Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:4]1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CN(C)C=O>O>[F:21][C:11]1[CH:10]=[C:9]([N:5]2[CH2:4][C@H:3]([CH2:2][N:26]3[C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]4[C:22]3=[O:32])[O:7][C:6]2=[O:8])[CH:14]=[CH:13][C:12]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=C1O[C@@H](CCl)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
The mixture of (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone (60 g), potassium phthalimide (40 g) and Dimethyl formamide (400 ml) is heated for 5 hours at reflux temperature. The reaction mixture is cooled to ambient temperature, poured in to 2 L water and filtered the solid to give 50 gm (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:17][CH:18]1[NH:22][C:21](=O)[CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:21]3[CH2:20][CH2:19][CH:18]([CH3:17])[N:22]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)N(C1=NC(C)CC1)c1ccccc1O2

Procedure:
Reaction of 2-methoxyphenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-METHOXY-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE as an oil. Conversion of the free base to the hydrochloride salt affords 2-METHOXY-10-(5-METHYL-1-PYRROLIN-2-YL)-PHENOXAZINE HYDROCHLORIDE, m.p. 223.5°-224.5° C. (dec.)(corr.), as the hemihydrate by trituration with acetone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]#[N:18])=[CH:8][C:7]=2[CH:19]=1.[CH3:20][NH2:21]>C1COCC1>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:21][CH3:20])=[CH:19][C:7]=2[CH:8]=1)#[N:18]
Reactant: N#Cc1ccccc1-c1cc2cc(CBr)ccc2o1
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C

Procedure:
5.3 g (17.0 mmol) 5-(bromomethyl)-2-(2-cyanophenyl)benzofuran (prepared according to EP 434 249) were dissolved in 100 ml THF, and 25 ml of a 40% aqueous solution of methylamine were added via a dropping funnel. The mixture was stirred at room temperature over night. 2×15 ml of the solution of methylamine were added, and the mixture was stirred for additional 5 h in each case. The work-up and the isolation of the title compound was carried out as described in Step A of the preceding example to give a colorless powder after crystallization of the remaining oil upon stirring with t-butylmethylether, m.p. 180° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:20])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.1 %

Procedure:
4-Chloro-1-(4-methoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (15 g) was added to 270 ml of a dichloromethane solution containing 16.2 g of aluminum chloride and 10 g of 1,3-ethanedithiol and the mixture was stirred at room temperature, whereupon the starting material dissolved once and then a precipitate separated out. The mixture was allowed to stand at room temperature for 6 hours. The supernatant was then discarded, and 50 ml of acetone and 20 ml of water were added to the precipitate. To the resulting solution was added 20 ml of lN-hydrochloric acid to give a precipitate, which was dissolved in 150 ml of 75% ethanol. The solution was passed through a column of 50 ml of Amberlite IRC-50 (trademark) (H-form) and the column was washed with 75% ethanol. The effluent and washings were combined and diluted with water to the ethanol concentration of 50%. The above procedure gave 12 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless scales, m.p. 190°-192 ° C. (decompn.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)(C)O2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(=O)C(C)(C)O2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (720 g) is added to a solution of 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (453 g, 2.1 mol) in acetone (2 L). A solution of benzyl bromide (423 g, 2.5 mmol) in acetone (200 mL) is added portionwise over a period of 10 min. A slight exotherm is observed. After 3 hrs, the mixture is heated to reflux. After 39 hrs, TLC shows complete conversion to product. The mixture is cooled to 50° C. and filtered using 1.5 L of ethyl acetate to remove the solids from the flask. The solids are washed with ethyl acetate (1.5 L). The filtrate is concentrated. The resulting solids are dissolved in ethyl acetate (7 L). This solution is washed with water, dried (magnesium sulfate) and concentrated. The resulting solids are placed on a tray for air-drying. After 2 days, 5-benzyloxy-2,2,4,6,7-pentamethyl-2,3-d3-onenzofuran-3-one is collected (638g, 99%). mp=114° C.-115° C.
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:45])[O:15][C:14]2[C:13]([CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[C:12]3[O:21][C@@:22]45[C@@:32]6([CH2:37]/[CH:38]=[C:39](\[C:41]([OH:43])=[O:42])/[CH3:40])[O:33][C:34]([CH3:36])([CH3:35])[C@@H:23]4[CH2:24][C@H:25]([C:30]6=[O:31])[CH:26]=[C:27]5[C:28](=[O:29])[C:11]3=[C:10]([OH:44])[C:9]=2[CH:8]=[CH:7]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C1COCC1>C(Cl)Cl>[CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5][C@@:6]1([CH3:45])[O:15][C:14]2[C:13]([CH2:16][CH:17]=[C:18]([CH3:19])[CH3:20])=[C:12]3[O:21][C@@:22]45[C@@:32]6([CH2:37]/[CH:38]=[C:39](\[C:41]([OH:43])=[O:42])/[CH3:40])[O:33][C:34]([CH3:35])([CH3:36])[C@@H:23]4[CH2:24][C@H:25]([C:30]6=[O:31])[CH2:26][CH:27]5[C:28](=[O:29])[C:11]3=[C:10]([OH:44])[C:9]=2[CH:8]=[CH:7]1
Reactant: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(=C[C@@H]4C[C@H]1C(C)(C)O[C@@]2(C/C=C(/C)C(=O)O)C4=O)C3=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)=CCC[C@]1(C)C=Cc2c(O)c3c(c(CC=C(C)C)c2O1)O[C@]12C(C[C@@H]4C[C@H]1C(C)(C)O[C@@]2(C/C=C(/C)C(=O)O)C4=O)C3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.7 %

