Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[O:12])[CH2:4][CH2:3]1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:31]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[O:12])[CH2:4][CH2:3]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (100 mg), benzoic acid (32.5 mg) and diethyl azodicarboxylate (46.3 mg) in anhydrous tetrahydrofuran (2 mL) was added triphenylphosphine (69.8 mg). The mixture was stirred for 4 hours at ambient temperature. The mixture was partitioned between an aqueous saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1 to 3:1). The obtained product was triturated with diisopropyl ether to give 2-[cis-4-(benzoyloxy)cyclohexylamino]-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (68.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21]>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1F
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)c2c(N)ncnc2Cl)cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4,6-Dichloro-N-(3-fluoro-4-methoxyphenyl)pyrimidine-5-carboxamide (720 mg, 2.28 mmol) was dissolved in dioxane (10 ml) and cooled in an ice bath. Ammonia solution (1.63 mL, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h and overnight at room temperature. After evaporation of the solvent under reduced pressure, the residue (675 mg, 100%) was used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][OH:13].CO.C(O)(=O)C>C(O)(C)C.[Ni].O.CO.O>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: Nc1c(CO)cc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(CO)c1N
Reaction time: 4 h
Yield: 83.4 %

Procedure:
(2-Amino-5-chloro-3-nitro-phenyl)-methanol (0.202 g, 1 mmol) was suspended in a mixture of iso-propanol (5 ml), water (2 ml), methanol (3 ml) and acetic acid (0.05 ml). Raney Nickel (0.015 g, as a slurry in water) was added carefully under nitrogen. The reaction mixture was shaken under a hydrogen atmosphere for 4 h, then diluted with methanol-water (1:1, 50 ml) and filtered to removed catalyst residues. Volatiles were removed in vacuo, and the remaining aqueous layer extracted with ethyl acetate (4×30 ml). The combined organics were washed with brine, dried (MgSO4) and reduced in vacuo to give (2,3-diamino-5-chloro-phenyl)-methanol as an orange solid (0.144 g, 84%). (LC/MS: Rt 0.85, [M+H]+ 173.03).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Li].[CH:12]1([C:18]2[CH:19]=[C:20](Cl)[CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CN(C)[CH:36]=[O:37]>O1CCCC1>[CH:12]1([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:36]=[O:37])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)C=O
Reactant: Clc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: c1ccc2ccccc2c1
Product: O=Cc1ccc(OCCN2CCOCC2)c(C2CCCCC2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
Naphthalene (3.48 g, 27.2 mmol) was added to a suspension of 30% lithium dispersion (3.2 g, 138 mmol, pre-washed with tetrahydrofuran) in tetrahydrofuran (80 ml). The suspension was stirred until a green color appeared (approximately 1 hour). The reaction was cooled to −78° C., and a solution of the 3-cyclohexyl-4-morpholinoethoxy-chlorobenzene (8 g, 24.7 mmol) in tetrahydrofuran (20 ml) was added. After 1 hour, the reaction was warmed to 0° C. and stirred for an additional hour. Dimethylformamide (9.6 ml, 123.5 mmol) was added, the reaction was stirred at 0° C. for one more hour and then warmed to room temperature and stirred for another hour. The reaction was quenched with methanol (30 ml), added to 1N hydrochloric acid (300 ml) and extracted with ethyl acetate (400 ml). The organic layer was washed with water (300 ml), saturated sodium bicarbonate solution (300 ml) and brine (300 ml), dried over magnesium sulfate and concentrated. Chromatography (silica, 40-60% ethyl acetate/hexanes) afforded 3 g (34%) of 3-cyclohexyl-4-morpholinoethoxybenzaldehyde as a light yellow oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:34][CH2:35]O)[C:5]([C:7]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[O:6])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C.O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:35][CH2:34][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1C1CC1
Reaction time: 1 h
Yield: 349.9 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacidcyclopropyl-(2-hydroxyethyl)-amide (451) (80 mg, 0.164 mmol), in dichloromethane (6 mL), TPP (150.33 mg, 0.574 mmol) and diisopropyl azodicarboxylate (0.097 mL, 0.492 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.2). After completion of the reaction, water (5 mL) was added and the mixture was extracted with dichloromethane (2×25 mL). The combined extracts were dried and concentrated to get crude 9-benzyloxy-2-cyclopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (452) (270 mg, Crude) as a yellow gummy liquid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]([C:14](=O)[CH2:15]Br)[CH:4]=1.[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[C:25]([NH2:27])=[S:26])[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:23]=[C:24]([C:25]2[S:26][CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([N:2]([CH3:1])[CH3:18])[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=3)[N:27]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:20]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(N(C)C)cc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cc(N(C)C)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-dimethylamino-6-ethoxycarbonyl-2-(α--bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-dimethylamino-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[CH:10]=1)(=[O:7])[CH3:6]>C(O)(C(F)(F)F)=O>[C:5]([NH:8][C:9]1[C:17]([N+:1]([O-:4])=[O:2])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(O)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
Nitric acid (fuming) (23.8 g, 378 mmol, 1.20 equiv) was added in portions under 50° C. to a mixture of 4-acetamido-2-hydroxybenzoic acid (61.4 g, 315 mmol, 1.00 equiv) and TFA (700 mL) in a 2-L round-bottom flask. The resulting solution was allowed to react, with stirring, for 3 hr at room temperature before being concentrated under vacuum. The residue was dissolved in 800 mL of acetone, stirred for 15 min. at reflux, then cooled. The solids were collected by filtration, giving 21.1 g (28%) of 4-acetamido-2-hydroxy-5-nitrobenzoic acid as an orange solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[C:37]1([Mg]Br)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.[Cr](O)(O)(=O)=O.C(C1CN2C(=O)C[C@H]2SC=1)=O>C(O)(C)C.CC(C)=O.C(OCC)(=O)C.O1CCCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([C:17](=[O:18])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: Br[Mg]c1ccccc1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)(O)O
Agent: Cl
Agent: O=CC1=CS[C@@H]2CC(=O)N2C1
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C(=O)c3ccccc3)=CS[C@H]12
Temperature: -73 °C

