Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ncn(-c2ccccn2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2ncn(-c3ccccn3)n2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
2-(3-Bromo-1H-1,2,4-triazol-1-yl)pyridine (0.25 g, 1.12 mmol) and 3-chlorophenylboronic acid (0.35 g, 2.23 mmol) were dissolved in toluene (20 mL) and methanol (2 mL), then deoxygenated via argon bubbling for 10 min. Potassium carbonate (0.23 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium (129 mg, 0.11 mmol) were added to this stirred solution. The reaction container was fitted with a reflux condenser and stirred at 90° C. for 16 h, after which time it was cooled to ambient temperature and poured into a separatory funnel containing EtOAc (100 mL). The EtOAc solution was washed with H2O (2×100 mL), then brine (100 mL) and the organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting crude residue was chromatographed on silica gel eluting with hexanes:EtOAc (8:2) to afford 2-[3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl]pyridine as a white powder which was dissolved in dichloromethane (10 mL) and precipitated as the hydrochloride salt (M.p.=125–128° C.) upon treatment with 1M HCl in diethyl ether (1 mL).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5])C.C[O-].[Na+]>CO>[CH3:1][O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH:10]=[C:9]([CH3:22])[S:8]1)=[O:5]
Reactant: CCOC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Yield: 83.5 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-tri-fluoromethylphenyl)-5-methylthiazoline (1.0 g) and sodium methoxide (28% methanolic solution; 0.6 g) in methanol (30 ml) was refluxed for 10 hours. After removal of the solvent, the residue was extracted with chloroform (100 ml), washed with water and dried over anhydrous magnesium. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.8 g of 2-methoxycarbonylimino-3- (3-trifluoromethylphenyl) 5-methylthiazoline (Compound No. 3).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:37][NH2:38]>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=2)=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: COc1ccc(CN)cc1OC
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COc1ccc(CNc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)cc1OC
Temperature: 25 °C
Yield: 49 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (218 mg, 0.523 mmol) obtained in Example 54 and 3,4-dimethoxybenzylamine (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (140 mg, 0.256 mmol, 49%) as an amorphous substance.
Reaction SMILES: CC(C)([O-])C.[CH2:6]([P:9]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([CH2:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH3:8].Cl[C:22]1[N:30]=[C:29]([I:31])[N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>C1COCC1>[CH2:6]([P:9]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:22]2[N:30]=[C:29]([I:31])[N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][N:26]3[CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[CH:18][CH:19]=1)([CH2:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH3:8]
Reactant: Clc1nc(I)nc2c1ncn2C1CCCCO1
Reactant: CCCP(=O)(CCC)c1ccc(N)cc1
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(I)nc3c2ncn3C2CCCCO2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Patasium tert-Butoxide (0.19 g, 1.65 mmol) was suspended in 4.5 mL anhydrous THF under nitrogen and cooled to −10° C. in an ice-salt bath. 4-(Dipropylphosphoryl)benzenamine (0.12 g, 0.55 mmol) was added to the suspension and the mixture was stirred at −10° C. for 30 min. 6-Chloro-2-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Tetrahedron 2002, 58, 7911-7923, 0.18 mg, 0.5 mmol) was then added to the reaction mixture and the content was warmed to room temperature and stirred over night. The reaction mixture was cooled to 0° C., and quenched by the addition of 0.1N HCl (˜500 mL). The mixture was concentrated on a rotavapor. The residue was partitioned between ethyl acetate (10 mL)/water (4 mL), organic layer was separated and washed with 0.1N HCl (4×4 mL), saturated NaHCO3 (4 mL), brine (4 mL), and dried over Na2SO4. The final product was obtained by flash column chromatography on silica gel (7.5% MeOH/DCM).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[C:16]([NH2:18])=[O:17])[N:12]([CH2:19][CH:20]([CH3:22])[CH3:21])[N:11]=[CH:10]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:37][N:38]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:39][CH2:40][CH2:41]N>C1COCC1>[CH3:37][N:38]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:39][CH2:40][CH2:41][NH:18][C:16]([C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:8][C:7]=1[O:6][C:5]1[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: CN(CCCN)c1ccccc1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(N)=O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3)c(C(=O)NCCCN(C)c3ccccc3)cc21
Reaction time: 18 h
Yield: 78 %

Procedure:
A solution of 5-(4-fluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (compound 10g, prepared as described in Example 46) in THF was treated with carbonyldiimidazole (1.2 equivalents) at room temperature under nitrogen atmosphere. After stirring for 18 hours, the reaction was treated with N1-Methyl-N1-phenyl-propane-1,3-diamine (1 equivalent). After 18 additional hours, the solvent was allowed to slowly evaporate and the residue was purified in a Sep Pak cartridge eluting with a gradient of 100% CH2Cl2 to 5% MeOH/CH2Cl2 to provide compound 11g-12 as an oil in 78% yield.
