Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:36]([CH3:37])=[CH:35][CH:34]=[N:33]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:38])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:38])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[C:36]([CH3:37])=[CH:35][CH:34]=[N:33]4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3nccc3C)cc2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc(Cn3nccc3C)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {4,6-Dimethyl-5-[({1-[4-(5-methyl-pyrazol-1-ylmethyl)-benzyl]-1H-[1,2,3]triazole-4-carbonyl}-amino)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (132 mg, 0.249 mmol) and 5 mL of TFA in 10 mL of DCM was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire Prep C18 OBD 5 μm 30×100 mm, Flow 40 mL/min, ACN/water (0.1% TFA) 5/95 over 2 min, then ACN/water (0.1% TFA) 5/95-100/0 over 15 min) to yield the title compound. 1H-NMR (DMSO-d6, 600 MHz) 8.59 (s, 1H), 8.29 (t, 1H), 7.33 (s, 1H), 7.28 (d, 2H), 7.09 (d, 2H), 6.09 (s, 1H), 6.05 (s, 1H), 5.63 (s, 2H), 5.59 (s, 2H), 5.26 (s, 2H), 4.32 (d, 2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H); [M+H]+=431.0.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])=[O:12])(C(C)(C)C)(C)C.[Cl-].[NH4+]>C(O)(=O)C.C1COCC1.O>[OH:8][CH2:9][CH2:10][C:11]([C@@H:13]1[CH2:17][S:16][CH2:15][N:14]1[C:18]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:19])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)OCCC(=O)[C@@H]1CSCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCO)[C@@H]1CSCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.3 %

Procedure:
(R)-4-[3-(tert-Butyldimethylsilyloxy)-1-oxopropyl]-3-[[(S)-1-(phenylmethyloxycarbonyl)-2-pyrrolidinyl]carbonyl]thiazolidine (215 mg) was dissolved in a mixture of acetic acid-THF-water (3:1:1, 3 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated ammonium chloride and extracted with chloroform. The organic layer was washed with water, saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (silica gel, developing solvent: chloroform-methanol) to give the title compound (97 mg) (see Table 5).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][C:15]([OH:17])=O)[C:6](=[O:7])[N:5](CC(F)(F)F)[C:4](=[O:13])[NH:3]1.[C:18]1([C:24]2[CH:37]=[CH:36][C:27]3[N:28]=[C:29]([CH2:31][C:32]([NH:34][NH2:35])=O)[S:30][C:26]=3[CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[CH3:1][C:2]1([CH2:14][C:15]2[O:17][C:32]([CH2:31][C:29]3[S:30][C:26]4[CH:25]=[C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:37]=[CH:36][C:27]=4[N:28]=3)=[N:34][N:35]=2)[NH:3][C:4](=[O:13])[NH:5][C:6]1=[O:7]
Reactant: CC1(CC(=O)O)NC(=O)N(CC(F)(F)F)C1=O
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Cc2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)NC(=O)NC1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a solution of Compound 31b (613 mg, 2.22 mmol) in dioxane (10 mL) was added 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (723 mg, 2.22 mmol), (described in WO 2011/074560), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (3.30 mL, 5.55 mmol) and DIPEA (1.0 mL, 5.55 mmol). The reaction mixture was stirred at 90° C. for 3 h. 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in EtOAc) (3.30 mL, 5.55 mmol) and DIPEA (1.0 mL, 5.55 mmol) were added. The reaction mixture was heated at 90° C. for 14 h. The reaction mixture was diluted with DCM, and the solution washed with 1.5 M potassium phosphate solution and 1.0 M HCl and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude residue. The crude residue was dissolved in DCM, loaded on CELITE, charged to a 80 g silica gel cartridge which was eluted with a 40 min gradient from 0-10% MeOH/DCM to give racemic 5-methyl-5-((5-((6-phenylbenzo[d]thiazol-2-yl)methyl)-1,3,4-oxadiazol-2-yl)methyl)imidazolidine-2,4-dione (943 mg, 1.88 mmol, 85% yield) as a brown solid. The enantiomers were separated by SFC separation (Berger Prep SFC; column: Lux Cellulose-4, 30×250 mm ID, 5 μm; Flow rate: 100 mL/min, 150 bar BP, 40° C.; Mobile Phase: 25% Isopropanol/75% CO2; Wavelength: 220 nm) to afford Isomer A as Compound 31c (414 mg, 0.817 mmol, 36.8%). LCMS=2.0 min using analytical method (B), 502.1 (M+H). Analytical SFC RT=7.8 min (Instrument, Berger SFC; Column: Lux Cellulose-4, 4.6×250 mm ID, 5 μm; Flow rate: 3 mL/min, 150 bar BP, 35° C.; Mobile Phase: 20% Isopropanol/80% CO2; 220 nm). 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.43 (d, J=1.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.83 (dd, J=8.5, 1.8 Hz, 1H), 7.78-7.68 (m, 2H), 7.54-7.46 (m, 2H), 7.44-7.34 (m, 1H), 4.86 (d, J=1.3 Hz, 2H), 4.10 (q, J=9.2 Hz, 2H), 3.34 (t, J=15.6 Hz, 2H), 1.46 (s, 3H) and Isomer B (Rt=12.8 min, 45 mg, 13% yield), LCMS=1.77 min using analytical method (B), 440.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([O:11]C(C)(C)C)=[O:10])=[O:4].Br.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.C(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]([CH2:5][O:6][N:7]=[C:8]([C:16](=[O:18])[CH3:17])[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)CON=C(C(C)=O)C(=O)OC(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)CON=C(C(C)=O)C(=O)O
