Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([O:16]CC)=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:19](O)(=O)[CH3:20]>N1CCCCC1>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:5]3[CH2:20][CH2:19][CH2:2][CH2:3][CH2:4]3)=[O:16])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1ccc(CN2CCC(O)CC2)o1
Solvent: C1CCNCC1
Product: O=C(c1ccc(CN2CCC(O)CC2)o1)N1CCCCC1
Yield: 151.8 %

Procedure:
In 30 ml of piperidine was dissolved 7.4 g (29.25 mmol) of Compound s followed by addition of 2.7 g (45 mmol) of acetic acid, and the mixture was heated under reflux for 27 hours. After cooling, the excess piperidine was distilled off under reduced pressure and the residue was diluted with 300 ml of chloroform and washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel column chromatography (acetone) to give 6.49 g (76.0%) of 1-[5-(4-hydroxypiperidinomethyl)-2-furancarbonyl]piperidine (Compound t) as light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)=CCBr
Product: CC(C)=CCSc1ccc(Br)cc1
Yield: 91.5 %

Procedure:
In a manner similar to that of Example 34(h), by reaction of 30.00 g (159.0 mmol) of 4-bromo-thiophenol with 26.00 g (175.0 mmol) of 1-bromo-3-methyl-2-butene, 37.40 g (93%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].[CH3:7][N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[OH-].[Na+]>O.C1C=CC=CC=1>[CH3:7][N:8]1[C:12](=[O:13])[NH:6][CH:2]([CH2:3][CH3:4])[NH:5][C:9]1=[O:10]
Reactant: CCC(=N)N
Reactant: CN(C(=O)Cl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCC1NC(=O)N(C)C(=O)N1
Yield: 49.6 %

Procedure:
10.9 g (0.1 mole) of propionamidine hydrochloride were suspended in 125 ml of water and 200 ml of benzene. 15.6 g (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 18 g (0.45 mole) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from two dropping funnels, with vigorous stirring. The reaction took place exothermically. The mixture was stirred for a further hour, the aqueous phase was separated off and acidified with glacial acetic acid and the mixture was evaporated in vacuo. The residue was repeatedly extracted by boiling with ethyl acetate. The solution was concentrated in vacuo and cooled. The precipitate was filtered off. 7.8 g (50%) of 1-methyl-4-ethyl-tetrahydro-1,3,5-triazine-2,6-dione were obtained as colorless needles of melting point 202°-203° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[CH:2]=1.C(Cl)Cl>O.[Fe]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])[CH:2]=1
Reactant: O=[N+]([O-])c1cccc(Oc2cccnc2)c1
Agent: [Fe]
Solvent: O
Solvent: ClCCl
Product: Nc1cccc(Oc2cccnc2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The 3-(3-pyridyloxy)aniline is prepared as follows: ferric chloride (0.4 g) is added, at a temperature between 90° and 98° C., to a suspension of 3-(3-pyridyloxy)nitrobenzene (16.2 g) and iron powder (37.5 g) in distilled water (40 cc) which is heated to a temperature in the vicinity of 90° C. The suspension obtained is heated at a temperature in the vicinity of 98° C. for 1 hour and 15 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours, treated with methylene chloride (550 cc) and distilled water (75 cc) and filtered. The organic phase is separated, dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude oil (13.1 g) is thereby obtained which is chromatographed on a 6 cm diameter column containing silica (0.02-0.045 mm; 450 g). Elution is carried out with mixtures of ethyl acetate and cyclohexane at a pressure of 0.4 bar (40 kPa), collecting 150 cc fractions. The first 15 fractions originating from elution with an ethyl acetate:cyclohexane (50:50 by volume) mixture are discarded. The following 5 fractions originating from elution with an ethyl acetate:cyclohexane (50:50 by volume) mixture and the following 5 fractions originating from elution with pure ethyl acetate are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. 3-(3-pyridyloxy)aniline in the form of an orange-yellow liquid [Rf=0.25; silica gel thin layer chromatography; eluant: cyclohexane:ethyl acetate (50:50 by volume)] is thereby obtained.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:9]([N:14]1[CH:13]=[C:12]2[C:7](=[CH:8][CH:9]([C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:27][CH:28]=3)[C:10](=[O:22])[NH:11]2)[C:6]([OH:35])=[C:5]1[C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(N4CCOCC4)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)C1=C(O)C2=CC(c3ccc(N4CCOCC4)cc3)C(=O)NC2=CN1Cc1ccccc1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-morpholin-4-yl-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (44 mg, 0.093 mmol), β-alanine (666 mg, 7.5 mmol) and NaOMe solution (11 mL, 5.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The organic layer was washed with brine, dried over MgSO4, and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 32 mg of the title compound. MS: (+) m/z 529.34 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)(=[O:5])=[O:4]>C(O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([NH:6][S:3]([C:2]([F:17])([F:1])[F:16])(=[O:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(NS(=O)(=O)C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(NS(=O)(=O)C(F)(F)F)c1
Yield: 99 %

