Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].O.[O:21]=[C:22]1[O:26][C@H:25]2[CH2:27][C@@H:28]([O:32][C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])[C@H:29]([CH:30]=O)[C@H:24]2[CH2:23]1>COC(C)(C)C>[F:15][C:9]([F:14])([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:16])/[CH:7]=[CH:30]/[C@@H:29]1[C@@H:24]2[C@@H:25]([O:26][C:22](=[O:21])[CH2:23]2)[CH2:27][C@H:28]1[O:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]
Reactant: O=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (0.378 g, 1.50 mmol) in t-butyl methyl ether (5 ml), lithium hydroxide monohydrate (60.8 mg, 1.45 mmol) was added and the mixture was stirred for one hour at room temperature. Water (0.15 ml) and (3aR,4R,5R,6aS)-2-oxo-5-phenylcarbonyloxyhexahydro cyclopenta[b]furan-4-carbaldehyde (10) (0.274 g, 1.00 mmol) were added thereto and the mixed solution was stirred for approximately 3 hours at room temperature. The reaction mixture was added to water and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 100 g; ethyl acetate:hexane =1:2), to give (3aR,4R,5R,6aS)-4-((E)-4,4-difluoro-3-oxo-1-octenyl)-2-oxo-5-phenylcarbonyloxyhexahydrocyclopenta[b]furan (11) (0.201 g; 0.495 mmol; yield: 49.5%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8]>CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON=C(C(=O)O)c1csnn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
1 N Aqueous solution of sodium hydroxide (6.7 ml.) was added to a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (syn isomer) (1.2 g.) in methanol (10 ml.) and the mixture was stirred for 1.5 hours at ambient temperature. Methanol are distilled off from the reaction mixture and water was added to the residue. The mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give prisms of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.7 g.), m.p. 110° to 113° C.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[OH:15].ClCl.[N+]([O-])(O)=[O:19]>O>[CH3:6][C:7]1[C:8](=[O:15])[C:9]([CH3:14])=[CH:10][C:11](=[O:19])[C:12]=1[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)c(O)c1C
Agent: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 2 h

Procedure:
1000 g of carbon tetrachloride was charged in a 5-liter four neck flask equipped with a stirrer, a condenser, a chlorine-bubbling pipe and a thermometer, and 408 g (3 moles) of 2,3,6-trimethylphenol was dissolved therein. Thereafter, 210 g (3 moles) of chlorine gas was bubbled thereinto at 40°C in 2 hours. After the completion of the bubbling, a mixture of 210 g of a commercially available nitric acid (63 percent by weight) and 600 g of water was immediately added dropwise thereto at 40°C for 2 hours. After the completion of the dropwise addition, the stirring was continued for further 1 hour. Then, the reaction solution was allowed to stand, and the separated lower layer of carbon tetrachloride was taken out, and washed with water, followed by distilling off carbon tetrachloride. Thus, 460 g of the residue was obtained as a red oil, in which 405 g of 2,3,6-trimethyl-p-benzoquinone was included. (90 percent in yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH2:16]([Sn](CCCC)(CCCC)C=C)[CH2:17]CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:7]=[C:2]([CH:16]=[CH2:17])[N:3]=[C:4]([CH3:15])[N:5]=2)[N:9]=1
Reactant: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Temperature: 110 °C