Procedure:
To a cooled (-73° C.), stirred solution of 1.04 g. of benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate and 8 ml. of tetrahydrofuran was added 2.4 ml. of a 2.5 molar phenylmagnesium bromide solution. After stirring the reaction mixture with cooling for four minutes, 8 ml. of 1N.HCl was added, and the reaction mixture was allowed to warm to 0°. Ethyl acetate was added, and the reaction mixture was then washed twice with cold 1 N.HCl, and twice with brine and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a residue which was chromatographed on a silica gel column using a toluene-ethyl acetate gradient. This chromatography failed to separate the unreacted starting material (3-formyl-2-cephem ester) and the product cephem secondary carbinol. Combining the fractions off the column and evaporating in vacuo to dryness gave 0.895 g. of a mixture which was dissolved in 50 ml. of acetone and reacted with 0.77 ml. of a 2.26 molar solution of chromic acid. This reaction mixture was allowed to stir for 15 minutes at room temperature after which time 5 ml. of isopropanol was added. After five minutes the reaction mixture was evaporated in vacuo to dryness, and the residue was dissolved in an ethyl acetate/water slurry and then transferred to a separatory funnel with the aid of ethyl acetate. The organic layer was separated and washed with water (4X) and brine (2X) and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness and chromatography of the residue thereby obtained on silica using a toluene-ethyl acetate gradient provided 0.213 g. of the 3-formyl-2-cephem starting material and 0.366 g. (41 percent) of the title product which crystallized from methylene chloride hexane as white needles (m.p. 179°-180°):
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][O:14][CH2:15][C:16]([CH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1)=[O:17].N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[C:18]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1)[C:16](=[O:17])[CH2:15][O:14][CH3:13])[C:7]#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: COCC(=O)Cc1nc(C)cs1
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1