Procedure:
To a solution of gambogic acid (17 mg, 0.027 mmol) in methylenechloride (2 mL) was added L-selectride solution in THF (1.0 mL, 0.5 mmol) dropwise at −78° C. After 30 min of stirring, the reaction was quenched with 1 mL of 2 N HCl. The mixture was then allowed to warm to room temperature and was diluted with 1:1 hexane/EtOAc (50 mL). The resulting mixture was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (2:3 hexane/EtOAc/) to give the title compound as an oil (0.6 mg, 0.001 mmol, 4%). 1H NMR (CDCl3): 11.96 (s, 1H), 6.67 (d, J=10.2, 1H), 6.54 (t, J=6.6, 1H), 5.46 (d, J=10.2, 1H), 5.13-5.05 (m, 2H), 3.33-3.16 (m, 3H), 2.85 (d, J=13.8, 1H), 2.60 (d, J=8.7, 1H), 2.43 (s, 1H), 2.08 (m, 1H), 1.97 (s, 3H), 1.74 (s, 3H), 1.67 (s, 6H), 1.64 (s, 3H), 1.57 (s, 3H), 1.37 (s, 3H), 1.36 (d, J=6.9, 3H), 1.31-1.22 (m, 5H), 1.14 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[N:4][S:5]([C:8]1[S:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][N:2]([CH3:17])[CH:3]=[N:4][S:5]([C:8]1[S:16][C:11]2=[CH:12][N+:13]([O-:26])=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1cc2ccncc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)C=NS(=O)(=O)c1cc2cc[n+]([O-])cc2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a solution of N,N-dimethyl-N'-(thieno[2,3-c]pyridine-2-sulfonyl)formamidine (2.05 g, 7.6 mmol) in chloroform (30 ml) was added dropwise a solution of m-chloroperbenzoic acid (1.82 g, 8.5 mmol) in ethyl acetate (17 ml). After stirring at room temperature for 18 hours, the precipitated product was collected on a filter. The filtrate was concentrated to obtain additional product. The combined material (2.08 g) was crystallized from chloroform to give 1.98 g (91% yield) of pure product; m.p. 237°-239° C.
Reaction SMILES: Cl[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1.C([O-])=O.[NH4+]>CO.[Pd]>[F:29][C:25]1[CH:24]=[C:23]([C:3]2[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]3[CH:2]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)c(Cl)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(F)c2)cn2c1CN(C(=O)OC(C)(C)C)CC2
Yield: 99.7 %

