Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]([S:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:20](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+].C(P(CCCC)CCCC)CCC>CC(C)=O.O.C1(C)C=CC=CC=1>[C:1]1(=[C:6]2[NH:20][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1SC(=O)C1CCCC1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=C2CCCC2)Sc2ccccc21
Temperature: -15 °C
Yield: 19 %

Procedure:
2-[(Cyclopentylcarbonyl)thio]benzoic acid (11.53 g, 46 mmol) was suspended in acetone (150 ml). While stirring under ice cooling, triethylamine (5.10 g, 50 mmol) and then ethyl chloroformate (6.68 g, 62 mmol) were dropwise added to the suspension. After stirring at the same temperature for an hour, an aqueous solution (15 ml) of sodium azide (5.00 g, 77 mmol) was dropwise added to the reaction mixture, followed by further stirring for an hour. The reaction mixture was diluted with water and the dilution was extracted with toluene (100 ml×3). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then filtered. The toluene solution was cooled to about −15° C. and a solution (10 ml) of tributylphosphine (10.50 g, 52 mmol) in toluene was dropwise added to the solution. After completion of the dropwise addition, the reaction temperature was reverted to room temperature and the mixture was heated under reflux for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was recrystallized from acetone-ethyl acetate to give the title compound (2.02 g, 19%) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][OH:17])[CH2:14][N:13]([CH3:18])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.CO>[Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:14][N:13]([CH3:18])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](CO)[C@H]1CO2
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](COS(C)(=O)=O)[C@H]1CO2
Reaction time: 0.25 h

Procedure:
To a solution of 1.69 g of (±)-[4R*,4aS*,10bR*]-7-bromo-4-(hydroxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2 H-[1]benzopyrano[4,3-c]pyridine and 0.82 ml triethylamine in 60 ml CH2Cl2 is added 0.42 ml of methanesulfonyl chloride. After 15 min. 1 drop methanol is added and the reaction mixture is washed with saturated NaHCO3 and dried over Na2SO4. Filtration and removal of solvents under reduced pressure yields (±)-[4R*,4aS*,10bR*]-7-bromo-4-(methylsulfonyloxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2-methyl-2H-[1]benzopyrano[4,3-c]pyridine.
Reaction SMILES: [OH2:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([OH:9])[CH3:8].ClCl>O1CCCC1>[CH3:8][C:7]1[O:9][CH:6]=[CH:5][C:4](=[O:1])[C:3]=1[OH:2]
Reactant: CC(O)c1ccco1
Reactant: O
Agent: ClCl
Solvent: C1CCOC1
Product: Cc1occc(=O)c1O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an addition funnel was added 20 ml of tetrahydrofuran and 50 ml of water. The solution was cooled to a temperature of 0° to 10° C. The addition funnel was charged with a solution of 1(2-furyl)-1-ethanol (0.089 moles) in 20 ml of tetrahydrofuran and this was added dropwise to the stirred reaction flask while chlorine (0.30 mole) was added via the gas inlet tube. The rate of addition was such that all the alcohol was added in the first 1.3-1.5 equivalents of chlorine (approximately 30 minutes) while maintaining the reaction temperature below 10° C. The reaction mixture was heated to reflux and the tetrahydrofuran removed by distillation. When the reaction mixture reached a temperature of about 105° C., a condensor was added and the refluxing continued for about 2 hours. The reaction mixture was then filtered hot, cooled, the pH adjusted to 2.2 and the reaction mixture was cooled to 5° C. Crystallization and filtration yielded 3.43 grams of crude 3-hydroxy-2-methyl-γ-pyrone (maltol). The aqueous filtrate was extracted with CHCl3 to obtain a second crop of 2.58 g of maltol. Distillation of the combined solids and recrystallization from methanol gave 5.5 g (49%) of pure white maltol, m.p. 159.5°-160.5° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:12])=[O:13])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N(C)S(C)(=O)=O)cc1
Yield: 64.1 %

