Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH2:19].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH:19][S:27]([CH3:26])(=[O:29])=[O:28]
Reactant: CCCc1noc(C=Cc2ccc(OC)c(N)c2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1noc(C=Cc2ccc(OC)c(NS(C)(=O)=O)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methoxy-5-[2-(3-propyl-[1,2,4]oxadiazol-5-yl)-vinyl]-phenylamine (compound of Example 8; 0.08 g, 3.08 mmol) was dissolved in dichloromethane (10 mL) followed by addition of pyridine (0.047 mL, 0.60 mmol) and methanesulfonyl chloride (0.034 mL, 0.45 mmol) at room temperature. After stirring for 8 h, dichloromethane was evaporated and the reaction mixture was cooled to room temperature. The crude residue obtained was purified by column chromatography (silica gel, petroleum ether) to afford the title compound.
Reaction SMILES: OC[C:3]([CH3:19])(C)[CH2:4][CH2:5][CH2:6][C:7](=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[N+](C(S(C1C=CC(C)=CC=1)(=O)=O)CCC[CH2:26][C:27](C)([CH3:36])[CH2:28][O:29]C1CCCCO1)#[C-].[H-].[Na+].CO>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O.Cl>[OH:14][CH2:13][C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:19][C:27]([CH3:36])([CH3:26])[CH2:28][OH:29]
Reactant: CC(C)(CO)CCCCC(=O)CCCC(C)(C)CO
Reactant: [C-]#[N+]C(CCCCC(C)(C)COC1CCCCO1)S(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(CO)CCCCCC(=O)CCCCC(C)(C)CO
Yield: 48 %

Procedure:
According to the procedure described for the synthesis of 217, 215 (6.98 g, 17.1 mmol) was reacted with NaH (0.82 g, 20.5 mmol, 60% in mineral oil), 207g (5.8 g, 18.9 mmol), and tetrabutylammonium iodide (0.63 g, 1.7 mmol) in anhydrous DMSO (100 mL) for 24 h at room temperature. The crude intermediate (10.9 g) obtained after aqueous workup was heated to reflux in concentrated HCl (18 mL) and methanol (100 mL) overnight. After extraction and column chromatography (silica gel; hexanes/ethyl acetate=80/20), 219 (2.3 g, 48%) was obtained as a colorless oil. 1H NMR (CDCl3): δ 3.30 (s, 4 H), 2.48-2.34 (m, 4 H), 1.85 (br., 2 H), 1.66-1.46 (m, 4 H), 1.24-1.14 (m, 10 H), 0.85 (s, 12 H). 13C NMR (CDCl3): δ 211.8, 71.8, 71.6, 42.7, 42.6, 38.4, 38.2, 34.9, 30.1, 24.6, 23.8, 23.8, 23.7, 23.6, 23.4. HRMS (LSIMS, gly): Calcd for C18H37O3 (Min: 301.2743, found: 301.2745. HPLC: 97.4% pure.
Reaction SMILES: [OH-].[K+].O.C([O:7][C:8](=[O:17])[C:9]([CH2:15][CH3:16])(CC)[C:10]([O-:12])=[O:11])C=C.[CH3:18]CCCCCC>>[CH2:15]([CH:9]([C:8]([OH:7])=[O:17])[C:10]([OH:12])=[O:11])[CH:16]=[CH2:18]
Reactant: C=CCOC(=O)C(CC)(CC)C(=O)[O-]
Reactant: CCCCCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CCC(C(=O)O)C(=O)O

Procedure:
Potassium hydroxide (15.6 g, 0.28 mol), 15 ml of distilled water and 50 ml of heptane are added to a round bottom flask. Allyldiethylmalonate (22.0 g, 1.1 mol) is added slowly to the reaction mixture with stirring and refluxed for sufficient time to complete hydrolysis. Ethanol is removed with a rotoevaporator. The resultant product is cooled in a beaker and acidified with sulfuric acid. The final solution is extracted with diethylether. The ether layer is collected, dried over MgSO4, and ether is removed with a rotoevaporator. The crude allylmalonic acid is crystalized from petroleum ether.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[OH:12][CH:13]1[CH2:16][NH:15][CH2:14]1.Cl>C1COCC1>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:16][CH:13]([OH:12])[CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CNC1
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CC(O)C2)c(F)c1
Yield: 75 %

