Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH2:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:28]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 64.7 %

Procedure:
0.99 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight in 2 g (16 mmol) of dibutylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.82 g (65%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 105°-110°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[C:28]([F:30])[C:27]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=4[F:45])=[O:33])=[CH:26][C:25]=3[F:46])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[C:25]([F:46])=[CH:26][C:27]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][C:36]=4[F:45])=[O:33])=[C:28]([F:30])[CH:29]=3)[CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cc(F)c(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3F)c3c(N)ncnn23)CC1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3cc(F)c(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3F)c12
Reaction time: 0.17 h
Yield: 42.1 %

Procedure:
A suspension of Example 274 (498 mg, 0.77 mmol) in 10 mL 1,2-dichloroethane was treated with 3 mL TFA at rt. The reaction quickly became homogeneous and at 10 min no starting material remained by RP-HPLC. The reaction mixture was concentrated in vacuo, and the residue taken up again in fresh 1,2-dichloroethane and concentrated again; this was repeated 2 times. The residue was taken up in THF (5 mL) and EtOAc (35 mL) and washed with aq. sodium carbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide a tan solid. Trituration with ethyl acetate provided the title compound (178 mg, 42%) as a tan solid. Concentration of the mother liquor provided an additional the title compound (201 mg, 48 mmol) of similar purity. 1H-NMR (DMSO-d6) δ 9.54 (bs, 2H), 8.70 (dd, 1H), 8.21 (dd, 1H), 7.96 (s, 1H), 7.60 (dd, 1H), 7.30-7.46 (m, 1H), 7.38 (dd, 1H), 6.57 (s, 1H), 3.16-3.31 (m, 1H), 3.02-3.12 (m, 2H), 2.60-2.74 (m, 2H), 1.89-2.02 (m, 2H), 1.60 (ddd, 2H), 1.42 (s, 9H); MS [M+H]+=550.2; LCMS RT=2.43
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]([NH:15][CH:16]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])[CH3:17])([CH3:14])[CH3:13].C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[CH:16]([NH:15][CH:12]([CH3:14])[CH3:13])[CH3:17])=[O:10]
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: CC(C)NC(C)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nn(C)c(F)c1C(=O)Nc1ccccc1C(C)NC(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 0.27 g (1.5 mmol) 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 10 ml dichloromethane is added dropwise to a solution of 0.27 g (1.5 mmol) 2-[1-(isopropylamino)ethyl]aniline (III-4) and 0.42 ml (3.0 mmol) triethylamine in 5 ml dichloromethane. The reaction mixture is stirred for 2 hours at 50° C. and thereafter for 16 hours at room temperature. The reaction mixture is worked up by adding it to water, then the organic phase is dried over magnesium sulfate and concentrated under vacuum. Column chromatography (4:1 hexane/acetone) yielded 0.27 g (56% of the theoretical yield) 5-fluoro-N-{2-[1-(isopropylamino)ethyl]phenyl}-1,3-dimethyl-1H-pyrazole-4-carboxamide [log P (pH 2.3)=0.58].
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])S[C:7]=1[NH2:13])=[O:5])C.CO[C:16]1[NH:17][CH2:18][CH2:19][CH:20]=1.P(Cl)(Cl)(Cl)=O>[Ni]>[CH3:11][CH:10]([C:6]1[C:4](=[O:5])[N:17]2[CH2:18][CH2:19][CH2:20][C:16]2=[N:13][CH:7]=1)[CH2:9][CH3:12]
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: COC1=CCCN1
Agent: [Ni]
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)c1cnc2n(c1=O)CCC2
Yield: 36.5 %

Procedure:
According to Khim. Geterosikl. Soedin. 6, 765, 1975 ethyl-2-amino-4,5-dimethyl-thiophene-3-carboxylate is reacted with 2-methoxy-pyrroline in the presence of phosphoryl chloride and the obtained 2,3-dimethyl-4-oxo-5,6-tetramethylene-4H thieno[2,3-d]pyrimidine is desulphurated in an alcoholic solution wih Raney-nickel and thus 3-(1-methyl-propyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrimidine is obtained. In the complicated two-step synthesis the pyrrolo-pyrimidine derivative is obtained with a yield of 36.5%.
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](OBr)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26]>>[CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:12][C:11]=1[OH:17])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: CC(C)CCCCCCCOBr
Product: CC(C)CCCCCCCOc1ccc(C(=O)Cc2ccccc2)c(O)c1