Procedure:
Ex-101A: A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 2.0 g, 9.4 mmol) in anhydrous DMF (300 mL) was treated with potassium carbonate (2.59 g, 18.8 mmol), followed by the addition of methyl iodide (5.85 mL, 94 mmol). The reaction mixture refluxed for two hours and was then treated with more methyl iodide (5.85 mL, 94 mmol). The reaction refluxed for another two hours, and reaction completeness was confirmed by HPLC analysis. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was collected, dried over sodium sulfate, and concentrated to a clear oil with residual DMF. Water (25 mL) was added to precipitate a white solid. The white solid was then filtered and dried by vacuum oven at 20° C. (−20 mm Hg) to give 1.37 g (64%) of N-(4-acetyl-phenyl)-N-methyl-methanesulfonamide. 1H-NMR (CDCl3) δ 7.88 (d, 2H), 7.48 (d, 2H), 3.38 (s, 3H), 2.86 (s, 3H), 2.60 (s, 3H). HRMS m/z: calc. 530.1307, found 530.1313.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[F:24][C:25]([F:43])([F:42])[S:26]([O:29][C:30]1[C:39]([CH2:40]Br)=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[CH:31]=1)(=[O:28])=[O:27].[NH4+].[Cl-]>C1COCC1>[F:42][C:25]([F:24])([F:43])[S:26]([O:29][C:30]1[C:39]([CH2:40][N:17]2[C@@H:16]([CH3:21])[C@@H:15]([C:7]3[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:5]([C:4]([F:3])([F:22])[F:23])[CH:6]=3)[O:19][C:18]2=[O:20])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[CH:31]=1)(=[O:27])=[O:28]
Reactant: O=S(=O)(Oc1cc2c(cc1CBr)CCCC2)C(F)(F)F
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydride (6-8 mg, 60% dispersion in mineral oil, 0.205 mmol) was added to a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (49.0 mg, 0.156 mmol) in dry THF (2 mL) at room temperature under N2. After stirring for 15 min at room temperature a solution of 3-(bromomethyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (48.6 mg, 0.130 mmol) in dry THF (3 mL) was added via cannula. The reaction mixture was stirred for 4 h at room temperature. Saturated NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 3-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate, as a colorless oil. Rf=0.51 (20% EtOAc/hexanes). LCMS calc.=606.1; found 606.2 (M+1)+. 1H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H); 7.76 (s, 2H); 7.20 (s, 1H); 6.99 (s, 1H); 5.69 (d, J=7.9 Hz, 1H); 4.80 (d, J=15.6 Hz, 1H); 4.25 (d, J=15.6 Hz, 1H); 4.08-4.02 (m, 1H); 2.81-2.74 (m, 4H); 1.82-1.80 (m, 4H); 0.77 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 74 %

Procedure:
A solution of 9.3 g of 6-methoxy-1-indanone, 11.8 ml of 3-buten-2-ol and 100 mg of p-toluenesulfonic acid in 100 ml of 2,2-dimethoxypropane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 4:1). 9.2 g (74%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone were obtained as a yellow oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:46]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[CH:36][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:46])[C:30](=[O:35])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]c(=O)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(ccc(=O)n5C)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-oxo-1,2-dihydroquinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (13.0 mg, 0.020 mmol) in DMF (0.8 mL) was added Cs2CO3 (13.0 mg, 0.041 mmol) and methyl iodide (3.0 μL, 0.050 mmol). The reaction mixture was heated at 80° C. for 3 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H35ClN3O4S: 652.2; found: 652.3.
Reaction SMILES: [CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.CCOC(C)=O.CCN(CC)CC>CCO.CCOC(C)=O>[CH:1]([C@H:14]1[O:19][CH2:18][C@@H:17]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH2:28])=[CH:26][CH:27]=2)[CH2:16][CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Agent: Cl[Sn]Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(CN[C@H]2CC[C@@H](C(c3ccccc3)c3ccccc3)OC2)cc1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A mixture of cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-nitro-benzyl)-amine (16f) (0.16 g, 0.39 mmol) and SnCl2/2H2O (0.35 g, 1.55 mmol) in EtOH/EtOAc (20 ml, 7:3) was heated to reflux for 1.5 h (monitored by TLC, Hex/EtOAc/Et3N 5:5:0.4). After removal of the solvent, the residue was diluted with 10% NaHCO3 and EtOAc and stirred vigorously for 30 min. After filtration the organic phase was separated and the aqueous phase was extracted with EtOAc (20 ml×2). The combined organic phase was dried over Na2SO4. After removal of the solvent, flash chromatography gave 16o, cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-amino-benzyl)-amine (0.087 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl.CO>[NH2:1][C:2]1[N+:7]([O-:32])=[C:6]([NH:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1
Reactant: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(N)[n+]1[O-]

