Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a stirred suspension of 3-bromopropylamine hydrobromide (2 g, 9.14 mM) in 40 mL dry THF was added, via hypodermic syringe, benzyl chloroformate (1.64 g, 9.60 mM) at room temperature. After cooling to 0° C., diisopropylethylamine (1.6 mL, 9.20 mM) was added dropwise via syringe and the reaction mixture was allowed to stir at 0° C. for 1 hour. The crude reaction mixture was filtered over a pad of Celite and solvents were evaporated. The residue was flash chromatographed on silica gel, eluting with 10-20-30% EtOAc/hexane to afford 1.56 g desired product as a liquid, homogeneous by TLC in 80:20 hexane-EtOAc;
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]#[C:13][C:14]([OH:17])([CH3:16])[CH3:15].Cl.NO>C(N)(C)C.CO.[Cu]Cl.[Cu+2]>[OH:17][C:14]([CH3:16])([CH3:15])[C:13]#[C:12][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: CC(C)(O)C#CBr
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Cu]
Agent: [Cu+2]
Agent: Cl
Solvent: CC(C)N
Solvent: CO
Product: COc1ccc(C#CC#CC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
100 mg of copper (I) chloride was dissolved in a mixture of 20 ml of isopropylamine and 20 ml of methanol in an atmoshpere of argon, and 1320 mg of 4-ethynylanisole were added to the resultant solution, followed by stirring at room temperature for 10 minutes. 2700 mg of 1-bromo-3-hydroxy-3-methyl-1-butyne were then dropwisely added to the solution over a time of about 3 hours, followed by stirring at room temperature fo 2 hours (If the solution is colored green owing to the production of copper (II) ion, an appropriate amount of hydroxilamine hydrochloride is added so as to reduce the copper (II) ion). The solvent was then evaporated from the reaction mixture, and the residue was neutralized and diluted by 1N hydrochloric acid, and then subjected to extraction with 50 ml of dichloromethane three times. The organic layer was dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel column chromatography using benzene as an eluent to obtain 1500 mg of 5-hydroxy-5-methyl-1-(4-methoxyphenyl)hexa-1,3-diyne.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[C:18](=[O:28])[C@H:19]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:20]>CS(C)=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[C:18]1([C@H:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:20])[CH2:2][O:28]1
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1cc(F)c(F)cc1F
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H](OC1CCCCO1)C1(c2cc(F)c(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 101.6 %

Procedure:
Trimethylsulfoxonium iodide (697 mg, 1.2 eq) was added portionwise to a stirred mixture of sodium hydride [60% mineral oil dispersion] (122 mg, 1.15 eq) and dry dimethyl sulfoxide (7 ml) at 0° C. The resulting mixture was stirred at room temperature for 40 min and then cooled in an ice bath. A solution of (2R)-2′,4′,5′-trifluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone (760 mg) in dry dimethyl sulfoxide (2 ml) was added to the mixture and stirring was continued for 2 h at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2-(2,4,5-trifluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (810 mg) as a pale yellow oil, which was a mixture of 4 diastereomers and was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Na].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>CS(C)=O.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Brc1cccc(-n2ccnc2)n1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A stirred solution of 2,6-dibromopyridine (2.0 g, 8.3 mmol) and imidazole sodium salt (1.0 g, 10.5 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. for 36 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with dichloromethane, then dichloromethane containing 5% methanol, gave 2-bromo-6-(1H-imidazol-1-yl)pyridine (0.18 g) as an off-white solid: δH (400 MHz, CDCl3) 7.20 (1H, m), 7.32 (1H, d, J 8), 7.47 (1H, d, J 8), 7.62 (1H, m), 7.68 (1H, dd, J 8 and 8), 8.35 (1H, s); m/z (ES+) 224/226 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([OH:11])[CH3:10])=[CH:3][C:2]=1[N:1]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(O)c1ccc(F)c(N)c1
Reactant: BrCCOCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(O)c1ccc(F)c(N2CCOCC2)c1
Yield: 88.4 %