Procedure:
To a solution of 4-chloro-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidine (1-2) (5.2 g, 23.2 mmol) in degassed toluene (200 mL) under nitrogen was added tetrakis(triphenylphosphine)palladium(O) (1.3 g, 1.16 mmol) followed by tributyl(vinyl)tin (8.8 mL, 30.2 mmol) and the reaction was heated at 110° C. for 3 h. The solvent was concentrated in vacuo and the crude residue was purified by silica gel column chromatography (0-50% EtOAc/hexanes) to afford 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 6.76 (dd, 1H, J=17.3, 10.6 Hz), 6.52 (br d, 1H, J=17.3 Hz), 5.72 (br d, 1H, J=10.6 Hz), 2.91 (s, 3H), 2.72 (s, 3H), 2.42 (s, 3H). MS m/z=216 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Methylsalicylic acid (100 g, 658 mmoles) was dissolved in anhydrous methanol (500 mL) and concentrated sulfuric acid (25 mL) was added carefully. The solution was refluxed for 18 hours, then cooled to room temperature. The reaction mixture was concentrated to about 150 mL, and ethyl acetate (250 mL) was added. The ethyl acetate solution was washed twice with saturated aqueous sodium bicarbonate (250 mL portions) and then with saturated aqueous sodium chloride (100 mL). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and evaporated to a clear, reddish-brown liquid. This crude product was vacuum distilled (oil pump) to afford a clear, viscous liquid that solidified on standing to afford 98.1 g (90% yield) of methyl 4-methylsalicylate.
Reaction SMILES: [H-].[Na+].[CH:3]([C@@H:6]1[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:5])[CH3:4].[F:20][C:21]1[CH:30]=[C:29](F)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[F:20][C:21]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29]([N:10]2[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C@H:6]([CH:3]([CH3:5])[CH3:4])[C:11]2=[O:12])[CH:30]=1
Reactant: CC(C)[C@@H]1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at −10° C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.66 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at −10° C. for 30 min. Then the mixture was added dropwise to a 1 L three-neck flask containing methyl 2,4-difluoro-5-nitrobenzoate (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at −20° C. over 10 min After addition, the resulting mixture was stirred between −20° C. and −30° C. for another 10 min. The reaction was quenched with sat. aq. NH4Cl (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were washed with water (3×1 L) and brine, and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with petroleum ether: EtOAc 8:1˜4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M-56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][O:6]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C2OCCO2)cc1Br
Reaction time: 4.5 h
Yield: 78.3 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (45.7 g), ethylene glycol (27.39 g), p-toluenesulphonic acid (0.225 g) and dry toluene (110 cm3) was heated at the reflux temperature under a Dean and Stark trap. After 4.5 hours, approximately 12 cm3 of water had collected in the trap, and analysis of the reaction mixture by gas liquid chromatography indicated that no starting aldehyde was present. The cooled mixture was washed with sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a yellow oil, which was purified by distillation under reduced pressure to give 2-(3-bromo-4-fluorophenyl)-1,3-dioxolane (43.56 g), boiling point 68°-106° C. at 0.004 mmHg.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.CN(C=O)C.Br[CH2:25][CH2:26][CH2:27][Cl:28]>[Cl-].[Na+].O>[Cl:28][CH2:27][CH2:26][CH2:25][N:6]1[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: ClCCCBr
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Temperature: 65 °C

Procedure:
A solution of 2-(trifluoromethyl)-10H-phenothiazine (2.04 g, 7.6 mmol) and DMF (16 mL) was mixed with CS2CO3 (7.5 g, 22.9 mmol) and 1-bromo-3-chloropropane (1.1 mL, 11.5 mmol) The reaction mixture was heated at 65° C. for 12 h. Once no starting material was observed by analytical LCMS, EtOAC (250 mL) and brine (250 mL) were added. The organic layer was separated, and the aqueous layer was washed with EtOAC (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, and concentrated to afford the title compound.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].S(=O)(=O)(O)O>>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
100 g of crude methyl cinnamate and 926.8 g of 2.8% caustic soda were placed in a 2-liter flask equipped with a thermometer and a stirrer, and the solution was then stirred at 80° C. for 30 minutes to carry out hydrolysis. An active carbon treatment was omitted. The abovementioned aqueous solution was maintained at 40° C., and 137.1 g of 25% sulfuric acid was added dropwise to precipitate the crystals of cinnamic acid. After the addition of sulfuric acid had been over, the temperature of the solution was lowered to 20° C., followed by filtering through Nutsche. The resultant filter cake was washed with 1000 g of water, and then vacuum-dried at 50° C. to obtain 87.1 g of cinnamic acid. The purity of cinnamic acid was 96.1%, and the contents of palladium, copper and manganese were 5 ppm or less, 260 ppm, 200 ppm, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36]Br)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:29][CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCBr)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2.0 g of 5-benzyloxy-3-[5-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester are stirred in 90 ml of acetonitrile. 498 mg of potassium iodide are added and the suspension is heated to 80° C. After 7 h 20 min, the following reactants are successively added: 394 μl of morpholine, 1.24 g of potassium carbonate, 150 mg of potassium iodide. The suspension is heated at 80° C. overnight. The insoluble material is filtered off and the filtrate is concentrated under vacuum. The reaction crude is taken up in 50 ml of dichloromethane. The organic phase is washed with 2 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate and filtered. The solvent is evaporated off in a rotary evaporator to obtain 1.90 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[N:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][N:16]=1>CN(C=O)C.O>[CH2:21]([C:18]1[CH:17]=[N:16][C:15]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)=[N:20][CH:19]=1)[CH2:22][CH3:23]
Reactant: CCCc1cnc(Cl)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cnc(N2CCC(O)CC2)nc1
Temperature: 100 °C

Procedure:
To a stirring solution of piperidin-4-ol (2.33 g, 23 0 mmol, Aldrich) and potassium carbonate (6.36 g, 46 0 mmol, EMD) in DMF (15 mL) at room temperature was added 2-chloro-5-propylpyrimidine (4.33 g, 27.6 mmol, Wako). The reaction mixture was heated at 100° C. for 3 h then diluted with H2O. The resulting mixture was extracted with EtOAc (2×). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to a brown oil. The oil was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 5.01 g of desired product as a white solid. MS (ESI) 222 (M+H).
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=O.[NH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>CCO>[CH3:15][C:2]1[N:16]=[C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]2[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ncccn1
Solvent: CCO
Product: Cc1nc2ncccn2c1-c1ccc(C(F)(F)F)cc1
Reaction time: 24 h
Yield: 46.8 %