Procedure:
The 2-hydroxy-4-isodecyloxyphenyl benzyl ketone was prepared by alkylation of 2,4-dihydroxyphenyl benzyl ketone with isodecyloxy bromide as follows:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][C:10]#[N:11].[Li].O.[OH-].[Na+]>CCOCC>[NH2:11][CH2:10][CH2:9][CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(CC#N)OC1CCCCO1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CCN)OC1CCCCO1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 3-(tetrahydro-2H-pyran-2-yloxy)caprylonitrile (4.05 g., 18 millimole) in dry ether (10 ml.) is added dropwise to a stirred suspension of lithium aluminumhydride (0.76 g., 20 millimole) in dry ether (90 ml.) maintained under a nitrogen atmosphere. Upon completing the addition, the reaction mixture is stirred and heated at reflux for 16 hours. After cooling to 25° C., the reaction mixture is treated successively with water (1 ml.) and 5% aqueous sodium hydroxide (3 ml.) added dropwise with caution, affording a fine suspension which is cooled to and maintained at 0°-5° C. for 30 minutes and filtered. In vacuo evaporation of the solvent leaves the title compound as a pale yellow oil (3.95 g., 95%), pmr (CDCl 3) δ 0.88 (3H, t), 2.79 (2H, m) and 4.68 (H, bs).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:18][C:17](=[O:27])[C@@H:16]([NH:28]C(OC(C)(C)C)=O)[CH2:15][C:14]2=[CH:36][CH:37]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[ClH:38]>O1CCOCC1>[ClH:38].[CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:18][C:17](=[O:27])[C@@H:16]([NH2:28])[CH2:15][C:14]2=[CH:36][CH:37]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl ester 5 (0.340 g, 0.654 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL). The solution was stirred at rt for 16 h before being concentrated in vacuo to yield a brown solid, 0.232 g, 78%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][NH2:12])=[CH:4][C:3]=2[O:2]1.[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([N:22]=[C:23]=[O:24])=[CH:16][C:15]=2[O:14]1>C1C=CC=CC=1>[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([NH:22][C:23]([NH:12][CH2:11][CH2:10][C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[O:24])=[CH:16][C:15]=2[O:14]1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: O=C(NCCc1ccc2c(c1)OCO2)Nc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-methylenedioxyphenylethylamine (0.25 g, 1.5 mmol) and 3,4-methylenedioxy-phenyl isocyanate (0.25 g, 1.5 mmol) in benzene (25 ml) was refluxed for 1 hour. The precipitate formed was filtered, washed with benzene then dried to give pure DC-0078B (0.43 g, 85%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=[CH2:14])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)Oc1cncc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cncc(OC(C)(C)C)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
After dissolving 5.25 g of 2-tert-butoxy-6-chloropyrazine in 80 ml of N,N-dimethylformamide, 9.66 g of tributyl(vinyl)tin and 0.97 g of dichlorobis(triphenylphosphine) palladium (II) were added and the mixture was stirred for 8 hours and 30 minutes at 80° C. under a nitrogen atmosphere. Saturated brine and ethyl acetate were added to the reaction solution, and the insoluble portion was filtered off. The ethyl acetate layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (4.24 g, 85% yield).
Reaction SMILES: [I:1]Cl.[CH3:3][O:4][CH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(=O)(O)[O-].[Na+]>O.Cl>[I:1][C:14]1[C:8]2[S:7][C:6]([CH2:5][O:4][CH3:3])=[N:10][C:9]=2[CH:11]=[CH:12][C:13]=1[NH2:15]
Reactant: ClI
Reactant: COCc1nc2ccc(N)cc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COCc1nc2ccc(N)c(I)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of iodine monochloride in water (1.5 mL) and 12 N hydrochloric acid (0.46 mL) was added 2-methoxymethyl-benzothiazol-6-ylamine (0.5 g, 2.57 mmol) in water (3 mL) and 12 N hydrochloric acid (0.23 mL). The reaction mixture stirred at RT for 2 h and was then neutralized with saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification of the residue by column chromatography (20 to 30% ethyl acetate:hexanes) afforded 800 mg (91%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.74 (d, J=8.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 1H), 4.77 (s, 2H), 4.23 (br. s, 2H), 3.53 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:19]=[CH:18][C:11]([CH:12]=[CH:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1>CO.[OH-].[Na+]>[CH3:7][C:4]1[N:3]([C:8]2[CH:19]=[CH:18][C:11](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)C=Cc1ccc(-n2c(C)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)O)cc1

