Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(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>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(C(C)=O)nc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-(5-bromopyridin-2-yl)ethanone (1.0 g, 5.0 mmol) in toluene (30 mL) and ethanol (20 mL) was added (4-methoxyphenyl)boronic acid (1.52 g, 10 mmol), 2M Na2CO3 (14 mL), Pd(PPh3)4 (0.057 g, 0.05 mmol), the reaction was purged with argon and heated at 80° C. for about 6 h. The reaction mixture was concentrated, diluted with water (100 mL), and extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine solution (20 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 10% ethyl acetate in hexane eluent to afford 1-(5-(4-methoxyphenyl)-pyridin-2-yl)ethanone as off white solid (1 g, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.20 (d, 1H), 7.96 (d, 1H), 7.76 (d, 2H), 7.027 (d, 2H), 3.80 (s, 3H), 2.63 (s, 3H). LC-MS m/z calcd for [M+H]+ 228.09. found 228.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1ccc2c(c1)C(C)NCC2
Product: Cc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2
Yield: 55 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,7-Dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:22][CH2:21][CH:20]=[CH:19][C:16]=3[CH:17]=2)[CH2:12][C:11]1=[O:23])[CH3:9].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([CH:12]2[C:13]3[C:18](=[CH:17][C:16]4[CH:19]=[CH:20][CH2:21][O:22][C:15]=4[CH:14]=3)[N:10]([CH2:8][CH3:9])[C:11]2=[O:23])=[O:33])=[CH:27][CH:26]=1
Reactant: CCN1C(=O)Cc2cc3c(cc21)C=CCO3
Reactant: O=C=Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2)c2cc3c(cc21)C=CCO3
Temperature: 0 °C
Yield: 60 %

Procedure:
To a slurry of 128 mg. (3.2 mmoles) of sodium hydride (washed with petroleum ether) in 4 ml. of dimethylformamide was added 500 mg. (2.3 mmoles) of 1-ethyl-2-oxo-2,3-dihydro-pyrano[2,3-f]indole followed after 15 minutes of stirring by 0.36 ml. (3.2 mmoles) of 4-fluorophenylisocyanate. The reaction mixture was allowed to stir at room temperature for 30 minutes, and was then added to a mixture of dichloromethane (50 ml.) and ice water (50 ml.). The aqueous layer was extracted with 35 ml. of dichloromethane and was then acidified with 4N hydrochloric acid. The acidified layer was extracted with fresh dichloromethane, and the organic phase separated, dried over magnesium sulfate and concentrated under vacuum to dryness, 1.6 g. The residue was taken up in ethyl acetate, washed with a brine solution and dried over magnesium sulfate. Removal of the solvent gave 709 mg. of crude product. Recrystallization from dichloromethane-diisopropyl ether gave 490 mg. (60% yield) of product, m.p. 212°-214° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:7]1=2.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25]>C(O)C.C([O-])(O)=O.[Na+]>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH:16][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[NH:25])[CH:14]=[CH:15][C:7]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCCN1CCSc2cc(N)ccc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A solution of 4-(3-(dimethylamino)propyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-7-amine (0.22 g, 0.875 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.499 g, 1.750 mmol) at room temperature, and the resulting mixture was stirred over night (18 hours) at room temperature. The reaction was diluted with saturated NaHCO3 solution (25 mL), and the product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (5:95 (2M NH3 in MeOH):CH2Cl2) on silica gel to obtain the title product 22 (0.27 g, 86%) as a solid. 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=3.0 Hz), 7.56 (d, 1H, J=5.1 Hz), 7.06 (dd, 1H, J=3.9, 4.8 Hz), 6.69 (d, 1H, J=8.7 Hz), 6.52-6.45 (m, 2H), 6.33 (brs, 2H), 3.51-3.48 (m, 2H), 3.25 (t, 2H, J=7.2 Hz), 3.04-3.01 (m, 2H), 2.25 (t, 2H, J=6.9 Hz), 2.14 (s, 6H), 1.70-1.61 (m, 2H); ESI-MS (m/z, %): 361 (MH+, 93), 276 (100); HPLC purity: 98.23% by area.
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>CN(C)C=O>[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[N:4]1
Reactant: Oc1ccc(-n2cccn2)cc1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(N2CCN(CCCOc3ccc(-n4cccn4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
0.66 g (0.0152 mole) of sodium hydride (55% strength in liquid paraffin) is added to 2.1 g (0.0131 mole) of 4-(pyrazol-1-yl)-phenol in 60 ml of absolute dimethylformamide, and the mixture is stirred for 1 hour at room temperature. 3.99 g (0.0131 mole) of 1-(3-chloropropyl)-4-(4-fluorophenyl)-piperazine are added, the reaction mixture is stirred for 3 hours at 90° C., under nitrogen as a protective gas, cooled and poured onto ice water, and the precipitate is filtered off under suction. The crude product is recrystallized from ethanol and a product of melting point 151°-153° C. is obtained (yield: 72%).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12]1C=C(O)C(O)=CC=1>>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]2[O:11][CH2:12][O:1][C:2]=12)([OH:6])=[O:5]
Reactant: Oc1ccccc1O
Reactant: O=C(O)c1cccc(O)c1O
Product: O=C(O)c1cccc2c1OCO2

