Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC#N.[OH2:4].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.OF>CC#N>[CH2:7]([CH:6]1[CH2:5][O:4]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O
Reactant: C=CCCCCCCCCCC
Agent: OF
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCC1CO1
Yield: 85 %

Procedure:
Under a flow of F2 (10% in N2) of 8.9 ml min−1 (1.49 mmol h−1) fed through conduit 12, MeCN:H2O (4:1, 5.50 ml) was added to conduit 16 at a rate of 5.50 ml −1 (60.4 mmol h−1). A solution of dodec-1-ene 24 (0.25 g, 1.49 mmol) (in a 1:1 mixture of DCM:MeCN) was added to pot reactor 22 prior to reaction. The HOF.MeCN thus generated was passed via conduit 20 into the pot reactor 22. Following reaction and purging with nitrogen, the reaction mixture was then transferred from pot reactor 22 to a vessel containing 100 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 2-decyloxirane (0.233 g, 1.27 mmol, 85%) as a pale yellow oil, with no further purification required.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:8]([C:7]1[C:2]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)=[N:3][CH:4]=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C#N)CC1

Procedure:
A mixture of 2-chloro-3-cyanopyridine (15.2 g, 0.11 mol), tert-butyl 1-piperazinecarboxylate (25 g, 0.13 mol) and triethylamine (18 ml, 0.13 mol) in toluene (200 ml), was heated under reflux for 24 hours. The cooled mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate (250 ml), and washed with water (3×). The organic solution was dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried in vacuo, at 60° C., to afford the title compound as a cream coloured solid, 24.2 g.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].[CH3:17][C:18]1[O:22][N:21]=[CH:20][C:19]=1[C:23](Cl)=[O:24]>O>[CH3:17][C:18]1[O:22][N:21]=[CH:20][C:19]=1[C:23]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:9][CH:8]=1)=[O:24]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1oncc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 50 °C

Procedure:
4-Trifluoromethylaniline (5.75 g, 35.7 mm) was suspended in a solution of NaHCO3 (3.16 g, 37.6 mm) in water (30 ml). The suspension was warmed to 50° C. and then rapid stirring was begun. 5-Methylisoxazole-4-carboxylic acid chloride prepared by the procedure of Example 1 (5 g, 34.4 mm) was added dropwise to the rapidly stirred suspension over 20 min. After cessation of the addition, the mixture was stirred for another 2 h. The mixture was then allowed to cool to ambient temperature and leflunomide was isolated as a white powder by filtration. Drying at 60° C. gave leflunomide (8.2 g, 88%) in 96% purity by HPLC analysis.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 120 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (2.5 g, 14 mmol), 1-methylpiperizine (3.2 mL, 30 mmol), and potassium carbonate (K2CO3) (2.0 g, 14 mmol) in dimethylformamide (DMF) (20 mL) was stirred at 120° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (150 mL). The precipitated crude product was collected by filtration, dried in vacuo, and purified by recrystallization from ethyl acetate (EtOAc) (75 mL) to yield yellow-green crystals (1.8 g, 54%). See, J. Med. Chem., 39:997 (1996).
Reaction SMILES: [P:1]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][CH2:15]I>C1C=CC=CC=1>[P:1]([O:13][CH2:15][Cl:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:2]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: ClCI
Solvent: c1ccccc1
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The tetrabutylammonium salt of bis-tert butyl phosphate (45.1 g, 0.1 mol) and chloroiodomethane (200 g, 1.14 mol) were combined in 100 ml of benzene and the mixture was stirred at room temperature for four hours and then the benzene was removed under vacuum. A portion of 500 ml of ethyl ether was added to the residue and insoluble solid was filtered away. Concentration of the filtrate in vacuo and removal of the volitiles on a vacuum pump provided di-tert-butyl chloromethyl phosphate, as a light yellow or light brown oil which was utilized in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH:11]1([CH2:16][C:17](Cl)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(#N)C>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:17](=[O:18])[CH2:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: O=C(Cl)CC1CCCC1
Solvent: CC#N
Product: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 92 %

Procedure:
4-Bromo-2,6-dimethylaniline (5.92 g) and cyclopentylacetyl chloride (4.87 mL) were dissolved in acetonitrile (26 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction was cooled to 0° C., the product filtered off and washed with cold acetonitrile (50 mL) affording 8.43 g (92% yield) of the title compound as a brown solid. The crude product was used without further purification. LC-MS (m/z) 312 (MH+); tR=3.10, (UV, ELSD) 89%, 99%. 1H NMR (500 MHz, CDCl3): 1.22 (m, 2H), 1.52 (m, 2H), 1.63 (m, 2H), 1.77 (m, 2H), 2.06 (s, 6H), 2.31 (m, 1H), 2.64 (d, 2H), 7.15 (s, 2H), 9.98 (b, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:4]1=[O:19])[CH3:2].CS([C:24]1[N:25](COCC[Si](C)(C)C)[C:26]2[C:27]([N:32]=1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O.[H-].[Na+]>CN(C=O)C.CO>[CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:24]3[NH:32][C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[N:25]=3)=[CH:16][CH:17]=2)[C:4]1=[O:19])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2ncccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4[nH]3)cc2)c2ncccc21
Temperature: 200 °C
Yield: 14.7 %