Yield: 51 %

Procedure:
To a solution of tert-butyl 2-methoxycarbonylmethoxyimino-3-oxobutyrate (syn isomer) (10 g) in glacial acetic acid (5 ml) was added 30% hydrobromic acid in acetic acid (10 ml) at ambient temperature with stirring. The reaction mixture was stirred at 40° C. for 3 hours. The resultant solution was concentrated under reduced pressure and the residual oil was dissolved into ethyl acetate (100 ml). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride four times and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude oil (8.6 g). The oil was dissolved in methylene chloride (100 ml). To the solution was added potassium carbonate (1.87 g) and the suspension was stirred at ambient temperature for 30 minutes. The solution was diluted with n-hexane (100 ml.) The solvent was decanted and the residual glassy mass was dissolved in ethyl acetate and 10% hydrochloric acid. The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (4.0 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: Cc1ccc(F)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-fluoro-2-methyl-pyridine (0.75 g) (J. Med. Chem. 1989, 32, 1970) in CCl4 (25 ml) is added N-bromosuccinimide (0.96 g; 5.4 mmol) and benzoyl peroxide (200 mg; 0.8 mmol). The mixture is heated at reflux for 3 h, cooled to RT and stirred for additional 12 h. The suspension is filtered through celite and the filtrate is washed with Na2SO4, dried over MgSO4 and evaporated. The crude material (0.22 g) containing approximately 50% of the dibrominated species is used without further purification.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6]>O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Yield: 34464.9 %

Procedure:
A mixture of 2-keto-L-gulonic acid (125 g, 0.579 mol, content: 89.9%, water: 8.7%) and trimethylcetylammonium chloride (0.137 g) was stirred in toluene (240 ml) and diisopropyl ether (170 ml), and 36% conc. hydrochloric acid (15.6 g) was added. At this time, the amount of water in the reaction system was calculated as 2.0 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (15.5 g) in diisopropyl ether (70 ml) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 500 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (720 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by HPLC showed that the solution contained L-ascorbic acid (93.8 g, yield: 92.0%) and 2-keto-L-gulonic acid (0.3 g, residual ratio: 0.3%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N-:14]=[N+]=[N-].[Na+]>C(#N)C.C1COCC1>[NH2:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: [N-]=[N+]=[N-]
Reactant: OCCCCCCCCCCCBr
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: NCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11-bromoundecan-1-ol (the compound 31) (15.1 g) was dissolved in 250 ml of acetonitrile, and 15.7 g of sodium azide was added to that, followed by 18-hour reaction caused by refluxing. After cooled down to room temperature, the solid components were removed by filtration. The solvent of the filtrate was distilled away under reduced pressure, to obtain 13.9 g of a transparent, viscous liquid. Of this liquid, 8.34 g was dissolved in 60 ml of THF distilled from calcium hydride in a nitrogen atmosphere, and was cooled in an ice bath. Lithium aluminum hydride (2.53 g) was then dried, and was dissolved in 250 ml of THF. The resultant was dripped, and was then stirred in an ice bath for one hour. After that, 2.5 ml of ion-exchange water, 3.5 ml of 15 wt % aqueous sodium hydride solution, and 7.5 ml of ion-exchange water were added so as to stop reactions. The precipitate generated was removed by filtration, and the solvent of the filtrate was distilled away under reduced pressure. After the filtrate was dried under reduced pressure, the dried filtrate was dissolved in 60 ml of THF, and the same volume of heptane was added to that. The precipitate generated was collected by filtration, to obtain 5.1 g of a white solid 32.
