Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=O)C1C=CC=CC=1.C(O)C.C1COCC1.[C:41]1([S:51](Cl)(=[O:53])=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1>CN(C)C=O.CN(C1C=CN=CC=1)C.[C].[Pd]>[C:41]1([S:51]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])(=[O:53])=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol (55 g), palladium-carbon (5%, 50% wet, 30 g) and ethanol (50 ml)-THF (300 ml) was subjected to catalytic hydrogenation at room temperature and atmospheric pressure. After the catalyst was filtered off, the filterate was concentrated under reduced pressure to yield an oily substance. The oil was dissolved in N,N-dimethylformamide (300 ml), and 1-naphthalenesulfonyl chloride (30 g) and 4-(N,N-dimethylamino)pyridine (DMAP) (17 g) were added to the ice-cooling mixture. After stirring at 0° C. for 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off and the residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (3:2,v/v) gave N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophanol (51 g, 82%) as crystals.
Reaction SMILES: N[CH2:2][C@H:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.Cl[C:10]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([F:30])[CH:21]=2)[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.[OH2:31]>CC(N(C)C)=O>[F:30][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:31][CH2:2][C@H:3]3[CH2:7][NH:6][C:5](=[O:8])[CH2:4]3)[N:19]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH:27]([CH3:29])[CH3:28]
Reactant: NC[C@H]1CNC(=O)C1
Reactant: CC(C)Oc1ccc(-c2cc3ncccc3c(Cl)n2)cc1F
Reactant: O
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1ccc(-c2cc3ncccc3c(OC[C@H]3CNC(=O)C3)n2)cc1F
Temperature: 100 °C

Procedure:
224 mg (R)-4-Hydroxymethyl-pyrrolidine-2-one (2.2) was placed in 1.5 mL of dimethylacetamide at ambient temperature under nitrogen. The reaction was stirred for 10 min before 5-chloro-7-(3-fluoro-4-isopropoxy-phenyl)-[1,6]naphthyridine (6.41) as a solution in 3 mL dimethylacetamide was introduced. The reaction was heated to 100° C. for 3 h and then cooled to ambient temperature. Water was added and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (ethyl acetate/methanol: 100:0 to 90:10) gave the title compound.
Reaction SMILES: C(N1C=NN=C1C1C=CN=CC=1)C.C(N1C(C2C=CN=CC=2)=NN=C1[CH2:27][OH:28])C.C(N1C(C2C=CN=CC=2)=NN=C1C=O)C.[F:44][C:45]1[CH:46]=[C:47]([C:52]2[N:53]([CH3:58])[C:54](=S)[NH:55][N:56]=2)[CH:48]=[C:49]([F:51])[CH:50]=1>>[F:44][C:45]1[CH:46]=[C:47]([C:52]2[N:53]([CH3:58])[C:54]([CH:27]=[O:28])=[N:55][N:56]=2)[CH:48]=[C:49]([F:51])[CH:50]=1
Reactant: Cn1c(-c2cc(F)cc(F)c2)n[nH]c1=S
Reactant: CCn1c(CO)nnc1-c1ccncc1
Agent: CCn1c(C=O)nnc1-c1ccncc1
Agent: CCn1cnnc1-c1ccncc1
Product: Cn1c(C=O)nnc1-c1cc(F)cc(F)c1

Procedure:
The title compound is prepared analogously to the sequence described for 4-(4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine (example 21), (4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (example 22), and 4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-carbaldehyde (example 23a) by using 5-(3,5-Difluoro-phenyl)-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione as starting material.
Reaction SMILES: [N:1]1([C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[CH2:20][CH2:19][C@H:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17]3)=O)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.B.C1COCC1.[ClH:34].CCOCC>C1COCC1.C(Cl)Cl>[ClH:34].[N:1]1([C:10]2[CH:27]=[CH:26][C:13]([CH2:14][N:16]3[CH2:20][CH2:19][C@H:18]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17]3)=[CH:12][CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(c1ccc(-n2cnc3ccccc32)cc1)N1CC[C@H](N2CCCC2)C1
Agent: B
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc2c(c1)ncn2-c1ccc(CN2CC[C@H](N3CCCC3)C2)cc1
Reaction time: 12 h
Yield: 65 %

