Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=1)[C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.N1C=CC=CC=1>[Cl:15][C:14]1[CH:13]=[N+:12]([O-:16])[CH:11]=[C:10]([Cl:17])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:6][C:4](=[O:5])[C@@H:3]([NH:2][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)Oc1ccc(C[C@H](N)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
4-((S)-2-((S)-2-amino-3-(4-(methylsulfonyloxy)phenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (30 mg, 0.05 mmol) was dissolved in DCM (2 ml) and pyridine (100 μl), then methanesulfonyl chloride (7 mg, 0.06 mmol) was added. The mixture was stirred at RT for 2 h, then was washed with HCl 1N (2×). The crude was purified by semi-preparative HPLC to give 29 mg of the final compound (Yield: 80%)
Reaction SMILES: [Cl:1]C(OC(Cl)=O)C.[Cl:8][C:9]1[C:29]([C:30]#[N:31])=[CH:28][C:12]([C:13]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20]CC2C=CC=CC=2)=[O:14])=[C:11]([O:32][CH3:33])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C>[ClH:1].[Cl:8][C:9]1[C:29]([C:30]#[N:31])=[CH:28][C:12]([C:13]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH3:20])=[O:14])=[C:11]([O:32][CH3:33])[CH:10]=1
Reactant: COc1cc(Cl)c(C#N)cc1C(=O)NCCNCCCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: CCNCCNC(=O)c1cc(C#N)c(Cl)cc1OC
Product: Cl
Temperature: 0 °C

Procedure:
While stirring at 0° C., 2.7 g (19 mmol) of α-chloroethylchloroformate (cf. J. Org. Chem. 49, 2081 (1984)) are added dropwise to a solution of 4.7 g (12.7 mmol) of 4-chloro-5-cyano-N-(2-benzylethylaminoethyl)-2-methoxybenzamide (cf. Example 2) and 90 mg (0.6 mmol) of potassium carbonate in 200 ml of dichloroethane. The whole is then heated under reflux for 3 hours. The reaction mixture is then concentrated to dryness in vacuo, 200 ml of methanol are added to the residue and the whole is heated for 2 hours under reflux. Concentration is repeated, and the residue is taken up in 200 ml of 2N sodium hydroxide solution and extracted three times with chloroform. The combined organic phases are dried over magnesium sulphate, filtered and concentrated by evaporation. The resulting crude material is purified by chromatography over 200 g of silca gel using methylene chloride/methanol/ammonia in a ratio of 100:10:1. The fractions containing the desired product are combined and concentrated by evaporation. The residue is taken up in 50 ml of methanol and, while cooling, the pH is adjusted to 3 using hydrochloric acid. Ether is then added, the hydrochloride crystallising out. 4-chloro-5-cyano-N-(2-ethylaminoethyl)-2-methoxybenzamide hydrochloride having a melting point of 190° -192° C. is obtained.
Reaction SMILES: CN(C)/[CH:3]=[C:4]1\[C:5](=O)[CH:6]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=2)[CH2:7][CH2:8][CH2:9]\1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]2[N:46]=[CH:3][C:4]3[CH2:9][CH2:8][CH2:7][CH:6]([C:10]4[CH:11]=[C:12]([F:18])[C:13]([F:17])=[C:14]([F:16])[CH:15]=4)[C:5]=3[N:45]=2)[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1
Reactant: CN(C)/C=C1/CCCC(c2cc(F)c(F)c(F)c2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2cc(F)c(F)c(F)c2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-[1-dimethylamino-meth-(Z)-ylidene]-6-(3,4,5-trifluoro-phenyl)-cyclohexanone (120 mg, 0.42 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (131 mg, 0.35 mmol) using in analogous manner the procedure described in example 45b). Obtained as a yellow solid (64 mg, 64%). MS ISP (m/e): 466.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.57 (s, 1H), 8.36 (s, 1H), 7.60 (m, 2H), 7.01-7.18 (m, 4H), 6.98 (s, 1H), 4.18 (m, 1H), 3.55 (s, 3H), 2.73 (m, 2H), 2.13 (s, 3H), 1.70-2.20 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(OCC)C>[O:4]=[C:1]([N:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14][CH2:15]1)[CH:2]=[CH2:3]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 13 %

Procedure:
A solution of acryloyl chloride (4.52 g, 0.05 mole) in 25 ml of ethyl ether was added to a cold solution of 1-benzylpiperazine (8.8 g, 0.05 mole) and triethylamine (30 ml, 0.20 mole) in 500 ml of ethyl ether. A white precipitate formed. The reaction mixture was stirred overnight, filtered and the precipitate washed well with ethyl ether. The solvent and triethylamine were removed and the product chromatrographed on silica, eluting with ethyl acetate/hexane [30:70(v/v)] to yield 1.5 g of the title compound. The structure was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=2[C:25]([OH:27])=O)[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O>C1COCC1>[ClH:1].[Cl:1][C:2]1[N:3]2[C:4](=[N:22][C:23]3[C:24]([C:25]2=[O:27])=[C:28]([F:32])[CH:29]=[CH:30][CH:31]=3)[C:5]2[C:10]([F:11])=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Nc4cccc(F)c4C(=O)O)nc(Cl)nc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Product: Cl
Yield: 164.3 %