Reaction SMILES: O.Cl.[N+:3]([O-:6])([O-])=[O:4].[Na+].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1>ClCCl.C(OCC)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:14]=1[N+:3]([O-:6])=[O:4]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Cc1ccc(O)c([N+](=O)[O-])c1)Oc1ccccc1
Reaction time: 2.5 h
Yield: 80.8 %

Procedure:
Water (2.5 ml), concentrated aqueous hydrogen chloride solution (1.17 ml) and sodium nitrate (297 mg) were added to a solution of ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate (1.00 g), which is the product of Reference example 4(c), in a mixture of dichloromethane (4.0 ml) and diethyl ether (8.0 ml) at ambient temperature. The mixture was stirred for 2.5 hours at the same temperature and allowed to stand for 14 hours. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (935 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][NH:11][CH2:12][CH2:13][OH:14])[CH:3]=[CH:2]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCCl>[CH2:26]([O:25][C:23](=[O:24])[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCNCc1cccc2cc[nH]c12
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N(CCO)Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
To a solution of 2-[(1H-indol-7-ylmethyl)-amino]-ethanol (4.4 g) in 1,2-dichloroethane (40 mL) was added triethylamine (4.85 mL, 34.6 mmol) followed by benzyl chloroformate (3.57 mL, 25.34 mmol). The mixture was allowed to stir at room temperature for 2 hours. The mixture was quenched by addition of water (20 mL), and 1.0 M sodium hydroxide (10 mL). The organic layer was separated and the aqueous layer extracted with 1,2-dichloroethane (20 mL). The combined organic extracts were washed with 1.0 M hydrochloric acid (20 mL), water (20 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to afford (2-hydroxy-ethyl)-(1H-indol-7-ylmethyl)-carbamic acid benzyl ester (2.79 g, 52% combined yield for two steps) as a colorless oil. 1H NMR (CDCl3) 400 MHz δ: 9.97 (br s, 1H), 7.75-6.9 (m, 8H), 6.54 (br s, 1H), 5.21 (s, 2H), 4.9-4.6 (m, 3H), 3.85-3.57 (m, 2H), 3.55-3.23 (m, 3H); LCMS M+H=325.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([F:32])([F:31])[F:30])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[NH:19][C:18]3[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15]([C:24]#N)=[N:14][C:13]=3[N:12]=2)[CH:8]=[N:7]1.[OH-:33].[Na+].C(O)C.[OH2:38]>>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[C:29]([F:31])([F:30])[F:32])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[NH:19][C:18]3[C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH3:23])[C:15]([C:24]([OH:38])=[O:33])=[N:14][C:13]=3[N:12]=2)[CH:8]=[N:7]1
Reactant: CCCn1c(C#N)nc2nc(-c3cnn(Cc4ccc(C(F)(F)F)c(F)c4)c3)[nH]c2c1=O
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: CCCn1c(C(=O)O)nc2nc(-c3cnn(Cc4ccc(C(F)(F)F)c(F)c4)c3)[nH]c2c1=O
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A mixture of 8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-prop yl-6,7-dihydro-1H-purine-2-carbonitrile (65 mg, 0.145 mmol), NaOH (11 mg, 0.290 mmol) and Ethanol:water (3:1) (6 ml) were stirred at 55-60° C. for 2 hours. Reaction mixture was cooled and organic volatiles were evaporated and to the residue water (2 ml) was added and acidified by 2N HCl upto pH (1-2), solid filtered off. The crude product was purified by preparative HPLC to obtain pure 8-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6-oxo-1-propyl-6,7-dihydro-1H-purine-2-carboxylic acid (21 mg, 31%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:15])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23](=[O:24])[NH:15][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N:8]2[CH2:13][CH:12]3[CH:10]([O:11]3)[CH2:9]2)=[C:2]([F:1])[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(F)c(N2CC3OC3C2)c(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(F)c(N2CC3OC3C2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3,5-Difluoro-4-(6-oxa-3-aza-bicyclo[3.1.0]hex-3-yl)-phenylamine (0.14 g, 0.66 mmol) was dissolved in dichloromethane (1.0 mL) and pyridine (0.11 mL, 1.32 mmol) and stirred at 0° C. Benzyl chloroformate (0.1 mL, 0.72 mmol) was added and the mixture was stirred at 0° C. for one hour. The reaction mixture was allowed to warm to room temperature, washed with water, brine and dried (MgSO4). The title compound was isolated by silica gel chromatography (0-1% MeOH-DCM) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:24][CH:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:27][CH2:26][CH:25]([NH:24][C:1](=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22])[CH3:35]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate (2.10 g, 4.34 mmol) in DCM (100 mL) at 0° C. was slowly added TFA (30 mL). The mixture was stirred (0° C., 2 h), warmed to RT and stirred (16 h). The mixture was basified to pH=10 with saturated aqueous Na2CO3 and extracted with EA (2×200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford (4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 98%) as a light yellow oil. Mass calculated for C25H40N2O=384.6. found: [M+H]+=385.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]=[O:11])=[CH:4][CH:3]=1.CC(C)=[O:14].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=CCCc1ccc(O)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
