Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH3:49][CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:25])[C:22]([N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH3:49])[CH2:51]3)=[O:24])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC1CCCNC1
Reactant: C[C@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN(C(=O)[C@@H](C)N2CC[C@H](NS(=O)(=O)c3ccc4cc(Cl)ccc4c3)C2=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.018 g) in DCM (0.5 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.018 g), HOBT (0.013 g) and triethylamine (0.039 ml) and the mixture was stirred at room temperature for 75 min. 3-Methylpiperidine (0.010 ml) was added and the resultant mixture stirred at room temperature for 48 h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract concentrated under reduced pressure and the residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 2:1, 1:1; ethyl acetate; ethyl acetate:methanol 2:1, 1:1) to give the title compound (0.007 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[CH3:25][O:26][CH2:27][C:28](Cl)=O>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:28]2[CH2:27][O:26][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (8001) at 0° C. was added methoxyacetyl chloride (49.7 μl, 0.545 mmol). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[(methyloxy)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (16 mg, 14%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.23 (s, 3H), 3.49-3.54 (m, 4H), 3.57-3.65 (m, 4H), 4.36 (s, 2H), 5.54 (s, 2H), 6.54 (d, J=7.6 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=7.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9](O)=[CH:8][C:7]1=[O:13]>C(N)C1C=CC=CC=1>[CH2:5]([NH:6][C:9]1[CH:10]=[CH:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)[C:7](=[O:13])[CH:8]=1)[C:4]1[CH:14]=[CH:15][CH:16]=[CH:2][CH:3]=1
Reactant: O=c1cc(O)ccn1Cc1cccc(F)c1
Solvent: NCc1ccccc1
Product: O=c1cc(NCc2ccccc2)ccn1Cc1cccc(F)c1
Temperature: 185 °C

Procedure:
A mixture of 1-(3-fluorobenzyl)-4-hydroxypyridin-2(1H)-one (1.005 g, 4.5 mmol) in benzylamine (15 mL) was heated at reflux (185° C.) under nitrogen atmosphere for 24 hours. The reaction was monitored by ES-MS (MH+ 309). The solvent was removed by vacuum distillation to give a yellow residue. 1H-NMR (CD3OD, 400 MHz) δ7.31 (m, 7H), 7.03 (m, 3H), 5.98 (d, 1H, J=7.2 Hz), 5.45 (s, 1H), 5.00 (s, 2H), 4.30 (s, 2H); ES-HRMS m/z 309.1403 (M+H calculated for C19H18N2OF requires 309.1375).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:17]=1)[CH3:11]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)o1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (150 mg, 0.78 mmol) was coupled to aniline (60) (150 mg, 0.78 mmol) using Method C to give the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C=O)C>[F:13][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:51]=[C:50]([C:52]3[CH:61]=[CH:60][CH:59]=[C:58]4[C:53]=3[CH:54]=[CH:55][N:56]=[CH:57]4)[N:49]=2)=[CH:11][CH:12]=1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1
Temperature: 120 °C
Yield: 46 %

Procedure:
4-[(Trifluoromethyl)oxy]benzoic acid (Aldrich; 132 mg, 0.642 mmol) was stirred in DMF (1 ml) with HATU (244 mg, 0.642 mmol) and DIPEA (0.28 ml, 1.605 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 100 mg, 0.535 mmol) in DMF (1 ml). The resulting mixture was heated to 120° C. for 30 mins in a Biotage Initiator microwave. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-80% ethyl acetate in cyclohexane. The relevant fractions were combined and concentrated under vacuum to give the title compound as a white solid (88 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([OH:19])=O)[CH:14]([CH3:16])[CH3:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:17]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH:14]([CH3:15])[CH3:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CC(C)[C@H](NC(=O)CCCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)CCCc1ccccc1)C(=O)N1CCCC1
Temperature: 25 °C