Procedure:
500 mg (3.10 mmol) of the compound from example 3A and 632 mg (3.41 mmol) of the compound from example 13A are dissolved in 15 ml of dichloromethane, and 0.307 ml (3.10 mmol) of piperidine and 0.178 ml (3.10 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 200 mg (20% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[CH:11])=[CH:5][CH:4]=1.Br[C:13]1[C:14]([NH:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][N:21]1[C:14]2[N:15]=[C:16]([C:19]#[N:20])[N:17]=[CH:18][C:13]=2[CH:11]=[C:10]1[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#CCc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 80 °C

Procedure:
1-Methoxy-4-prop-2-ynyl-benzene (3.01 mmol) is dissolved in DMF (7 ml) at room temperature under nitrogen atmosphere. To the solution, 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (2.01 mmol), triethylamine (6 mmol), copper(I) iodide (0.2 mmol), and dichlorobis(triphenylphosphine)palladium (II) (0.1 mmol) are added successively. The mixture is heated at 80° C. under nitrogen atmosphere for 3 h. After cooling at room temperature, the mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=7:1) to give 7-(2,2-dimethyl-propyl)-6-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 57%.
Reaction SMILES: O[C:2]1([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:6]2[C:7]([CH3:21])=[C:8]([CH3:20])[C:9]([CH3:19])=[C:10]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22]>C(OCC)(=O)C.CCCCCC>[CH:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:2]2[C:6]3[C:7]([CH3:21])=[C:8]([CH3:20])[C:9]([CH3:19])=[C:10]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:5]=3[O:4][C:3]2([CH3:23])[CH3:22])=[CH:29][CH:28]=1)([CH3:32])[CH3:31]
Reactant: Cc1c(C)c(NC(=O)CC(C)(C)C)c2c(c1C)C(O)(c1ccc(C(C)C)cc1)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c(NC(=O)CC(C)(C)C)c2c(c1C)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 53 %

Procedure:
Using N-(3-hydroxy-3-(4-isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamide obtained in Example 260, the title compound was synthesized in the same manner as in Example 271. Yield: 53%. Melting point: 152-153° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6](I)[CH:5]=1.C([Mg]Cl)(C)C.C1COCC1.[Cl:23][C:24]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:24]=2[Cl:23])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
A dry flask was charged with 3-iodo-4-methylbenzoic acid methyl ester (21.6 g, 78.2 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (140 mL) was added, and the solution cooled to −50° C.; then isopropylmagnesium chloride (41 mL, 2.0 M in diethyl ether, 82 mmol) was added slowly over 15 min keeping the temperature below −40° C. On completion of the addition the reaction mixture was stirred at −40° C. for 45 min. A THF solution of ZnCl2 (10.78 g, 79.1 mmol, 0.8 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 65 min; then 2-chloro-4-nitro-benzoyl chloride (17.2 g, 78.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.03 g, 3.49 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 4 h the reaction mixture was poured into a mixture of toluene/EtOAc/water, then shaken and separated. The aqueous phase was extracted with two more portions of EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. Crystallization from mixtures of EtOAc/petroleum ether (40-60) gave the title compound as yellow solid. The mother liquid was concentrated in vacuo and purified by chromatography using DCM as the eluent to give a second crop of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[CH:4].[O:13]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=2)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]#[C:4][C:23]1[N:22]=[C:21]([CH:20]2[O:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCC1OC1c1cccc(Br)n1
Reactant: C#CC(O)CCCCCCCC
Product: CCCCCCCCC(O)C#Cc1cccc(C2OC2CCCCO)n1
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
3-Hydroxy-undec-1-yne (33 mg, 0.194 mmole) and 5,6-epoxy-6[6-bromopyridine-2yl]hexane-1-ol (44 mg, 0.162 mmole) are combined in 1 ml degassed triethylamine in a 25 ml one-neck round bottom flask under argon. The solution is treated with (bis)triphenylphosphine palladium dichloride (3 mg, 0.004 mmole), warmed to 55° C., and is treated with cuprous iodide (1 mg, 0.005 mmole). The reaction mixture is stirred 1.5 hours at 55° C., cooled to room temperature, and the volatiles are removed in vacuo. The residue is partitioned between 1×10 ml diethyl ether and 1×10 ml saturated sodium chloride/ammonium chloride (1:1). The aqueous layer is further extracted with 3×10 ml diethyl ether. The combined organics are dried over magnesium sulfate and concentrated in vacuo to a pale oil.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)([O-:34])=[O:33]>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N+:32]([O-:34])=[O:33])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccccc1[N+](=O)[O-]
Yield: 21.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-nitrophenylboronic acid (31 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with 30% ethyl acetate/hexanes and then by RP HPLC to afford the product as a white solid (12 mg, 21%). MS m/e 452.18 (M+H+)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)C1C=CC=CC=1>C(O)C.O.[Pd]>[F:29][C:26]([F:27])([F:28])[C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=1)[CH2:15][O:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][C@@H:9]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2OCCN(Cc3ccccc3)[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cc(CO[C@H]2OCCN[C@@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 36 h
Yield: 69.6 %

