Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:3]=1.[OH-].[Na+:38]>C(O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[C:18]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[O:13][N:12]=3)[CH:9]=2)[N:4]([CH2:30][CH2:31][C:32]([O-:34])=[O:33])[CH:3]=1.[Na+:38]
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(-c5ccccc5)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)[O-])no2)cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-(3-chloro-5-{5-[6-(methyloxy)-3-biphenylyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)propanoate (D107) (90 mg, 0.18 mmol) was heated in ethanol (10 ml) to give a clear solution. This solution was treated with 2N sodium hydroxide (3 ml, 6 mmol) and stirred at 50° C. for 30 minutes. Evaporated off the ethanol and filtered off the white solid that precipitated out of solution, washing the solid with a small amount of water and ether. Stirred solid in a small amount of acetone for 1 hour, filtered, washed with a small amount of ether and dried to yield the title compound as 45 mg of white solid. δH (400 MHz, d6-DMSO) 2.34 (2H, t), 3.91 (3H, s), 4.34 (2H, t), 7.41-7.46 (2H, m), 7.48-7.50 (2H, m), 7.57-7.59 (2H, m), 7.63-7.66 (2H, m), 7.80 (1H, d), 8.10 (1H, d), 8.10-8.25 (2H, m). MS (ES) C26H2035ClN3O4 requires 473; found 474 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[Cl:23][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:11]([C:12]#[N:13])[C:3]=2[C:2]([F:14])([F:1])[F:15])[NH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Cl)c2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To an ice-cold solution of 4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.015 g, 0.071 mmol) in DMF (2 mL), under N2, was added a solution of NCS (0.011 g, 0.079 mmol) in DMF (0.5 mL). The mixture was stirred at rt for 1 h and then heated at 75° C. for 40 min. Upon cooling, the mixture was partitioned between Et2O and 0.1N HCl. The organic phase was washed with water and sat'd brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by radial chromatography (50-100% CH2Cl2 hexanes gradient, followed by 1-5% MeOH—CH2Cl2 gradient) to afford the title compound (0.014 g, 82% yield): MS (ES) m/z 245 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([F:21])=[CH:14][C:13]=1F>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[CH:14]=[C:15]([F:21])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[F:11])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 401.8 %

Procedure:
Sodium hydride (136 mg, 3.4 mmol, 60% in mineral) was added to a 0° C. solution of 2-chloropyridin-4-ol (2 g, 15.4 mmol) in DMF (38 mL) under Ar. The mixture was stirred at 0° C. for 1 h. A solution of 1,2,4-trifluoro-5-nitrobenzene (626 mg, 3.1 mmol) in DMF (7.6 ml) was added and the reaction was stirred under Ar at 90° C. for 3 h. The mixture was cooled to RT and stirred overnight. The solvent was removed under reduced pressure and the crude product was partitioned between water (50 ml) and EtOAc (50 ml). The mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by silica gel column chromatography (hexanes/EtOAc) to yield 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.43-8.33 (m, 2H), 7.85-7.79 (m, 1H), 7.33 (d, 1H), 7.20-7.18 (m, 1H); MS (ESI) m/z: 287.0 (M+H+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:11]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:25])=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9](=[O:38])(=[O:37])[N:8]([CH3:39])[C:7]=2[CH:40]=1.S([O-])(=O)(=O)C.[NH3:46]>>[NH2:46][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:11]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)(=[O:24])=[O:25])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][S:9](=[O:37])(=[O:38])[N:8]([CH3:39])[C:7]=2[CH:40]=1
Reactant: CN1c2cc(CO)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O
Reactant: N
Agent: CS(=O)(=O)[O-]
Product: CN1c2cc(CN)ccc2C(NC(=O)CC(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2)CS1(=O)=O

Procedure:
The title compound was prepared from N-(7-hydroxymethyl-1-methyl-2,2-dioxo-1,2,3,4-tetrahydro-2λ6-benzo[c][1,2]thiazin-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 12, Step E) via its mesylate and addition of NH3 by a method similar to that described in Example 12, Step E. MS (+ESI, m/z): 579 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9]>>[CH:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1.[OH:10][S:8]([O-:11])=[O:9]
Reactant: O=S(=O)(O)O
Solvent: Oc1ccccc1
Product: O=S([O-])O
Reaction time: 5 h