Procedure:
The mixture of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (281 mg), 2-(methylsulfonyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazo[4,5-b]pyridine (240 mg) and NaH (35.2 mg) in DMF (dry) (3 ml) was heated at 200° C. for 3 h under microwave irradiation. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was diluted with 6N HCl. The mixture was neutralized with aq. NaHCO2 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-3-[4-(3H-imidazo[4,5-b]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (40 mg) as white crystals.
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Br:9][CH2:10][C@@H:11]([C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1)[OH:12].N1C=CN=C1.CCCCCC>CN(C=O)C>[Br:9][CH2:10][C@H:11]([O:12][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])[C:13]1[CH:24]=[CH:23][C:16]2[O:17][C:18]([CH3:22])([CH3:21])[O:19][CH2:20][C:15]=2[CH:14]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC[Si](CC)(CC)O[C@@H](CBr)c1ccc2c(c1)COC(C)(C)O2
Temperature: 15 °C
Yield: 99.9 %

Procedure:
Triethylsilyl chloride (205 g) was added dropwise to a stirred mixture of (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g) and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete addition the mixture was warmed to 15° C. and stirred, at this temperature for 1 h. n-Hexane (3500 ml) was then added to the mixture which was washed with water (3×1750 ml). The organic layer was dried over anhydrous MgSO4 before being filtered and concentrated under reduced pressure to give the title compound (488.6 g) as an oil, δ (DMSO-d6) 7.18 (1H, d, J 8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m), 4.78 (2H, d, J 6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1 Hz), 0.51 (6H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[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.[I-].[Na+].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 78.3 %

Procedure:
(R)-8-(Benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)-quinolin-2(1H)-one (5.0 g, 10.2 mmol) was dissolved in dimethyl formamide (90 mL) and water (10 mL). Sodium iodide (1.7 g, 11.3 mmol) and sodium azide (0.7 g, 11.3 mmol) were added sequentially. The reaction mixture was stirred at RT until all the solid was in solution. The solution was heated at 80° C. for 40 hours then cooled to RT and diluted with water (300 mL). The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude residue was recrystallised from ethyl acetate and iso-hexane to afford the desired compound, (3.6 g, 78%), used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O.CCOCC>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 8.00 g. of p-chlorocinnamic acid and 4.72 ml. of thionyl chloride in 50 ml. ether is added 1.01 ml. of dimethyl formamide. Two liquid phases are then formed and the reaction mixture is stirred overnight at room temperature. The upper phase is decanted and the solvent evaporated from it to yield p-chlorocinnamoyl chloride.
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: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CC(C)[C@@H]1C(=O)NCCN1C(=O)OC(C)(C)C
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]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[N-:12]=[N+]=[N-].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:12][CH2:6][CH2:5]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 6.9 %

Procedure:
A suspension of 5-bromo-1-indanone (15 g, 71 mmol) in concentrated sulfuric acid (75 mL) was cooled to 0° C. Sodium azide (6.5 g, 100 mmol) was added portionwise over 1 hour. The reaction was allowed to warm to room temperature and stirred for 24 hours. The mixture was poured onto ice, neutralised with 4N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by dry flash chromatography using 50–100% ethyl acetate/isohexane to give 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1.1 g, 7%). δH (500 MHz, CDCl3): 7.92 (1H, d, J=8.3 Hz), 7.49 (1H, dd, J=1.4, 8.3 Hz), 7.39 (1H, d, J=0.9 Hz), 6.46 (1H, s), 3.57–3.55 (2H, m), 2.98 (2H, t, J=6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][OH:9])[N:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:3]=1
Reactant: Nc1cccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
1.26 g (10.2 mmol) of 2-amino-6-hydroxymethylpyridine (Journal of Heterocyclic Chemistry, 2001, 38, 173) was dissolved in 5.1 mL of dimethylformamide and 1.7 g (25 mmol) of imidazole was added thereto. Under cooling with ice, 1.8 g (12 mmol) of tert-butyldimethylsilyl chloride was added thereto followed by stirring at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and the organic layer was washed with water and brine. This was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a silica gel column chromatography to give 1.9 g of the title compound as an orange-colored oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].CN1CCOCC1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:8]1)=[O:6]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Solvent: Cc1ccccc1
Solvent: CN1CCOCC1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 12 h