Procedure:
Dissolve 2-bromo-1-[4-(trifluoromethyl)phenyl]propan-1-one (7.120 g, 25.332 mmol) and 2-aminopyrimidine (5.464 g, 55.729 mmol) in EtOH (40.0 mL). Heat the mixture to reflux, and stir for 24 hours. Concentrate in vacuo. Dissolve the residue in EtOAc (750 mL); and wash sequentially with saturated aqueous NaS2O3 (250 mL), saturated aqueous NaHCO3 (250 mL), and saturated NaCl (350 mL). Crystallize the orange residue from heptanes/EtOAc to give the title product as a white solid (3.29 g, 46.85% yield). 1H NMR (399.83 MHz, d6-DMSO) δ 8.84 (dd, J=1.9, 7.0 Hz, 1H), 8.54 (dd, J=2.0, 4.2 Hz, 1H), 8.06-8.04 (m, 2H), 7.83-7.81 (m, 2H), 7.10 (dd, J=4.1, 6.9 Hz, 1H), 2.68 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15].[N+:16]([O-])([O-:18])=[O:17].[K+].O>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)CCCc1ccc(F)c(C)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)CCCc1cc(C)c(F)cc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
The compound obtained in (2) above (10.9 gm) was added to 6 ml of cold concentrated sulfuric acid, and to the mixture was dropwise added 5.8 gm of potassium nitrate in 15 ml of concentrated sulfuric acid, while maintaining the internal temperature below 5° C. After the addition, the mixture was stirred for a further 20 minutes. The reaction product was poured into ice-cooled water and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (90:7) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 7.1 gm of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1cccc2c(C3CCNCC3)c[nH]c12
Temperature: 90 °C
Reaction time: 72 h
Yield: 199.9 %

Procedure:
A 100 mL round bottom flask was charged with 4-nitrophenyloxycarbonyloxyethyl polystyrene (4.0 g, 4.3 mmol), 7-chloro-3-(1-tert-butoxycarbonylpiperidin-4-yl)-1H-indole (2.7 g, 8.1 mmol), diisopropylethylamine (3.5 mL, 20.2 mmol), 4-dimethylaminopyridine (0.5 g, 4 mmol) and dry dimethyl formamide (50 mL). The mixture was stirred at 90° C. for 72 h. After cooling to room temperature, the resin was filtered off and washed with dry dimethyl formamide (3×25 mL), dry acetonitrile (3×25 mL) and dry dichloromethane (3×25 mL). The resin was transferred to a 250 mL glass cylinder with a fritte and a three way junction in the bottom. The resin was then treated for 20 minutes with 60 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w), using a flow of nitrogen to agitate the resin (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (25 mL), a 1:1 mixture of dichloromethane:triethylamine (3×25 mL) and dry dichloromethane (3×25 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (3.8 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8](Cl)=[O:9].O>C1COCC1>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of dimethylamine (2M in THF, 3 mL) and THF (2 mL) is added 2,6-dimethoxybenzoyl chloride (200.6 mg, 1 mmol) in THF (2 mL) dropwise. After the addition, the solution is stirred at RT for 1 h. Water is added and the suspension is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound: 1H NMR (CDCl3) δ 7.26-7.22 (t, J=8.34 Hz, 1H), 6.56-6.53 (d, J=8.33 Hz, 2H), 3.79 (s, 6H), 3.12 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]([S:16]Cl)=[O:15]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14](=[O:15])[S:16][N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: COc1cc(Cl)ccc1C(N)=O
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1nsc(=O)o1
Yield: 71.7 %

Procedure:
In tetrahydrofuran (100 ml), 4-chloro-2-methoxybenzamide (5.67 g, 30.5 mmol) prepared in the Step 7-1-1 and chlorocarbonylsulfenyl chloride (4.40 g, 33.6 mmol) were suspended, and the mixture was heated under reflux for 1.5 hours. After being allowed to cool, the mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=7:1) to give the title compound (5.33 g, 71%).
Reaction SMILES: C([O:4][CH2:5][CH:6]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])C=C.FC(F)(F)C(O)=O>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:27][CH:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:5][OH:4])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: C=CCOCC(COCCCCCCCC/C=C\C/C=C\CCCCC)OCCCCCCCC/C=C\C/C=C\CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a solution of (6Z,9Z)-18-(3-(allyloxy)-2-((9Z,12Z)-octadeca-9,12-dienyloxy)propoxy)octadeca-6,9-diene (9.1 g, 14.3 mmol) in ethanol (100 ml) was added trifluoroacetic acid (15.0 mL) and tetrakis(triphenylphosphine)palladium(0) (1.65 g, 1.43 mmol). The solution was refluxed for 16 hours, cooled to room temperature and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel 60 (eluted with a gradient of 100% hexanes to 1:1 hexanes/DCM to 100% DCM) to afford 2,3-bis((9Z,12Z)-octadeca-9,12-dienyloxy)propan-1-ol as a colorless oil (6.1 g, 54%).