Procedure:
A mixture of 21.4 g of methyl 4-aminocinnamate and 50 g of acetonylacetone in 500 ml of toluene is heated under reflux using a Dean Stark water separator for 16 hours. The solution is washed with ice cold dilute hydrochloric acid, brine, and then dried over magnesium sulfate. The organic phase is filtered through silica gel, evaporated at 60° under reduced pressure and the residue is crystallized from hexane to yield methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamate, m.p. 73°-75°. A solution of the ester in 150 ml of methanol and 100 ml 1N aqueous sodium hydroxide is stirred at room temperature for 16 hours. Methanol is evaporated at 60° under reduced pressure. The basic solution is washed with ethyl acetate, then made acidic with ice cold 5N aqueous hydroxhloric acid, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, treated with charcoal, and evaporated to dryness at 60° under reduced pressure. The residue is crystallized from ether/hexane (2:1) to yield (E)-4-(2,5-di-methyl-1H-pyrrol-1-yl)-cinnamic acid, m.p. 189°-191°, also named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid.
Reaction SMILES: [CH:1](O)=O.[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH:15]1[C:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=2[CH:26]=1)=[O:21])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C=O.[OH-].[Na+]>O>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH3:1])[CH2:16][CH:15]1[C:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:25]=2[CH:26]=1)=[O:21])=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=CO
Reactant: O=C(c1cc2cc(F)ccc2o1)C1CNCCN1C(=O)OCc1ccccc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCN(C(=O)OCc2ccccc2)C(C(=O)c2cc3cc(F)ccc3o2)C1
Yield: 96 %

Procedure:
97% Formic acid (0.19 g, 4 mmol) was added to a stirred mixture of (RS)-2-[1-(5-fluoro-benzofuran-2-yl)methanoyl]-piperazine-1-carboxylic acid benzyl ester, D49 (0.57 g, 1.5 mmol) in water (5 ml). Stirring was continued as a 37% formaldehyde solution in water (0.155 g) was added. The resultant mixture was heated at 100° C. for 3.5 h, cooled, diluted with water (30 ml) and basified with 2N sodium hydroxide. The mixture was extracted with ethyl acetate (2×) and the combined extracts dried (Na2SO4) and the solvent removed in vacuo to afford the title compound (0.57 g, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].CC([N+:22]([O-])=O)(C)C.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10](=[O:12])[CH3:11])[N:22]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Nc1cc(Br)cnc1C
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2ncc(Br)cc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
A solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (2.8 g, 12 mmol) and potassium acetate (3.59 g, 36.6 mmol) in toluene (50 mL) was heated at 80° C. under nitrogen. After 30 min, 2-methyl-2-nitropropane (3.77 g, 36.6 mmol) and acetic anhydride (3.73 g, 36.6 mmol) were added, and the resulting mixture was stirred at 80° C. for another 18 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (50 mL). The aqueous mixture was extracted with ethyl acetate (3×60 mL). The collected organic extractions were concentrated in vacuo. Purification by flash column chromatography (5→10% ethyl acetate in petroleum ether) afforded 1-(6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)ethanone (1.4 g, 48.% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1 H), 8.75 (s, 1 H), 8.32 (s, 1 H), 2.79 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1)=[O:13].I[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:31][CH:30]=1>>[CH3:24][O:23][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([NH:14][C:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[O:1][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:31][CH:30]=2)[C:6]([O:8][CH3:9])=[O:7])=[O:13])[CH2:16]1)=[O:22]
Reactant: ICCOc1ccc(/C=C\CCCOc2ccccc2)cc1
Reactant: COC(=O)c1ccc(O)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCOc2ccc(/C=C\CCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Preparation takes place in analogy to Example 22 from the (+)-B-enantiomer of methyl 4-hydroxy-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate (see Example IX, method 2) and 1-(2-iodoethoxy)-4-[(1Z)-5-phenoxypent-1-en-1-yl]benzene.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[N:13][OH:14])[CH2:9][CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28]Br)[CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:14][N:13]=[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: ON=C1CCCC=C1c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCC=C2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 336 h
Yield: 37.2 %

Procedure:
A mixture of the above oxime (0.55 g, 2.9 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (1.0 g, 2.9 mmol, EP 374801A), potassium carbonate (1.0 g, 7.3 mmol) and acetone (25 ml) was stirred at ambient temperature for 14 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (125 g, heptane/ethyl acetate=1/1) to give 0.4 g of (R)-1-(2-(((2-phenylcyclohex-2-enylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:29])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH3:27])([CH3:26])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[C:9]([Cl:28])[CH:8]=1)=[O:5].[C:30](OCC)(OCC)(OCC)[CH3:31]>>[Cl:28][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:29])[N:1]=[C:30]2[CH3:31])[CH:12]=[CH:11][C:10]=1[NH:13][C:14]([CH3:26])([CH3:27])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: C/C(N)=C/C(=O)Nc1ccc(NC(C)(C)Cc2ccc3ccccc3c2)c(Cl)c1
Product: Cc1cc(=O)n(-c2ccc(NC(C)(C)Cc3ccc4ccccc4c3)c(Cl)c2)c(C)n1
Temperature: 150 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
A mixture of (Z)-3-amino-N-(3-chloro-4-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino)phenyl)but-2-enamide and (2.0 g, 4.90 mmol) and triethyl orthoacetate (20 mL) was stirred at 150° C. for 12 h. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (1.59 g, 76%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:17]([OH:19])=[O:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].O=S(Cl)Cl.[CH3:31][CH2:32]O>>[NH2:1][C@H:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])[C:17]([O:19][CH2:31][CH3:32])=[O:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](N)CCCNC(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 55 %