Procedure:
Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N-methylmorpholine (0.97 mmol) in toluene (10 mL). Add dropwise, methanesulfonyl chloride (0.066 g, 0.57 mmol). After 12 hours, dilute with toluene (20 mL) and extract with 1M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>O.C(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
The starting material is prepared as follows: To the stirring mixture of 244 g of p-hydroxybenzaldehyde, 360 g of potassium carbonate, 32 g of potassium iodide, 1.2 lt of 95% aqueous ethanol and 160 ml of water is added slowly 367 g of m-chlorobenzyl chloride. The mixture is stirred at reflux for four hours, cooled to 80° and 2 lt of warm water are added while stirring. The mixture is cooled, the precipitate collected, washed with water and recrystallized from methanol, to afford the 4-(3-chlorobenzyloxy)-benzaldehyde melting at 51°-54°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH3:16][NH2:17]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:16])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A solution of 4-chloro-3-nitrobenzenesulfonyl chloride (10 g, 39.1 mmol) in THF (100 mL) was cooled to −40° C. before being treated with a solution of methylamine hydrochloride (2.64 g, 39.1 mmol) in 10 ml of water followed by TEA (5.44 mL, 39.1 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 1 hour before being partitioned between 350 mL EtOAc and 30 mL brine. The organic layer was washed twice with brine, dried over MgSO4 and subjected to flash chromatography (330 g silica gel, 0-40% EtOAc/hexane) to afford 4-chloro-N-methyl-3-nitrobenzenesulfonamide (6.38 g, 65%) as a light yellow solid. MS (m/z) 251.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>ClCCl.O.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:10][CH2:9][C:3]1[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(I)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(I)cc1CBr
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a mixture of 2-chloro-5-iodotoluene (4.07 g, 16.12 mmol), N-bromosuccinimide (3.16 g, 17.73 mmol) in dichloromethane (258 mL) and water (258 mL) was added 2,2′-azodiisobutyronitrile (0.132 g, 0.81 mmol). The reaction mixture was irradiated with a halogen sun lamp (150 watt) for 2 h and then cooled to room temperature. The two-phase reaction mixture was separated, and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were washed with water (2×150 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an orange oil (5.20 g).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH3:10].[C:12](OC)(=[O:16])[C:13]([CH3:15])=[CH2:14].O.COC1C=CC(O)=CC=1>CO>[C:12]([O:11][CH:8]([CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCCCCC(O)CC
Agent: COc1ccc(O)cc1
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)OC(CC)CCCCCCC

Procedure:
In the same reactor as used in Example 1, 760 kg (5 kmoles) of tricyclo[5.2.1.02,6 ]deca-8-yl alcohol and 1500 kg (15 kmole) of methyl methacrylate were placed and well mixed with stirring. The water content of the resulting mixture was 2500 ppm. To the mixture, 550 g of hydroquinone monomethyl ether was added and heated while introducing thereinto dried air at a rate of 4 m3/ hr and reluxing methyl methacrylate through the distillation column to remove water by azeotropic distillation. After 1 hour from the beginning of the reflux of methyl methacrylate, the water content in the reactor became 630 ppm. Then, 3 kg of anhydrous lithium hydroxide was charged into the reactor to carry out the reaction. While removing methanol by-produced by the reaction from the reaction system by distillation, the reaction was continued until almost no methanol was distilled (about 7 hours), followed by removal of unreacted methyl methacrylate under reduced pressure. After cooling, the mixture was filtered under pressure (2 kg/cm2) using a filter paper (pore size 0.1 mm, area 5 m2) placing thereon 10 kg of diatomaceous earth to yield 990 kg of tricyclo[5.2.1.02,6 ]deca-8-yl methacrylate with the filtrating time of 2 hours.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].C([O-])(=[O:46])C.C([OH:50])C.[ClH:51]>C(OCC)(=O)C>[CH3:1][CH2:2][C:3]1[C:12]2[CH2:13][N:14]3[C:19](=[O:20])[C:18]4[CH2:21][O:22][C:23]([C@:25]([OH:28])([CH2:26][CH3:27])[C:17]=4[CH:16]=[C:15]3[C:11]=2[N:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:36][CH2:37]1)=[O:31])[CH:7]=[CH:8]2)=[O:24].[OH2:46].[OH2:50].[OH2:20].[ClH:51]
Reactant: CCO
Reactant: CC(=O)[O-]
Agent: CCc1c2c(nc3ccc(OC(=O)N4CCC(N5CCCCC5)CC4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: Cl
Solvent: CCOC(C)=O
Product: O
Reaction time: 1 h

Procedure:
To a 16 L reactor was charged amorphous irinotecan acetate (234 g) and ethanol (1300 g). The reaction mixture was heated to reflux. 9N Hydrochloric acid (14.3 wt %, about 89 g) was added until the pH value of the solution was less than 4 in order to dissolve the solid particles. Ethyl acetate (2040 g) was added slowly to the mixture. The mixture was cooled to 0˜10° C. and stirred at this temperature for 1 hour. The solid particles were filtered and washed with cooled ethyl acetate (420 g). The wet cake was dried in vacuum to give 160 g of irinotecan hydrochloride trihydrate form IV.