Procedure:
A mixture of 1-(3-amino-4-fluoro-phenyl)ethanol (3.1 g), bromoethyl ether (5.413 g), and i-Pr2NEt (6.1921 g) in toluene (15 mL) was refluxed for 4 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give 3.98 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=3[O:20][CH3:21])=[CH:11][CH:12]=2)=[C:4]([O:22][CH3:23])[CH:3]=1.[C:24]1([NH2:35])[C:29](F)=[C:28](F)[C:27](F)=[C:26]([NH2:33])C=1F.Cl.Cl>CCOC(C)=O.CCOCC>[CH3:21][O:20][C:14]1[CH:15]=[C:16]([N:19]=[N:33][C:26]2[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=2)[CH:17]=[CH:18][C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]=[N:33][C:26]3[CH:27]=[CH:28][CH:29]=[CH:24][N:35]=3)=[CH:3][C:4]=2[O:22][CH3:23])=[CH:12][CH:11]=1
Reactant: COc1cc(N)ccc1-c1ccc(-c2ccc(N)cc2OC)o1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(N=Nc2ccccn2)ccc1-c1ccc(-c2ccc(N=Nc3ccccn3)cc2OC)o1
Yield: 75 %

Procedure:
2,5-Bis[2-methoxy-4-(2-pyridylimino)aminophenyl]furan (41, DB709) was prepared according to the procedure for 4f using diamine 3c and S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide as starting materials. Free base: Bright yellow crystalline solid, mp 196-197° C. (EtOAc/Et2O). Yield: 75%. 1H NMR (DMSO-d6): 3.92 (s, 6H), 6.64 and 6.67 (d, 2H and s, 2H, overlapping a broad NH signal), 6.89 (s, 2H), 7.55 (dd, 2H), 7.86 (d, 2H), 7.95 (m, 2H), 8.32 (d, 2H), 8.63 (d, 2H). Dihydrochloride: brick orange solid, mp >180° C. dec. 1H NMR (DMSO-d6): 4.00 (s, 6H), 7.16 (s, 2H), 7.18 (d, 2H), 7.34 (s, 2H), 7.85 (dd, 2H), 8.13 (d, 2H), 8.22 (t, 2H), 8.49 (d, 2H), 8.89 (d, 2H), 9.39 (br s, 2H), 10.15 (br s, 2H), 11.89 (br s, 2H), MS (EI): m/z 518 (M+, 100), 414 (90.0), 371 (13.3), 310 (12.7), 267 (9.7), 155 (6.02), 104 (25.9), 77 (9.6), 43 (13.6). Anal Calcd. for C30H26N6O.2.0HCl.2.0H2O (627.51): C, H, N, Cl.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22]C(=O)OCC=C)[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.C([SnH](CCCC)CCCC)CCC.CC(O)=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Yield: 80.5 %

Procedure:
To a solution containing 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}carbamate (5.3 g, 12.77 mmol) and DCM (225 mL) was added tri-n-butyltin hydride (5.95 g, 20.43 mmol), followed by trans-dichlorobis(triphenylphosphine)palladium (II) (0.53 g, 0.64 mmol) and HOAc (1.84 g, 30.65 mmol). At the conclusion of the reaction, silica was added and the volatiles removed under reduced pressure. The residue was purified by flash column chromatography with (84% DCM, 15% MeOH, and 1% NH4OH): DCM 0% to 100% to afford 3.4 g of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=5.1 Hz, 1H), 7.16 (d, J=5.1 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.72-6.75 (m, 1H), 6.64-6.69 (m, 1H), 6.60-6.63 (m, 1H), 5.28 (s, 2H), 3.27-3.40 (m, 1H), and 1.38 (d, J=7.0 Hz, 6H). MS (ESI): 331 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:5][C:6]=1[Cl:7].S(=O)(=O)(O)O.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15]([O:17][CH3:23])=[O:16])[S:5][C:6]=1[Cl:7]
Reactant: CO
Reactant: O=C(O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1cc(Cl)c(Cl)s1
Yield: 80 %

Procedure:
To a solution of 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionic acid (1.60 g) in methanol (30 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, iced water was poured on the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals (1.34 g, yield 80%) of methyl 3-[5-(4,5-dichloro-2-thienyl)-4-isoxazolyl]propionate was obtained from a fraction eluted with ethyl acetate-hexane (1:7, volume ratio). The crystals were recrystallized from diethyl ether-hexane to give a colorless needle. melting point: 49–50° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (75 mg, 0.21 mmol) and TBTU (73 mg, 0.23 mmol) in DMF (0.8 mL) was added DIPEA (177 μL, 1.03 mmol). Then isopropylamine (19 μL, 0.23 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane, then 0 to 10% methanol in dichloromethane) afforded the title compound (57 mg, 68%) as a white solid. MS: m/e=405.4 [M+H]+.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1.[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]=[O:35])[CH:25]=1.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH:34]([C:19]2[S:18][C:17]3[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][C:16]=3[CH:20]=2)[OH:35])[CH:25]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: COc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2sc(C(O)c3cc(Br)c4ccccc4c3)cc2c1
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.48 ml, 2.36 mmol) was added dropwise to a solution of 5-methoxybenzo[b]thiophene (388 mg, 2.36 mmol) in THF (6 ml) at −78° C. and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (530 mg, 2.25 mmol) in THF (4 ml) was added dropwise. The reaction mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution added and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (725 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C@@H:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:70]([CH2:72][NH2:73])[OH:71]>CN(C)C=O.C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C@@H:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([NH:73][CH2:72][CH2:70][OH:71])=[O:30])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CC[C@@H]3[C@@H]2C2CCCC2)cc1Cl
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)NCCO)cc4CC[C@@H]3[C@@H]2C2CCCC2)cc1Cl
Yield: 33 %