Procedure:
A slurry of 2-({2-chloro-5-fluoro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid (0.68 g, 1.420 mmol) in THF (100 mL) was treated with a drop of DMF, followed by a solution of oxalyl chloride (2M in CH2Cl2, 2.84 mL, 5.48 mmol). After 30 min Et20 (50 mL) was added. The resulting slurry was filtered and the solids were washed with Et2O, then dried in vacuum to obtain 5-chloro-1,8-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride as a pale yellow solid (580 mg, 82%). 1H NMR (400 MHz, THF-d8) δ ppm 2.41 (s, 3H), 7.14 (dd, J=10.07, 8.61 Hz, 1H), 7.45 (d, 8.06 Hz, 3H), 7.56 (d, J=2.56 Hz, 1H), 7.69-7.83 (m, 1H), 8.09 (d, J=8.42 Hz, 2H), 10.84 (br s, 1H); ESIMS (M+H)+=460.98.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]2[O:19][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[FH:26].C(=O)(O)[O-].[Na+]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([F:26])[C@@H:10]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H]2O[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@@H](F)[C@@H]1O
Temperature: 0 °C
Reaction time: 9 h

Procedure:
To a solution of (±)-(1S,2R,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-1,2,3,4-tetrahydro-naphthalene (100 mg) in anhydrous diethyl ether (6 ml) cooled in an ice-bath was added 70% hydrogen fluoride pyridine (0.24 ml). The mixture was stirred at 0° C. for 9 hours, ice was added and the reaction mixture was neutralized by addition of solid sodium bicarbonate (1.2 g) at 0° C. and extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated to afford the crude title compound as an oil (65 mg). This crude material was purified by chromatography on silica gel (10 g, elution with ethyl acetate:cyclohexane, 2:8) and the resulting material (35 mg) was crystallized from a diethyl ether/pentane mixture to afford the title compound as a white solid, m.p. 98-99° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12]Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:15])=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[NH2:16][C:17]1[N:21]=[C:20]([SH:22])[NH:19][N:18]=1.C(N(CC)CC)C.[F-].[K+].[O:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:35][CH2:34][CH2:33]1>CN(C=O)C>[Cl:15][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:14])[N:10]=[C:11]([CH2:12][S:22][C:20]1[NH:21][C:17]([NH2:16])=[N:18][N:19]=1)[C:2]([N:39]1[CH2:40][CH2:41][C:36]3([O:35][CH2:34][CH2:33][O:32]3)[CH2:37][CH2:38]1)=[N:3]2
Reactant: C1CC2(CCN1)OCCO2
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Reactant: Nc1n[nH]c(S)n1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nnc(SCc2nc3cc(Cl)c(Cl)cc3nc2N2CCC3(CC2)OCCO3)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2,6,7-trichloro-3-chloromethylquinoxaline (107 mg, 0.38 mmol) in DMF (5 ml) was added 3-amino-5-mercapto-1,2,4-triazole (44 mg, 0.38 mmol) followed by addition of triethylamine (0.05 ml, 0.38 mmol). After 5 hours, potassium fluoride 40% wt on alumina (143 mg, 1.1 mmol) was added, followed by 1,4 dioxa-8-aza-spiro[4,5]decane (0.05 ml, 0.42 mmol). The reaction was stirred overnight at room temperature. Purification by flash column chromatography using ethyl acetate afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:16](=[O:17])[CH:11]3[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:19]2=[O:18])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1ccc(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(Cl)cc1F

Procedure:
9.44 parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° C. to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5°.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[O:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:6][NH:5][CH2:4]1.Cl[C:18]1[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:19]=1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:2][C:3]1([CH3:16])[O:8][CH:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:6][N:5]([C:18]2[N:23]([CH3:24])[C:22](=[O:25])[CH:21]=[C:20]([C:26]3[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=3)[N:19]=2)[CH2:4]1
Reactant: CC1(C)CNCC(c2ccc(F)cc2)O1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(N2CC(c3ccc(F)cc3)OC(C)(C)C2)nc(-c2ccncc2)cc1=O
Yield: 85.7 %