Procedure:
To a stirred solution of 1,2-difluoro-4-nitrobenzene (200 mg, 1.25 mmol, 1 eq) in THF (5 mL) was added TEA (0.26 mL, 1.88 mmol, 1.5 eq) and 3-hydroxyazetidine.HCl (205 mg, 1.88 mmol, 1.5 eq) at RT and refluxed for 24 h. THF was evaporated and the residue was washed with water (10 mL) to obtain 1-(2-fluoro-4-nitrophenyl)azetidin-3-ol (200 mg, 75%) as a solid (TLC: EtOAc/PE (3:7), Rf: 0.30).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)[N:3]=1.[NH2:20][C:21]1[CH:25]=[C:24]([CH:26]2[CH2:28][CH2:27]2)[NH:23][N:22]=1>>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([NH:20][C:2]3[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]4[CH2:13][CH2:12][CH2:11][CH:10]4[C:14]4[O:18][N:17]=[C:16]([CH3:19])[CH:15]=4)[N:3]=3)[CH:25]=2)[CH2:28][CH2:27]1
Reactant: Cc1cc(C2CCCN2c2nc(C)cc(O)n2)on1
Reactant: Nc1cc(C2CC2)[nH]n1
Product: Cc1cc(C2CCCN2c2nc(C)cc(Nc3cc(C4CC4)[nH]n3)n2)on1

Procedure:
Starting materials: 4-hydroxy-6-methyl-2-[2-{3-(methyl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 31) and 3-amino-5-cyclopropyl-1H-pyrazole (Method 7 of WO-03/048133).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34])#[N:27]>O1CCOCC1.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]>[F:34][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)([CH3:12])[CH3:11])=[CH:4][CH:3]=2)=[CH:29][C:28]=1[C:26]#[N:27]
Reactant: CC(C)(CNc1ccc(Cl)nn1)c1ccc(F)cc1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(CNc1ccc(-c2ccc(F)c(C#N)c2)nn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a solution of 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine (5.0 g, 23 mmol, 1.0 equiv) and K2CO3 (9.4 g, 68 mmol, 3.0 equiv) in dioxane (35 mL) was added Pd(dppf)Cl2 (1.7 g, 2.3 mmol, 0.1 equiv) and 3-cyano-4-fluorophenylboronic acid (5.0 g, 30 mmol, 1.3 equiv). The mixture was stirred at 80° C. for 3 hours after which it was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with EtOAc, washed with saturated NaHCO3, dried over Na2SO4 and evaporated to dryness. The residue was purified by reverse phase HPLC using a CH3CN/water gradient to give the desired product (5.3 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][CH3:18])=[N:15][N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>N1C=CC=CC=1>[CH2:17]([C:14]1[S:13][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:16][N:15]=1)[CH3:18]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CCc1nnc(NS(=O)(=O)c2ccc(N)cc2)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CC)s2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 121.4 %

