Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8]C(=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: CC(=O)N1CCC(=O)CC1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(C(C)=O)CC1
Yield: 89.2 %

Procedure:
A solution of 1-acetyl-4-piperidone (17.0 g, 121 mmol), trimethyl orthoformate (26.4 mL, 241 mmol) and para-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) in dry methanol (34 mL) was refluxed for one hour. Then 1.0 M methanolic NaOMe (0.42 mL, 0.42 mmol) and excess of methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure afforded 1-acetyl-4,4-dimethoxy-piperidine (20.2 g, 89%) 1H NMR (DMSO) δ 3.45-3.32 (m, 4H), 3.10 (s, 6H), 1.99 (s, 3H), 1.72-1.62 (m, 2H), 1.61-1.52 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:37])=O.N1C=CC=CC=1.C(=O)(O)[O-]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][Cl:37])=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:33])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CO)cc2)nn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(CCl)cc2)nn1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of [5-({[1-(4-Hydroxymethyl-benzyl)-1H-[1,2,3]triazole-4-carbonyl]-amino}-methyl)-4,6-dimethyl-pyridin-2-yl]-carbamic acid tert-butyl ester (690 mg, 1.331 mmol) in 10 mL of DCM was added dropwise a solution of thionyl chloride (0.107 mL, 1.464 mmol) and pyridine (1.615 μL, 0.02 mmol) in 10 mL of DCM. The reaction mixture was stirred for 3 h at 40° C. and saturated aqueous bicarbonate solution was added. The layers were separated and the aqueous layer was extracted with DCM. The combined organic solution was dried over MgSO4, filtered and concentrated under vacuum to yield the crude product which was used in the next step without further purification. LCMS (Method A) RtA=1.681; [M+H]+=485.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1>C1COCC1>[CH3:22][S:21][C:17]1[N:18]=[C:19]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[CH:20]=[CH:15][N:16]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(Oc2cccc(C(F)(F)F)c2)n1

Procedure:
In THF, a phenoxide was prepared from 3-(trifluoromethyl)phenol (4.54 g, 0.0187×1.5 mol) was mixed with NaH (1.12 g (ca. 60% in mineral oil), 0.0187×1.5 mol), and 4-chloro-2-(methylthio)pyrimidine (Compound No. VII-1) (3.0 g, 0.0187 mol) was added thereto and the mixture was refluxed for about 10 hours. The reaction solution was partitioned between ethyl acetate and aqueous saturated sodium hydrogen carbonate to separate an organic phase. The organic phase was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated, then recrystallized from a methanol/water system to obtain the intermediate compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10].N1CCCCC1>C1(C)C=CC=CC=1>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15](/[C:18](=[CH:6]\[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)/[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: O=Cc1ccsc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(/C(=C\c2ccsc2)C(=O)O)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-thiophenecarboxaldehyde (1.40 mL, 15.0 mmol), (4-methanesulfonylphenyl)acetic acid (3.23 g, 15.0 mmol), and piperidine (0.45 mL, 4.5 mmol) in PhMe (21 mL) was heated under reflux with stirring for 16 h. On cooling, the PhMe was decanted off from the oily solid that had settled at the bottom of the reaction vessel. This solid was partitioned between 1M HCl (60 mL) and EtOAc (400 mL), then the aqueous phase was extracted further with EtOAc (60 mL). The combined organic layers were washed with H2O (60 mL), before being shaken with saturated aqueous Na2CO3 (100 mL). The resulting emulsion was filtered through Celite. The organic layer was extracted further with saturated aqueous Na2CO3 (2×100 mL). The combined aqueous layers were washed with Et2O (80 mL), before being filtered through Celite and carefully acidified with AcOH to adjust the pH to 4. The off-white precipitate formed was collected, washed thoroughly with H2O, and air dried to furnished the title compound: m/z (ES+)=634.2 [2M+NH4]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH2:13][OH:14])[CH:19]=[CH:18][CH:17]=1
Reactant: O=c1oc(CO)c(Br)c2ccccc12
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1oc(CO)c(-c2cccc(F)c2)c2ccccc12
Yield: 39.6 %

Procedure:
The title compound was made in a similar way as that of the intermediate B2 using 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.5 g, 1.960 mmol), 3-fluorophenylboronic acid (0.4 g, 2.86 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and Cs2CO3 (0.96 g, 2.94 mmol) to afford the title compound (0.21 g, 40%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:25][CH:27]3[CH2:28][O:29]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH3:24])[CH:18]=3)[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(-c2n[nH]c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2nn(CC3CO3)c3c2CN(C(=O)OC(C)(C)C)CC3)ccc1Cl
Reaction time: 72 h
Yield: 56.1 %

