Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Br:11][C:12]1[C:17]2[N:18]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)[C:19]([CH:21]([NH2:23])[CH3:22])=[N:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.O>C(O)CCC.CCOC(C)=O.CCCCCC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:23][CH:21]([C:19]2[N:18]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)[C:17]3[C:12]([Br:11])=[CH:13][CH:14]=[CH:15][C:16]=3[N:20]=2)[CH3:22])[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(N)c1nc2cccc(Br)c2n1-c1cncc(F)c1
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccc(Br)c2n1-c1cncc(F)c1
Temperature: 120 °C
Reaction time: 23 h

Procedure:
A mixture of 4-amino-6-chloropyrimidine-5-carbonitrile (0.368 g, 2.381 mmol), 1-(7-bromo-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine (0.798 g, 2.38 mmol), and DIEA (1.24 mL, 7.14 mmol) in 1-butanol (23.8 mL) was stirred at 120° C. After 23 h, the mixture was removed from the heat and left at rt. After cooling, the mixture was concentrated in vacuo to give a dark purple solid. To the dark purple solid was added water (50 mL) followed by sonication. The resulting precipitate was collected by filtration, washed with water, and air-dried to give the product. The solid was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 50% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide a purple solid. The purple solid was suspended in EtOAc-hexane (1:5, 10 mL), filtered, and washed with EtOAc-hexane (1:5, 40 mL) to provide 4-amino-6-(1-(7-bromo-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylamino)pyrimidine-5-carbonitrile as a purple solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47-8.79 (2H, m), 7.88-8.34 (1H, m), 7.67-7.85 (3H, m), 7.44 (1H, dd, J=7.8, 0.8 Hz), 7.22 (3H, t, J=7.9 Hz), 5.29-5.47 (1H, m), 1.57 (3H, d, J=6.8 Hz); LC-MS (ESI) m/z 453.0 [M+H (79Br)]+ and 454.9 [M+H (81Br)]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2)([O:3][CH3:4])=[O:2].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][CH2:22][C:23]([C:13]1[N:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][C:5]=1[C:1]([O:3][CH3:4])=[O:2])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc2ccccn2c1
Reactant: O=C(Cl)COCc1ccccc1
Product: COC(=O)c1cc2ccccn2c1C(=O)COCc1ccccc1

Procedure:
Following the procedure of Example 3, 2-carbomethoxyindolizine was reacted with benzyloxyacetyl chloride to give 3-benzyloxyacetyl-2-carbomethoxyindolizine (VII) Cyclization of VII with hydrazine and reaction of the resulting pyridazino[4,5-b]indolizin-1-one with POCl3 gave the corresponding chloro compound (VIII). The reaction of VII with 4-(2-pyrimidinyl)-1-piperizinyl)ethyl amine gave the title compound. Treatment with ethereal HCl in ether gave the product as the trihydrochloride salt: m.p. 140° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[H+].[B-](F)(F)(F)F.CCOCC.[Br:21]N1C(=O)CCC1=O>CC#N>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:21])=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred, cooled (−20° C.) solution of 2-cyanophenol (30 g, 252 mmole) in dried MeCN (400 mL) was added HBF4.Et2O (45 g, 277.1 mmole), and N-bromosuccinimide (53.8 g, 302.3 mmole). After addition was completed, the mixture was warmed to RT, and stirred in 4 h. The mixture was cooled and quenched by 50% aqueous NaHSO3. The mixture was concentrated to removed excess of MeCN. The off-white solid thus obtained was filtered and dried by air (42.4 g, 85%). 1H-NMR (300 MHz, DMSO-d6): δ6.99 (d, J=8.9 Hz, 1H), 7.67 (dd, J=2.5, 8.9 Hz,1H), 7.88 (d, J=2.5 Hz,1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.O1CCOCC1>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH2:14])[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2c(-c2ccccn2)c1-c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(N)c1nc2ccc(F)cc2c(-c2ccccn2)c1-c1ccccn1
Reaction time: 3.5 h

Procedure:
A mixture of tert-butyl 1-(6-fluoro-3,4-di(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.4146 g, 0.933 mmol) was dissolved in hydrochloric acid, 4 M solution in 1,4-dioxane (4.66 mL, 18.65 mmol) and the mixture was stirred at rt. After 3.5 h, the mixture was partitioned between DCM (50 mL) and water (50 mL). The acidic aq mixture was washed with DCM (30 mL×2) to remove organic impurities and then basified to ˜pH 10 with 10 N NaOH (3.5 mL), extracted with DCM (50 mL×3). The combined organic layers were washed with water (100 mL×1), brine (100 mL×1), dried over MgSO4, filtered, and concentrated in vacuo to give 1-(6-fluoro-3,4-di(pyridin-2-yl)quinolin-2-yl)ethanamine as an orange syrup: LC-MS (ESI) m/z 345.1 [M+H]+. The orange syrup was carried on crude without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:4]=1[NH2:5].I[C:20]1[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:24]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[CH:24]=2)[CH:7]=[CH:6][C:4]=1[NH2:5]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: CN1CCN(CCn2cc(I)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cnn(CCN3CCN(C)CC3)c2)ccc1N
Yield: 35.5 %