Procedure:
By substituting pyrocatechoic acid (ie., 2,3-dihydroxybenzoic acid) for the pyrocatechin of Example 1, and otherwise following the procedure described therein, the product 1-carboxy-methylenedioxybenzene is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[O:24])[NH:20][C:21](=[S:23])[S:22]/1.[CH3:25]CN(C(C)C)C(C)C.IC>C(O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[O:24])[N:20]=[C:21]([S:23][CH3:25])[S:22]/1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CCO
Product: CSC1=NC(=O)/C(=C/c2ccccc2Nc2c(Cl)ccc(C)c2Cl)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To room temperature suspension of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone (3.177 g, 8.04 mmols) in 125 mL of ethanol is added Hunig's base (1.57 mL, 9.03 mmols) followed by iodomethane (600 μL, 9.63 mmols). After stirring at room temperature overnight the yellow solid is collected by filtration to give 2.861 g (87%) of (Z)-5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-(methylthio)-4(5 H)-thiazolone. An analytical sample is obtained by recrystallization from hexane-ethyl acetate; mp 233°-236° C. Calc'd for C18H14Cl2N2OS2:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=1>>[C:8]([C:7]1[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:18][CH:19]=2)=[N:3][C:4]([S:11][CH3:12])=[N:5][C:6]=1[CH3:10])#[N:9]
Reactant: CSc1nc(C)c(C#N)c(Cl)n1
Reactant: Nc1ccc(NC(=O)N2CCCC2)cc1
Product: CSc1nc(C)c(C#N)c(Nc2ccc(NC(=O)N3CCCC3)cc2)n1

Procedure:
The compound was prepared from 4-chloro-6-methyl-2-(methylthio)-5-pyrimidinecarbonitrile and N-(4-aminophenyl)-1-pyrrolidinecarboxamide following procedure similar to that described for Intermediate 23.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:16]([O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:8][CH:7]=3)=[CH:14][CH:13]=2)[CH2:17][CH3:18])=[CH:20][CH:21]=1
Reactant: COC(=O)CCN
Reactant: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of 4-[1-(4′-Trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (270 mg, 0.68 mmol) in methylene chloride (7 mL) are added triethyl amine (0.28 mL, 2.03 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (141 mg, 1.01 mmol) and EDCI (389 mg, 2.03 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving 3-{4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoylamino}-propionic acid methyl ester (215 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:23]1[C:28]([I:29])=[C:27]([CH:30]([Cl:32])[CH3:31])[N:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Cl:32][CH:30]([C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:12][CH2:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)[C:28]=1[I:29])[CH3:31]
Reactant: CC(Cl)c1ncnc(Cl)c1I
Reactant: NCCc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Cl)c1ncnc(NCCc2ccc(OC(F)(F)F)cc2)c1I
Temperature: 60 °C