Procedure:
350 g of methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate are suspended in 6.3 l of methylene chloride and 1 l of methanol. At room temperature there are added thereto 370 g of m-chloroperbenzoic acid and the mixture is stirred for a further 16 hours. The yellowish solution is subsequently extracted with 3 l of 2N soda solution. The aqueous phase is extracted with 1 l of methylene chloride. The combined organic phases are washed with 2 l of water and evaporated in vacuo. The crystalline residue is suspended in 1.5 l of ether while stirring. The pale yellowish crystals are filtered off under suction and washed with 0.5 l of ether. After drying at 40° in vacuo, there is obtained methyl 2-amino-6-[(p-tolylsulfonyl)oxy]-4-pyrimidinecarbamate-3-oxide.
Reaction SMILES: O.[N:2]1[C:15]2[C:6](=C[CH:8]=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[O-:18][Mn](=O)(=O)=O.[K+]>O>[CH:10]1[C:9]2[C:8](=[O:18])[C:6]3[C:15](=[N:2][CH:3]=[CH:4][CH:5]=3)[C:14]=2[N:13]=[CH:12][CH:11]=1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1c2cccnc2-c2ncccc21
Yield: 0 %

Procedure:
To a boiling solution of phenanthroline monohydrate (2.2 g, 11.1 mol) and KOH (2 g, 35.5 mol) in water (130 ml), a hot solution of KMnO4 (5 g, 31.5 mol) in water (80 ml) was added dropwise over ca. 1 h. The mixture was refluxed for another 2 h, and then filtered hot. The orange filtrate was cooled and extracted with chloroform, the combined organic extracts were dried over anhydrous Na2SO4. After solvent removal, the crude product was further purified by column chromatography on silica gel using acetone/petroleum ether (2:1) as the eluent, the product was isolated as a yellow solid (980 mg, 48%). 1HNMR (ACETONE-D6,400 MHz): δ=8.80(d, J=5.0 Hz, 2H), 8.06 (d, J=7.5 Hz, 2H), 7.50 (dd, J1=7.5 Hz, J2=5.0 Hz, 2H). HRMS calcd for 182.1782, found 182.0369.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([CH2:27][CH2:28][CH2:29]O)[CH:4]=[N:3]1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>O1CCCC1.O1CCOCC1.O>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[CH2:27][CH2:28][CH2:29][N:35]1[C:31](=[O:41])[C:32]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:33]2[C:34]1=[O:36]
Reactant: Cn1ncc(CCCO)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cn1ncc(CCCN2C(=O)c3ccccc3C2=O)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
To a solution of 3-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)propanol (4.0 g, 10 mmol), phthalimide (1.5 g, 10 mmol) and triphenylphosphine (4.0 g, 15 mmol) in tetrahydrofuran (20 ml) was added diisopropyl azodicarboxylate (3.0 g, 15 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 4 mol/l hydrogen chloride solution in dioxane (10 ml), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the mixture was washed with ethyl acetate. The organic layer was separated, and the aqueous layer was adjusted to pH 9 with 10% aqueous sodium carbonate solution. The solution was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate and dried in vacuo to give 5-amino-1-methyl-4-(3-phthalimidopropyl)pyrazole (2.2 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:16]1C=CC(S(O)=O)=[CH:21][C:17]=1C(O)=O.BrCC1CC1>C1(CO)CC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][CH:21]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Agent: BrCC1CC1
Agent: OCC1CC1
Product: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and Bromomethyl-cyclopropane (+catalytic amount 12) in 20 ml cyclopropyl methanol/20 ml water and obtained in 8% yield. MS (m/e): 273.1 (MH−, 100%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(=O)(O)[O-].[Na+].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2.Cl>C(Cl)Cl>[CH3:16][N:17]([C:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:9])[CH2:18][CH2:19][CH2:20][N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2
Reactant: O=C(Cl)c1cccnc1
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCN1c2ccccc2CCc2ccccc21)C(=O)c1cccnc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Freshly prepared nicotinoyl chloride hydrochloride (0.55 g, 0.003 mol) was suspended in methylene chloride (12 ml) cooled to 5° C. and sodium bicarbonate (0.053 g, 0.0063 mol) was added. After 5 minutes, desipramine hydrochloride (0.75 g, 0.0025 mol) was added and the mixture was stirred for 3 hours at 5° C. The sodium chloride was removed by filtration and the organic solution was extracted with aqueous sodium bicarbonate, dried over sodium sulfate, filtered through Celite™ and concentrated. Ethyl ether (5 ml) was added to the oily