Procedure:
A solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (210 mg, 0.843 mmol), 1-(2-(4-iodo-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine (Preparation 59, 206 mg, 0.643 mmol) and Pd(dppf)Cl2.DCM (52 mg, 0.064 mmol) was dissolved in THF (4.5 mL) and 2M sodium carbonate in water (1.5 mL) and heated to 60° C. for 18 hours. The mixture was concentrated under reduced pressure. The residue was partitioned between water and DCM. The aqueous layer was extracted with DCM three times and the combined organic layers dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 15% MeOH in DCM to give the title compound (72 mg, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:30]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:30])[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2Sc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reaction time: 0.08 h

Procedure:
4-{5-[(4-Chlorophenyl)thio]-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 1, 222 mg, 0.57 mmol) was dissolve in THF (6 mL), to which was added NaH (60% wt, 27.5 mg, 0.687 mmol) at 0° C. After stirring for 5 min, MeI (0.05 mL, 0.86 mmol) was added. The reaction was stirred at 0° C. for 2 h, and then quenched with aq NH4Cl to adjust the pH to 6-8. The product was extracted with EtOAc and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was subject to silica column chromatography (0-20% EtOAc in hexanes) to give the title compound as the major region isomer. 1H NMR (500 MHz, (CD3OD): 8.18 (d, 2H), 7.77 (m, 2H), 7.76 (d, 2H), 7.68 (m, 3H), 7.34 (d, 2H), 7.09 (d, 2H), 3.70 (s, 3H). LCMS: m/z 402 (M+H)+. The minor region isomer was the title compound of Example 3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][NH2:37].O>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[N:36][NH2:37])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=NN)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) in THF (2 mL) was added hydrazine.H2O (10 μL, 0.20 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 1.5 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure to give the title compound which was used directly in the next step without any purification.
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([C:11]1[N:15]2[C:16]([CH2:20]Cl)=[CH:17][CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)([O:8]CC)=O.C1CCN2C(=NCCC2)CC1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][NH2:48])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].[I-].[Na+]>C(#N)C.C(N(CC)CC)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][CH2:47][N:48]2[CH2:20][C:16]3[N:15]4[C:11](=[CH:12][N:13]=[C:14]4[CH:19]=[CH:18][CH:17]=3)[C:6]2=[O:8])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 37.5 %

Procedure:
In 50 ml of acetonitrile was suspended 6.73 g (20.0 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine sulfate followed by addition of 5.97 ml (40.0 mM) of DBU at room temperature with stirring. To the resulting solution was added 4.57 g (20.0 mM) of 2-(1-tert-butoxycarbonylpiperidin-4-yl)-1-ethylamine as well as 5.54 ml (40.0 mM) of triethylamine and 3.00 g (20.0 mM) of sodium iodide and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of 2-butanone. The organic layer was washed with 100 ml of saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-ethanol=5:1) to provide 2.88 g (yield 37.5%) of the title compound as yellow oil.
Reaction SMILES: [Cl-].[CH2:2]([N:4]1[C:8](=[O:9])[C:7](=[CH:10][CH:11]=[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[S:13]2)[S:6][C:5]1=[CH:22][C:23]1[S:24][C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[N+:27]=1[CH3:28])[CH3:3].[CH3:34][S:35]([OH:38])(=[O:37])=[O:36]>CO>[S:35]([O-:38])(=[O:37])(=[O:36])[CH3:34].[CH2:2]([N:4]1[C:8](=[O:9])[C:7](=[CH:10][CH:11]=[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[S:13]2)[S:6][C:5]1=[CH:22][C:23]1[S:24][C:25]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:26]=2[N+:27]=1[CH3:28])[CH3:3]
Reactant: CS(=O)(=O)O
Agent: CCn1c(=Cc2sc3ccc(F)cc3[n+]2C)sc(=CC=C2Sc3ccccc3N2C)c1=O
Agent: [Cl-]
Solvent: CO
Product: CS(=O)(=O)[O-]