Procedure:
1,1,1-trifluoro-N-(3-nitrophenyl)methanesulfonamide 42 (0.5 g, 1.85 mmol) was dissolved in ethanol (20 mL) treated with H2 (30 psi, Parr hydrogenator) for 2 h in the presence of Pd/C (catalytic, 50 mg). The reaction was monitored by TLC until the starting material was no longer detected. The Pd/C residue was removed by filtration over celite pad, followed by rotary evaporation of the solvent obtained 0.44 g of N-(3-aminophenyl)-1,1,1-trifluoromethanesulfonamide 43 (100% yield). The crude product was further used without further purification. MS (ES) m/z 241 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13])=[O:7].CO.O1CCCC1.[CH3:27][S-:28].[Na+]>O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][S:28][CH3:27])=[C:12]([CH3:13])[C:11]=2[CH:14]=1
Reactant: C[S-]
Reactant: COc1ccc2oc(C(=O)CCCCCl)c(C)c2c1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(=O)CCCCSC)c(C)c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a mixture of 5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one (1.30 g) synthesized above, methanol (15 mL) and tetrahydrofuran (15 mL) was added a 15% aqueous solution (4.33 mL) of sodium methanethiolate, and the mixture was stirred at room temperature for 1 hr and at 50° C. for 1 hr. Sodium methanethiolate (325 mg) was additionally added and the mixture was stirred at 50° C. for 1 hr. Sodium methanethiolate (325 mg) was additionally added again, and the mixture was stirred at 50° C. for 1 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (492 mg, 36%) as a yellow solid.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N:27]2[CH2:32][CH2:31][N:30](CCC3C=C(C=CC=3)N)[CH2:29][CH2:28]2)[N:18]=1>>[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][C:5]3[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[CH2:29][CH2:28]2)[N:18]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CS(=O)(=O)Nc1cccc(CCC=O)c1
Product: Cc1ccc2c(N3CCN(CCCc4cccc(NS(C)(=O)=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared from N-[3-(3-oxo-propyl)-phenyl]-methanesulfonamide and of 2-methyl-5-(1-piperazinyl)quinoline (D3) according to the methods in Description 4 and Description 5.
Reaction SMILES: C1(S([CH:10]([C:61]2[C:66]([CH3:68])([CH3:67])[CH2:65][CH2:64][CH2:63][C:62]=2[CH3:69])[CH:11](O)[C:12]([CH3:59])=[CH:13][CH2:14][CH2:15][C:16]([CH3:58])=[CH:17][CH:18](S(C2C=CC=CC=2)(=O)=O)[CH2:19][CH:20]=[C:21]([CH3:48])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:47])[CH:26](O)[CH:27](S(C2C=CC=CC=2)(=O)=O)[C:28]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=2[CH3:36])(=O)=O)C=CC=CC=1.N1C=CC=CC=1.P(Br)(Br)Br>C(Cl)Cl>[CH3:69][C:62]1[CH2:63][CH2:64][CH2:65][C:66]([CH3:67])([CH3:68])[C:61]=1/[CH:10]=[CH:11]/[C:12](/[CH3:59])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:58])=[CH:17]/[CH:18]=[CH:19]/[CH:20]=[C:21](\[CH3:48])/[CH:22]=[CH:23]/[CH:24]=[C:25](\[CH3:47])/[CH:26]=[CH:27]/[C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36]
Reactant: CC(=CCC(C=C(C)CCC=C(C)C(O)C(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1)CCC=C(C)C(O)C(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)CCCC2(C)C)C(C)(C)CCC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of the C40 diol compound (O) (0.13 g, 0.15 mmol) in CH2Cl2 (5 mL) at 0° C. were added pyridine (0.054 mL, 0.60 mmol) and PBr3 (0.011 mL, 0.12 mmol). The mixture was stirred at 0° C. for 40 min, diluted with CH2Cl2 (20 mL), washed with 1 M HCl solution (10 mL×3), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the di-bromination product (P-1) (0.17 g, 0.15 mmol) in 100% crude yield. This compound was not purified and directly utilized in the elimination reaction to produce β-carotene (see Example 15-A).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:19])=[C:14]([CH:18]=1)[C:15]([O:17][CH3:22])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
To a solution of 5-{[(tert-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (1.0 g, 3.50 mmol) in DMF (5.0 mL) were added methyl iodide (496 mg, 3.50 mmol) and K2CO3 (966 mg, 7.00 mmol). The reaction mass was stirred at rt for 18 h. The reaction mass was diluted with EtOAc and the organic layer was washed with water and brine. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 440 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.66 (s, 1H), 7.49-7.52 (m, 2H), 7.42 (d, J=6.3 Hz, 1H), 4.13 (d, J=5.7 Hz, 2H), 3.85 (s, 3H), 1.38 (s, 9H).
Reaction SMILES: C1(C)C=CC(S([C:10]([CH3:23])([CH3:22])[CH:11]([CH:17]([O:20]C)[O:18]C)[CH2:12][C:13]([O:15]C)=O)(=O)=O)=CC=1.CCOCC.[Cl-:30].[Li+].Cl>O>[Cl:30][C:10]([C@H:11]1[C@H:17]([OH:18])[O:20][C:13](=[O:15])[CH2:12]1)([CH3:22])[CH3:23]
Reactant: [Cl-]
Reactant: COC(=O)CC(C(OC)OC)C(C)(C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(Cl)[C@@H]1CC(=O)O[C@H]1O
Temperature: 25 °C
Reaction time: 54 h
Yield: 109.4 %