Procedure:
To a solution of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 (90 mg, 0.20 mmol) in N,N-dimethylformamide (1 mL) was added 1-hydroxybenzotriazole (43 mg, 0.32 mmol), triethylamine (0.06 mL, 0.40 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (103 mg, 0.32 mmol). The solution was stirred for twenty-five minutes followed by addition of ethanolamine (0.02 mL, 0.32 mmol). The solution was stirred for twenty hours at ambient temperature. The reaction was quenched with water and the resulting yellow solid was collected by vacuum filtration. Chromatography (reverse phase, acetonitrile/water) provided (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-N-(2-hydroxyethyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxamide (yellow solid, 30 mg, 33% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.00 minutes (10 to 90% acetonitrile/water over 6 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 463 (M+H); HRMS Calculated for C26H27ClN4O2: 463.1895 (M+H)+. Found: 463.1875; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.50 (m, 6H), 1.66-1.84 (m, 2H), 2.17-2.25 (m, 1H), 2.87-2.93 (m, 1H), 2.99-3.06 (m, 1H), 3.26-3.34 (m, 2H), 3.48 (t, J=6.18 Hz, 2H), 3.53-3.63 (m, 2H), 4.92 (dd, J=9.13, 6.18 Hz, 1H), 7.17 (dd, J=8.46, 1.75 Hz, 1H), 7.38 (d, J=2.15 Hz, 1H), 7.65 (d, J=8.86 Hz, 1H), 7.73 (d, J=8.59 Hz, 1H), 7.76 (s, 1H), 8.03 (d, J=8.06 Hz, 1H), 8.46 (t, J=6.31 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:52][CH2:51][CH2:50][CH2:49][CH:43]1[C:44]([O:46]CC)=[O:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:42]2[CH2:52][CH2:51][CH2:50][CH2:49][CH:43]2[C:44]([OH:46])=[O:45])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Reactant: CCOC(=O)C1CCCCN1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N3CCCCC3C(=O)O)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and ethyl pipecolinate (31 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.29-13.30 (br.s, 1 H), 8.95 (s, 1 H), 7.24 (m, 8 H), 7.04 (m, 1 H), 6.95 (m, 4 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 5.07 (d, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (m, 2 H), 3.77 (d, 1 H), 3.09 (m, 1 H), 2.91 (s, 3 H), 2.49 (m, 2 H), 2.40 (s, 3 H), 2.12 (m, 1 H), 1.90 (m, 2 H), 1.62 (m, 2 H), 1.49 (m, 1 H), 1.35 (m, 1 H), 1.21 (m, 1 H); MS (APCI+) m/z 685.9 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>CN(C=O)C.O>[Si:11]([O:1][CH2:2][CH2:3][C:4]#[CH:5])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 89.1 %

Procedure:
A solution of 1-hydroxybut-3-yne (2.0 g, 0.028 mol) and imidazole (2.9 g, 0.043 mol) in DMF (5 ml) was treated with t-butyldimethylsilyl chloride (6.4 g, 0.043 mol). After 24 hr. at RT, the reaction was diluted with water and extracted with diethyl ether. The organic extracts were washed with water, dried, evaporated, and the volatile organics were removed by vacuum to afford the title compound as an oil (4.6 g, 89%). 1H NMR (400 MHz, CDCl3): δ 3.67 (t, J=7.1 Hz, 2H), 2.32 (m, 2H), 1.88 (s, 1H), 0.82 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>>[OH:23][C:20]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=3[CH:12]=2)[CH2:21][CH2:22][C:17]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Reactant: O=C1CCC2(CC1)OCCO2
Product: Cn1c(=O)oc2ccc(C3(O)CCC4(CC3)OCCO4)cc21