Procedure:
A solution of 3.6 g (7.27 mmol) of 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine in 100 mL of ethanol and 5 mL of water, containing 0.72 g of 10% Pd/C was hydrogenated on a Parr apparatus for 36 h. The catalyst was filtered and thoroughly washed with EtOAc. The filtrate was concentrated and the residue was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography using a gradient of 10-60% EtOAc/hexane to isolate 2.05 g (70%) of 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenylmorpholine.
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:22]([Sn](=O)CCCC)[CH2:23][CH2:24]C.C(Br)C=C>C1C=CC=CC=1.[Br-].C([N+](CC)(CC)CC)C>[CH2:24]([O:6][C@H:5]1[C@@H:7]([OH:8])[C@@H:9]([CH2:11][OH:12])[O:10][C@@H:2]([O:1][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[C@@H:3]1[OH:4])[CH:23]=[CH2:22]
Reactant: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: CCCC[Sn](=O)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: C=CCBr
Solvent: c1ccccc1
Product: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](OCCCCCC(=O)OC)[C@@H]1O
Temperature: 25 °C
Reaction time: 36 h
Yield: 71.7 %

Procedure:
Compound 2 was prepared from 1 according to the literature procedure (J. Carbohydr. Chem. 8 (1989) 145) as follows. Compound 1 of Example 1 (20.0 g) was refluxed in anhydrous benzene (500 mL) containing 3 Å molecular sieves (20 g) for 1 h followed by the addition of di-n-butyltin oxide (24.0 g) and the refluxing was continued for 4 more h. To this tetraethylammonium bromide (7.0 g) and allyl bromide (80 mL) were added and refluxed for another 1 h followed by stirring at room temperature for 36 h. The reaction mixture was evaporated to dryness and the product was extracted with CH2Cl2, washed with 10% aqueous KF solution, ice cold 1M hydrochloric acid (HCl) and saturated sodium bicarbonate (NaHCO3) solution. Chromatography of the crude product on a column of Silica gel using ethyl acetate-hexane-ethanol=10:10:1 as eluant gave the titled compound 2 (16.2 g). [ α]D25 -3.5±2° (c 0.96, CHCl3). 1H n.m.r. (CDCl3 +D2O<5%) ∂: 5.97 (m, --CH=C), 5.35, 5.30, 5.24 and 5.20 (m, CH2 =C), 4.23 (m, O--CH2 --C=, H-1, J1,2 =7.5 Hz), 4.05 (d, J=3.5 Hz, H-4), 3.96-3.80 and 3.50-3.40 (m, O--CH2 --C, H-6a,b, H-5), 3.72 (dd, J=7.5, 9.5 Hz, H-2), 3.36 (dd, J=3.5, 9.5 Hz, H-3), 2.32 (t, J=7.0 Hz, CH2COO), 1.64 and 1.40 ((6 H, hydrogens of pentyl group). 13C n.m.r.(CD3OD) ∂: 176.0, 136.7, 117.3, 105.1 (C-1), 82.6 (C-3), 76.6 (C-5), 71.94, 71.89, 70.6, 67.6 (C-4), 62.7 (C-6), 52.0, 34.9, 30.5, 26.8, 25.9. Anal. Calcd for C16H28O8.H2O: C, 52.46; H, 8.20. Found: 52.84; H, 7.93.