Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:16])=[O:4].C(N(CC)CC)C.[CH3:24][O:25][CH2:26]Cl.O>CN(C=O)C>[OH:15][C:14]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([O:16][CH2:24][O:25][CH3:26])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)c1c(O)cc2ccccc2c1O
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCOc1c(C(=O)OC)c(O)cc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of 1,3-dihydroxy-2-naphthoic acid methyl ester 109 mg (0.53 mmol) in DMF (2 mL) was added triethylamine (200 μL, 1.43 mmol) and chloromethyl methyl ether (MOMCl) (125 μL, 1.65 mmol). The mixture was stirred at ambient temperature for 16 hours, poured into water (10 mL) and extracted with diethyl ether (2×5 mL). The combined ether layers were washed with 1M HCl (1×3 mL), brine (1×5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to an oil. The oil was purified on silica gel eluting with 20% ethyl acetate/hexanes to provide the titled compound (83 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[O:26])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CCCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), and CH2Cl2 (2 mL) were added piperidine (3.9 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.[CH:37]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:37]1([CH2:40][CH2:41][NH:42][C:34]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=3)[C:19]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:17]2)=[O:35])[CH2:39][CH2:38]1
Reactant: NCCC1CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCC2CC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 59.6 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 25a (0.16 g, 0.37 mmol) was reacted with 2-cyclopropylethylamine (Bridge Organics) (0.1 g, 1.1 mmol), HATU (0.2 g, 0.5 mmol) and iPr2NEt (0.3 g, 2 mmol) in CH2Cl2 (20 mL) at room temperature for 20 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-cyclopropyl-ethyl)-amide as a white solid (0.11 g, 37%).
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[OH:21][CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([OH:30])[C:26]([CH3:31])=[CH:25][N:24]=1.[O-]CC.[Na+]>C(O)C.C(OCC)(=O)C>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([OH:5])([C:7]([F:9])([F:10])[F:8])[CH2:6][N:24]3[CH:25]=[C:26]([CH3:31])[C:27](=[O:30])[C:28]([CH3:29])=[C:23]3[CH2:22][OH:21])=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: Cc1cnc(CO)c(C)c1O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cn(CC(O)(CC(C)(C)c2cccc3c2OCC3)C(F)(F)F)c(CO)c(C)c1=O
Temperature: 85 °C
Yield: 22.6 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (30.0 mg) and 2-hydroxymethyl-3,5-dimethylpyridin-4-ol (32.2 mg) in anhydrous ethanol (0.25 mL) was added sodium ethoxide (21 wt. % solution in ethanol, 39.0 μL). After heating at 85° C. for 18 hours, the reaction mixture was diluted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography with silica gel (eluted with 4% to 7% methanol-methylene chloride) to give the title compound as a white solid (10.4 mg), m.p. 160° C.-162° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:47]C2CCCCO2)[CH2:21][N:22]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:47])[CH2:21][N:22]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2c([C@H](CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1ccc2c([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)ccc(OCc3ccccc3)c2[nH]1
Yield: 47.4 %

Procedure:
A solution of 8-(benzyloxy)-5-[(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one (80 mg) in acetic acid (4 ml), THF (2 ml) and water (1 ml) was heated at 80° C. for 17 h prior to concentration in vacuo. The residue was purified by chromatography (Hexane-EtOAc 2:1, biotage) to give the title compound (33.5 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)[CH2:4][CH3:5].Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][CH:7]=1)[CH2:4][CH3:5]
Reactant: CCCCCCCC(Br)C(=O)OCC
Reactant: CCCc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCC(Sc1ccc(CCC)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
1.6 g (0.033 mole) sodium hydride (50% dispersion in mineral oil) was added to a solution of 5.0 g (0.033 mole) 4-propylthiophenol in 25 ml anhydrous dimethylformamide. After 15 minutes, 8.8 g (0.033 mole) ethyl 2-bromononanoate (prepared according to J. Labelled Compounds Radiopharm. 14, 713 (1978)) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with 150 ml ethyl acetate and the resulting mixture was washed with 5×60 ml water and then with 60 ml saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting oil was chromatographed on 600 g silica gel, eluting with 7:3 hexane/methylene chloride to yield 9.0 g (81% yield) of the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=2)[C:9]#N)=[CH:4][CH:3]=1.[CH:22]([CH:24]=C)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][CH:13]=3)[CH:22]=[CH:24][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)cc1
Reactant: C=CC=O
Product: NS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-fluorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and acrolein as starting materials, the title compound was obtained as a brown powder (yield 11%), melting at 198-199° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[N:27]=[N:26][C:25]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[C@H:30]([CH3:41])[CH2:29]2)=[CH:24][CH:23]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:22]4[N:27]=[N:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][C@H:30]([CH3:41])[CH2:29]5)=[CH:24][CH:23]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[C:19]([F:20])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ncc2c3ccnc(F)c3n(C3CCCC3)c2n1
Reactant: C[C@@H]1CN(c2ccc(Cl)nn2)CCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nn2)CCN1
Yield: 12 %