0.79 g (5.19 mmoles) of 3-(4-hydroxyphenyl)-1-propanal were dissolved in acetone (20 ml) and Jones reagent (chromic anhydride in sulphuric acid) (8 ml) was added to it drop by drop until the yellow-brown colour persisted. The solution was stirred for one hour at 0° C. The excess reagent was destroyed with methanol and the solution was filtered and evaporated at reduced pressure. The residue was extracted in ethyl acetate, dried over anhydrous sodium sulphate and concentrated, diving an impure residue (0.6470 g), which was chromatographed over silica gel, obtaining 0.545 g (63.1% yield) of 3-(4-hydroxyphenyl) propionic acid. Recrystallisation in methanol gave m.p.=121° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1.C(O)C.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][O:17][C:14](=[O:16])[CH3:15])=[N:7][CH:8]=1
Reactant: COc1ccc(C)[n+]([O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1ccc(COC(C)=O)nc1
Temperature: 115 °C

Procedure:
5-Methoxy-2-methyl-pyridine 1-oxide (9.25 g, 66.5 mmol) was suspended in acetic anhydride (31 ml) under an argon atmosphere. The mixture was heated to ca.115° C. and this temperature was maintained for a further 5 h and the mixture turned black. Ethanol (2.5 ml) was added and the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with 10% K2CO3 and water. The aqueous phases were back extracted with ethyl acetate and the combined organic phases were dried (MgSO4) filtered and concentrate under reduced pressure. The crude oil was purified using Kugelrohr distillation (90-100° C./0.1 mbar) yielding a colorless oil: 10.7 g (80%); 1H NMR (CDCl3) δ 2.13 (s, 3H), 3.86 (s, 3H), 5.16 (s, 2H), 7.18-7.31 (m, 2H), 8.30 (d, 1H) MS: m/e=181.2 (M), 138.0 (M−COCH3)
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7](=[O:9])[CH3:8].[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(OCC)C>[C:24]([O:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:7](=[O:9])[CH3:8])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)C(C)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[N-(4-hydroxynonyl)acetamido]-heptanoic acid (9.8 g., 0.03 mole) (Example 1, Step C) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and taken up in 80 ml. of ethyl ether. The solution is extracted with and ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatoraphy on slica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-[N-(4-acetoxynonyl)acetamido]heptanoic acid as a viscous oil.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([CH2:14][OH:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:17]([CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH:21]1[C:26]([O:28][CH3:29])=[O:27])[CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl.Cl.[Cl-].[Na+]>[CH3:29][O:28][C:26]([CH:21]1[CH:20]([CH2:17][CH2:18][CH3:19])[CH2:25][CH2:24][CH2:23][N:22]1[S:2]([NH:5][C:6]([O:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])(=[O:4])=[O:3])=[O:27]
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCC1CCCNC1C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CCCN(S(=O)(=O)NC(=O)OCc2ccccc2)C1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred solution of 3.01 ml (34.72 mmol) of chlorosulfonyl isocyanate in 200 ml of dry methylene chloride was added phenylmethanol (3.61 ml, 34.72 mmol) at 0° C. After stirring the above solution for 1 hour at this temperature, a solution of 7.3 g (33.07 mmol) of methyl 3-propyl-piperidine-2-carboxylate hydrochloride in methylene chloride containing triethylamine (13.75 ml; 99.21 mmol) was added at 0° C., and the resulting mixture was stirred overnight (17 hours) allowing the mixture to warm to room temperature. The reaction mixture was diluted with the same volume of methylene chloride and 200 ml of 10% aq. HCl solution, saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with methylene chloride and the combined organic layer was washed with brine, dried and concentrated in vacuo. The residual oil was purified by flash chromatography (30% ethyl acetate in hexane) to yield 11.43 g (86.7%) of N-(carbobenzyloxyaminosulfonyl)-3-propyl-2-piperidinecarboxylic acid methyl ester(Formula XIV: R=CH3;R1 =H; R2 and R3 together =-[CH(propyl)(CH2)3 ]-) as an oil.