Procedure:
After completion of the reaction, the mixture was extracted twice with ethyl ether to remove the unreacted acid chloride. The water phase was acidified by addition of hydrochloric acid. The resulting precipitate was extracted three times with ethyl acetate and the solvent was removed under vacuum, whereby N-(γ-phenyl)butyryl-L-valine was obtained. N-(γ-phenyl)butyryl-L-valine (1 equivalent) was then dissolved in dry methylene chloride (ca. 100 ml) together with pyrrolidine (1 equivalent), WSCD (1 equivalent) was added thereto and the mixture was continuously stirred at room temperature for one whole day and night. After the reaction the product had been washed successively with 1N hydrochloric acid, brine, saturated sodium bicarbonate and brine in that order, and had then been dried over anhydrous magnesium sulfate, the solvent was distilled off under vacuum and the residue was purified by column chromatography on silica gel, whereby the titled compound was obtained.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.C(=O)([O-])[O-].[K+].[K+].Br[CH:41]1[CH2:45][CH2:44][NH:43][C:42]1=[O:46].O>CS(C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH:41]2[CH2:45][CH2:44][NH:43][C:42]2=[O:46])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C1NCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.7 %

Procedure:
15.8 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 70 ml of dimethylsulfoxide, and 5.8 g of anhydrous potassium carbonate are added thereto. The mixture is stirred at room temperature for 20 minutes. 6.6 g of 3-bromo-2-pyrrolidone are added to said mixture, and the mixture is stirred at room temperature for 20 hours. The mixture is poured into 800 ml of water, and crystalline precipitates are collected by filtration and washed with water. The crystals are dissolved in chloroform, washed with water and then dried. Then, the chloroform solution is evaporated under reduced pressure to remove solvent. 100 ml of ethyl acetate are added to the residue, and allowed to stand at room temperature. Crystalline precipitates thus obtained are collected by filtration and dried. 16.0 g of ethyl (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetate are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:10]=[N:11][C:12](F)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1COCC1>[NH2:1][C:2]1[C:21]([Br:22])=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:10]=[N:11][C:12]([O:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)nc2)oc2cc(N)c(Br)cc12
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)nc2)oc2cc(N)c(Br)cc12
Temperature: 90 °C
Yield: 59.1 %

Procedure:
To a degassed solution of 6-amino-5-bromo-2-(6-fluoropyridin-3-yl)-N-methylbenzofuran-3-carboxamide (500 mg, 1.41 mmol) and 4-fluorophenol (460 mg, 5.21 mmol) in DMF/THF (1 mL/7 mL) was added K2CO3 (260 mg, 5.62 mmol) under N2. The mixture was heated at 90° C. for 8 h. The reaction mixture was concentrated in vacuo and it was extracted with EtOAc. It was washed with H2O, brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EA=4:1) to give the product of 6-amino-5-bromo-2-(6-(4-fluorophenoxy)pyridin-3-yl)-N-methylbenzofuran-3-carboxamide (380 mg, yield: 61%). 1H-NMR (CDCl3, 400 MHz) δ 8.61 (d, J=2.4 Hz, 1H), 8.23˜8.25 (m, 1H), 7.74 (s, 1H), 7.02˜7.09 (m, 4H), 6.91 (d, J=8.8 Hz, 1H), 8.85 (d, J=4.8 Hz, 1H), 5.76 (s, 1H), 4.20 (s, 2H), 2.95 (d, J=5.2 Hz, 3H). (M+H)+: 456/458.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1cc2ccccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3ccccc3n2)n1
Yield: 16.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (204 mg, 1.07 mmol) and 2-but-3-ynyl-2H-indazole (183 mg, 1.07 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 50 mg (0.18 mmol, 17%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24](=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[O:31]=[C:24]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 18 h
Yield: 7.4 %

Procedure:
To a stirred solution, under N2 atmosphere, of 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) (10.0 g, 38 mmol), and triethylamine (15.35 g, 150 mmol) in methylene chloride (100 mL) was added ethyl 3-chloro-3-oxopropionate (6.32 g, 42 mmol). The reaction was stirred for 18 hours. The reaction mixture was concentrated down in vaco and purified by flash silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give an orange solid (0.86 g, 7%); 1H NMR (300 MHz, CDCl3) δ 1.32 (t, J=7.2 Hz, 3 H), 2.55 (t, J=6 Hz, 4 H), 3.46 (s, 2 H), 3.56 (t, J=6 Hz, 4 H), 4.22 (q, J=7.2 Hz, 2 H), 6.93(d, J=9.0 Hz, 2 H), 7.47(d, J=9.0 Hz, 2 H), 9.09 (s, 1 H); MS (ES) m/z: 305.3(MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH3:32][CH:33]1[CH2:42][CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34]1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41][CH2:42][CH:33]2[CH3:32])=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: CC1CCc2ccccc2N1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2ccccc2N1C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 18.1 %

