Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:12]=2)=[CH:4][CH:3]=1.[C:30]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)=[C:11]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[N:12]=3)=[CH:4][CH:3]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(-c2[nH]c(-c3ccc(Br)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Product: CC(C)(C)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc([N+](=O)[O-])cc4)[nH]3)cc2)cc1

Procedure:
2-(4-Bromo-phenyl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1H-imidazole (prepared according to general procedure A) (979 mg, 2 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (712 mg, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-yl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1 H-imidazole, which was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (0.7 mL, 4 mmol) to give 2-(4′-tert-butyl-biphenyl-4-yl)-4-(2,4-dichloro-phenyl)-5-(4-nitro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22](=[O:32])[NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=4)=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:33])[CH:7]=1.[OH-].[Na+]>CO>[CH3:31][C:26]1[CH:25]=[C:24]([NH:23][C:22]([C:20]2[CH:19]=[CH:18][C:16]3[NH:17][C:13]([C:9]4[C:8]([CH3:33])=[CH:7][C:6]([NH:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:11][C:10]=4[CH3:12])=[N:14][C:15]=3[CH:21]=2)=[O:32])[CH:29]=[CH:28][C:27]=1[CH3:30]
Reactant: COC(=O)CNc1cc(C)c(-c2nc3cc(C(=O)Nc4ccc(C)c(C)c4)ccc3[nH]2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc3[nH]c(-c4c(C)cc(NCC(=O)O)cc4C)nc3c2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of {4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethyl-phenylamino}-acetic acid methyl ester (160 mg) in MeOH (5 mL) was added 1N NaOH (5 mL) and the mixture was stirred at room temperature for 18 h. The solution was washed with Et2O and the aqueous layer was carefully acidified to pH=2-3 with 1N HCl. The resulting suspension was filtered, washed with water and dried to give {4-[5-(3,4-dimethylphenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethylphenylamino}-acetic acid as a white solid. MS (ESI)m/z 443 (M+H). 1H NMR (MeOD, 400 MHz) δ 8.22 (s, 1H), 7.91 (dd, 1H), 7.70 (d, 1H), 7.46 (d, 1H), 7.42 (dd, 1H), 7.12 (d, 1H), 6.44 (s, 2H), 3.91 (s, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.10 (s, 6H).
Reaction SMILES: OC1C2C(=CC=CC=2)C=CC=1.C(OC1C=CC(C2C=CC(C([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]([O:44][CH:45]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:46]([F:49])([F:48])[F:47])=[O:43])=[C:38]([F:56])[CH:37]=3)=O)=CC=2)=CC=1)CCCCCCC.C(N(CC)CC)C>C(Cl)Cl>[F:56][C:38]1[CH:37]=[C:36]([OH:35])[CH:41]=[CH:40][C:39]=1[C:42]([O:44][CH:45]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:46]([F:48])([F:49])[F:47])=[O:43]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Agent: Oc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F

Procedure:
To a solution of the hydroxynaphthalene (0.64 g) obtained in (2) above and triethylamine (0.3 g) in methylene chloride (40 ml) was added drop by drop the 6-(1,1,1-trifluoro-2-octyloxycarbonyl)naphthalene-2-carboxychloride (0.8 g) obtained in (1) above. To the solution was added dimethylaminopyridine (0.02 g) and the mixture was stirred at room temperature overnight. The solution was neutralized with dilute aqueous hydrochloric acid solution and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer: hexane/ethyl actate=20/1) to obtain the titled compound (0.4 g) having specific rotation, [α]D20 =+45.5°.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:15]([O:16][C:17](=O)[CH3:18])[NH:14][C:13]1=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]CCO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([O:16][CH2:17][CH2:18][Br:21])[NH:14][C:13]1=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reactant: OCCBr
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(N[C@@H]1C(=O)N[C@@H]1OCCBr)OCc1ccccc1
Yield: 14.1 %

