Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:21])[CH2:9][N:10]([CH2:18][CH2:19]O)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][C:3]=1[F:22].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>COC(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:21][CH2:19][CH2:18][N:10]([C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH2:9]2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N(CCO)C[C@H](O)c1ccc(Cl)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(Cl)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
(R)-tert-butyl 2-(4-chloro-3-fluorophenyl)-2-hydroxyethyl(2-hydroxyethyl)carbamate (2.5 g, 7.49 mmol) was dissolved in methyl-t-butylether (20 mL) and triphenylphosphine (2.36 g, 8.99 mmol) was added. To this mixture was added diisopropyl azodicarboxylate (1.8 mL, 8.99 mmol) by dropwise addition. The solution was stirred at room temperature for 1 h. The white solid was filtered off and the filtrate was concentrated. The residue was purified by ISCO flash column chromatography (220 g silica gel, 0% to 20% ethyl acetate in hexanes) to afford (R)-tert-butyl 2-(4-chloro-3-fluorophenyl)morpholine-4-carboxylate as a white solid (1.02 g). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 9H) 2.75 (t, J=11.71 Hz, 1H) 2.94-3.11 (m, 1H) 3.67 (td, J=11.71, 3.02 Hz, 1H) 3.86-4.17 (m, 3H) 4.40 (dd, J=10.58, 2.64 Hz, 1H) 7.09 (dd, J=8.31, 1.51 Hz, 1H) 7.21 (dd, J=9.82, 1.89 Hz, 1H) 7.38 (t, J=7.93 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]4)=[CH:23][CH:22]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:37]1([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:43]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[CH:3]=[CH:4][C:5]([CH2:6][C:7]4[N:8]([CH2:20][C:21]5[CH:26]=[CH:25][C:24]([N:27]6[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]6)=[CH:23][CH:22]=5)[CH:9]=[C:10]([C:12]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=5[Cl:19])[N:11]=4)=[CH:35][CH:36]=3)=[CH:41][CH:42]=2)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: O=C1CN(c2ccc(Cn3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: O=C1CN(c2ccc(Cn3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-cyclohexylphenylboronic acid (41 mg, 0.2 mmol) to give 5-{-4-[2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([O:32]C)=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:34])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C>Br>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:34])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1c(NN=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)cccc1-c1cccc(C(=O)O)c1
Agent: Br
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(=O)O)c2)c1O

Procedure:
A solution of 3′-{N′-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]hydrazino}-2′-methoxybiphenyl-3-carboxylic acid (4 g), prepared as in Example 3, in 48% aqueous hydrobromic acid (35 mL) and glacial acetic acid (35 mL) was stirred and heated under reflux for about 60 hours. The reaction mixture was concentrated under vacuum to a thick residue. Water (40 mL) was added and basified to pH 7-8 using saturated solution of sodium bicarbonate (20 mL). The mixture was filtered to give an orange solid, which was washed with water (25 mL) and dried in an oven at 55° C. about to about 60° C. for about 12 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.Cl>O1CCCC1>[CH2:11]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([Br:1])[CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccc(F)c(Br)c1
Reactant: ClCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(COCc2ccccc2)cc1Br
Temperature: 40 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol were added to a solution of 12.3 g (0.11 mol) of potassium tert.-butylate in 200 ml of tetrahydrofuran at 20° C. During this addition, the temperature increased to about 40° C. The mixture was subsequently stirred at 20° C. for about 1 hour and 12.6 g (0.1 mol) of benzyl chloride were then added dropwise to the reaction mixture. Thereafter, the mixture was heated under reflux for one hour. It was then cooled. About 200 ml of water and 50 ml of concentrated hydrochloric acid were added to the reaction mixture and the mixture was extracted twice with 200 ml of diethyl ether each time. The combined extracts were concentrated, dried over sodium sulphate and then subjected to fractional distillation. 14.2 g (48.2% of theory) of 3-bromo-4-fluoro-benzyl benzyl ether were obtained in the form of a light yellow oil of boiling point 165° C./7 mbars.
Reaction SMILES: [Na].[CH:2]([CH:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])=O.Cl.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[NH:12]([CH:2]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: N#CC(C=O)CNC=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N#CC(=CNc1ccccc1)CNC=O