Procedure:
A solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (34.1 mg, 0.12 mmol, 1.0 equiv; Example 31, Step 1) in thionyl chloride (492 mg, 300 μL, 4.14 mmol, 34.5 equiv; [CAS RN 7719-09-7]) was heated to 100° C. over night. The reaction mixture was concentrated under reduced pressure, remaining thionyl chloride removed by azotropic distillation with toluene and the residue dissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (155 mg, 204 μL, 1.20 mmol, 10.0 equiv; [CAS RN 7087-68-5]) and 2-methyl-1,2,3,4-tetrahydro-quinoline (22.1 mg, 0.15 mmol, 1.25 equiv; [CAS RN 1780-19-4]) and the reaction mixture heated by microwave irradiation to 100° C. for 15 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9 mg (18%) of the title compound. MS (ISP): 412.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](O)=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[C:7]=1[NH:15][CH3:16])=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19]>CN(C)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:19])=[CH:10][C:9](=[O:13])[N:8]([CH3:14])[C:7]=1[NH:15][CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)cc(=O)n(C)c1NC
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(Cl)cc(=O)n(C)c1NC
Temperature: 25 °C
Reaction time: 21 h
Yield: 86.6 %

Procedure:
Dimethylaniline (0.770 mL, 0.61 mmol) was added to a stirring solution of example 31b (15 g, 66.1 mmol) in POCl3 (36 mL, 397 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 21 h. The reaction was concentrated in vacuo, poured onto ice, and the resulting precipitate was collected by filtration to give 14 g (87%) of clean desired product as a beige solid. The filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure to give an additional 2 g (12%) of clean desired product. 1H NMR (400 MHz, DMSO-d6): δ 6.99 (q, 1H, J=4.8 Hz), 5.80 (s, 1H), 4.23 (q, 2H, J=7.2 Hz), 3.32 (s, 3H), 2.76 (d, 3H, J=4.8 Hz), 1.27 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C10H13ClN2O3, 245; found 245.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:5](=[O:6])[CH2:4][CH2:3]1.C[O-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=O)=[CH:17][CH:18]=1.S(=O)(=O)(O)O>C(OC)(C)(C)C.O>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[C:4]2[CH2:3][CH:2]([CH3:1])[O:7][C:5]2=[O:6])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC1CCC(=O)O1
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: COc1ccc(C=C2CC(C)OC2=O)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
74 g (0.5 mol) of 4-methyl-γ-butyrolactone are added to a suspension of 27 g (0.50 mol) of sodium methoxide in 400 g of methyl tert-butyl ether and, over the course of 1 h, 68 g (0.5 mol) of anisaldehyde are added thereto with stirring at room temperature. The mixture is maintained under reflux for a further 1 h and then cooled, and 200 g of iced water are added to the mixture and the pH is adjusted to 5 using 10% sulphuric acid. After the phases have separated, the product is distilled. This gives 65 g of the desired compound in a yield of 48% of theory. The specific absorbance E{fraction (1/1)} of the novel compound according to the present invention is 1.250, measured at a wavelength of λmax 310 nm.
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:45])C=1>C(Cl)Cl.O>[OH:45][N:14]([CH:15]1[CH2:16][N:17]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)=[CH:23][CH:22]=2)=[O:20])[CH2:18]1)[C@H:11]1[CH2:12][CH2:13][N:9]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:8])[CH2:10]1
Reactant: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1)N1CC(N[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1)N1CC(N(O)[C@H]2CCN(C(=O)c3ccccc3)C2)C1
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of Compound 16 (60 mg, 0.12 mmol) in dry CH2Cl2 (1 mL) was added mCPBA (77%, 33 mg, 0.146 mmol) at 0° C. and the resulting mixture was stirred at this temperature for 30 min. The reaction mixture was diluted with CH2Cl2 and water. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 5% MeOH/EtOAc) gave compound 54 (7 mg). MS m/z (M+Na+) 510.0, MS m/z (M+Na+) 532.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[S:7][CH:8]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:21][S:22]([O:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[S:7][CH:8]=1)(=[O:24])=[O:23]
Reactant: COc1cc(-c2nc(CCO)cs2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(-c2nc(CCOS(C)(=O)=O)cs2)cc(OC)c1OC
Reaction time: 1.5 h