Procedure:
A mixture of (3S,4S)-3-benzyloxycarbonylamino-4-acetoxy-azetidin-2-one (11.76 g, 42.3 mmole) which prepared by the known method (Eur. J. Med. Chem. 1992, 27, 131-140), 2-bromoethanol (3 ml, 42.3 mmole), and zinc acetate dihydrate (9.28 g, 42.3 mmole) in a mixture of benzene (100 ml) and toluene (100 ml) was refluxed for 5 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (800 ml), acetone (100 ml) and water (500 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (6:4) as eluent and 2.04 g of (3S,4R)-3-benzyloxycarbonylamino-4-bromoethoxy-azetidin-2-one was obtained as white solid (yield: 14%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:28]([O:37][CH3:38])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH2:31]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[CH3:38][O:37][C:28](=[O:36])[C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH:31][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1ccccc1NC(=O)CNC(=O)OCc1ccccc1
Yield: 10.7 %

Procedure:
To a solution of N-α-Cbz-glycine (2.0 g, 9.56 mmol) in tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (1.64 g, 10.13 mmol), followed 2 h later by methyl anthranilate (1.28 g, 8.47 mmol). After stirring overnight the tetrahydrofuran was removed in vacuo and the residue was redissolved in ethyl acetate, washed with 10% aqueous hydrochloric acid (2×), saturated aqueous sodium hydrogen carbonate (2×), dried (MgSO4) and concentrated to give an oily residue which was subjected to silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 30:70, ν/ν->Ethyl acetate] to give the title benzoate (1) (0.31 g, 11%) as a white solid:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:16]=1)=[O:10].Cl.[CH3:31][O:32][NH2:33]>CO.O>[CH3:31][O:32]/[N:33]=[C:2]1/[C@H:3]([NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH:16]=2)=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]/1
Reactant: O=C(N[C@@H]1CCCCC1=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: O
Product: CO/N=C1\CCCC[C@H]1NC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.2 %

Procedure:
To a solution of 100 mg of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid ((R)-2-oxo-cyclohexyl)-amide in 0.5 ml methanol and 0.5 ml water, was added 98 mg O-methylhydroxylamine hydrochloride and the mixture was stirred at ambient temperature for 3.5 h. The solvents were evaporated and the residue was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 91 mg of the title compound as white foam. MS (EI): 457.3 (M+H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1.OP(O)=O.O[Mo](O)(=O)=O>[OH:1][C@@H:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[C:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)c1cccc(C#Cc2ccccc2)c1
Agent: O=[Mo](=O)(O)O
Agent: O=[PH](O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](c1cccc(C#Cc2ccccc2)c1)[C@@H](O)c1ccccc1
Reaction time: 1 h
Yield: 53 %

Procedure:
To (S)-tert-butyl 2-oxo-1-(3-(phenylethynyl)phenyl)ethylcarbamate (95 mg, 0.283 mmol) in tetrahydrofuran (5 mL) at −78° C. was added phenylmagnesium bromide (0.198 mL, 0.595 mmol) dropwise. After half of the phenylmagnesium bromide was added the stir bar stopped spinning due to a gum which formed around it. The ice bath was removed allowing the reaction to warm until the stir bar began to stir again. The addition of Grignard reagent was continued and after 1 h, a fine precipitate was evident. TLC (25% ethyl acetate/hexane; UV and phosphomolybdic acid) showed a single major spot just below starting material (Rf=0.45). After 1.5 h total, the reaction was quenched with 1N HCl (10 mL) and extracted into ethyl acetate (3×10 mL). The combined organics were washed with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo to 126 mg amber oil which was loaded with dichloromethane onto a 12 g silica gel column prepacked with 5% ethyl acetate/hexanes. Elution with 5 to 30% ethyl acetate/hexanes over 250 mL provided 62 mg tert-butyl (1S,2S)-2-hydroxy-2-phenyl-1-(3-(phenylethynyl)phenyl)ethylcarbamate as a colorless oil which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[NH:22][C:21](=[O:27])[CH:20]=[C:19]2[CH3:28])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].[O-][CH2:32]C.[Tl+].CI.CO>CN(C)C=O>[F:30][C:2]([F:1])([F:29])[C:3]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[N:22]([CH3:32])[C:21](=[O:27])[CH:20]=[C:19]2[CH3:28])([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: Cc1cc(=O)[nH]c2c(C)cc(C(OCc3ccccc3)(C(F)(F)F)C(F)(F)F)cc12
Reactant: CC[O-]
Agent: [Tl+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CI
Product: Cc1cc(=O)n(C)c2c(C)cc(C(OCc3ccccc3)(C(F)(F)F)C(F)(F)F)cc12