Procedure:
A mixture of 6.00 g (14.2 mmol) of 2-tert-butyl 8-ethyl 6-chloro-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate, 13.4 g (212 mmol) of ammonium formate (CAS 540-69-2) and 0.6 g of 10% palladium-on-charcoal containing 50% water in 50 ml of methanol is stirred at reflux for 45 minutes. After cooling, the mixture is filtered through a Büchner funnel and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, the solution is washed with aqueous 2N sodium hydroxide solution and then dried over sodium sulfate, and the solvent is evaporated off under reduced pressure, to give 5.5 g of 2-tert-butyl 8-ethyl 7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in the form of a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=O)C.[NH:28]1[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C:4]([C:6]2[O:7][C:8]3[C:14]([N:15]4[CH2:20][CH2:19][N:18]([CH2:21][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:17][CH2:16]4)=[CH:13][CH:12]=[CH:11][C:9]=3[CH:10]=2)=[O:3])[CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1
Reactant: C1CNC1
Product: O=C(c1cc2cccc(N3CCN(Cc4ccccc4)CC3)c2o1)N1CCC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 39c starting from ethyl 7-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (1.0 g, 2.74 mmol) (Example 39b) and azetidine (0.20 mL, 3.02 mmol). Yield: 0.52 g (51%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([CH:22]=[O:23])[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CN(C)C=[O:28].OOS([O-])=O.[K+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22]([OH:28])=[O:23])[N:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:24]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C=O)ncc1OCC2
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(C(=O)O)ncc1OCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carbaldehyde (0.250 g, 0.771 mmol) was dissolved in N,N-Dimethylformamide (2 mL, 0.02 mol). Oxone® (0.569 g, 0.925 mmol) was added and the reaction mixture was stirred overnight at room temperature. A light-brown precipitate formed and was collected by filtration. LC-MS analysis verified precipitate as desired product, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine-10-carboxylic acid which was carried on without further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:34][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: COc1ccc(C(N)c2cccc(C(F)(F)F)c2)cc1
Product: COc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-methoxy-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[Br:13]N1C(=O)CCC1=O>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:10])=[C:8]([Br:13])[CH:9]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid methyl ester (1.0 g) in THF (10 mL) was added N-bromosuccinimide (1.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1, v/v) to give the title compound (1.16 g). (In the above, THF is tetrahydrofuran)
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[C:11]1[C:20]([O:21][S:22]([C:25]([F:28])([F:27])[F:26])(=[O:24])=[O:23])=[CH:19][CH:18]=[CH:17][C:12]=1[C:13](OC)=[O:14].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[N:4]1([C:1]2[O:3][C:11]3[C:20]([O:21][S:22]([C:25]([F:26])([F:27])[F:28])(=[O:23])=[O:24])=[CH:19][CH:18]=[CH:17][C:12]=3[C:13](=[O:14])[CH:2]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COC(=O)c1cccc(OS(=O)(=O)C(F)(F)F)c1O
Reactant: CC(=O)N1CCOCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=c1cc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12

Procedure:
Condensation of the lithium enolate of N-acetyl morpholine (2.2 ml) with methyl 2-hydroxy-3-trifluoromethanesulfonyloxy-benzoate (3.56 g, 11.9 mmol) yielded the salicylacatamide (3.6 g). Cyclodehydration of the product with trifluormethanesulfonic anhydride (5.5 ml) as described above yielded the product as a colourless solid (1.21 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25]3)=[O:23])=[N:12]2)=[CH:7][CH:6]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:14][C:13]([C:22]([N:24]3[CH2:28][CH2:27][C:26](=[O:29])[N:25]3[CH3:32])=[O:23])=[N:12]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(-n2nc(C(=O)N3CCC(=O)N3)cc2-c2ccccn2)cn1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(-n2nc(C(=O)N3CCC(=O)N3C)cc2-c2ccccn2)cn1
Reaction time: 0.25 h
Yield: 16 %