Procedure:
188 g (2.0 moles) of phenol (J. T. Baker, Phillipsburg, N.J.) was added to 208 g (2.1 moles) of 96-98% sulfuric acid, and the mass held at 100°-105° C. for 5 hours, which produced an orange/red sulfonation mass of phenol sulfonic acid. 800 cc of water was added to the mass, followed by 539 g of 30% sodium hydroxide to produce an aqueous phenol sulfonate salt having a pH of 10. Then 4.0 g sodium dodecylbenzene sulfonate surfactant was added, followed by 1.0 liter of mixed xylenes, and the mass was refluxed overnight. The total amount of water removed was 1250 cc and the moisture content of the fine, uniform slurry at that point was 0.4 wt %. This slurry was then treated directly with 237 g (2.09 moles) of chloroacetyl chloride (Aldrich, Milwaukee, Wis.) in refluxing xylene for two additional hours. The product was filtered and pan dried to give a mixture of 616.6 g of sodium chloroacetylphenol sulfonate, sodium chloride, and surfactant versus a theoretical yield of 670.0 g.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH2:21][OH:22])[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:23]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[CH2:21][O:22][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OC[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reaction time: 2.5 h
Yield: 95.6 %

Procedure:
To a stirred solution of {(1R, 2R)-2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropyl}-methanol (3.712 g, 10.03 mmol) in Et3N (8.5 mL, 61.1 mmol) and anhydrous CH2Cl2 (100 mL ) at 0° C. under N2 was added dropwise CH3SO2Cl (930 uL, 12.02 mmol ). Stirring was continued at 0° C. for 2.5 h. The reaction was quenched with H2O (20 mL). A solution of K2CO3 (4.28 g, 31.01 mmol) in H2O (60 mL) was then added. The resulting mixture was stirred at rt for 15 min, then extracted with CH2Cl2, washed with brine, dried over Na2SO4. Filtration, concentration and drying afforded the desired product (4.301 g, 96%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[CH3:33][S:34]([C:37]1[CH:38]=[C:39]([C:43]2[N:48]3[N:49]=[C:50]([NH2:52])[N:51]=[C:47]3[CH:46]=[CH:45][CH:44]=2)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CO.C(Cl)(Cl)Cl>[C:1]([NH:4][CH2:5][C:6]([NH:52][C:50]1[N:51]=[C:47]2[CH:46]=[CH:45][CH:44]=[C:43]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:38]=3)[N:48]2[N:49]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCC(=O)O
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)Nc1nc2cccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a solution of N-Acetylglycine (406 mg, 3.47 mmol, 5.00 equiv) in pyridine (10 mL) was added triphenylphosphine (910 mg, 3.47 mmol, 5.00 equiv) at 0° C. After 5 min, carbon tetrabromide (1.15 g, 3.47 mmol, 5.0 equiv) was added, and the resulting yellow solution was maintained at 0° C. for 1.5 h. 5-(3-(Methylsulfonyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.200 g, 0.693 mmol, 1 equiv) was then added to the reaction mixture at 0° C. After 5 min, the reaction mixture was warmed to 24° C. and stirred overnight. Saturated aqueous sodium bicarbonate solution (20 mL), chloroform, and methanol were sequentially added to the reaction mixture. The solution was concentrated, and the resulting residue was purified by flash column chromatography (10% methanol, 1% ammonium hydroxide in dichloromethane) to afford product as white solid (220 mg, 78% yield). 1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.29 (dd, J=7.9, 1.1 Hz, 1H), 8.08 (dd, J=7.9, 1.0 Hz, 1H), 7.85-7.70 (m, 2H), 7.66 (dd, J=8.9, 1.2 Hz, 1H), 7.36 (dd, J=7.2, 1.2 Hz, 1H), 4.17 (s, 2H), 3.22 (s, 3H), 2.04 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([O:35]C)=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6]>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([OH:35])=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:12]=1[C:13]([OH:15])=[O:14])([CH3:6])[CH3:7]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
A solution of 247 mg of lithium hydroxide monohydrate dissolved in 3 ml of water was added to a solution of 447 mg of ethyl 4-(1-hydroxy-1-methylethyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] dissolved in 5 ml of dioxane, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this time, the dioxane in the reaction mixture was removed by evaporation under reduced pressure, and 5.9 ml of 1N aqueous hydrochloric acid were added to the residue. The crystals thus precipitated were collected by filtration and dried in air, to give 310 mg of the title compound, softening at 163° C. and melting at 183°-185° C.
Reaction SMILES: C(NC(=O)[O-])C.[OH:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:7][C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Reactant: Fc1cccc(CBr)c1
Agent: CCNC(=O)[O-]
Product: CC1c2cc(Cl)c(OCc3cccc(F)c3)cc2C2CNCC12

