0.20 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM (30 mL) and washed with water (3×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (25.0% CH3CN up to 38.0% in 7 min, up to 100.0% in 3 min, down to 25.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (5.9 mg, 12%). m/z (ES+) 455 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J=8.0 Hz, 2H), 7.59-7.53 (m, 2H), 7.53-7.47 (m, 3H), ˜4.9-4.75 (m, 1H partially obscured by water peak), 4.72 (s, 2H), 3.99-3.85 (m, 1H), 3.52 (s, 3H), ˜3.3 (m, 1H overlapped with methanol solvent peak), 3.08-2.93 (m, 2H), 2.37 (s, 3H), 2.08-1.93 (m, 1H), 1.93-1.65 (m, 4H), 1.02-0.94 (m, 2H), 0.74-0.68 (m, 2H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN=[N+]=[N-])O1
Temperature: 80 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (5.73 g, 20.00 mmol) in DMF (40 mL) was added sodium azide (2.6 g, 40.00 mmol) and the reaction mixture was stirred at 80° C. for 18 hr. The solvent was evaporated under reduced pressure, diluted with water (100 mL) and extracted 3 times with ethyl acetate (3×75 mL), which was consecutively washed with H2O (100 mL), brine (100 mL) and finally dried over MgSO4. The solvent was removed under vacuum to afford 2.2 g of 13 as brown oil (76% yield). 1H NMR (CDCl3, 400 MHz) δ: 4.21-4.27 (m, 1H), 4.02 (dd, J=6.4, 8.4 Hz, 1H), 3.74 (dd, J=6.0, 8.4 Hz, 1H), 3.36 (dd, J=4.8, 12.8 Hz, 1H), 3.26 (dd, J=5.6, 12.8 Hz, 1H), 1.43 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH:14]=O)([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2].[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].Cl>C(O)C.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2[O:12][C:11]([CH:14]=[N:29][NH:28][C:25]([NH2:27])=[NH:26])([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=O)O2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C=NNC(=N)N)O2
Yield: 98.3 %

Procedure:
In a mixed solvent of 20 ml of ethanol and 8 ml of pyridine was dissolved 3.9 g of 5-acetoxy-4,6-di-t-butyl-2-formyl-2-methyl-2,3-dihydrobenzofuran, and 1.42 g of aminoguanidine hydrochloride was added at room temperature. After heating under reflux for 14 hours and then cooling, ethanol and excess pyridine were distilled off using an evaporator, and the concentrate was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 10% methanol to give 4.48 g of 1-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methylideneamino]guanidine (rotamer mixture) as a pale yellow oil (yield 99%).
Reaction SMILES: [F:1][CH:2]([CH2:17][CH2:18][CH2:19][CH3:20])[C:3](=[O:16])[CH2:4][CH2:5][C@H:6]1[C@H:13]([OH:14])[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:15])[O:10]2.[C:21]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[F:1][CH:2]([C:3]1([O:16][CH3:21])[CH2:4][CH2:5][CH:6]2[CH:13]([CH2:12][CH:11]3[CH:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:14]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(F)C(=O)CC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCCCC(F)C1(OC)CCC2C(CC3OC(=O)CC32)O1

Procedure:
According to a similar manner as described in example 4, using (1S,5R,6R,7R)-6-[4(RS)-fluoro-3-oxo-1-octyl]-7-hydroxy-2-oxabicyclo[3.3.0]octane-3-one (0.263 g) and camphor sulfonic acid (0.021 g), the title compound was obtained (yields: 0.236 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].Cl.O1CCOCC1>C(O)(=O)C.[Zn]>[NH2:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(N)cc1C(=O)O
Temperature: 30 °C
Reaction time: 2 h
Yield: 204.9 %

Procedure:
Cyclobranyl ester of 2-methoxy-5-nitrobenzoic acid (25.0 g, 0.040 mole) prepared according to the procedure of Example 172 was suspended in acetic acid (1 l), and thereto 6N-HCl-dioxane (21 ml) and zinc powder (25.0 g) were added. The mixture was stirred at 30° C. for 2 hours. After the reaction, zinc powder was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was extracted with chloroform. The extracts were washed successively with water and saturated aqueous NaHCO3 solution, then dried, concentrated, and the residue was recrystallized from chloroform-ethanol (1:2, v/v), giving cyclobranyl ester of 5-amino-2-methoxybenzoic acid (13.7 g) in a 57.5% yield. m.p. 193°-195° C.
Reaction SMILES: C(OC(C(C[C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1)C(O)=O)=O)C.N1CCCCC1.[C:26](O)(=[O:28])C>C1C=CC=CC=1>[CH3:26][O:28][C:11]1[CH:16]=[CH:15][C:14]2[O:17][CH2:18][O:19][C:13]=2[CH:12]=1
Reactant: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(=O)O
Reactant: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)OCO2
Reaction time: 18 h