Procedure:
To a solution of 3-(4-chloro-3-methyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (18.26 g, 53 mmol) and epichlorohydrin (41.12 mL, 526 mmol) in DMF (100 mL) was added cesium carbonate (20.56 g, 63 mmol). The reaction mixture was allowed to stir for 72 h, diluted with EtOAc (200 mL) and washed with saturated NaHCO3 and brine. The organic layer was dried over Na2SO4, concentrated and purified by column chromatography (silica, 20% acetone/CH2Cl2) to afford 3-(4-chloro-3-methyl-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (12.0 g, 57%). TLC (silica, 20% acetone/CH2Cl2): Rf=0.68. MS (electrospray) m/z 491.2 (491.2, calculated for C27H31ClN6O, [M+H]+). 1H NMR (400 MHz, CDCl3) 7.55 (s, 1H), 7.36 (m, 2H), 4.61 (m, 2H), 4.38-4.47 (m, 1H), 4.11 (dd, J=14.3, 5.7 Hz, 1H), 3.67-3.79 (m, 2H), 3.34 (m, 1H), 2.83 (t, J=4.5 Hz, 1H), 2.75 (m, 2H), 2.51 (m, 1H), 2.41 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [OH-].[K+].[CH2:3](N)[CH2:4]N.[CH3:7][O:8][C:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C:18]2=[O:28])[CH:10]=1>C(O)(C)(C)C>[C:3]([C@@:18]1([OH:28])[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]12[CH3:20])[C@:24]1([CH3:27])[C:11]([CH:10]=[C:9]([O:8][CH3:7])[CH2:26][CH2:25]1)=[CH:12][CH2:13]3)#[CH:4]
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reactant: NCCN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C#C[C@@]1(O)CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 4 h

Procedure:
Potassium hydroxide (7.75 g), calcium carbide (21.0 g), t-butanol (19 ml) and ethylene diamine (187 ml) are combined in a 500 ml Parr pressure bottle which is sealed with a foil covered rubber stopper which is wired to the bottle. The heterogenous mixture is stirred at 40° for about 16 hr (though about 4 hr is sufficient). The mixture is cooled to 20°-25° and 3-methoxyandrosta-3,5-dien-17-one (IAa, 11.80 g) is added as a solid. The reaction mixture is then stirred at 20°-25° for 5 hr. The mixture is transferred to a flask with a mechanical stirrer. The mixture is washed with methylene chloride (300 ml), cooled to 0°, quenched under a nitrogen atmosphere by the slow addition of acetic acid (57.2 ml). Water (300 ml) is added at a sufficiently slow rate to keep foaming under control. The mixture is filtered and the solids washed with methylene chloride. The filtrate phases are separated, the aqueous phase is back-extracted (twice) with methylene chloride. The organic phases are combined, washed with water (three times), dried over sodium sulfate and concentrated to an oil. The oil in ethyl acetate (75 ml) is heated to reflux and is allowed to crystallize at 20°-25° overnight to give the title compound, NMR (CDCl3) 0.90, 1.0, 2.47, 3.59, 5.15 and 5.23 δ.
Reaction SMILES: COC1N=CC(C#N)=CC=1.[CH3:11][O:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([C:20]#[N:21])=[CH:15][CH:14]=1.CO[C:24](OC)([N:26]([CH3:28])[CH3:27])[CH3:25].CN(C)C=O>CO>[CH3:27][N:26]([CH3:28])[C:24]([CH3:25])=[CH:19][C:17]1[C:16]([C:20]#[N:21])=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[N:18]=1
Reactant: COC(C)(OC)N(C)C
Reactant: COc1ccc(C#N)c(C)n1
Agent: COc1ccc(C#N)cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(C#N)c(C=C(C)N(C)C)n1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
2-2-(Dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile--A mixture containing 47.2 g of 6-methoxy-2-methyl-3-pyridinecarbonitrile, 100 ml of dimethylacetamide dimethyl acetal and 100 ml of dimethylformamide was heated with stirring in an oil bath at 130° C. for 1 hour and 45 minutes. The temperature of the oil bath was raised to 150° C. and the methanol formed by the reaction was distilled off using a 12" distillation column (Vigreux) while continuing the heating at 150° C. for 14 hours. The reaction mixture was concentrated, 50 ml of ether was added to the concentrated solution whereupon the product crystallized out. The mixture was chilled and the crystalline solid collected. The solid was washed with cold ether, dried and recrystallized from ethyl acetate using decolorizing charcoal to yield 33.5 g of 2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p. 103°-104° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5](=[O:25])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14](=[O:24])[C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[CH:8][CH:7]=1)C.[OH-].[Na+].O>CO>[O:24]=[C:14]([C:15]1[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21])[CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[O:25])[C:4]([OH:26])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)c1ccc(OCC(=O)c2c(C)cc(C)cc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c(C(=O)COc2ccc(C(=O)C(=O)O)cc2)c(C)c1
Yield: 73.6 %