Procedure:
60% Sodium hydride (142.4 mg) was added to the above-obtained 1-[1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)pyrazole-3-carbonyl]-3-oxopyrazolidine (0.542 g) in N,N-dimethylformamide (5 mL) at room temperature, followed by stirring for 15 minutes. Subsequently, methyl iodide (0.828 mL) was added to the resultant mixture, followed by stirring for 10 days. Potassium carbonate (0.614 g) and methyl iodide (0.276 mL) were added to the reaction mixture. The resultant mixture was stirred at 60° C. for 2 hours, and then cooled in air. The reaction mixture was partitioned between saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate. The mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (ethyl acetate-hexane), to thereby give the title compound as a solid (89.8 mg, 15%).
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]=[C:40]=[O:41]>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:39]([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[F:31])[C:40]2=[O:41])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccc(F)cc3F)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 21, step 3) was reacted with sodium iodide and 2,4-difluorophenylisocyanate to give the title compound as a colorless solid. MS: 554.8 ([M+H]+)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1.Cl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=3)[S:39]([C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc(OCC(=O)OC)cc3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)c3cccs3)cc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 56.1 %

Procedure:
To a cold solution (0° C.) of methyl {4-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-phenoxy}acetate (40 mg, 0.091 mmol) in anhydrous pyridine (2 ml) was added 2-thiophenesulfonyl chloride (Aldrich, 82 mg, 0.45 mmol) and the reaction mixture was stirred at 0° C. for 4 hrs and at rt for an additional 15 hours. The reaction mixture was diluted with an aqueous solution of HCl (1N) and extracted with DCM (3×). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to give 30 mg (56%) of the title compound as a yellow oil. HPLC, Rt: 5.9 un purity: 92.5%). 1H NMR (CDCl3) δ: 7.61 (dd, J=5.3, 1.5 Hz, 1H), 7.58 (dd, J=3.8, 1.5 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.39 (d, J=7.9 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 7.12 (dd, J=5.3, 3.8 Hz, 1H), 7.04 (m, 4H), 6.78 (d, J=8.7 Hz, 2H), 4.61 (s, 2H), 4.33 (s, 2H), 4.30 (s, 2H), 3.81 (s, 3H), 2.63 (t, J=7.7 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20].[Cl-]>O1CCOCC1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(NC(=O)CBr)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-aminophenylacetic acid (3.0 g, 19.8 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (4.00 g, 1.74 mL, 19.8 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the chloride was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water. The resulting precipitate was filtered, washed with water, add then dried in a vacuum dessicator overnight to afford 2.75 (51%) of the title compound as a pale yellow crystals, mp 168°-171° C.: 1H NMR (DMSO-d6) δ12.28 (bs, 1H), 10.36 (s, 1H), 7.50 (d, J=8.8, 2H), 7.20 (d, J=8.4, 2H), 4.02 (s, 2H), 3.51(s, 2H); 13C NMR (DMSO-d6) δ172.70, 164.65, 137.12, 130.45, 129.76, 119.12, 40.12, 30.40; MS (EI, m/z) 271 (M+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[CH2:13][NH:12][C@@H:11]([CH2:14][OH:15])[CH2:10]1.[S:17](Cl)(Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:8][C:9]1([CH3:16])[CH2:13][N:12]2[S:17](=[O:19])(=[O:18])[O:15][CH2:14][C@H:11]2[CH2:10]1
Reactant: CC1(C)CN[C@@H](CO)C1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@@H]2COS(=O)(=O)N2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
A solution of triethylamine (4.94 mL, 35.4 mmol) and (R)-(4,4-dimethylpyrrolidin-2-yl)methanol (2.29 g, 17.72 mmol) in DCM (89 mL) was cooled to −78° C. To this mixture was added sulfuryl chloride (1.0 M in DCM, 21.27 mL, 21.27 mmol) over 15 seconds. The reaction was maintained at this temperature for ˜3 h, allowed to warm to room temperature and stirred overnight (16 h). The mixture washed with aqueous 1 N HCl (30 mL×2), brine (40 mL), dried over MgSO4, filtered and concentrated affording crude product as a brown-orange oil that crystallized upon standing. The crude material was absorbed onto a plug of silica gel and purified by chromatography on an ISCO Combiflash™ RF (40 g Grace Reverlis column, using a gradient of 0-60% EtOAc in heptane) affording (R)-5,5-dimethyltetrahydro-3H-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (708 mg, 3.70 mmol, 21% yield) as a white crystalline solid. MS (ESI) 192.1 [M+H]+.