Procedure:
In toluene (50 ml) were dissolved 2-(4-trifluoromethoxyphenyl)ethylamine (1.0 g) and triethylamine (1.0 g), then, 4-chloro-6-(1-chloroethyl)-5-iodopyrimidine (1.5 g) was added to the solution, and the mixture was heated at about 60° C. for 3 hours while stirring.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.[C:10](Cl)(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[NH2:9][C:5]1[N:4]([C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[N:3]=[C:2]([NH:1][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(N)n[nH]c1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nn(C(=O)C(C)(C)C)c(N)c1C#N

Procedure:
The above compound was prepared from 3,5-diamino-4-cyanopyrazole, prepared as in Example 13, by reaction thereof with two moles of pivaloyl chloride in pyridine in an analogous manner to that described in Example 1(b). Melting point 181°-184° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[N+:17]([C:3]1[CH:4]=[C:5]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:6]=[CH:7][C:2]=1[S:27][C:24]1[CH:25]=[CH:26][C:21]([NH2:20])=[CH:22][CH:23]=1)([O-:19])=[O:18]
Reactant: Nc1ccc(S)cc1
Reactant: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 0 °C
Yield: 92.3 %

Procedure:
A solution of the compound from Example 216A (1.86 g, 6.95 mmol), 4-aminothiophenol (0.88 g, 7.00 mmol), cesium carbonate (2.3 g, 7.00 mmol) in dimethylformamide (10 ml) was heated at 40° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, and dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving an orange oil as the title compound, (2.35 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:16]([CH2:18]Cl)=O)[CH3:12].O>CCO>[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:18]=1)[CH3:12]
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1csc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Dissolve 4-chlorothiobenzamide (74.0 g, 431.1 mmol) in EtOH (470 mL) and treat with ethyl-4-chloroacetoacetate (58.0 mL, 70.1 g, 426.0 mmol). Stir the resulting solution mechanically at reflux for 2 h. Cool to room temperature, add water (1000 mL), and extract with Et2O (2000 mL, then 2×500 mL). Combine the organic solutions and wash with brine (950 mL). Concentrate in vacuo to give an oil that solidifies upon standing (121.8 g). Recrystallize the crude material from isopropanol/water to give the title compound (107.3 g, 89% yield). ES/MS m/z (35Cl) 282.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=O)[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26][CH2:27][C:28](=[N:30]O)[NH2:29]>>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]([C:9]1[O:11][N:30]=[C:28]([CH2:27][CH2:26][O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:29]=1)[CH3:12]
Reactant: NC(CCOC1CCCCO1)=NO
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCOC2CCCCO2)no1

Procedure:
According to substantially the same procedure as that of Example 1, treatment of 5.38 g of 2-(2-fluoro-4-biphenylyl)propionic acid with 4.56 g of 3-tetrahydropyranyloxypropionamidoxime yielded 5-(3-fluoro-4-phenyl-α-methylbenzyl)-3-(2-tetrahydropyranyloxyethyl)-1,2,4-oxadiazole.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].C[Si]([N:32]=[C:33]=[O:34])(C)C>C(Cl)Cl>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][NH:1][C:33]([NH2:32])=[O:34])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Solvent: ClCCl
Product: C/C(=N\OCCNC(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-aminoethyl oxime (example 34) (15 mg, 0.041 mmol) in DCM (5 mL) was added trimethylsilyl isocyanate (19.07 mg, 0.166 mmol). The mixture was stirred for 24 h. After concentration, the crude product was purified by chromatography on silica gel to afford 11.6 mg (69%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.32 (s, 1H), 8.89 (dd, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.21 (s, 2H), 6.05 (t, 1H), 5.50 (s, 2H), 4.27 (t, 2H), 3.35 (m, 2H), 2.32 (s, 3H). LCMS (method B): [MH]+=406, tR=1.91 min.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2>O.C(O)(=O)C>[CH3:5][C:6]1[C:7]([N:1]=[O:3])=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=N[O-]
Reactant: COC(=O)c1c(C)cc2ccccn12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C)c(N=O)c2ccccn12
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of sodium nitrite (2.2 g, 31.90 mmol) in water (10 mL) was added slowly at 0-5° C. to a stirred solution of methyl 2-methylindolizine-3-carboxylate 2 (3.9 g, 20.61 mmol) in glacial acetic acid (50 mL). After 30 min, the brown reaction mixture was poured into water. Green crystals were collected by filtration, washed with water and then dried under vacuum to give 3.7 g of expected compound; m.p.: 131-132° C. 1H NMR (CDCl3): 9.63 (d, J=7.0 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.23-7.18 (m, 1H), 4.03 (s, 3H), 3.26 (s, 3H), 13C NMR (CDCl3): δ 162.5, 154.5, 141.7, 135.7, 127.9, 123.2, 118.4, 118.3, 114.5, 51.7, 11.1. Analysis calculated for C11H10N2O3: C, 60.55; H, 5.54; N, 12.84, found: C, 60.65; H, 5.60; N, 12.90.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCO1
Reaction time: 1 h
Yield: 49 %