Procedure:
A solution of 4-[2-oxo-2-(2,4,6-trimethylphenyl]ethoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.357 g) in hot methanol (5 mL) was treated with 1N sodium hydroxide (2 mL). Water (20 mL) was added, then after the methanol was removed in vacuo, the solution was acidified with 1N hydrochloric acid (2.5 mL) and extracted with dichloromethane methane (1×40 mL, 1×7 mL). The combined organic layers were washed with brine, then dried (MgSO4) and evaporated. The resulting residue was crystallized from diethyl ether-hexane to furnish 0.242 g of 4-[2-oxo-2-(2,4,6-trimethyl-phenyl]ethoxy]-alpha-oxobenzeneacetic acid, mp 144°-145° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5](N)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[BrH:13].N([O-])=O.[Na+].[OH-].[Na+]>O.Br.O.C(OCC)(=O)C>[Br:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH2:3][N:2]([CH3:1])[CH2:11][CH2:10]2
Reactant: Br
Reactant: CN1CCc2cccc(N)c2C1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCc2cccc(Br)c2C1
Temperature: 0 °C

Procedure:
Into a 50 mL 3-necked round bottom flask (named A), was placed 2-methyl-1,2,3,4-tetrahydroisoquinolin-8-amine (500 mg, 3.08 mmol). This was followed by the addition of a solution of HBr (5 mL) in H2O (5 mL), which was added dropwise with stirring, while cooling to a temperature of 0° C. To the above was added NaNO2 (230 mg, 3.33 mmol) in several batches, while cooling to a temperature of 0° C. and the mixture was stirred for 30 mins at that temperature. Then into another 50 mL 3-necked round bottom flask (named B), was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of CuBr (550 mg, 3.83 mmol) in HBr/H2O (3 mol/L) (10 mL), while cooling to a temperature of 0° C. The mixture was stirred for 10 minutes. Then was followed by the addition of the reaction solution of flask A with dropwise while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for 30 minutes while the temperature was maintained at 0° C. The resulting solution was allowed to react, with stirring, for an additional 2 hours at room temperature. The reaction progress was monitored by TLC(ethyl acetate:petroleum ether=1:1). Adjustment of the pH to 9 was accomplished by the addition of NaOH (10%). The resulting solution was extracted three times with 50 mL of CH2Cl2 and the organic layers combined and dried over K2CO3. A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 1:1 ethyl acetate; petroleum ether solvent system. This resulted in 0.45 g (65%) of 8-bromo-2-methyl-1,2,3,4-tetrahydroisoquinoline as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[C:4]([CH3:15])[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[S:25])=[C:4]([CH3:15])[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cc(N)ccc1N1CCCCC1=O
Solvent: Cc1ccccc1
Product: Cc1cc(N)ccc1N1CCCCC1=S
Reaction time: 0.67 h
Yield: 171.5 %