Procedure:
The title compound was prepared as a white solid from 5-bromo-3-methyl-3H-benzooxazol-2-one (prepared by methylation of 5-bromo-3H-benzooxazol-2-one from Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[CH2:31][C:30](=O)[CH2:29][CH2:28]2>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][CH:30]2[CH2:29][CH2:28][C:27]3[C:32](=[C:33]([F:35])[CH:34]=[C:25]([F:24])[CH:26]=3)[CH2:31]2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: Diast #1 (RT 12 min) 14.2, 19.5, 2.9, 26.0, 28.2, 28.9, 29.7, 36.5, 52.9, 55.5, 58.9, 60.9, 67.5, 68.9, 101.1, 104.5, 110.7, 131.2, 137.4, 172.4; MS m/z 490.3 (M+1). Diast #2 (RT 18 min) 14.2, 19.6, 25.9, 26.0, 28.3, 28.9, 29.6, 36.5, 52.5, 55.5, 58.8, 60.4, 67.5, 68.9, 101.1, 104.5, 110.6, 131.2, 137.3, 172.2; MS m/z 490.3 (M+1). Chiral sep using a Kromasil TBB column, elute 95/5, heptane/IPA, flow rate 85 ml/min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Oc1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccccc1OCc1ccccc1
Temperature: 90 °C
Yield: 92.6 %

Procedure:
To a stirred solution of 4-fluoro-3-nitrobenzotrifluoride (2.1 g) and 2-benzyloxyphenol (2.0 g) in 10mL of DMF was added potassium carbonate (1.4 g). The reaction was heated at 90° C. for 16 hours. The solution was cooled to room temperature and H20 (10mL) was added. The mixture sas wxtraced with CH2Cl (2×10mL), and the combined extracts were dried (MgSO4), filtered, and concentrated to afford an oil. Silica gel chromatography (ethyl acetate/hexanes) afforde 3.6 g of the title compound. 1H NMR (400 MHz, CDCl3) δ8.19 (s, 1H), 7.60 (d, 1H), 7.26 (m, 5H), 7.08 (m, 4H), 6.88 (d, 1H), 5.02 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[CH2:9])=[CH:6][C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:4][N:3]=1>CO.[Pt]>[Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:4][N:3]=1
Reactant: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Agent: [Pt]
Solvent: CO
Product: CCc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1Cl
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A suspension of 5% Pt on carbon and 2-chloro-3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (Example 26 above, 440 mg, 1.36 mmol) in MeOH (10 mL) were stirred overnight under an atmosphere of hydrogen (balloon). The mixture was filtered and the filtrate was concentrated to afford 2-chloro-3-ethyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as a colorless oil (219 mg, 51%): 1H NMR (CDCl3, 300 MHz) δ1.25 (t, J=7.5 Hz, 3H), 1.42 (s, 9H), 2.32 (m, 2H), 2.71 (q, J=7.5 Hz, 2H), 3.89 (t, J=7.8 Hz, 2H), 4.12 (dd, J=3.0, 9.8 Hz, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.16 (d, J=3.1 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H); MS (CI/NH3) m/z 327 (M+H)+. To a solution of the product from above (216 mg, 0.66 mmol) in CH2Cl2 (2 mL) at 0° C. was added trifluoroacetic acid (1.8 mL). The solution was allowed to warm to room temperature, then adjusted to pH 11 with aqueous 10% NaOH, and extracted with CH2Cl2. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; CH2Cl2/MeOH, 100:3 to 100:15) to afford the free base of the title compound as an oil (60 mg, 40%): 1H NMR (CDCl3, 300 MHz) δ1.22 (m 3H), 2.38 (m, 2H), 2.71 (q, J=7.5 Hz, 2H), 3.57 (m, 1H), 3.80 (m, 1H), 4.08 (m, 2H), 4.38 (m, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.92 (d, J=3.0 Hz; 1H); MS (CI/NH3) m/z: 227 (M+H)+. The free base was dissolved in THF and treated with 1 M HCl in Et2O to afford the hydrochloride salt, which was triturated with Et2O and dried under vacuum to afford the title compound as a white solid: mp 102-104° C.; [α]D23 −9.68 (c 0.62, MeOH); 1H NMR (D2O) δ1.24 (t, J=7.5 Hz, 3H), 2.71 (m, 4H), 4.11 (m, 2H), 4.42 (d, J=4 Hz, 2H), 4.95 (m, 1H), 7.51 (d, J=3 Hz, 1H), 8.00 (d, J=3 Hz, 1H). Anal. Calcd. for C11H15N2OCl.1.1 HCl: C, 49.52; H, 6.08; N, 10.50. Found: C, 49.63; H, 5.89; N, 10.20.