Procedure:
4-(2-Hydroxyethyl)-2-(3,4,5-trimethoxyphenyl)-thiazole (1.60 g) was dissolved in pyridine (15 mL), and to the solution methanesulfonyl chloride (807 mg) was added at 0° C., and the mixture was stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:10]
Reactant: Nc1cc(Cl)ccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Nc1cc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
In a 2 L 3-neck round bottom flask, the stirred solution of (2-amino-4-chlorophenyl)methanol 2 (32 g, 203.82 mmol) in DCM (765 mL), manganese (IV) oxide (150 g, 1.724 mol) was added at rt. The resulting reaction mixture was stirred at rt under argon atmosphere for 40 h. On completion of reaction the reaction mixture was filtered through CELITE™ pad and solid residue was washed thoroughly with DCM (1000 mL). The combined filtrate was concentrated under reduced pressure to give 2-amino-4-chlorobenzaldehyde as orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][N:14]1[S:18](=[O:20])(=[O:19])[N:17]2[CH2:21][CH2:22][CH2:23][CH:16]2[C:15]1=[O:24]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:13][N:14]1[S:18](=[O:20])(=[O:19])[N:17]2[CH2:21][CH2:22][CH2:23][CH:16]2[C:15]1=[O:24])=[O:5]
Reactant: O=C1C2CCCN2S(=O)(=O)N1CCl
Reactant: O=C(O)c1c(Cl)cccc1Cl
Solvent: CO
Product: O=C(OCN1C(=O)C2CCCN2S1(=O)=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a solution of CS2CO3 (0.47 g; 1.44 mmol) in 10 ml of methanol was added 0.55 g (2.88 mmol) of 2,6-dichlorobenzoic acid and the resulting mixture was stirred under nitrogen at room temperature for 3 hours. The above mixture was concentrated in vacuo to remove the excess methanol, the residue suspended in 10 ml of DMF and 2-chloromethyl-tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (0.5 g; 2.6 mmol) was added. The resulting mixture was allowed to react at 90° C. for 3 hours and then cooled. The mixture was poured into ice/water, extracted with ether/ethyl acetate (3:1; 250 ml), and the organic layer was washed with water and brine, and dried. The organic layer was concentrated in vacuo and the residue was purified by silica gel flash chromatography (35% ethyl acetate in hexane) to afford 0.6 g (61%) of 2-(2,6-dichlorophenylcarbonyloxymethyl) tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 and R3 together =-(CH2)3 -) as a solid, m.p. 92°-93.5° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Na+:12].[C:13]1(=[O:29])[N:17]([CH:18]([CH3:23])[CH2:19][C:20](Cl)=[O:21])[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:14]12>C1(C)C(C)=CC=CC=1>[C:16]1(=[O:24])[N:17]([CH:18]([CH3:23])[CH2:19][C:20]([O:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:8]([O-:11])(=[O:9])=[O:10])=[O:21])[C:13](=[O:29])[C:14]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:15]12.[Na+:12]
Reactant: CC(CC(=O)Cl)N1C(=O)c2ccccc2C1=O
Reactant: O=S(=O)([O-])c1ccccc1O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(CC(=O)Oc1ccccc1S(=O)(=O)[O-])N1C(=O)c2ccccc2C1=O

Procedure:
148.0 g (755 mmol) of anhydrous sodium phenolsulfonate and 190.0 g (755 mmol) of γ-phthalimidobutanoyl chloride are reacted in 200 g of xylene at 140° C. for 4 hours and the mixture is worked up as in Example 1. The crude product is recrystallized from methanol and the white crystalline product is dried at 40° C. under a water pump vacuum.