Reaction SMILES: [CH2:1]([C:3]1[O:7][CH:6]=[N:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[F:29][C:30]([F:38])([F:37])[C:31]([C:33]([F:36])([F:35])[F:34])=[O:32]>O1CCCC1>[CH2:1]([C:3]1[O:7][C:6]([C:31]([C:33]([F:36])([F:35])[F:34])([C:30]([F:38])([F:37])[F:29])[OH:32])=[N:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCc1ocnc1-c1ccc(SC)cc1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1oc(C(O)(C(F)(F)F)C(F)(F)F)nc1-c1ccc(SC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2.50 g (11.4 mmol) of 5-ethyl-4-(4-methylthiophenyl)oxazole and 2.0 ml (13.3 mmol) of tetramethylethylenediamine in 50 ml of tetrahydrofuran at -78° C. was added dropwise 12.6 ml (20.2 mmol) of n-butyl lithium (1.6M in hexane). The resulting solution was stirred for 1 hour at -78° C., and then 3.5 ml (31 mmol) of hexafluoroacetone was added dropwise. The mixture was stirred for 1 hour at -78° C. and then quenched by the rapid addition of 30 ml of sodium bicarbonate solution. After warming to 25° C., the organic and aqueous phases were separated and the aqueous phase was extracted with tetrahydrofuran. The combined organic phases were then washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was dissolved in a mixture of 100 ml of ethanol and 20 ml of 4N hydrochloric acid; and the solution was stirred overnight at 25° C. The solution was concentrated in vacuo to remove the ethanol and the resulting aqueous mixture was extracted with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (elution-benzene) to provide 3.28 g of 5-ethyl-4-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)oxazole-2-methanol as a light orange oil.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH2:11]([NH2:13])[CH3:12]>[Pt]=O.C(O)C>[CH2:11]([NH:13][CH:2]([CH3:10])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH3:12]
Reactant: CCN
Reactant: CC(=O)CCn1ccnc1
Agent: O=[Pt]
Solvent: CCO
Product: CCNC(C)CCn1ccnc1

Procedure:
A mixture of 1-(3-oxobutyl)imidazole, ethylamine and ethanol is hydrogenated using platinum oxide as catalyst, by the procedure of Example 3, to give 1-(3-ethylaminobutyl)imidazole.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][OH:18])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([N:8]([CH2:16][CH2:17][O:18][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCOc1ccc(F)cc1)Cc1ccccc1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a solution of 2-(N-benzyl-N-tert-butoxycarbonylamino)ethanol (6.85 g, 27.3 mmol), 4-fluorophenol (3.07 g, 27.3 mmol) and PPh3 (7.83 g, 30.0 mmol) in THF (100 mL) was added DIAD (6.00 mL, 30.0 mmol) at room temperature. After being stirred for 3 hr, the reaction mixture was concentrated. Chromatography of the residue with hexane-EtOAc (8:1, v/v) as eluent gave 1-[2-(N-benzyl-N-tert-butoxycarbonylamino)ethoxy]-4-fluorobenzene (8.19 g, 64%) as a yellow oil. 1H-NMR (CDCl3) δ1.42-1.50 (m, 9H), 3.41-3.67 (m, 2H), 3.92-4.11 (m, 2H), 4.51-4.63 (m, 2H), 6.73-6.85 (m, 2H), 6.89-6.98 (m, 2H), 7.24 (m 5); FAB-MS m/z 346 (M++1).