Procedure:
After dissolving Compound A, which was obtained in Synthesis Example 1, in methanol, the anion thereof was replaced with methanesulfonic acid according to an ordinary method to give 2-((3-ethyl-5-(2-(3-methylbenzo[d]thiazol-2(3H)-ylidene)ethylidene)-4-oxothiazolidin-2-ylidene)methyl)-5-fluoro-3-methylbenzo[d]thiazol-3-ium mesylate (Compound D) as a dark-green solid. The physical property values and analytical values of this compound are as described below:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(OCC)(=O)C>C(COC)OC.O>[O:3]=[C:4]([CH2:11][CH3:12])[CH:5]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)CC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.75 g, 43.7 mmol) was added in portions over 1 minute to an ice-cooled, stirring solution of ethyl 3-oxopentanoate (6.30 g, 43.7 mmol) in dry dimethoxyethane (87 mL). After 5 minutes, the flask was removed from the cooling bath and stirring continued at room temperature. After 30 minutes, a solution of 4-(trifluoromethyl)benzyl bromide (10.4 g, 43.7 mmol) in dry dimethoxyethane (10 mL) was added dropwise over 2 minutes. After 2.5 hours, ethyl acetate (300 mL) and water (100 mL) were added. The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue was purified by flash-column chromatography on silica gel eluting with hexanes initially, grading to 50% dichloromethane-hexanes to provide the title compound as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCCCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(C(=O)OCC)c1ccc(N)cc1
Yield: 97.1 %

Procedure:
12 g of (RS)-ethyl 2-(4-nitrophenyl)-heptanoate dissolved in 100 ml of ethanol was treated with 2.4 g of 10% palladium on carbon. The mixture was stirred at room temperature for 18 hours under 40 psi of hydrogen. The mixture was filtered on a pad of Celite and concentrated in vacuo. The product was purified by flash chromatography (SiO2, 25% ethyl acetate/hexanes), yielding 10.4 g of a pale yellow oil. 1H NMR (CDCl3): 7.10 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 4.20-4.00 (m, 2H), 3.61 (br. s, 2H), 3.40 (t, J=7.7 Hz, 1H), 2.05-1.90 (m, 1H), 1.75-1.60 (m, 1H), 1.30-1.15 (m, 6H), 1.20 (t, J=7.2 Hz, 3H), 0.85 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C(=O)=O.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([B:29]([OH:34])[OH:30])=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1-c1ccccc1OCc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 2′-benzyloxy-2-bromobiphenyl (2.41 g, 7.09 mmol) in tetrahydrofuran (50 ml) was stirred under nitrogen and cooled to −100° C. (diethyl ether/liquid nitrogen). 1.6M nButyllithium in hexanes (4.87 ml, 7.80 mmol) was added over 15 mins. at −100° C. and the mixture warmed to −78° C. (acetone/Drikold) and stirred for 1 h. Triisopropyl borate (4.00 g (5.02 ml, 21.30 mmol) was added at −78° C. and the reaction allowed to warm to room temperature with stirring over 1.5 h. 1M Hydrochloric acid (50 ml) was added and the mixture stirred vigorously for 1 h. The organic layer was separated and the aqueous layer extracted with diethyl ether (50 ml). The combined organic phase were washed with water, dried (MgSO4) and the solvent removed in vacuo. The yellow oil was flash chromatographed (silica gel, 10-20% EtOAc-isohexane) to give the title compound as a clear oil (1.74 g, 80%). LC/MS RT=3.28 min [(2M−H2O)H−]=589.3
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:25]2[C:30]([C:31]([OH:33])=[O:32])=[CH:29][N:28]=[C:27]([NH:34][C:35]3[CH:40]=[N:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=3)[CH:26]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].CN(C(O[N:51]1N=N[C:53]2C=CC=[N:57][C:52]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O/N=C(/N)\C.[Na+].[Cl-]>CN(C=O)C>[NH2:57]/[C:52](=[N:51]/[O:32][C:31]([C:30]1[C:25]([NH:24][CH2:23][CH:20]2[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:16])[CH2:22][CH2:21]2)=[CH:26][C:27]([NH:34][C:35]2[CH:40]=[N:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=2)=[N:28][CH:29]=1)=[O:33])/[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C/C(N)=N\O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C/C(N)=N\OC(=O)c1cnc(Nc2cnc(C#N)cn2)cc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
DIPEA (96 μL, 0.55 mmol) was added to a solution of 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylamino)-6-(5-cyanopyrazin-2-ylamino)nicotinic acid (Synthesis 75-A) (50 mg, 0.11 mmol), HATU (54 mg, 0.14 mmol) in DMF (6 mL) under argon. The reaction mixture was stirred for 15 min at r.t. and (E)-N′-hydroxyacetimidamide (25 mg, 0.34 mmol) in DMF (0.5 mL) was added. The resulting solution was stirred at r.t. for 12 hr. Aqueous NaCl solution (15 mL) was added and the resulting precipitate was collected. The solid was washed with water and n-hexane to give a yellow powder (43 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][NH:7][C:8](=O)[C:9]([CH3:22])([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH3:10])=[O:5].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]1[O:5][C:8]([C:9]([CH3:22])([O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[CH3:10])=[N:7][N:6]=1
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cc1)C(=O)NNC(=O)c1ccncc1Cl
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(Oc1ccc(C(F)(F)F)cc1)c1nnc(-c2ccncc2Cl)o1
Temperature: -10 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
3-chloro-N′-{2-methyl-2-[4-(trifluoromethyl)phenoxy]propanoyl}isonicotinohydrazide (282 mg) was dissolved in dichloromethane (5 ml) and pyridine (130 μl) was added thereto. The reaction solution was cooled to −10° C., trifluoromethanesulfonic anhydride (230 μl) was added thereto, followed by standing to warm to room temperature and then stirring overnight. The reaction solution was diluted with saturated aqueous sodium bicarbonate, the organic layer was separated and the aqueous layer was extracted with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 3-chloro-4-(5-{1-methyl-1-[4-(trifluoromethyl)phenoxy]ethyl}-1,3,4-oxadiazol-2-yl)pyridine (231 mg) as a light yellow solid.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(N(CC)CC)C.S(Cl)([Cl:25])=O.S(=O)=O.Cl>C1(C)C=CC=CC=1>[Cl:1]/[C:2](/[C:12]([F:15])([F:14])[F:13])=[CH:3]\[C@@H:4]1[C@H:6]([C:7]([Cl:25])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 45 °C
Reaction time: 5 h