Procedure:
74 parts of 75 percent pure sodium salt of α-formyl-β-formylaminopropionitrile are refluxed for 1 hour with 58.3 parts of aniline hydrochloride in 400 parts by volume of methanol, the reaction mixture is filtered, and the filtrate is concentrated to half its volume. 59.6 parts of α-anilinomethylene-β-formylaminopropionitrile are obtained, followed by a further 6.3 parts after concentrating the mother liquor; this corresponds in total to 87.4% of theory, based on the Na salt.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[O:9])=[CH:4][CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[F:19][C:16]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)=[O:9]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccccc4C(F)(F)F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Under argon, 2-trifluoromethylphenyl 4-hydroxyphenyl ketone (959 mg) obtained in Example 145 and 4-dimethylaminopyridine (484 mg) were added to xylene (7 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (805 mg) was added, and the admixture was then refluxed with heat overnight. The reaction mixture was treated in the same manner as described in Example 130 to obtain 899 mg of the title compound (yield: 55%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.C([O:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C>O1CCCC1.C1(C)C=CC=CC=1.[Cl-].[NH4+]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17](=[O:16])[C:18]([F:21])([F:20])[F:19])=[N:3][CH:4]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cn1)C(F)(F)F
Reaction time: 0.29 h
Yield: 68.8 %

Procedure:
To a stirred solution of 2, 5-Dibromo-pyridine (4 g, 6.87 mmol) in dry tetrahydrofuran (30 mL) and dry toluene (40 mL) is added drop wise n-Butyl lithium (1.62 g, 25.31 mmol) at −78° C. After stirring for 15-20 minutes, added trifluoro-acetic acid ethyl ester (3.56 g, 25.31 mmol) at −78° C. then stirred at −78° C. for another 30 minutes. The reaction mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 20% ethyl acetate in hexane to afford the title compound (1.2 g). 1HNMR (400 MHz, DMSO-d6) δ: 7.72 (d, J=8.32 Hz, 1H), 7.85-7.88 (dd, J1=8.32 Hz, J2=2.44 Hz 1H), 8.52 (d, J=2.36 Hz, 1H). LC-MS (m/z): [M+H]=255.8.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH:11]1([N:16]2[C:20]([NH2:21])=[C:19]([C:22]#[N:23])[C:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:17]2)[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([N:16]2[C:20]([NH:21][C:8]([C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)=[O:9])=[C:19]([C:22]#[N:23])[C:18]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:17]2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)c1ccncc1
Temperature: 200 °C
Yield: 85.3 %

Procedure:
4-Pyridinecarboxylic acid chloride hydrochloride (4.3 g, 24 mmol), and 1-cyclopentyl-3-phenylmethyl-4-cyano-5-amino-1H-pyrazole (3.2 g, 12.0 mmol) were combined and heated to 200° C. under argon for 5 minutes. The reaction mixture was cooled to room temperature and the residue was partitioned between chloroform and sat. NaHCO3. The organic layer was separated, washed with additional sat. NaHCO3, dried over anhydrous MgSO4 passed through a plug of silica and the solvent was removed in vacuo to afford 3.8 g (84%) of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(4-pyridinecarboxamido)-1H-pyrazole as white crystals, m.p. 189°-191° C. when recrystallized from ethyl acetate and dried at 80° C. for 8 hours in high vacuum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:19])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Br>CN(C)C=O.O>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:19])[CH:3]=1
Reactant: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate from step 1) (24.00 g, 92.57 mmol) and K2CO3 (15.35 g, 111.08 mmol) were dissolved in N,N-dimethylformamide (220 mL). 2,4-Difluorobenzyl bromide (20.12 g, 97.20 mmol) was then added and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with H2O (1 L) and the precipitate collected by filtration to afford a white solid (4.08 g, 11%). The resulting oil was purified by chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford an off white solid (11.88 g, 33%). The two solids were combined. 1H NMR (400 MHz, CDl3) δ 8.11 (dt, J=1.41, 7.79 Hz, 1H), 7.87 (app t, J=1.78 Hz, 1H), 7.58 (app t, J=7.69 Hz, 1H) 7.45-7.38 (m, 2H), 6.94-6.84 (m, 2H), 5.97 (d, J=2.68 Hz, 1H), 5.90 (ddd, J=0.94, 1.74, 1.74 Hz, 1H), 5.97 (s, 1H), 3.90 (s, 3H), 1.89 (s, 3H). ES-HRMS m/z 386.1179 (M+H C21H17F2NO4 requires 386.1198).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[O:13][CH2:14][CH3:15])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1F
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A solution of 6.9 grams (47 mmole) of 4-chloro-2-fluoroaniline in 75 mL of pyridine was stirred and cooled in an ice bath. During 15 minutes, 5.4 grams (50 mmole) of ethyl chloroformate was added dropwise. Upon completion of the addition the reaction mixture was heated at 60°-70° C. for 1.5 hours, then concentrated under reduced pressure to a residue. The residue was stirred with 150 mL of aqueous 3N hydrochloric acid, and the resulting precipitate was collected by filtration. The precipitate was washed with aqueous 3N hydrochloric acid and then with water. The precipitate was dried under ambient conditions for about 18 hours, then dried under vacuum for two hours, yielding 9.6 grams of ethyl N-(4-chloro-2-fluoro-phenyl)carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Na].[OH-].[K+].Br[CH2:5][CH2:6][C:7](=[O:19])[CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.[CH3:20][CH:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][CH2:8][C:7](=[O:19])[CH2:6][CH2:5][C:21]2([CH3:20])[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(CCCC(=O)CCBr)c1
Reactant: CC1C(=O)CCC1=O
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Product: COc1cccc(CCCC(=O)CCC2(C)C(=O)CCC2=O)c1