Procedure:
Boc-Orn(Z)—OH (1 equivalent, 0.4 g, 1.1 mmol) was dissolved in EtOH (4 mL). The reaction mixture was cooled at −10° C., and SOCl2 (1.5 equivalent, 119 μl, 1.65 mmol) was added dropwise. The mixture was allowed to warm to room temperature, then heated at 40° C. for 20 h (TLC control). The reaction mixture was concentrated and the crude was purified by flash chromatography (CH2Cl2/MeOH) to afford the compound 188 (178 mg, 55%) as a white solid Rf=0.23 (CH2Cl2/MeOH 90/10). 1H NMR (300 MHz, CDCl3): δ 7.37-7.27 (m, 5H), 5.54 (broad s, 1H), 5.05 (s, 2H), 4.17 (q, J=6.9 Hz, 2H), 3.95 (broad s, 1H), 3.30-3.13 (m, 2H), 2.10-1.85 (m, 2H), 1.85-1.55 (m, 2H), 1.22 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:29]([O-])=O)[CH:3]=1.C(=O)(O)[O-].[Na+].O>CO.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:29][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]=1[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[O:27][CH3:28])[C:13](=[O:17])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)N(Cc1ccc(OC)cc1OC)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: [Ti+3]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CCOC(=O)N(Cc1ccc(OC)cc1OC)c1c(N)cc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.1 %

Procedure:
To a solution of ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenyl(2,4-dimethoxybenzyl)carbamate (1.204 g) in methanol (90 ml) was added titanium(III) chloride solution (20% wt) (31.5595 g) in an ice bath. The reaction mixture was stirred for 20 minutes at 0° C. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and water, and the mixture was extracted 5 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1.1345 g, quantitative yield).
Reaction SMILES: [BH4-].[Na+].C(COC)OC.[C:9]([O:19][C:20]([C:26]([O:29][C:30]([C:36]([O:39][C:40]([C:46]([O:49][C:50]([C:56]([O:59][C:60]([C:66]([O:69][C:70]([C:76](OC)=[O:77])([C:72]([F:75])([F:74])[F:73])[F:71])([F:68])[F:67])([C:62]([F:65])([F:64])[F:63])[F:61])([F:58])[F:57])([C:52]([F:55])([F:54])[F:53])[F:51])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[F:41])([F:38])[F:37])([C:32]([F:35])([F:34])[F:33])[F:31])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[F:21])([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10].Cl>O.CO>[C:9]([O:19][C:20]([C:26]([O:29][C:30]([C:36]([O:39][C:40]([C:46]([O:49][C:50]([C:56]([O:59][C:60]([C:66]([O:69][C:70]([CH2:76][OH:77])([C:72]([F:73])([F:74])[F:75])[F:71])([F:67])[F:68])([C:62]([F:63])([F:64])[F:65])[F:61])([F:58])[F:57])([C:52]([F:53])([F:54])[F:55])[F:51])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[F:41])([F:38])[F:37])([C:32]([F:35])([F:34])[F:33])[F:31])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[F:21])([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10]
Reactant: COC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A stirred mixture of 30 g NaBH4 (Aldrich), 50 mL HFE, and 400 mL dry dimethoxyethane was treated over 6 hours with 1000 g C3F7O(CF(CF3)CF2O)5CF(CF3)COOCH3, resulting in an exotherm, and the mixture was stirred at 50° C. overnight. After cooling, the mixture was cautiously treated with first 50 mL MeOH and then 75 mL 5% HCl, with the first few mL of HCl causing vigorous foaming. Addition of 300 mL water, filtration of some white solid at the interphase, and stripping the lower layer gave 931 g C3F7O(CF(CF3)CF2O)5CF(CF3)CH2OH. A solution of 322 g of this and 38.9 g diisopropylethylamine (Aldrich) in 150 mL HFE was treated dropwise with 25.0 g acryloyl chloride (Aldrich), forming a white solid. This was stirred overnight at 50° C., cooled, treated with 4 mL water, 5.0 g K2CO3, and 25 g silica gel, waiting about 2 hours between each addition. The mixture was filtered and stripped to give 297.5 g of HFPO-5-DHA.