Reaction SMILES: C([Mg]Br)C.C1C[O:8][CH2:7][CH2:6]1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C(Cl)(=O)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:7]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)(=[O:8])[CH3:6]
Reactant: C1CCOC1
Reactant: CSc1nc(I)n2ccsc12
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: CSc1nc(C(C)=O)n2ccsc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A 1 M ethylmagnesium bromide/THF solution (4.78 ml) was added in an argon atmosphere at −40° C. to a solution of 963 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 30 ml of dry THF. The mixture was stirred at the same temperature for 30 min. Acetyl chloride (0.35ml) was added thereto. The temperature of the system was raised to −5° C. over a period of 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=2:1:1) to give 384 mg of 5-acetyl-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[NH:5]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@@H:6]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH:5]([C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])[C@@H:6]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:7][CH2:8][CH2:9][C:10]([O:12][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:11]
Reactant: C=C(C)C
Reactant: O=C(O)CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 72 h

Procedure:
400 ml of isobutylene are added to a solution of 40 g (approx. 104 mmoles) of Z-D-Aad-OBzl in 400 ml of methylene chloride, followed, at -20°, by 4 ml of concentrated sulfuric acid. The mixture is allowed to stand in an autoclave for 3 days at room temperature. The batch is stirred with NaHCO3 solution in order to neutralize the sulfuric acid and the excess isobutylene is removed by means of a stream of nitrogen. The methylene chloride phase is extracted by shaking with water and is dried over Na2SO4 and concentrated. This leaves 46.3 g of an oil, which is chromatographed on 500 g of silica gel using a 9:1 mixture of methylene chloride and acetone. The eluate, which contains Z-Aad-(OBut)-OBzl, is concentrated. Yield: 42.35 g of a pale oil (92%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:30])[F:31])=[CH:29][CH:28]=3)[CH2:27][CH2:26]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 99.6 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (500 mg, 2.30 mmol) and 4-(4-trifluoromethylphenoxy)piperidine (730 mg, 3.0 mmol) in DMF (10 ml) were stirred at 70-75° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethylphenoxy)piperidin-1-yl]propan-2-ol (1.06 g, yield 99%) as a yellow oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20]>>[F:24][C:23]1[CH:22]=[CH:21][C:19]([NH:20][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=2)=[N:2][OH:1])=[CH:18][C:17]=1[C:16]([F:15])([F:25])[F:26]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COCCNc1nonc1C(Cl)=NO
Product: COCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The desired compound was prepared according to the procedure of Example 13, step A, using N-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride [made according to Example 1, steps A through E] and 3-trifluoromethyl-4-fluoroaniline [Aldrich, product #217778] as the starting materials in quantitative yield. LCMS for C13H14F4N5O3 (M+H)+: m/z=364.0. 1H NMR (400 MHz, CD3OD): δ 7.15 (m, 2H), 7.08 (m, 1H), 3.60 (t, J=5.3 Hz, 2H), 3.46 (t, J=5.3 Hz, 2H), 3.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21][CH3:22])=[CH:15][C:14]=3[F:23])=[O:9])=[CH:4][CH:3]=1.CN(C=[O:30])C.ClC1C=CC=C(C(OO)=O)C=1.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([S:21]([CH3:22])=[O:30])=[CH:15][C:14]=3[F:23])=[O:9])=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: CSc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.17 h

Procedure:
A suspension of 150 mg of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(methylsulfanyl)-3-quinolinecarboxamide from Example No. 170 and 0.75 mL of DMF in 15 mL of chloroform is treated with 79 mg of m-chloroperbenzoic acid. After stirring for 10 min the mixture is treated with 10 mL of a concentrated aqeous solution of sodium bisulfite. After stirring an addtional 5 min the phases are separated and the organic layer is washed with 15 mL of a saturated aqueous solution of sodium bicarbonate. The organic layer is dried (MgSO4) and the solvent was evaporated at reduced pressure. The residual solid is washed with a small volume of diethyl ether and dried to give 95 mg of a white solid.