Procedure:
Add sodium (0.05 g) to a 0.12% methanolic potassium hydroxide solution (15 cc). To this solution add 1-bromo-6-(m-methoxyphenyl)hexan-3-one (0.9 g) in methaol (5 cc) and 2-methylcyclopentane-1,3-dione (0.4 g), and reflux the mixture for 6 hours. After working up as in the preparation of the title compound in a previous example, obtain the crude Michael adduct 2-(6-m-methoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione as a yellow gum.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[F:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=1)([F:9])[CH3:8]
Reactant: NNc1ccccc1
Reactant: CC(F)(F)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(F)(F)c1cc(N)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 31.5 %

Procedure:
A stirred mixture of 4,4-difluoro-3-oxopentanenitrile (prepared as described in Example 152A Step 1) (1 g, 7.52 mmol) and phenyl hydrazine hydrochloride (1.08 g, 7.52 mmol) in ethanol (30 mL) was heated at 70° C. for 8 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (200 mL) and saturated aqueous sodium hydrogen carbonate solution (200 mL). The organic layer was separated and dried over magnesium sulfate and filtered. Concentration under reduced pressure gave an oil, which was purified via silica gel column chromatography (eluting with a gradient of 5% to 65% ethyl acetate in hexanes) to afford 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-amine (528 mg, 31%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.57 (m, 5H), 5.81 (s, 1H), 3.84 (brs, 2H), 2.01 (t, J=18 Hz, 3H); LC-MS (ESI) m/z 224 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=[C:3]1[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[Na].[CH2:29](N(CC)CC)C.S(Cl)(Cl)=O>ClCl.CO>[CH3:29][O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([C:3]2[N:2]([CH3:1])[C:6]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[C:5]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:4]=2)=[CH:27][CH:26]=1
Reactant: CCN(CC)CC
Reactant: Cn1c(-c2ccc(C(=O)O)cc2)nc(-c2ccccc2)c1-c1ccncc1
Agent: ClCl
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3)c(-c3ccncc3)n2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a suspension of 4-[1-methyl-4-phenyl-5(4-pyridyl)-imidazol-2-yl]benzoic acid, sodium salt (20 mg, 0.06 mmol) [See Ex. 5 above] in CH2 Cl2 (2 mL.) was added triethylamine (24 mL, 0.17 mmol), followed by thionyl chloride (10 mL, 0.14 mmol). The reaction mixture was stirred at rt for 30 min, at which time MeOH (0.5 mL) was added. The mixture was stirred at rt for an additional 2 h and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 0-1% MeOH/CHCl3 and recrystallized from EtOAc to afford the title compound as an off-white crystalline solid (1.6 mg, 8%): mp 208°-209° C.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([O:17]C=O)[CH3:16])[C:9]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])(=[O:3])[CH3:2].[OH-].[Na+].C(OC(=O)C)C>O1CCOCC1>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([OH:17])[CH3:16])[C:9]=1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)OC=O)[C@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The formate ester (e4, 425 mg,0.89 mM) was dissolved in 20% aqueous 1,4-dioxan (80 ml) and cooled to 0° C. 0.1 N Sodium hydroxide solution (10.74 ml, 1.07 mM) was added and stirring continued for 5 minutes. Ethylacetate (150 ml) was then added and the organic solution washed with water, saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After filtration, the solvent was removed to yield a pale yellow solid. This solid was chromatographed over silica gel (15 gm). Elution with 10% ethanol/chloroform gave the pure p-nitrobenzyl (5R,6S)-3-(E-2-acetamidoethenylthio)-6-[(R)-1-hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (e5) as a white solid. This solid was digested in dry diethyl ether and collected by filtration (100 mg), λmax (EtOH) 325 nm (εm 16880), 263 nm (εm 17968), νmax (KBr) 3420, 3260, 1778, 1700, 1675, 1624, 1554, 1520, 1380, 1350, 1335 cm-1 ; δH (d7 -DMF) 10.50 (1H, d. J 10 Hz, NH), 8.30 (2H, d, aromatic protons), 7.85 (2H, d, aromatic protons), 7.22 (1H, dd, J 10 Hz and 14 Hz, NHCH=CH), 6.02 (1H, d, J 14 Hz), 5.47 (2H, q, CH2Ar), 4.28 (dt, 1H, J 3 Hz and 9 Hz, 5-CH), 4.08 (1H, dq, 8-CH), 3.43 (1H, dd, J 3 Hz and 6.3 Hz, 6-CH), 3.27 (2H, ABX, 4-CH2) 2.03 (3H, s, COCH3), 1.23 (3H, d, J 6 Hz, CH3CH).
Reaction SMILES: C[Mg]Br.[Cl:4][C:5]1[CH:12]=[CH:11][C:8](C#N)=[C:7]([CH3:13])[CH:6]=1.Cl.C([O:17][CH2:18][CH3:19])C>>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([C:18](=[O:17])[CH3:19])=[C:7]([CH3:13])[CH:6]=1
Reactant: CCOCC
Reactant: Cc1cc(Cl)ccc1C#N
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1ccc(Cl)cc1C
Temperature: 40 °C