Procedure:
Compound 408 was prepared from compound 245 and compound 11 using chemistry similar to that described in example 4. The two step yield is 12%. 1H NMR (500 MHz, CD3OD) δ ppm 9.48 (1 H, s), 8.10-8.14 (2 H, m), 8.00 (1 H, d, J=10 Hz), 8.05 (1 H, d, J=10 Hz), 5.66 (1 H, t, J=9.0 Hz), 4.43-4.49 (2 H, m), 3.52-3.62 (2 H, m), 3.29-3.48 (2 H, m), 3.20 (1 H, dd, J=14.4, 10.8 Hz), 2.45 (2 H, ddd, J=9.2, 7.0, 4.5 Hz), 2.13-2.27 (4 H, m), 1.87-1.88 (2 H, m), 1.46 (3 H, d, J=6.6 Hz); LCMS-ESI (POS), M/Z, M+1: Found 448.1, Calculated 448.2.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:18])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:6]=1.CC(C)=[O:21]>O>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]=[C:5]([NH:6][C:2](=[O:21])[CH3:1])[C:4]([OH:3])=[O:18])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc(C=C2N=C(C)OC2=O)cc1
Reactant: CC(C)=O
Solvent: O
Product: CC(=O)NC(=Cc1ccc(OC(C)=O)cc1)C(=O)O

Procedure:
75.8 g (0.3 mol) of 2-methyl-4-(p-acetoxy-benzylidene)-5(4H)-oxazolone are dissolved in a mixture of 725 ml of acetone and 281 ml of water and thereafter the solution is heated to the boil, under a reflux condenser, for 15 hours. Hereupon, a yellowish precipitate separates out. The reaction mixture is cooled and then filtered. The resulting crystals are recrystallised from acetone-water. p-Acetoxy-α-acetylaminocinnamic acid of melting point 236°-237° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[OH:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C(N(CC)CC)C.O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([Cl:21])[CH:14]=2)=[N:9][C:8]([N:26]2[CH2:27][CH2:28][CH2:29][C@H:25]2[CH2:24][OH:23])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OCC1CCCN1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncc(N2CCC[C@H]2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-chloropyrazine (150 mg), 2-hydroxymethylpyrrolidine (88.6 mg), and triethylamine (0.12 ml) in tetrahydrofuran (5 ml) is stirred at room temperature for 4 hours, and the mixture is heated at 50° C. for 2 hours. To the mixture is added 2-hydroxymethylpyrrolidine (44.3 mg), and the mixture is stirred at 50° C. for one hour. After cooling, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting yellow oil is purified by silica gel column chromatography (solvent; chloroform:hexane=1:1) to give (S)-2-methoxycarbonyl-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)-pyrazine (123 mg) as pale yellow powder, MS (m/z): 407 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(#N)C.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([C:4]1[NH:5][CH:6]=[C:2]([CH3:1])[N:3]=1)=[O:22]
Reactant: Cc1c[nH]cn1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(C(=O)c2cccc(F)c2)n1
Temperature: 140 °C
Yield: 67.7 %