Procedure:
The subtitle compound was prepared by the method of Example 6, Step A utilizing N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5 Step A) and 3-fluorobenzyl bromide. The crude product was obtained without further purification. MS calculated for C22H23ClFNO3+H: 404, observed: 404.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[NH:27][C:19]3=[N:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H][H]>[Pd].CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]2[NH:27][C:19]3=[N:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[CH:23]=[C:18]3[CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)C=C(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)O)cnc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)O)cnc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
A mixture of 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-but-1-enyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (540 mg, 1.40 mmol) and 10% palladium on activated carbon (162 mg) in methanol (300 mL) was heated at 50° C. under 50 bar of hydrogen in a steel bomb and kept for 5 h. The mixture was cooled to 25° C., filtered off solids and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 2-[1-(4-methanesulfonyl-phenyl)-3-methyl-butyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid (400 mg, 73%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]>>[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:20][C:12](=[O:14])[C@H:10]([CH3:11])[NH:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)Nc1cc(Cl)cc(Cl)c1

Procedure:
Following General Procedure D and using N-(3,5-dichlorophenyl)-D,L-alanine and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction product was purified by silica gel chromatography using 50% ethyl acetate/hexane.
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].BrBr.C([OH:23])(C)(C)C>>[C:12]([C:9]1[CH:8]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])[CH:16]=[O:23])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: BrBr
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O

Procedure:
In a 5 1., four-neck, round-bottom flask equipped with a thermometer, mechanical stirrer, dropping funnel and vent tube were placed 600 gm. of 2.6-di-t-butyl-p-cresol and 3600 ml. of t-butyl alcohol. To this stirred solution at 25°-35° C were added 908 gm. of Br2 over a period of ten hours. The resulting solid was separated by filtration, washed with hexane and dried. The yield was 440 gm. (71%) of aldehyde melting at 187°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]([OH:15])=O)=[N:9]2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:43]([O:45][C:46](=[O:66])[C@@H:47]([CH3:65])[CH2:48][CH:49]([NH2:64])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[CH:58]=2)=[CH:53][CH:52]=1)[CH3:44]>CN(C=O)C>[CH2:43]([O:45][C:46](=[O:66])[C@@H:47]([CH3:65])[CH2:48][CH:49]([NH:64][C:13]([C:10]1[N:11]=[N:12][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[N:9]=1)=[O:15])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([Cl:63])[CH:58]=2)=[CH:53][CH:52]=1)[CH3:44]
Reactant: CCOC(=O)[C@@H](C)CC(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: COc1ccc(Cn2nnc(C(=O)O)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid (Intermediate 32) (149 mg, 0.636 mmol) in DMF (2 mL) is added HATU. The mixture is stirred at room temperature for 15 minutes then (S)-4-amino-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31) (200 mg, 0.578 mmol) is added and the mixture is stirred at room temperature for 2 hours. Any insoluble material is filtered and the filtrate is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) to give (S)-5-(3′-chloro-biphenyl-4-yl)-4-{[2-(4-methoxy-benzyl)-2H-tetrazole-5-carbonyl]-amino}-2-methyl-pentanoic acid ethyl ester; HPLC Retention time 1.79 minutes (condition C): MS 562.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH3:15][Mg+].[Br-]>C1COCC1>[C:12]([C:5]1[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)(=[O:13])[CH3:15]
Reactant: C[Mg+]
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cnc(Cl)nc1C(F)(F)F
Reaction time: 0.75 h
Yield: 44.5 %