Procedure:
Compound 109 (250 mg, 0.88 mmol) was suspended in pyridine (1.3 mL). Decanoyl chloride (134 mg, 0.70 mmol) was added slowly at 0° C. The reaction mixture was then heated to 95° C. and was stirred for 1 h. The reaction mixture was then added to aqueous 3 N HCl solution (4.5 mL) and the mixture extracted with ethyl acetate (3×10 mL). The organic extracts were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous Na2SO4, and filtered. Evaporation of the solvent left a residue which was crystallized from hexanes and ethyl acetate (1:2) to give the product (372 mg, 0.85 mmol, 97%) as a solid, mp 121-122° C.; 1H NMR (500 MHz, DMSO) δ 0.82 (3, t, J=7.0 Hz), 1.17-1.30 (14, m), 1.57 (2, t, J=7.0 Hz), 2.32 (3, t, J=7.0 Hz), 2.80 (2, q, J=7.0 Hz), 7.72 (2, d, J=8.5 Hz), 7.76 (2, d, J=8.5 Hz), 10.21 (1, s), 13.89 (1, s); 13C NMR (125 MHz, DMSO) δ 12.2, 13.9, 22.1, 23.6, 24.9, 28.6, 28.7, 28.8, 28.9, 31.2, 36.5, 118.5, 126.8, 135.5, 142.7, 159.7, 167.2, 171.8; MS (LCQ, ESI+) Calculated for C20H31N4O3S2 439.2, found 439.1 (M+H)+; HRMS (FAB+, m/z) Calculated for C20H31N4O3S2 439.1838, found 439.1843 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)[N:15]=2)[CH:11]=1
Reactant: Fc1ccc2[nH]ncc2c1
Reactant: Oc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Oc1ccc(-n2cc3cc(F)ccc3n2)cc1
Yield: 6.8 %

Procedure:
4-bromophenol (1.27 g, 7.35 mmol) was combined with 5-fluoro-1H-indazole (1.000 g, 7.35 mmol), CuI (69.9 mg, 0.367 mmol), K3PO4 (3.282 g, 15.4 mmol), toluene (15 mL), and dimethylethylenediamine (0.158 mL, 1.47 mmol). This was refluxed as a mixture for 3 d. The reaction was cooled and partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with ethyl acetate and the combined organics were dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 4-(5-fluoro-indazol-2-yl)-phenol (0.114 g) impure with the indazole starting material. Used as is. The other regioisomer was also observed but was separated by chromatography. MS (M+1): 229.2.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][CH2:29]O)[CH:24]=[CH:23][CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:20][C:21]1[N:26]=[C:25]([CH2:27][CH2:28][CH2:29][O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(CCCO)n1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OCCCc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.230 g (1.5 mmol) of 3-(6-methyl-pyridin-2-yl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:1) to obtain the product as a oil (0.23 g).
Reaction SMILES: [CH3:1][C:2]([NH:21][C:22](=O)OC(C)(C)C)([CH3:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:6][CH:5]=1.[ClH:29].C([O:33][CH2:34][CH3:35])(=O)C>CO>[ClH:29].[CH3:20][C:2]([CH3:1])([NH:21][CH2:22][C@H:34]([OH:33])[C:35]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1)[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(Cc1ccc(NC(=O)Cc2ccccn2)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: CC(C)(Cc1ccc(NC(=O)Cc2ccccn2)cc1)NC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 490 mg of tert-butyl N-[1,1-di-methyl-2-[4-[[2-(2-pyridyl)acetyl]amino]phenyl]ethyl]-carbamate in 10 ml of methanol was added 30 ml of a 4N hydrochloride-ethyl acetate solution. After the reaction solution was stirred at room temperature for eight hours, the solvent was evaporated in vacuo. To the residue were added an aqueous solution of sodium hydrogen carbonate and potassium carbonate to adjust to pH about 12. The resulting aqueous phase was extracted with a mixed solvent of chloroform and tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated, the resulting residue was dissolved in 2 ml of 2-propanol and 2 ml of methanol, and 120 mg of (R)-styrene oxide was added thereto. After the reaction solution was heated to reflux for 24 hours, the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1→15/1) and dissolved in methanol, 0.1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, and the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=5/1) and a reversed phase column chromatography (eluent: water/methanol=2/1→1/1) to give 35 mg of (R)-4′-[2,2-dimethyl-2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-2-(2-pyridyl)acetanilide hydrochloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([O:12][CH2:13][CH2:14][F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([O:12][CH2:13][CH2:14][F:15])[N:9]=1
Reactant: COC(=O)c1ncc(OCCF)nc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(OCCF)cnc1C(=O)O
Reaction time: 48 h
Yield: 128.8 %