Procedure:
A solution of (3′S)-1′-[4-(1H-benzimidazol-1-yl)benzoyl]-1,3′-bipyrrolidine (0.041 g, 0.113 mmol) in THF is treated with 1.0 M Borane-THF (0.098 g, 1.13 mmol) at room temperature, stirred for 12 hours and concentrated under vacuum. The resultant residue is dissolved in methanol, and treated with 1.0 M HCl-Et2O (0.004 g, 0.113 mmol), heated at reflux temperature for 3 hours and concentrated under vacuum to afford an oil residue. The residue is dissolved in CH2Cl2, washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. Purification of the concentrate by flash column chromatography (silica, 2% NH4OH:MeOH:CH2Cl2 5:3:95), followed by treatment with ethereal HCl, provides the title product as a yellow solid, 0.036 g (65% yield), identified by NMR and mass spectral analyses. MS [347.2 m/e (M+H)].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>>[Cl:13][C:14]1[C:15]([O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:25])([F:24])[F:26])[C:20]([C:27]([OH:29])=[O:28])=[CH:19][C:18]=2[CH:32]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(OC(F)(F)F)cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-(trifluoromethoxy)phenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 198.0-199.2° C. 1H NMR (acetone-d6/300 MHz) 7.91 (s, 1H), 7.73 (s, 1H), 7.43 (d, 2H, J=9.1 Hz), 7.25 (d, 2H, J=9.1 Hz), 6.70 (s, 1H), 5.82 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)−59.4 (s, 3F), −79.4 (d, 3F, J=7.2 Hz). ESLRMS m/z 453 (M−H). ESHRMS m/z 452.9950 (M−H, Calc'd 452.9964). Anal. Calc'd for C18H9ClF6O5: C, 47.55; H, 2.00; Cl, 7.80. Found: C, 47.47; H, 1.89; Cl, 8.02.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.C([O-])(=O)C1C=CC=CC=1.[K+].[CH3:51][C:52]([C:54]1[CH:59]=[CH:58][C:57](F)=[CH:56][CH:55]=1)=[O:53]>CN1C(=O)CCC1>[C:52]([C:54]1[CH:59]=[CH:58][C:57]([O:1][C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])=[CH:56][CH:55]=1)(=[O:53])[CH3:51]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: O=C([O-])c1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(C)=O)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 200 °C
Yield: 49.8 %