Procedure:
To a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride (0.50 g, 2.0 mmol) in THF at -78° C. under N2 was added MeMgBr (0.75 ml, 2.3 mmol). The reaction was stirred 0.75 h, quenched with H2O (1 ml) and diluted with EtOAc (30 ml). The organic layer was washed with H2O, brine and then dried over MgSO4. The residue was chromatographed (SiO2, hexanes/EtOAc, 2:1) to provide the 5-acetyl-2-chloro-4-trifiuoromethylpyrimidine (0.20 g) in 43% yield. The title compound was then prepared as described for ethyl 2-[N-(1'-aminocitraconamide)]-4-trifluoromethylpyrimidine-5-carboxylate of Example 20, resulting in a 29% yield (0.08 g); m.p. 61-62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[S:19]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]=[CH:9][C:2]=1[Cl:1])(=[O:21])(=[O:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
To an ice cooled solution of 2-chloro-5-(Boc-amino)benzyl alcohol (7.4 g; 29 mmol; from step (i) above) in CH2Cl2 (100 mL) was added TEA (2.9 g; 29 mmol), followed by MsCl (3.3 g, 29 mmol; added dropwise). After stirring for 2 hours the resultant mixture was poured onto water. The organic layer was separated, washed with water, dried (Na2SO4) and concentrated to yield 10 g (100%) of the sub-title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[N:16]=3)[C:12]([Cl:30])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.FC(F)(F)S(O[CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:20]1[C:15]([C:13]2[C:12]([Cl:30])=[CH:11][N:10]=[C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][CH2:44][CH2:45][O:46][C:47]([F:50])([F:49])[F:48])[CH2:3][CH2:4]3)[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][CH:19]=1
Reactant: O=S(=O)(OCCOC(F)(F)F)C(F)(F)F
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: FC(F)(F)OCCN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N2′-(trans-4-aminocyclohexyl)-3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine (45 mg, 0.10 mmol) and triethylamine (0.028 mL, 0.20 mmol) in chloroform (0.4 ml) was added 2-(trifluoromethoxy)ethyl trifluoromethanesulfonate (39 mg, 0.15 mmol). The mixture was stirred at ambient temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC, and lyophilized to give 29 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-(2-(trifluoromethoxy)ethylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 562.4 (MH+), retention time=0.67 min.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.32 (m, 4H) 1.36-1.52 (m, 2H) 1.58 (d, J=12.91 Hz, 2H) 1.65-1.84 (m, 1H) 2.07 (d, J=10.56 Hz, 4H) 2.99-3.17 (m, 3H) 3.23 (t, J=10.76 Hz, 2H) 3.35 (br. s., 2H) 3.64 (br. s., 1H) 3.72-3.89 (m, 2H) 4.34 (t, J=4.89 Hz, 2H) 6.32-6.47 (m, 1H) 6.49-6.65 (m, 1H) 6.67-7.10 (m, 2H) 7.49 (d, J=9.00 Hz, 1H) 8.03 (s, 1H) 8.75 (d, J=3.91 Hz, 1H)
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:10]([Br:11])=[C:9]([F:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N(OC(C)(C)C)=O>C1COCC1>[Br:11][C:10]1[C:4]2[S:3][CH:2]=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[F:12]
Reactant: Nc1nc2ccc(F)c(Br)c2s1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Fc1ccc2ncsc2c1Br
Temperature: 50 °C
Reaction time: 7 h
Yield: 34 %

Procedure:
To a solution of impure 2-amino-7-bromo-6-fluorobenzothiazole from Step A in THF (10 mL) was added tert-butyl nitrite (90%, 1.25 mL, 9.46 mmol). The mixture was stirred at 50° C. for 7 h and then purified by ISCO chromatography (0 to 40% EtOAc:heptane) to afford 114 mg (34%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.54 (dd, J=2.4, 8.0 Hz, 1H), 7.62 (dd, J=2.4, 8.0 Hz, 1H), 9.03 (s, 1H); 19F NMR (376 MHz, CDCl3): δ−113.77; MS (ESI): 231.92/233.92 [M+H]+; HPLC tR=1.38 min (TOF: polar—3 min).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([F:13])[F:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1COCC1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[C:20]#[CH:21].N1C(C)=CC=CC=1C>[Cu]I.C(OCC)(=O)C.O.CS(C)=O>[F:13][CH:11]([F:12])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[CH:21]=[C:20]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[N:3]=[N:2]2)=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=Nc1ccc(OC(F)F)cc1
Reactant: C#CC(=O)OCC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(OC(F)F)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
In a 50 ml round-bottomed flask, 1-azido-4-(difluoromethoxy)benzene (540 mg, 2.92 mmol) was combined with THF (10 ml) and dimethylsulfoxide (0.16 ml) to give an orange solution. Then ethyl propiolate (858 mg, 0.89 ml, 8.75 mmol), copper (I) iodide (556 mg, 2.92 mmol) and 2,6-lutidine (625 mg, 0.68 ml, 5.83 mmol) were added and the reaction mixture was stirred for 2 hours at room temperature. Water and ethyl acetate were added and the layers were separated. The organic layer was washed with 1 N hydrochloric acid and brine, dried over MgSO4 and filtered. The filtrate was concentrated under vacuum to yield a brown solid, which was adsorbed on silica gel and purified by flash chromatography (20 g Silica gel, 20% ethyl acetate in heptane) yielding 698 mg (84%) of a light yellow solid. MS (ISP): 284.2 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:6]=1[F:15])=O.[NH2:16][C:17](=[S:29])[CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>CO>[F:15][C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:16]=[C:17]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[S:29][CH:2]=1
Reactant: COC(=O)c1ccc(CC(N)=S)cc1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1F
Solvent: CO
Product: COC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3F)cs2)cc1
Yield: 75.9 %

Procedure:
To a solution of the compound (285 mg, 1.0 mmol) obtained in Example 186a in methanol (5 mL) was added the compound (209 mg, 1.00 mmol) obtained in Example 178a, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diluted aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (300 mg, 76%) as a colorless solid.