Procedure:
At 0° C., tert-butyl (2S)-1-hydroxy-3-(tetrahydro-2H-pyran-2-yl)propan-2-ylcarbamate (1.41 g, 5.44 mmol) in CH2Cl2 (50 mL) was treated with Et3N (2.3 mL, 16.3 mmol) followed by methanesulfonyl chloride (1.1 mL, 13.6 mmol). The reaction was allowed to stir for 1 h and quenched with water. The organic layer was washed with satd aq NaHCO3 and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude material was purified using chromatography on silica gel (EtOAc/Hex) to afford (2S)-2-(tert-butoxycarbonylamino)-3-(tetrahydro-2H-pyran-2-yl)propyl methanesulfonate (0.90 g) as a solid. MS m/z 360 (M+Na).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([OH:43])=[N:41][CH:42]=1.[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH:57](O)[CH3:58])[CH:53]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=2)[CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][CH:54]([CH:57]([O:43][C:40]2[CH:39]=[CH:38][C:37]([Cl:36])=[CH:42][N:41]=2)[CH3:58])[CH:53]([C:60]2[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=2)[CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cn1)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL three-necked round bottom flask (flame dried) charged with a magnetic stirrer and under inert atmosphere to 1080 mg polymer bound triphenylphosphine (3 mmol/g) in 10 mL THF was added 502 mg (2.18 mmol) di-tert-butyl azodicarboxylate in 5 mL THF and 265 mg (2.04 mmol) 5-chloro-2-hydroxypyridine in 10 mL THF at 0-5° C. The brownish suspension was stirred for 20 min at 0-5° C. 450 mg (1.36 mmol) (RS)-1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol in 5 mL THF was added and the ice bath was removed and the reaction was stirred for 63 h at room temperature. The suspension was filtered over a Dicalit-filter. The filtrate was concentrated under vacuum and the residue was purified by chromatography over silica eluting with a gradient formed from i-propanol and heptane to yield after evaporation of the product containing fractions 480 mg (80%) of the title compound as yellow viscous oil. MS (m/e): 441.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])[CH3:39]>>[CH2:36]([C:29]1[CH:30]=[C:31]([OH:35])[C:32]([F:34])=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]2[C:27]([C:19]([C:17]3[NH:16][C:13]4[CH2:14][CH2:15][N:10]([C:8]([C:5]5[N:6]=[CH:7][C:2]([N:44]6[CH2:45][CH2:46][N:41]([CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]6)=[N:3][CH:4]=5)=[O:9])[CH2:11][C:12]=4[N:18]=3)=[N:20][NH:21]2)=[CH:26][CH:25]=1)[CH3:37]
Reactant: CC(C)N1CCNCC1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CCN(C(C)C)CC5)cn3)C4)n[nH]c2c1
Yield: 19.2 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and 1-isopropyl-piperazine, (40 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method D to afford (18 mg, 19%) of the title compound as off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1>>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: Clc1cc(-c2ccco2)nc2c1CCC2
Product: CCOC(=O)Cc1ccc(Nc2cc(-c3ccco3)nc3c2CCC3)cc1
Yield: 71.4 %

Procedure:
Following general procedure B1, 4-chloro-2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.064 g, 0.29 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.073 g, 0.41 mmol) to afford the title compound (0.075 g, 61%) as a white foam. MW=362.42. 1H NMR (CDCl3, 500 MHz) δ 7.45-4.43 (m, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.24 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.93-6.89 (m, 1H), 6.48-6.44 (m, 1H), 5.73 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.62 (s, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 363 [M+H]+.