Procedure:
To a solution of 6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-4,8-dimethyl-2(1H)-quinolinone in dimethylformamide is added an equivalent of thallium ethoxide. The solution is stirred under nitrogen. To the solution is added methyl iodide, and the solution is stirred and heated to 50° until thin layer chromatography indicates the reaction is complete. The solution is cooled and treated with 5 ml of methanol. The cooled solution is filtered and evaporated at reduced pressure. The residual material is extracted with hexane and the filtered solution is evaporated at reduced pressure. The residual material is heated to 250° in a nitrogen atmosphere for 4 hours. At the end of this period, the residual material is chromatographed on silicic acid to give 6-[2,2,2-trifluoro-1-benzyloxy-1-(trifluoromethyl)ethyl]-1,4,8-trimethyl-2(1H)-quinolinone.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][S:27]([NH2:30])(=[O:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[CH2:26]([S:27]([NH:30][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([Cl:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:28])=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: CCCCCCCCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1cccc(Cl)c1C2=O

Procedure:
1,5-dichloroanthraquinone (1.0g), n-octanesulfonamide (0.77g), potassium carbonate (1.0g), cupric acetate monohydrate (1.0g) and chlorobenzene (15ml) were refluxed for 4 hours. The solvent was evaporated at reduced pressure and the residue was extracted with toluene. After filtration the extract was separated by chromatography on silica using toluene as eluent to give the desired product as the second fraction.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24].O>CCO>[CH3:22][N:23]([CH3:24])[C:2]1[S:6][C:5]([C:7]([C:9]2[C:10]3[S:21][CH:20]=[CH:19][C:11]=3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccc(Br)s1)c1nc(C(F)(F)F)nc2ccsc12
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C(=O)c2nc(C(F)(F)F)nc3ccsc23)s1
Yield: 42 %

Procedure:
A suspension of 5-bromo-2-thienyl 2-trifluoromethylthieno[3,2-d]pyrimidin-4-ylmethanone (0.3 g, 0.76 mmol) in EtOH (20 mL) was treated with 40% aqueous dimethylamine (5 mL), refluxed for 1 h, cooled, treated with water (25 mL), concentrated in vacuo and the aqueous mixture extracted with EtOAc (2×25 mL), the combined extracts washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo. The resulting red oil was purified by chromatography [SiO2; heptane-EtOAc (1:1)] to give the title compound (0.115 g, 42%) as a red solid.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:16]([O:23][C:24]([N:26]([CH2:47][C:48]([N:50]1[CH2:54][C@@H:53]([F:55])[CH2:52][C@H:51]1[C:56]#[N:57])=[O:49])[C:27]12[CH2:34][CH2:33][C:30]([C:35](ON3C4C=CC=CC=4N=N3)=[O:36])([CH2:31][CH2:32]1)[CH2:29][CH2:28]2)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl>[CH2:16]([O:23][C:24]([N:26]([CH2:47][C:48]([N:50]1[CH2:54][C@@H:53]([F:55])[CH2:52][C@H:51]1[C:56]#[N:57])=[O:49])[C:27]12[CH2:34][CH2:33][C:30]([C:35]([N:6]3[CH2:7][CH2:8][CH:3]([F:2])[CH2:4][CH2:5]3)=[O:36])([CH2:31][CH2:32]1)[CH2:29][CH2:28]2)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: FC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)N3CCC(F)CC3)(CC1)CC2
Reaction time: 0.58 h
Yield: 78.4 %