Procedure:
A mixture of 1 g of the product of Example 2, 25 ml of ether and 1 g of dry lithium chloride was stirred under a current of gaseous hydrogen chloride at -30° C. for 2 hours and then at 0° C. for 2 hours after which the current of gaseous hydrogen chloride was stopped. The mixture was stirred at room temperature for 48 hours and after 54 hours of contact, the mixture was poured into iced water. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The 1.1 g of residue was chromatographed over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to obtain 545 mg of dl trans 4-(2-chloro-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one in the form of crystals melting at 80° C.
Reaction SMILES: [C:1]([N:9]1[C@H:13]([CH3:14])[C:12](=[O:15])[O:11][C@H:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1.[NH4+].[Cl-]>C1COCC1>[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][C@:13]2([CH3:14])[C:12](=[O:15])[O:11][C@@H:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:9]2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:36][CH:35]=1
Reactant: C[C@@H]1C(=O)O[C@@H](c2ccccc2)N1C(=O)c1ccccc1
Reactant: COc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C[C@]2(C)C(=O)O[C@@H](c3ccccc3)N2C(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 80.1 %

Procedure:
Compound 2.2 (6.35 g, 0.023 mol) in 50 mL of THF at −78° C. was added over 20 min to a solution of LHMDS in THF (25 mL of 1 M solution in THF). After 10 min, 1.1 eq. of 4-methoxybenzyl bromide (25 mmol, 5 mL) was added in one portion. The mixture was stirred at −78° C. for 3 h and then room temperature overnight. Saturated NH4Cl solution was added, the THF was removed in vacuo, 100 mL of Et2O was added and the phases were separated. The organic layer was washed with 50 mL of NaHCO3 solution and brine. After drying (Na2SO4), filtration and removal of the solvent, the residue was purified by chromatography using Si Gel ISCO column with 9% EtOAc in Hexanes as eluent. Concentration of the product fractions gave 7.4 g (82%) of 2.3 as a white solid. MP 128-129° C.; [α]25D=−260 (c 0.8, MeOH); 1H NMR δ 7.27 (1H, d, J=8 Hz), 7.19-7.14 (2H, m), 7.09-7.05 (4H, m), 6.94 (d, 2H, J=8 Hz), 6.76-6.72 (m, 4H), 5.68 (s, 1H), 3.88 (d, 1H, J=12 Hz), 3.86 (s, 3H), 3.27 (d, 1H, J=12 Hz), 2.14 (s, 3H); C NMR 175.1, 169.4, 159.6, 136.7, 131.5, 130.1, 130.0, 128.8, 128.7, 128.2, 127.2, 126.3, 114.6, 90.7, 65.9, 55.8, 40.5, 24.6; ESI MS 402 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cccc(O)c1-n1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c1-n1cccc1C1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
To a solution of 3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 16.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.6 g, 18.2 mmol) in dry dichloromethane (57.4 mL) was added TFA (2.5 mL, 33.1 mmol) over a 15 minutes period and the reaction was stirred at 25° C. for 12 hours. Another portion of TFA (2.5 mL, 33.1 mmol) was added at 25° C. and the reaction was stirred for 2 hours after which time a third portion of TFA (2.55 mL, 33.1 mmol) was added and the mixture was stirred at 25° C. for an additional 12 hours. The reaction mixture was diluted with CH2Cl2 (350 ml) and washed with 1M NaOH (50 ml). The organic phase was dried with MgSO4, filtered, evaporated to dryness and the resulting residue was purified by silica gel chromatography eluting with 0.5-40% MeOH in CH2Cl2 to yield 9-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (2.0 g, 48%) obtained as a yellow oil. ESI-MS m/z calc. 254.1, found 255.3 (M+1)+. Retention time: 1.08 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[CH2:16]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:7]1[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Reactant: Nc1ccccc1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccccc1Cc1ccccc1