Procedure:
A 1 liter dry, clean jacketed split reaction vessel equipped with agitator, thermometer, condenser, nitrogen blanket and vent to a scrubber system was charged with toluene (450 ml) and agitated whilst cis-Z (+) 3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropane carboxylic acid (89.4 gm=0.369 mol) was added followed by triethylamine (0.21 gm=2.1 mmol). The reaction mixture was then heated to 45° C., using oil circulation on the jacket, and thionyl chloride (62.0 gm=0.52 mol) was then charged over 105 minutes maintaining on temperature. The reaction mass was then agitated for 5 hours at 45° C. then tested by GLC for completion of reaction showing 2% residual acid. A further addition of thionyl chloride (4.4 gm=37 mmol) was then made and the reaction mass allowed to cool with stirring overnight. The following day, residual thionyl chloride, dissolved sulphur dioxide and hydrogen chloride gases were removed by distillation of about 320 ml toluene under vacuum. GC, GCMS and NMR analysis of the product were consistent with the structure of the acid chloride (IIIa). Yield, 175 gm of a 54% solution of the acid chloride in toluene, ˜97% theory. αD=+46°
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH3:19])=[N:7]2.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH3:19][C:8]1[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:25](=[O:27])[CH3:26])[N:7]=1
Reactant: Cc1nc2cccc(Br)c2nc1Nc1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cccc2nc(C)c(Nc3ccccc3)nc12
Temperature: 160 °C
Yield: 21 %

Procedure:
A mixture of 8-bromo-3-methyl-N-phenylquinoxalin-2-amine (0.64 g, 2.037 mmol), tributyl(1-ethoxyvinyl)stannane (1.032 ml, 3.06 mmol; Aldrich), Pd2(dba)3 (0.187 g, 0.204 mmol), XPhos (Strem, Newburyport, Mass.; 0.097 g, 0.204 mmol), CuI (0.078 g, 0.407 mmol), and cesium fluoride (0.928 g, 6.11 mmol) in dioxane (10.19 ml) was heated in a microwave reactor (Biotage Initiator) for 20 min at 160° C. The mixture was diluted with EtOAc (200 ml), added to a separatory funnel, and washed with saturated aq. NH4Cl (3×150 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% hexanes to 30% EtOAc/hexanes) provided 1-(2-methyl-3-(phenylamino)quinoxalin-5-yl)ethanone (183b, 21% yield) as a brown, amorphous solid. MS (ESI, pos. ion) m/z: 278.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:21])[CH3:20]>>[CH2:19]([N:21]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Reactant: CCN
Product: CCN(CC(CC1CCCCC1)NC(=O)OC(C)(C)C)CC(CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
The product from Example 15A and ethylamine were processed as described in Example 7B to provide the title compound.