Procedure:
4-Fluoropiperidine hydrochloride (18.2 mg) was suspended in tetrahydrofuran (0.87 mL). While this suspension was chilled in an ice bath, triethylamine (18.2 μL) was added and the mixture was stirred at the same temperature for 35 minutes. Subsequently, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed sequentially with 0.1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluant:ethyl acetate:methanol=20:1) to give (2S,4S)-1-[[N-benzyloxycarbonyl-[4-(4-fluoropiperidin-1-yl)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (37.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (3.7 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After stirring for 4 h, the solvents were removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. After standing at room temperature overnight, the mixture was filtered to give 6.4 g (79%) of a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](/[C:38](=[CH:42]\[CH2:43][CH3:44])/[C:39]([OH:41])=O)=[CH:34][CH:33]=1)(=[O:31])=[O:30].[NH2:45][C:46]1[S:47][CH:48]=[CH:49][N:50]=1>C(Cl)Cl>[S:47]1[CH:48]=[CH:49][N:50]=[C:46]1[NH:45][C:39](=[O:41])/[C:38](/[C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:30])=[O:31])=[CH:37][CH:36]=1)=[CH:42]/[CH2:43][CH3:44]
Reactant: CC/C=C(/C(=O)O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C(/C(=O)Nc1nccs1)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
A solution of triphenylphosphine (1.23 g, 4.7 mmol) in methylene chloride (15 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (836 mg, 4.7 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-(4-(methanesulfonyl)-phenyl)-pentenoic acid (703 mg, 2.76 mmol) in methylene chloride (5 mL). The clear solution was stirred for 10 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (829 mg, 8.28 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (100 mL) and a 1N aqueous hydrochloric acid solution (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (2×50 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-(4-methanesulfonyl-phenyl)-pent-2-enoic acid thiazol-2-ylamide (150 mg, 16%) as crystalline solid: mp 155-158° C.; EI-HRMS m/e calcd for C15H16N2O3S2 (M+) 336.0602, found 336.0601.
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: CCO
Solvent: ClCCl
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: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]=1[CH:4]=[N:5][OH:6].[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.C(OC(=O)C)C.CCCCCC>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]=1[C:4]([Cl:16])=[N:5][OH:6]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)COc1cccc(F)c1C=NO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)COc1cccc(F)c1C(Cl)=NO
Temperature: 50 °C
Yield: 90.1 %

Procedure:
To a solution of 2-fluoro-6-isobutoxybenzaldehyde oxime (0.99 g, 6.1 mmol, EXAMPLE 16, Step 3) in N,N-dimethylformamide (20 mL) was added N-chlorosuccinimide (0.63 g, 4.7 mmol) at 0° C. The mixture was heated at 50° C. for 1 h and cooled to room temperature. The mixture was diluted with ethylacetate (30 mL) and hexane (30 mL). The organic layer was washed with water (30 mL×2), dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 9:1 to 4:1) to give 1.04 g (90%) of the title compound as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:23][N:24]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([NH:19][C:20]1[S:21][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:23][N:24]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1nnc(-c2ccncc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1nnc(-c2ccncc2)s1
Reaction time: 3 h
Yield: 94 %

Procedure:
Into a solution of (S)-tert-butyl 1-oxo-3-phenyl-1-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-ylamino)propan-2-ylcarbamate (0.426 g, 1.00 mmol) in CH2Cl2 (5.0 mL) was injected trifluoroacetic acid (7.44 ml, 100 mmol) and let stir for 3 h. Reaction stripped of solvent. The residue was purified by silica gel flash chromatography (0-10% MeOH/CH2Cl2) to afford (S)-2-amino-3-phenyl-N-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)propanamide (0.306 g. 93.9% yield)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[CH2:25]1[O:27][CH2:26]1>C1COCC1>[OH:27][CH2:26][CH2:25][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2cc3ccc(Br)cc3cn2)cc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc3ccc(CCO)cc3cn2)cc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
The product from Example 74A (4 mmol) is dissolved in 20 mL THF and is cooled to −60° C. under nitrogen. n-BuLi (4.4 mmol) is added dropwise, and the mixture is stirred at −60° C. for additional 30 minutes. A solution of ethylene oxide (20 mmol) in 10 ml THF is added and the mixture is allowed to warm to 10° C. and is stirred to complete the reaction. The mixture iss cooled back down to 0° C. and is slowly quenched with 2N HCl to pH=3. The solvent is removed under vacuum and the residue is dissolved in 20 mL methylene chloride, is washed with water, and is concentrated under reduced pressure. The residue is chromatographed on silica gel (5:95 MeOH:CHCl3) to provide the title compound.