Procedure:
To a 350 mL pressure vessel was added 4-methylimidazole (17.85 g, 217 mmol, 1 eq.) and a stirbar. Acetonitrile (53 mL, 1022 mmol, 4.7 eq.) was added. Triethylamine (88 mL, 631 mmol, 2.9 eq.) was added and the mixture was stirred until it became homogeneous. 3-Fluorobenzoylchloride (100 g, 631 mmol, 2.9 eq.) was added. Upon addition of the acyl chloride, the mixture became warm and viscous. The vessel was sealed and heated at 140° C. for 2 hours with stirring. During heating, the mixture turned black in color. The vessel was removed from the heat, allowed to cool, and its contents were diluted with acetone (250 mL). The mixture was stirred and transferred to a 2 L round-bottomed flask containing 7% aqueous HCl (1000 mL). Charcoal was added to the flask and the mixture was refluxed at 85° C. for 1 hour. The mixture was allowed to cool slightly and then was filtered through a Celite pad followed by a rinse with 1N HCl (˜200 mL). The filtrate was made alkaline with NH4OH whereupon a solid precipitate formed. The solid was filtered and washed with copious amounts of dilute NH4OH to remove triethylamine hydrochloride salts. The solid was collected and placed under high vacuum, yielding ketone 3 as an off-white solid (30.0 g, 80%). LC/MSD (HP Series 1100 MSD) Expected MW: 204.07, Observed M+H: 205.0, Retention time: 1.48. Analytical HPLC: >95% purity, retention time: 3.00 (8 minute run) 1H NMR, DMSO-d6, Varian 400 MHz δ 13.10 (br s, 1H), 8.28 (m, 2H), 7.60 (m, 1H), 7.52 (m, 1H), 7.30-7.06 (d, 1H), 2.29 (s, 3H).
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([CH2:41]CCC)=[N:37]OC=2C)=NC=1>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:37][CH:36]([CH3:41])[CH3:35])=[O:23])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCC3)noc2C)nc1
Product: Cc1onc(C2CCCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 62 %

Procedure:
As described for example 5d, 6-(3-cyclopentyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (230 mg, 0.73 mmol) was converted, instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (155 mg, 62%) which was obtained as a white solid after purification by chromatography (silica, 0 to 80% ethyl acetate in heptane). MS: m/e=344.0 [M+H]+.
Reaction SMILES: [C:1](=O)([O:7]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][O:5][CH3:6].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:35][C:36]1[CH:72]=[CH:71][CH:70]=[CH:69][C:37]=1[CH2:38][NH:39][C:40]([C@@H:42]1[C:46]([CH3:48])([CH3:47])[S:45][CH2:44][N:43]1[C:49](=[O:68])[C@@H:50]([OH:67])[C@@H:51]([NH:59][C:60](=[O:66])[C@H:61]([CH:63]([CH3:65])[CH3:64])[NH2:62])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:41]>CN(C=O)C.C(OCC)(=O)C>[CH3:35][C:36]1[CH:72]=[CH:71][CH:70]=[CH:69][C:37]=1[CH2:38][NH:39][C:40]([C@@H:42]1[C:46]([CH3:48])([CH3:47])[S:45][CH2:44][N:43]1[C:49](=[O:68])[C@@H:50]([OH:67])[C@@H:51]([NH:59][C:60](=[O:66])[C@@H:61]([NH:62][C:1]([O:2][CH2:3][CH2:4][O:5][CH3:6])=[O:7])[CH:63]([CH3:65])[CH3:64])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:41]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Reactant: COCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Methoxyethyl p-nitrophenyl carbonate (112 mg), HOBt (41 mg), triethylamine (104 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (130 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH3:33])[CH2:6][CH2:7][NH:8][C:9](=[O:32])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]=1[CH3:31].CN(C(ON1N=N[C:44]2[CH:45]=[CH:46][CH:47]=N[C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][C:59](N(C)C)=[O:60]>CC#N.CCOC(C)=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:13]2[C:14]3[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:11]([CH2:10][C:9]([NH:8][CH2:7][CH2:6][N:5]([CH3:33])[CH2:4][CH2:3][NH:2][C:59](=[O:60])[CH2:58][CH2:43]/[CH:44]=[CH:45]\[CH2:46]/[CH:47]=[CH:43]\[CH2:44]/[CH:45]=[CH:46]\[CH2:47]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:31]\[CH2:47]/[CH:46]=[CH:45]\[CH2:44][CH3:43])=[O:32])=[C:12]2[CH3:31])=[O:30])=[CH:24][CH:25]=1
Reactant: CC(=O)N(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(c1)c(CC(=O)NCCN(C)CCN)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCN(C)CCNC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 219.5 %