Procedure:
A mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (400 mg, 1.31 mmol), PS-BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diaza-phosphorine, polymer-bound, loading 2.2 mmol/g) (894 mg, 1.97 mmol), potassium benzoate (210 mg, 1.31 mmol) and 4-fluoroacetophenone (0.160 mL, 1.31 mmol) in NMP (10 mL) was heated to 200° C. in a ‘Smith Creator’ microwave for 1 hour. The polymer supported base was filtered off and the resin washed with ethyl acetate (100 mL). The organic phase was partioned with water (100 mL) at which point brine had to be added to resolve the layers. The aqueous phase was washed twice with ethyl acetate (50 mL) and then discarded. The combined organic extracts were Washed with saturated aqueous lithium chloride solution (2×100 mL), 2M sodium hydroxide solution (2×100 mL), water (2×100 mL), brine (100 mL) and dried (MgSO4). The volatiles were removed and the resulting oil purified by on silica, eluting with 0-100% ethyl acetate in iso-hexane, to give the desired product as a colourless foam (276 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](=O)([O:36]N1C(=O)CCC1=O)[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:36])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step A, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid: 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J=2.0 Hz, 1 h), 8.03 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 4.15 (m, 2H), 3.90 (d, J=7.0 Hz, 2H), 3.07 (s, 3H), 2.80-2.68 (m, 2H), 2.10 (m, 1H), 1.75 (m, 2H) 1.52 (m, 1H), 1.37-1.29 (m, 2H), 1.13 (m, 1H), 1.01-0.87 (m, 2H), 0.70-0.53 (m, 4H), 0.27 (m, 2H), −0.11 (q, J=5.0 Hz, 1H); MS (ESI) m/z 423 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]=[C:7]1[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]1=2.CO>C1COCC1>[OH:6][C:7]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: COC(=O)c1cccc2c1CCCC2=O
Reactant: c1cscn1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc2c1CCCC2(O)c1nccs1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an oven-dried, N2-purged flask was added isopropyl magnesium chloride lithium chloride complex (7.91 mL, 10.3 mmol) and THF (18.4 mL) and the solution was cooled to 0° C. A solution of thiazole (0.813 g, 9.55 mmol) in THF (9.18 mL) was then added, and the reaction was stirred for 45 min at 0° C., and then cooled to −10° C. A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carboxylate (1.5 g, 7.34 mmol) in THF (9.18 mL) was then added, after which the reaction was allowed to warm to rt over a period of 4 h. MeOH (5 mL) was then added and the reaction was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL), then the combined organic phases were dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography using a gradient solvent system of 0-70% EtOAc/DCM. The product-containing fractions were collected and concentrated to give racemic methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1-carboxylate as a yellow oil. The enantiomers were resolved by chiral SFC using a Chiral Technology AY-H 2.1×25 cm, 5 uM column, eluting with 20%-50% MeOH+0.25% dimethyl ethylamine/CO2. At a flow rate of 70 mL/min, the two enantiomers eluted at 2.38 min and 2.79 min.
Reaction SMILES: C(S([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:17]3[C:13]=2[C:14]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=O)=O)C.[C:35](O)([C:37](F)(F)F)=[O:36]>>[CH2:35]([O:36][C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:17]3[C:13]=2[C:14]2[CH:33]=[C:32]([CH3:34])[CH:31]=[N:30][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)[CH3:37]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1
Product: CCOc1cccc(-c2ccc(OCC3CCN(C)CC3)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized using an analogous procedure to that outlined in the preparation of Compound 176. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (t, J=6.95 Hz, 3 H) 1.44-1.56 (m, 2 H) 2.10-2.18 (m, 1 H) 2.25 (br. s., 5 H) 2.80 (d, J=4.80 Hz, 3 H) 2.97-3.07 (m, 2 H) 3.52 (d, J=11.62 Hz, 2 H) 4.06-4.09 (m, 4 H) 6.98-7.14 (m, 5 H) 7.44 (t, J=7.71 Hz, 1 H) 7.64 (s, 1 H) 8.25 (s, 1 H) 9.28 (br. s., 1 H) 11.87 (s, 1 H); [M+H] calc'd for C27H32N3O2, 430.2; found, 430.5; [M+H+TFA] calc'd for C29H33N3O4F3, 544.2; found, 544.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1.[C:31]1(C)C=[CH:35][C:34](S(O)(=O)=O)=[CH:33][CH:32]=1.C(=O)(O)[O-:43].[Na+]>O1C=CCCC1>[O:43]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C@H:9]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C:19](=[O:21])[CH3:20])[CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C1=COCCC1
Agent: [Na+]
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCOC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
A solution of pregn-5-en-20-one-3β-yl 6-hydroxyhexyl ether (6.22 g) and p-toluenesulfonic acid (20 mg) in dihydropyran (100 ml) was stirred at room temperature for 18 hours. Solid sodium bicarbonate (1 g) was added and the mixture stirred for 30 minutes. The mixture was filtered through a pad of silica gel which was subsequently washed with 50% ethyl acetate in hexanes. The solvent was removed by rotoevaporation to give the product as a clear colorless oil. TLC data and Rf values for compounds A-D are given in the above Table.
Reaction SMILES: C(O)(C)(C)C.[CH2:6]([O:8][C:9]([NH:11][C@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:13]([OH:20])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:10])[CH3:7].[CH2:27]([O:29][C:30]([NH:32][C@@H:33]([C@H:40]([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:31])[CH3:28]>O>[CH2:6]([O:8][C:9]([NH:11][C@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:13]([OH:20])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:10])[C:7]1[CH:42]=[CH:41][CH:40]=[CH:33][CH:34]=1.[CH2:27]([O:29][C:30]([NH:32][C@@H:33]([C@H:40]([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:31])[C:28]1[CH:22]=[CH:21][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)N[C@H](c1ccccc1)[C@H](O)C(=O)OC(C)C
Reactant: CCOC(=O)N[C@H](C(=O)OC(C)C)[C@H](O)c1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)OC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@H](O)c1ccccc1
Product: CC(C)OC(=O)[C@@H](O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Yield: 9 %
Yield: 9 %

Procedure:
tert-BuOH (36 mL) and water (12 mL) following the procedure outlined for the preparation of 11a and 11b (vide supra) to yield 12a (175 mg, 9%) and 12b (175 mg, 9%) as off-white solids, and a 1:1 mixture of 12a and 12b (1.45 g, 77%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]23[CH2:20][CH2:19][C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([CH2:17][CH2:18]2)[O:15][CH2:14]3)(=O)=O)=CC=1.[C-:34]#[N:35].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CS(C)=O.CCOC(C)=O>[O:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:16]12[CH2:19][CH2:20][C:13]([CH2:12][C:34]#[N:35])([CH2:18][CH2:17]1)[CH2:14][O:15]2)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4Oc4ccccc4)(CC2)OC3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCC12CCC(c3ccccc3Oc3ccccc3)(CC1)OC2
Temperature: 135 °C
Reaction time: 20 h
Yield: 94.9 %