Procedure:
To a solution of 3-amino-5-(2-fluoro-ethoxy)-pyrazine-2-carboxylic acid methyl ester (176 mg, 0.818 mmol) in THF (6.8 ml) was added a solution of 1M NaOH (900 μl, 0.900 mmol). The reaction was stirred at it for 48 h. A solution of 1M HCl (1096 μL, 1.096 mmol) was added, the mixture was evaporated to dryness and then co-evaporated with toluene to give a light purple solid (212 mg). The crude material was used directly for the coupling reactions.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[C@H:14]([CH3:20])[NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)[CH3:19]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)[C@H](C)Nc1ccc(CCC(=O)O)cc1

Procedure:
This compound was prepared in a manner analagous to the process described in synthesis example 14, except using ethyl-4-aminobenzoate and ethyl 2-bromoproprionate.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([CH3:23])=[N:19][O:20][C:21]=3[CH3:22])=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C1(C)C=CC=CC=1.[OH-].[Na+]>C(#N)C.[Cl-].[Na+].O>[CH3:23][C:18]1[C:17]([C:14]2[CH:15]=[CH:16][C:10]3[O:9][C:8]([CH2:7][CH2:6][N:26]4[CH2:27][CH2:28][CH2:29][C@H:25]4[CH3:24])=[CH:12][C:11]=3[CH:13]=2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: Cc1noc(C)c1-c1ccc2oc(CCOS(C)(=O)=O)cc2c1
Reactant: C[C@@H]1CCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cc1noc(C)c1-c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
A 3.3 mL (1 mmol) aliquot of the product from Example 161B in 8.33 mL of acetonitrile was transferred to a separate flask. Mono-(L)-tartaric acid salt of (R)-2-methylpyrrolidine (0.82 g, 3.5 mmol) was converted to the free base by shaking with 1 mL of toluene, 0.5 mL of 50% wt/vol sodium hydroxide, and 2 mL of brine. After separating, the toluene layer was decanted by pipette and added to the 3.3 mL aliquot of the product from Example 161B. After stirring for one week at room temperature, the reaction was poured into dichloromethane and washed with aqueous ammonia, dried over sodium sulfate, and purified by flash chromatography, eluting with 97:3 dichloromethane/methanol/0.1% NH3, to give 225 mg (69%) of the title compound as a clear oil. MS (DCI) m/z 325.2 (M+H)+; 1HNMR (300 MHz, CDCl3) δ 1.18 (d, 1H, J=6.3 Hz), 2.24 (s, 3H), 2.40 (s, 3H), 1.5-2.0 (m, 6H), 2.5 (m, 1H), 3.02 (t, 2H, J=7.5 Hz), 3.23 (m, 2H), 6.48 (s, 1H), 7.08 (dd, 1H, J=9.0, 2.1 Hz), 7.34 (d, 1H, J=2.1 Hz), 7.44 (d, 1H, 9.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([Mg]Br)[CH3:16].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:14])[CH2:15][CH3:16])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1nnc(-c2ccc(F)cc2)s1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1nnc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde (0.2 g, 0.961 g mmol) in THF (8 mL) was added ethyl magnesium bromide in diethyl ether (3.0 M; 0.96 mL, 2.88 mmol) at 0° C., the reaction mixture was allowed to warm to room temperature and the mixture then stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and water (15 mL), extracted with ethyl acetate (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol as yellow solid (0.1 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.0-8.03 (m, 1H), 7.39-7.35 (m, 2H), 6.36 (d, 1H), 4.92-4.89 (m, 1H), 1.89-1.78 (m, 2H), 0.95 (t, 3H); LC-MS m/z calculated for [M+H]+239.06. found 239.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:32]=[CH:31][C:12]2[N:13]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)#[N:2].CO.Cl.CCOC(C)=O>C(Cl)Cl>[O:16]=[C:14]1[N:13]([CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:12]2[CH:31]=[CH:32][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][C:11]=2[S:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)sc3cc(-c4ccccc4C#N)ccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccccc1-c1ccc2c(c1)sc(=O)n2CC1CCNCC1
Reaction time: 2 h