Procedure:
Methylmagnesium bromide (6.29 g, 52.8 mmol) was added to a stirred solution of 4-chloro-2-methyl-benzonitrile (5.00 g, 33.0 mmol) in diethyl ether (44 mL). The mixture was heated to 40° C. After 72 h the mixture was cooled to room temperature and poured into a stirred mixture of anhydrous diethyl ether (120 mL), ice water (100 mL), and 10% aqueous HCl (100 mL). The aqueous layer was separated, stirred at reflux for 1 h, then was cooled to room temperature and was extracted into diethyl ether (4×50 mL). The organic layers were combined, washed with saturated NaHCO3 and brine, dried (Na2SO4) and concentrated in vacuo. 1-(4-Chloro-2-methylphenyl)ethanone was obtained as an oil. 1H NMR (CDCl3, 400 MHz) δ 2.52 (s, 3H), 2.56 (d, J=0.7 Hz, 3H), 7.24 (m, 2H), 7.65 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([CH:18]([F:20])[F:19])[N:15]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S:27]([C:31]1[CH:32]=[C:33]([NH2:37])[CH:34]=[CH:35][CH:36]=1)(=[O:30])(=[O:29])[NH2:28]>>[S:27]([C:31]1[CH:32]=[C:33]([NH:37][C:24]([C:23]2[CH:22]=[N:21][N:15]3[C:16]([CH:18]([F:19])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:34]=[CH:35][CH:36]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.15) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Brown solid. MS (ISP) 543.9 [(M−H)−]; mp 272° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[F:40])=[O:12])=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=2)=[O:12])=[C:34]([F:40])[CH:35]=1
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(Cl)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2ccc(Cl)cc2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a mixture of rac-4-{[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid methyl ester (142.6 mg, 0.24 mmol) in THF/MeOH (3.4 mL/0.8 mL) was added 4 N LiOH (1.4 mL), and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and quenched with 2 NH2SO4, extracted with EtOAc, and washed with water, brine. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-{[(2S,3S,4S)-2,3-bis-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (111.6 mg, 80.6%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H): 586.1471; Found: 586.1472.