Procedure:
A mixture of (1-(2-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl 4-methylbenzene-sulfonate (230 mg, 0.495 mmol), Bu4NI (2 mg, 4.95 μmol), and NaCN (73 mg, 1.49 mmol) in DMSO (10 mL) was stirred at 135° C. under N2 for 20 h, then cooled to rt. The reaction was diluted with EtOAc (10 ml) and washed with water (20 ml×4). The organic layer was concentrated in vacuo to give a crude brown oil, which was purified by flash chromatography (SiO2) using a gradient from 0% to 30% EtOAc/hexane (20 min) to give the title compound (150 mg, 0.470 mmol, 95% yield) as a clear oil. LCMS [M+Na]+=342.1. 1H NMR (CDCl3) δ: 7.77-7.72 (dd, J=7.7, 1.9 Hz, 1H), 7.38-7.33 (m, 2H), 7.22-7.16 (m, 1H), 7.15-7.10 (m, 2H), 7.01-6.95 (m, 2H), 6.83-6.79 (dd, J=8.0, 1.3 Hz, 1H), 3.98 (s, 2H), 2.70-2.58 (m, 2H), 2.22 (s, 2H), 2.05-1.94 (m, 2H), 1.88-1.74 (m, 4H).
Reaction SMILES: [C:1]([O:16][CH2:17][CH2:18][N:19]([C:38](=[O:45])[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH2:20][CH2:21][O:22][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:46][CH2:47][CH2:48][OH:49]>C(#N)C>[Br-:46].[C:23]([O:22][CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:5][CH2:6][CH2:7][CH3:8])[C:38](=[O:45])[CH2:39][CH2:40][CH2:41][N+:42]([CH2:47][CH2:48][OH:49])([CH3:43])[CH3:44])(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCCCC)C(=O)CCCN(C)C
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCC[N+](C)(C)CCO
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a sealed system, ((4-(dimethylamino)butanoyl)azanediyl)bis(ethane-2,1-diyl) ditetradecanoate (400 mg, 0.535 mmol) was dissolved in ACN (5 mL) and 2-Bromoethanol (500 uL) was added. The reaction vessel was flushed with inert gas and then sealed. Reaction was heated to 80° C. and stirred overnight, then concentrated. Purification by silica gel chromatography with DCM/MeOH gradient yielded 4-(bis(2-(oleoyloxy)ethyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-4-oxobutan-1-aminium bromide (255 mg). LCMS ESI+: m/z 792.5 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.ClC1C=CC=[C:17]([C:21]([O:23]O)=[O:22])C=1>O1CCCC1>[C:21]([O:23][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1)(=[O:22])[CH3:17]
Reactant: Cc1ccc(-c2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of 2-methyl-5-phenylpyridine (3.00 g), 3-chloroperbenzoic acid (4.79 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight, and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with tetrahydrofuran. A solution of the resulting colorless oily substance in acetic anhydride (50 ml) was added slowly to acetic anhydride (50 ml) heated at 130° C., which was stirred at 2 hours, and concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate solution, and with saturated aqueous sodium chloride solution, and then dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 5-phenyl-2-pyridylmethyl acetate (3.68 g, yield 92%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 71–72° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N+:12]=1[O-:18].OO.[OH2:21].C(O)(=[O:24])C>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N+:12]=1[O-:18])(=[O:24])=[O:21]
Reactant: O
Reactant: CC(=O)O
Reactant: Cc1ccc(C)c(CSc2cc(C)cc[n+]2[O-])c1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1ccc(C)c(CS(=O)(=O)c2cc(C)cc[n+]2[O-])c1
Temperature: 40 °C

Procedure:
The sulfide isolated in step (a) above was dissolved in 20 ml of glacial acetic acid and 1.5 ml of 30% hydrogen peroxide was added along with 100 mg of sodium tungstate. The reaction mixture was heated at 40° C. for one hour, cooled, and poured into water to percipitate the product. Yield, 1.46 or 89%. NMR supported the proposed structure.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:13]([S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:14]=[CH:13][S:15]([CH:18]=[CH2:19])(=[O:17])=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)(C)c1ccc(SCl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CS(=O)(=O)C=CSc1ccc(C(C)(C)C)cc1

Procedure:
In a manner analogous to Example 1, 4-t-butylphenylsulfenyl chloride was added in 1:1 proportion to divinyl sulfone, subjected to treatment with triethylamine in benzene, and purified by column chromatography. The product, vinyl 2-(4-t-butylphenylthio)vinyl sulfone, was obtained as a brown oil which crystallized on standing, m.p. 62-64° C; calculated for C14H18O2S2 :S, 22.7; found: S, 22.0; Cl, O.