Procedure:
10 g (48.95 mmol) of 1-(4-amino-2-methylphenyl)piperidin-2-one are heated to the boil in 70 ml of anhydrous toluene together with 9.9 g (24.48 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent). After 40 minutes, the solvent is removed, and the residue is taken up in dichloromethane (DCM)/1 M aqueous hydrochloric acid. After repeated washing with DCM, a pH of 12 is set using conc. sodium hydroxide solution. Extraction with DCM, drying over Na2SO4 and evaporation of the solvent give 9.25 g (41.98 mmol) of 1-(4-amino-2-methylphenyl)piperidine-2-thione.
Reaction SMILES: CCCCCCCCCCCCCCCCCCSC1SC(=C2S[C:27]3[CH:29]=[C:30]([C:33]4[N:37]([O-])C(C)(C)C(C)(C)[N+]=4[O-])[CH:31]=[CH:32][C:26]=3S2)SC=1SCCCCCCCCCCCCCCCCCC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O1CCCC1.O.NOS(O)(=O)=O.O1CCCC1>[C:30]1([CH3:33])[CH:31]=[CH:32][C:26]([C:29]2[CH:27]=[CH:26][CH:32]=[CH:31][C:30]=2[C:33]#[N:37])=[CH:27][CH:29]=1
Reactant: CCCCCCCCCCCCCCCCCCSC1=C(SCCCCCCCCCCCCCCCCCC)SC(=C2Sc3ccc(C4=[N+]([O-])C(C)(C)C(C)(C)N4[O-])cc3S2)S1
Agent: NOS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
1 molar equivalent of o-(p-tolyl)-N-cyclohexylbenzaldimine is dissolved in a 1/1 mixture of tetrahydrofuran/water and X molar equivalents of aminohydroxysulphonic acid are added. This mixture is maintained at a temperature T for 1 hour, which gives a mixture of OTBO/OTBN. This mixture is diluted in tetrahydrofuran, 10 molar equivalents of phosphorus pentoxide are then added and the mixture is allowed to react for a further 1 hour at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[CH:30]=[CH:31][NH:32]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)noc2c1
Reaction time: 68 h
Yield: 103.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mmol) CH3CN (100 ml) was stirred at reflux under N2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H2O and saturated NaCl and after drying over MgSO4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH-CH2Cl2 as eluent) to yield 3.4 g (61%) of a beige solid. Two consecutive recrystallizations from EtOH provided 2.3 g (41%) of a white powder, m.p.=129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]2[C:23](=[O:24])[C:22]3[CH2:25][CH2:26][CH2:27][CH2:28][C:21]=3[C:20]2=[O:29])=[C:4]([F:30])[CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([O:18][CH:17]1[CH2:16][O:15][CH2:14][CH:13]1[O:12][C:10]([CH2:9][O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:30])=[C:5]([N:19]2[C:20](=[O:29])[C:21]3[CH2:28][CH2:27][CH2:26][CH2:25][C:22]=3[C:23]2=[O:24])[CH:6]=1)=[O:11])(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: O=C(COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl)OC1COCC1O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1COCC1OC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.1 %

Procedure:
In 15 ml of benzene were dissolved 0.66 g of N-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethoxy)phenyl)-3,4,5,6tetrahydrophthalimide and 0.20 g of triethylamine, followed by dropwise addition of a solution of 0.14 g of acetyl chloride in benzene. After stirring at room temperature for 4 hours, the reaction mixture was washed with water and subsequently with aqueous saturated sodium chloride solution, and 'dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane=2/3), to obtain 0.55 g of a compound described in Table 1 (No.3) (76%).
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[CH:28]=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
H2O2 (70%, 0.12 mL, ca. 2.4 mmol) was added dropwise to a stirred solution of TFAA (0.34 mL, 2.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 172 (70 mg, 0.2 mmol) and TFA (95 μL, 1.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 173 (38 mg, 52%) as a red solid: mp (MeOH/EtOAc) 139-142° C.; 1H NMR δ 8.06 (d, J=8.9 Hz, 1H, H-5), 7.51 (d, J=8.9 Hz, 1H, H-6), 7.38 (br s, 1H, NH), 3.59-3.66 (m, 2H, CH2N), 3.49-3.55 (m, 2H, CH2), 2.83-2.92 (m, 2H, CH2), 2.61-2.65 (m, 2H, CH2N), 2.32 [s, 6H, N(CH3)2], 1.80-1.88 (m, 4H, 2×CH2).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15].Cl[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=2)=[CH:9][C:8]=1[C:14]([F:15])([F:16])[F:17]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A 250 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (50 ml), 4-chloro-3-trifluoromethyl-phenol (4.6 g), 2-chloro-3-methyl-5-nitro-pyridine (4.0 g) and potassium carbonate (6.4 g). The reaction mixture is heated at 100° C. for 2.5 hours. After cooling the mixture to room temperature it is then poured into water (200 ml). The mixture is then extracted with ethylacetate (2×40 ml). The combined organic layers are dried over sodium sulfate, filtered and the solvent is removed in vacuo to obtain 6.10 g of the compound as yellow solid (MP: 95-97° C.).