Yield: 87.2 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.0 g, 0.01 mol) in dry toluene (15 ml) was treated with 2-benzylaniline (1.83 g, 0.01 mol) and a catalytic amount of p-toluenesulfonic acid monohydrate (50 mg), and the mixture was heated at 60° C. for 1.5 h. The reaction was diluted with diethyl ether, and washed with water followed by brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to give the title compound as a brown foam (3.37 g) which was used in the next stage without purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH:9]1[CH2:21][CH2:20][C:19]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH:18]([OH:29])[CH:17]=[CH:16][CH:15]([CH3:30])[CH:14](/[C:31](/[CH3:58])=[CH:32]/[CH:33]=[CH:34]/[C:35]([O:52][CH:53]([O:55][CH2:56][CH3:57])[CH3:54])([CH3:51])[CH2:36][CH:37]2[O:50][CH:38]2[CH:39]([CH3:49])[CH:40]([O:43][CH:44]([O:46][CH2:47][CH3:48])[CH3:45])[CH2:41][CH3:42])[O:13][C:11](=[O:12])[CH2:10]1)[CH3:7])[CH3:4].[CH:59]([N:62]=[C:63]=[S:64])([CH3:61])[CH3:60].O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5][CH:6]([O:8][CH:9]1[CH2:21][CH2:20][C:19]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])([CH3:22])[CH:18]([O:29][C:63](=[S:64])[NH:62][CH:59]([CH3:61])[CH3:60])[CH:17]=[CH:16][CH:15]([CH3:30])[CH:14](/[C:31](/[CH3:58])=[CH:32]/[CH:33]=[CH:34]/[C:35]([O:52][CH:53]([O:55][CH2:56][CH3:57])[CH3:54])([CH3:51])[CH2:36][CH:37]2[O:50][CH:38]2[CH:39]([CH3:49])[CH:40]([O:43][CH:44]([O:46][CH2:47][CH3:48])[CH3:45])[CH2:41][CH3:42])[O:13][C:11](=[O:12])[CH2:10]1)[CH3:7])[CH3:4]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Reactant: CC(C)N=C=S
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=S)NC(C)C)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(=S)NC(C)C)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 2 mg, 0.052 mmol) in tetrahydrofuran (0.5 mL) was added dropwise a solution of (8E,12E,14E)-3,6,16,21-tetra(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (19 mg, 0.019 mmol) obtained in Example 3-(2) in tetrahydrofuran (0.5 mL) under ice-cooling and stirring, and the reaction mixture was stirred at room temperature for 10 minutes. Then, isopropyl isothiocyanate (6.6 mg, 0.066 mmol) was added dropwise thereto, and the reaction mixture was stirred at room temperature for three hours. Water was added to the reaction mixture under ice-cooling to terminate the reaction, followed by diluting with ethyl acetate and washing with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=25:75) to give the title compound (10 mg, 60%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([CH2:13][OH:14])[O:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].N1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([CH2:13][O:14][C:15](=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(CO)CO[Si](C)(C)C(C)(C)C
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CO[Si](C)(C)C(C)(C)C)OC
Yield: 99 %

Procedure:
To a solution of alcohol Compound 42 (1.1 g, 5.0 mmol) in CH2Cl2 (10 mL) was added oleoyl chloride (1.8 mL, 5.5 mmol) followed, after 5 min, by the addition of pyridine (0.44 mL, 5.5 mmol). After TLC analysis indicated that the reaction had gone to completion, the mixture was partitioned between ethyl acetate (100 mL) and H2O (30 mL), the organic extract was dried (MgSO4) and concentrated to give 1-O-t-butyldimethylsilyl-2-O-methyl-3-O-oleoyl-rac-glycerol (Compound 43) (2.4 g, 99%) as a dark brown oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=1>CS(C)=O.O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) in DMSO (2 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 0.27 g, 6.76 mmol) in DMSO (4 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. The mixture was allowed to cool to ambient temperature, and a solution of 2,5-dibromopyridine (1.12 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, poured in water, then extracted with EtOAc. The organic extract was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as an amber oil. The crude product was purified by chromatography on a silica gel column eluted with 1:8 EtOAc/hexane to give 1.40 g (84%) of 1,1-dimethylethyl 4-{[(5-bromo-2-pyridinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid after standing. 1H NMR (400 MHz, CDCl3): δ 8.16 (d, 1H, J=2.2 Hz), 7.64 (dd, 1H, Ja=8.7 Hz, Jb=2.3 Hz), 6.64 (d, 1H, J=8.8 Hz), 7.04 (d, 2H, J=8.8 Hz), 4.20-4.10 (m, 4H), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.85-1.70 (m, 2H), 1.45 (s, 9H), 1.30-1.20 (m, 2H); LRMS (ESI), m/z 371/373 (M+H).