Procedure:
This HCl salt of N-(2-((2-aminoethyl)(methyl)amino)ethyl)-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamide (0.38 mmol) was taken up in 5 mL of CH3CN along with DHA (210 mg, 0.64 mmol), HATU (267 mg, 0.67 mmol) and DMA (334 μL, 2.01 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (25 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 320 mg of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-((2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (65% yield). MS (EI) calcd for C46H59ClN4O4: 766.42; found 767 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1(C2C=[CH:15][C:16]3[CH2:17][C@H:18]4[N:29]([CH:30]=O)[CH2:28][CH2:27][C@@:24]5([C:25]=3[CH:26]=2)[C@H:19]4[CH2:20][CH2:21][CH2:22][CH2:23]5)C=CC=CC=1.[C:32]([O:35][CH2:36][CH3:37])(=O)[CH3:33].O>O1CCCC1>[O:35]([C:36]1[CH:37]=[CH:15][C:16]2[CH2:17][C@H:18]3[N:29]([CH3:30])[CH2:28][CH2:27][C@@:24]4([C:25]=2[CH:26]=1)[C@H:19]3[CH2:20][CH2:21][CH2:22][CH2:23]4)[C:32]1[CH:24]=[CH:25][CH:16]=[CH:15][CH:33]=1
Reactant: O=CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(-c2ccccc2)cc13
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Temperature: 25 °C
Yield: 73 %

Procedure:
To a suspension of 1.1 g of lithium aluminum hydride in 120 ml of anhydrous tetrahydrofuran, 10.8 g (0.03 mol) of crude (±)-3-phenyl-N-formylmorphinan in 50 ml of tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hrs, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give a dark brown oil which was distilled, bp 170°-180° (0.05 mm Hq) to afford 7.6 g (73%) of crude (±)-3-phenoxy-N-methylmorphinan.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[N:19]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:16]=[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=12
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Product: CCCCCCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 1 and 2-hydroxy-4-dodecyloxybenzophenone, the title compound is obtained as a yellow crystalline solid melting at 100°-105° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2COCC[Si](C)(C)C)=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][N:2]([CH3:25])[C:3]1[NH:4][C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[C:6]2[C:10]([N:11]=1)=[N:9][CH:8]=[N:7]2
Reactant: CN(C)c1nc(-c2ccco2)c2ncn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1nc2ncnc-2c(-c2ccco2)[nH]1
Yield: 76.3 %

Procedure:
A solution of N,N-dimethyl-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine-2-amine (200 mg, 0.56 mmol) in THF (5 mL) was treated with tetra-n butylammonium fluoride (1-M in THF, 0.67 mL, 0.67 mmol), refluxed for 4 h, cooled, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2; EtOAc) to give the title compound (98 mg, 76%) as a pale yellow solid.
Reaction SMILES: [S:1]([CH2:5][CH2:6][OH:7])([O-:4])(=[O:3])=[O:2].[Na+:8].[CH:9]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(OCC)C>[CH:9]1([C:15]([O:7][CH2:6][CH2:5][S:1]([O-:4])(=[O:3])=[O:2])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Na+:8]
Reactant: O=S(=O)([O-])CCO
Reactant: O=C(O)C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOCC
Product: O=C(OCCS(=O)(=O)[O-])C1CCCCC1
Temperature: 200 °C
Yield: 91 %

Procedure:
A mixture of 3.0 g (20 mmol) of sodium isethionate, 7.7 g (60 mmol) of cyclohexanecarboxylic acid, and 0.38 g (2 mmol) of tosylic acid was heated at 200° C. for 20 hours. Diethyl ether was added to the reaction solution, yielding 4.7 g of sodium 2-cyclohexanecarbonyloxyethanesulfonate. A 1.4-g portion of the sodium salt was combined with 23 g (10 mmol) of an aqueous solution of triphenylsulfonium chloride prepared in Synthesis Example 1-1 and 30 g of methylene chloride, followed by stirring for 12 hours at room temperature. At the end of stirring, the organic layer was taken out, washed with water, and concentrated in vacuum. Methyl isobutyl ketone was added to the concentrate, which was concentrated in vacuum again while distilling off the residual water. Diethyl ether was added to the residue, followed by decantation and purification by column chromatography. There was obtained the target compound, triphenylsulfonium 2-cyclohexanecarbonyloxyethanesulfonate. Colorless oily matter, 1.7 g, yield 66% as calculated from the sodium salt. The compound, designated PAG-4, has the following structure.