Procedure:
A mixture of the aldehyde of Example 1(p), (1.48 g, 5.25 mmol), 2-ethoxycarbonyl-3-(3,4-methylenedioxyphenyl)propanoic acid (2.34 g. 7.88 mmol), piperidine (223 mg, 0.26 ml, 2.7 mmol) and acetic acid (0. 17 ml) in benzene (50 ml) was stirred at reflux under argon using a Dean-Stark trap. After 18 hours, the benzene was removed in vacuo and the residue partitioned between t-butyl methyl ether and water. The layers were separated, and the aqueous further extracted (×3). The combined organic extracts were washed twice with water, 5% sodium bicarbonate solution, sat'd ammonium chloride, and brine, then dried (MgSO4), filtered and concentrated under reduced pressure. Silica gel chromatography (50% ether/hexanes) afforded the title compound as an oil. (1.048 g, 42%)
Reaction SMILES: CS(O[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]([C:22]3[N:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]4=[N:24][CH:23]=3)=[O:21])[CH:13]=2)[N:8]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C=O)C>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[C:7]([CH2:6][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:11][N:10]=2)=[CH:13][C:14]=1[NH:19][C:20]([C:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1)=[O:21]
Reactant: C1COCCN1
Reactant: Cc1ccc(-c2noc(COS(C)(=O)=O)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2noc(CN3CCOCC3)n2)cc1NC(=O)c1cnc2ccccn12

Procedure:
A solution of (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl methanesulfonate (44) (21.4 mg, 0.05 mmol), DIEA (13.0 mg, 0.1 mmol) and morpholine (13.0 mg, 0.15 mmol) in DMF (1 mL) was heated at 80° C. for 4 hours. The crude product was purified by preparative HPLC to yield N-(2-methyl-5-(5-(morpholinomethyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F22). 1H NMR (400 MHz, CD2Cl2) δ 9.60 (d, J=6.8 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.45 (s, 1H), 8.06 (s, 1H), 7.89 (dd, J=2.0, 8.0 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.54 (m, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.15 (m, 1H), 3.93 (s, 2H), 3.75 (m, 4H), 2.67 (m, 4H), 2.48 (s, 3H). MS m/z 419.2 (M+1)+. Note: if HCl salt of morpholine (0.15 mmol) was used, AgNO3 (0.15 mmol) was needed to avoid replacement of OMs group by Cl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH3:13])[C:5]=1[CH3:14])([O-:3])=[O:2].[N+:15](C1C=C(C)C(C)=C([N+]([O-])=O)C=1[N+]([O-])=O)([O-:17])=[O:16]>>[N+:15]([C:5]1([CH3:14])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]1[CH3:13])([O-:17])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1C
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Product: CC1C=C([N+](=O)[O-])C=C([N+](=O)[O-])C1(C)[N+](=O)[O-]
Yield: 91.7 %

Procedure:
The first filtrate from the separation of 1,2,6-trinitro-o-xylene was extracted three times with 80 ml portions of methylene chloride. The extracts were combined and the volatiles were evaporated to yield an oily mixture of 3,5-dinitro-o-xylene with both of the trinitro-o-xylene isomers. This oil was crystallized from 12 parts of isopropyl alcohol to afford 27.4 g (91.7% yield) of pure 1,4,6-trinitro-o-xylene having a melting point of 72° C. as given by Crossly et al.
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3].C1(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:24]([CH:2]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)[CH3:3])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1cnccn1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(N=[N+]=[N-])c1cnccn1
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2-(1-hydroxyethyl)pyrazine (0.859 g) and diphenylphosphoryl azide (2.48 g) in dry toluene (12 mL) at 0° C., under argon, was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.35 mL) dropwise. The resulting mixture was allowed to warm slowly to room temperature and stirred for 22 h then quenched with water (8 mL). The organic layer was removed and the aqueous phase extracted with 10 mL ethyl acetate. The combined extracts were concentrated, and the crude product was purified by flash column chromatography, eluting with hexane; 25% ethyl acetate to give 2-(1-azidoethyl)pyrazine (0.88 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.C(Cl)Cl.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[O:5][CH:6]=1
Reactant: O=Cc1cc(Br)co1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(Br)co2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 4-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and CH2Cl2 (10 mL) was added tert-butyl piperazine-1-carboxylate (1.06 g, 5.74 mmol) and sodium triacetoxyborohydride (1.2 g, 5.74 mmol). The mixture was stirred at room temperature overnight. The resultant mixture was diluted with EtOAc (100 mL), washed with brine then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-5% MeOH in CH2Cl2) to afford the sub-title compound (900 mg, 91%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[C:2]#[CH:3].S(Cl)([Cl:18])=O>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])[C:2]#[CH:3]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1ccc(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(=O)Cl)cc1OC
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To 100 ml of toluene were added 12.0 g of 4-(2-propynyloxy)-3-methoxybenzoic acid, 9.0 g of thionyl chloride and 50 mg of DMF, and the resulting mixture was heated to reflux for 3 hours. Thereafter, the reaction mixture which had been allowed to cool to near room temperature was concentrated under reduced pressure. The resulting solid was washed with hexane, and 11.0 g of 4-(2-propynyloxy)-3-methoxybenzoyl chloride was obtained.