Reaction SMILES: BrC1C=C2C(=CC=1[Cl:12])C=NC=C2.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[Cl:12])[C:20](=[O:24])[N:19]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[CH:18]=[CH:17]2
Reactant: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reactant: Clc1cc2cnccc2cc1Br
Product: COc1ccc(Cn2ccc3cc(Br)c(Cl)cc3c2=O)cc1

Procedure:
Starting from 6-Bromo-7-chloro-isoquinoline (263), the title compound was prepared by the method described for 6-Bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (13). Rt=1.66 min (Method C). Detected mass: 318.3 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C([O-])([O-])=O.[K+].[K+].[C:30]([C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.O>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([S:40][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:38][CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Sc2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
The product from Example 242a (600 mg, 1.828 mmol) was dissolved in DMF (20 ml) to which K2CO3 (505 mg, 3.656 mmol), and 4-tert-Butyl-benzenethiol (304 mg, 1.828 mmol) were added. This reaction mixture was then heated to 80° C. for 1 hr. At this time the reaction mixture was cooled to room temperature, diluted with water, and the title compound collected by filtration (311 mg, 35%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH:17]=[CH:16][N:15]=1.CN(C=O)C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(C)c1
Reactant: COC(=O)Cc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccnc(-c2ccnc(C)c2)c1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a flask containing methyl 2-(2-chloropyridin-4-yl)acetate 238-1 (1.00 g, 5.38 mmol), 2-methyl-4-(tributylstannyl)pyridine (2.06 g, 5.38 mmol), Pd(PPh3)4 (594 mg, 0.54 mmoL) under argon was added DMF (15 mL). The reaction mixture was stirred at 120° C. for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 5% methano in dichloromethane to give methyl 2-(2′-methyl-2,4′-bipyridin-4-yl)acetate 238-2 as dark orange oil. MS m/z 243.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:16](=O)[CH2:17][C:18](=O)[CH3:19])[C:10]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:47][OH:48].C([O-])(=O)C.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([N:15]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([C:33]([F:35])([F:36])[F:34])[CH:24]=2)[C:16]2[O:48][N:47]=[C:18]([CH3:19])[CH:17]=2)[C:10]2[CH:37]=[C:38]([CH3:45])[C:39]([C:41]([F:44])([F:42])[F:43])=[CH:40][C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(=O)CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CCCN(C(=O)OC(C)(C)C)c2cc(C(F)(F)F)c(C)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc(C(F)(F)F)c(C)cc32)on1
Yield: 16.8 %

Procedure:
To a solution of compound (S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (600 mg, 0.916 mmol) in methanol (5 mL) at 0° C., add hydroxylamine hydrochloride (96 mg, 1.37 mmol) and sodium acetate (3 mg, 0.046 mmol). Heat the reaction mixture under reflux for 4 h. Cool and remove the solvents under reduced pressure. Dilute the residue with ethyl acetate and brine. Separate the layers and dry the organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (20:1 to 3:1) to afford the title compound as an off-white solid (100 mg, 17%). 1H NMR (CDCl3, 300 MHz) δ 1.10-2.10 (m, 16H), 2.21 (s, 3H), 2.54 (s, 3H), 4.22-4.83 (m, 3H), 6.89-6.92 (m, 1H), 7.36-7.89 (m, 4H); ESI MS m/z 652 [C30H30F9N3O3+H]+.