residue and white crystals formed. Yield 62% (0.58 g), m.p. 84°-86° C. The product has the formula: ##STR1628##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH:33]1([N:36]2[CH2:41][C:40]3([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[O:39][CH2:38][C:37]2=[O:47])[CH2:35][CH2:34]1>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:44]2[CH2:45][CH2:46][C:40]3([O:39][CH2:38][C:37](=[O:47])[N:36]([CH:33]4[CH2:34][CH2:35]4)[CH2:41]3)[CH2:42][CH2:43]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: NC(=O)C(O)c1c(F)cc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)C(c1c(F)cc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 40 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (4.56 g, 17.1 mmol) and triethylamine (7.17 mL, 51.4 mmol) in anhydrous acetonitrile (25 mL) was added neat methanesulfonyl chloride (1.7 mL, 22.3 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had proceeded to completion. To the mesylate intermediate was added more triethylamine (7.2 mL, 51.4 mmol) followed by 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (4.23 g, 17.1 mmol). The reaction was heated at 90° C. for 3 h until starting material was consumed. The reaction was diluted with water (25 mL) then the phases were separated and the aqueous phase was extracted with ether (3×25 mL). The combined ether phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) provided the title product (1.26 g, 16% yield). MS(ES)+ m/e 458 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.59-0.69 (m, 2 H) 0.75-0.86 (m, 2 H) 1.61-1.74 (m, 2 H) 1.85-1.95 (m, 2 H) 2.21 (s, 1 H) 2.53-2.64 (m, 2 H) 2.66-2.76 (m, 3 H) 2.79 (br. s., 1 H) 3.96 (s, 2 H) 4.68 (s, 1 H) 5.64 (br. s., 1 H) 7.16-7.26 (m, 2 H) 7.35 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.O.[Cl:34][C:35]1[C:36]([OH:64])=[C:37]([S:42]([N:45]([CH2:50][C:51]2[CH:56]=[C:55]([CH2:57][NH:58][CH2:59][CH:60]([CH3:62])[CH3:61])[CH:54]=[C:53]([Cl:63])[CH:52]=2)[CH2:46][CH:47]([CH3:49])[CH3:48])(=[O:44])=[O:43])[CH:38]=[C:39]([Cl:41])[CH:40]=1>CN(C=O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:58]([CH2:57][C:55]2[CH:56]=[C:51]([CH2:50][N:45]([CH2:46][CH:47]([CH3:49])[CH3:48])[S:42]([C:37]3[CH:38]=[C:39]([Cl:41])[CH:40]=[C:35]([Cl:34])[C:36]=3[OH:64])(=[O:44])=[O:43])[CH:52]=[C:53]([Cl:63])[CH:54]=2)[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:8])=[CH:4][N:3]=1
Reactant: CC(C)CNCc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)CN(Cc1cc(Cl)cc(CN(CC(C)C)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1)C(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
To a solution of 6-chloronicotinic acid (34.1 mg, 0.22 mmol) in DMF (4 mL) were added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (60 mg, 032 mmol), HOBt.H2O (30 mg, 0.20 mmol) and 3,5-dichloro-N-(3-chloro-5-((isobutylamino)methyl)benzyl)-2-hydroxy-N-isobutylbenzenesulfonamide (100 mg, 0.20 mmol). The resulting reaction mixture was stirred at rt. for 18 h. The mixture was diluted with saturated NaHCO3 solution and ethyl acetate. The organic layer was concentrated. The residue was dissolved in 1 N NaOH solution and THF for 2 h. The mixture was concentrated and dissolved in MeOH, purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give the desired product as white solid (62 mg, 40%). 1H NMR (CD3OD): δ 8.50-8.35 (m 1H), 8.0-7.8 (m, 1H), 7.70-7.49 (m, 3H), 7.34 (m, 1H), 7.16 (m, 1H), 7.10 (m, 1H), 4.72-4.45 (m, 4H), 3.30-3.03 (m, 4H), 2.1-1.6 (m, 2H), 0.96-0.71 (m, 12H); MS (ESI): (M−H)−=646.0.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH:12]=1)[CH:10]=O.[C:25]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[C:25]([C:27](=[CH:10][C:9]1[CH:12]=[C:5]([O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:17][C:16]=2[Cl:24])[CH:6]=[CH:7][C:8]=1[N+:13]([O-:15])=[O:14])[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:26]
Reactant: O=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 52.6 %

Procedure:
19 g of 5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-benzaldehyde, 5.7 g of ethyl cyanoacetate, 0.6 g of acetic acid, 0.3 g of piperidine and 120 ml of toluene were mixed and heated to the boil for 6 hours under a water separator. 200 ml of toluene was then added and the organic phase was washed with water. The solvent was distilled from the organic phase and the residue was caused to crystallise by digestion with methanol. 12.5 g (53% of theory) of ethyl 2-cyano-3-(5-(2,6-dichloro-4-trifluoromethylphenoxy)-2-nitro-phenyl)-propenoate, of melting point 99° C., were obtained in the form of pale yellow crystals.