Procedure:
A solution of 2,2-dimethyl-6-(4-fluorophenyl)morpholine hydrochloride (127 mg, 0.517 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (109 mg, 0.491 mmol) and triethylamine (0.180 ml, 1.29 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature. After stirring for several hours, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (166 mg, 81%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[C:42]([F:50])[CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:48])[CH3:49])=[C:42]([F:50])[CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OC(C)C)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC(C)C)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-ethyl-1-(3-fluoro-4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.23 g, 48%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:32][CH3:33])[CH:3]=1.C(N(CC)CC)C.[C:41]1([C:46](Cl)=[O:47])[S:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:33][O:32][C:4]1[CH:3]=[C:2]([O:1][C:46]([C:41]2[S:45][CH:44]=[CH:43][CH:42]=2)=[O:47])[CH:7]=[CH:6][C:5]=1[C:8]1[C:9]([CH2:21][O:22][C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]2[CH3:20]
Reactant: O=C(Cl)c1cccs1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC(=O)c2cccs2)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
6-(4-Hydroxy-2-methoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 25.6 mg, 0.0577 mmol) was dissolved in anhydrous methylene dichloride (1 mL), and then triethylamine (19 μL, 0.14 mmol) and 2-thenoyl chloride (11.2 mg, 0.0764 mmol) were added thereto. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.8 mg) as a pale yellow amorphous product. (Yield 93%)
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[CH2:31][NH2:32])[CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH:32][CH2:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:35][CH:34]=2)[CH2:25]1)=[O:33])=[O:7]
Reactant: NCC(=O)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.060 mmol) in chloroform. (0.4 mL) was added to a solution of (S)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give (S)-3-[N-{3,5-bis(trifluoromethyl)benzoyl}glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 5) (14.4 mg, 57%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 508.0 (M++H, C22H20ClF6N3O2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]([F:29])([F:28])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]3[CH2:22]S[CH2:20]3)=[O:17])=[C:14]([F:25])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.O[O:31][S:32]([O-:34])=O.[K+]>CC(C)=O.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:26]([F:29])([F:28])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:24]=[CH:23][C:15]([C:16]([NH:18][CH:19]3[CH2:22][S:32](=[O:34])(=[O:31])[CH2:20]3)=[O:17])=[C:14]([F:25])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: O=C(NC1CSC1)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC1CS(=O)(=O)C1)c1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluoro-N-(thietan-3-yl)benzamide (100 mg, 0.2159 mmol) in acetone/water (1:1, 5.0 mL) was added oxone (266 mg, 0.4319 mmol) and the resultant reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) afforded the title compound as an off white solid (70.0 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 8.07 (t, J=8.4 Hz, 1H), 7.39 (t, J=1.6 Hz, 1H), 7.31 (d, J=1.2 Hz, 1H), 7.26 (m, 2H), 7.23 (m, 2H), 7.19 (d, J=1.6 Hz, 1H), 6.60 (d, J=16.8 Hz, 1H), 6.49 (dd, J=16.8, 7.6 Hz, 1H), 4.90 (m, 1H), 4.64 (m, 2H), 4.14 (m, 2H); ESIMS m/z 493.83 ([M−H]−); IR (thin film) 1527, 1113, 801, 1167, 1321 cm−1.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23](O)[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:34])CC)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23]([F:34])[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC(O)CC2C3)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OCC23CCC(F)CC2C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((4-hydroxybicyclo-[4.1.0]heptan-1-yl)methoxy)benzoate (0.13 g, 0.41 mmol) in chloroform (2 mL) was added diethylaminosulfur trifluoride (0.11 mL, 0.89 mmol). The reaction solution was stirred at ambient temperature for 16 h and quenched with slow addition of aqueous saturated sodium hydrogencarbonate. The reaction mixture was extracted with dichloromethane. The solvent was concentrated in vacuo to dryness. The residue (0.10 g) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.15 g, 1.30 mmol) was added. The reaction mixture was stirred for 2 h and the solvent was concentrated in vacuo to obtain the title compound as a gum (0.080 g, 95%). The residue was carried forward without any further purification in next reaction: MS (ES−) m/z 321.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>O1CCCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([O:22][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH:24]=2)[OH:27])=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
A solution of 4-bromothioanisole (10.0 g, 49.0 mmol) in 60 mL of anhydrous tetrahydrofuran was cooled to -78° C. under nitrogen and 32 mL (49 mmol) of 1.55M n-butyllithium in hexane was was added dropwise at a rate to maintain temperature below -60° C. The reaction was stirred an additional 15 minutes after addition was complete, and a solution of crude 3-(tert-butyldimethylsilyloxy)benzaldehyde (11.6 g, 49 mmol) in 50 mL of dry tetrahydrofuran was added dropwise over 20 minutes. The reaction was stirred another 30 minutes and quenched at -78° C. with saturated aqueous ammonium chloride. After warming to room temperature, the reaction was diluted with 200 mL of diethyl ether and washed with 50 mL of water and 50 mL of saturated aqueous sodium chloride. After drying over sodium sulfate, the solvent was removed to give 17.5 g (99%) of crude (4-methylthio-phenyl)(3-tert-butyldimethylsilyloxyphenyl)methanol as an orange oil.
Reaction SMILES: O=[O+][O-].[C:4]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])=[C:20](\O)/[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:51](Cl)Cl>>[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=[CH2:51])[CH3:21])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: O=[O+][O-]
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1

Procedure:
Analogously to Example 1d), 10.8 g (16.2 mM) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 1 l of methylene chloride and 1.1 equivalents of ozone give 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester; melting point 142°-143° C. (from ether/pentane).