Procedure:
To a round bottom flask was added tert-butyl 4-{[6-(2-cyanophenyl)-2-oxo-1,3-benzothiazol-3(2H)-yl]methyl}piperidine-1-carboxylate (11-2) (0.242 g, 0.538 mmol), MeOH (2.5 mL), DCM (2.5 mL), and a sat'd solution of HCl in EtOAc (˜4N) (1.346 mL, 5.38 mmol). The reaction mixture was capped and permitted to stir for two hours then concentrated to give 2-[2-oxo-3-(piperidin-4-ylmethyl)-2,3-dihydro-1,3-benzothiazol-6-yl]benzonitrile (11-3) as a tan solid. HRMS (M+H)+: observed=350.1322, calculated=350.1322.
Reaction SMILES: [CH2:1]([C:3]([C:5](C1C=NC=CC=1)=[CH:6][N:7]([CH3:9])[CH3:8])=[O:4])[CH3:2].C(C(C[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=O)C>>[CH2:1]([C:3]([C:5]([C:26]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)=[CH:6][N:7]([CH3:9])[CH3:8])=[O:4])[CH3:2]
Reactant: CCC(=O)Cc1cccnc1
Reactant: CCC(=O)C(=CN(C)C)c1cccnc1
Product: CCC(=O)C(=CN(C)C)c1ccncc1

Procedure:
A-11. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone using (3-pyridinyl)methyl ethyl ketone.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: COc1cccc(Cn2cnc(N)c2C(N)=O)c1
Reactant: O=C(Cl)c1ccccc1F
Product: COc1cccc(Cn2cnc(NC(=O)c3ccccc3F)c2C(N)=O)c1
Yield: 82 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 1.97 g (8.00 mmol) of 4-amino-1-(3-methoxybenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 81 and 2-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.42 g of 4-(2-fluorobenzoylamino)-1-(3-methoxybenzyl)-5-imidazole carboxamide (yield 82%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:20]([O:19][C:15](=[O:18])[CH2:16][O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH3:21]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCOC(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 5-nitrovanillin (2.00 g, 10.11 mmol) in tetrahydrofuran (100 mL) was added ethyl glycolate (0.960 mL, 10.11 mmol), triphenylphosphine (3.84 g, 14.65 mmol), and dropwise addition of diethyl azodicarboxylate (2.70 mL, 17.10 mmol). The reaction was stirred overnight at room temperature. The solution was then concentrated in under reduced pressure to yield a crude oil. Purification of the residue by silica gel flash chromatography (20% ethyl acetate/hexane to 40% ethyl acetate/hexane) afforded the title compound. 1H NMR (d6-DMSO) δ 1.15 (t, 3H), 3.94 (s, 3H), 4.10 (q, 2H), 4.93 (s, 2H), 7.79 (d, 1H), 8.02 (d, 1H), 9.94 (s, 1H). MS: M++1=284.2 Da.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:41])([F:42])[F:32])=[CH:35][CH:36]=1)=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of 5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (85 mg, 0.2004 mmol) in methylene chloride (5 ml) were added 4-trifluoromethylaniline (48 mg, 0.2981 mmol), triethylamine (41 mg, 0.4059 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (102 mg, 0.6035 mmol) followed by stirring at room temperature for 3 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (60 mg, 0.1060 mmol, 53%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[Br:22]N1C(=O)CCC1=O>C1COCC1>[NH2:1][CH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][C:12]([Br:22])=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCN)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCN)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of 3-(2-aminoethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (310 mg, 1.1 mmol) in THF (50 mL), was added N-Bromosuccinimide (0.29 g, 1.6 mmol). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated. The solid was filtered and washed with EtOAc to yield the desired product (300 mg, 76% yield). LCMS calculated for C13H19BrN7O (M+H): 368.1, 370.1. found: 368.0, 370.0.