Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.[C:44]([O:48][C:49]([N:51]1[CH2:55][CH:54]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[C:58]([Cl:63])[CH:57]=2)[CH:53]([C:64](O)=[O:65])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(Cl)Cl>[Cl:63][C:58]1[CH:57]=[C:56]([CH:54]2[CH:53]([C:64]([N:40]3[CH2:39][CH2:38][N:37]([C:35]4[C:36]5[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:42][CH2:41]3)=[O:65])[CH2:52][N:51]([C:49]([O:48][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:50])[CH2:55]2)[CH:61]=[CH:60][C:59]=1[Cl:62]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4CN(C(=O)OC(C)(C)C)CC4c4ccc(Cl)c(Cl)c4)CC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (35 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (50 mL) and washed with brine (5×50 mL). The organic phase was dried and concentrated to afford tert-butyl 3-(3,4-dichlorophenyl)-4-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (LCMS (APCI+) [M+H]+576.1; Rt: 2.90 min). The product was treated with 4N HCl in dioxane to afford (4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone as the HCl salt (30 mg, 64%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:20][CH2:19]1)(=O)C.Cl>CO>[CH:18]1([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=2[OH:10])[CH2:20][CH2:19]1
Reactant: CC(=O)Oc1c(F)cccc1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1c(F)cccc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Potassium carbonate (911 mg, 6.60 mmol) was added to a solution of 2-cyclopropyl-6-fluorophenyl acetate (640 mg, 3.30 mmol) in methanol (4 ml), and the mixture was stirred at room temperature for 1 hour. After 1M hydrochloric acid was added to the reaction mixture to adjust pH to 2, this was extracted with acetic acid. The organic layer was combined and washed with a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate. After the solid was removed by filtration, the filtrate was concentrated to obtain 497 mg of 2-cyclopropyl-6-fluorophenol.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][CH:9]([F:25])/[C:10](=[N:18]\[S@:19]([C:21]([CH3:24])([CH3:23])[CH3:22])=[O:20])/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]>C1COCC1.[Cu]Cl.[Zn]>[CH3:23][C:21]([CH3:24])([S@@:19]([NH:18][C@:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([CH:9]([F:25])[F:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:20])[CH3:22]
Reactant: CC(C)(C)[S@](=O)/N=C(/c1ccccc1F)C(F)F
Reactant: CCOC(=O)CBr
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@](N[S@@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
In a dry flask under an inert atmosphere copper(I) chloride (2.74 g, 27.7 mmol) and activated zinc powder (14.5 g, 221 mmol) were mixed and heated to 130° C. After cooling to r.t. dry THF (80 ml) was added and under stirring the dispersion was heated to reflux for 30 min. The external heating was removed and a solution of ethyl 2-bromoacetate (11.5 g, 7.65 ml, 69.1 mmol) in dry THF (40 ml) was added dropwise in a manner that the temperature was maintained at 55° C. After complete addition stirring at 55° C. was continued for 30 min. Thereafter, the mixture was cooled to 5° C. and a solution of the (S,Z)—N-(2,2-difluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (7.67 g, 27.7 mmol) in dry THF (40 ml) was added dropwise within 10 min while the temperature was kept below 5° C. In order to complete the reaction stirring was continued at 0° C. for 1 h. For the workup, the reaction mixture was filtered through a layer of Dicalite® which was washed with TBME. The filtrate was extracted with a saturated solution of NH4Cl, the organic layer was dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by 2 consecutive chromatographies on silica gel (eluent: heptane/AcOEt 4:1, then 3:1 for the mixture of isomers) to give the (R)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-1) (yellow oil, 5.17 g, 51.2% yield) as the first eluting isomer and the (S)-ethyl 3-((S)-1,1-dimethylethylsulfinamido)-4,4-difluoro-3-(2-fluorophenyl)butanoate (XV-2) (orange solid, 2.59 g, 25.7% yield) as the second eluting isomer.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:7]#[N:8])[CH3:2]>C(O)C.[Pd]>[NH2:12][C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc(C#N)ccc1N
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
3-Ethylamino-4-nitro-benzonitrile (0.3 g) was diluted with ethanol (5 mL) and was treated with 10% palladium on carbon (Pd/C)(0.070 g). The mixture was then shaken in a hydrogenation shaker under an atmosphere of hydrogen (40 psi) for 30 minutes. The resulting mixture was filtered through diatomaceous earth and concentrated. Silica gel chromatography using 20% ethyl acetate in hexanes as eluent gave 4-amino-3-ethylamino-benzonitrile (0.08 g).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=2)[CH2:7][CH2:6]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[CH3:1][CH:2]([CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([C:21]([F:24])([F:23])[F:22])[CH:13]=2)[CH2:7][CH2:6]1)=[S:51]
Reactant: C[C@@H](CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(CN1CCN(c2ccc(C(F)(F)F)cc2)CC1)C(=S)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1

Procedure:
2-Methyl-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-propane-1-thione (24 mg; 0.041 mmol, prepared in accordance with Example 68) is reacted with Lawesson's reagent (8 mg; 0.020 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (11 mg; 0.018 mmol). The structure was confirmed using Protocol I-B. Calculated mass=604; observed mass=604; HPLC retention time=4.74 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([F:31])([F:30])[F:29]>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Product: Cc1cc(SCC#Cc2ccccc2C(F)(F)F)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-iodo-2-trifluoromethyl-benzene gave the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[O:28][C:27]([CH2:29][OH:30])=[CH:26][CH:25]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[O:28][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:25][CH:26]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Reactant: OCc1ccc(C(F)(F)F)o1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)o4)cc3=O)cn12
Temperature: 100 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a suspension of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (120 mg) and (5-(trifluoromethyl)furan-2-yl)methanol (87 mg) in toluene (2 ml) was added potassium tert-butoxide (117 mg) at room temperature, and the mixture was stirred at 100° C. for 1 h. The mixture was quenched with water, and the precipitate was collected by filtration and washed with IPE to give the title compound (75 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O.CCOC(C)=O.CN(C=O)C>[NH2:1][C:2]1[C:7](/[CH:27]=[CH:26]/[C:25]([NH2:29])=[O:28])=[N:6][C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1cc(-c2nc(/C=C/C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), acrylamide (55 mg), Pd(OAc)2 (3 mg), tris(2-methylphenyl)phosphine (8 mg), NEt3 (0.11 ml), and DMF (1.0 ml) was heated with stirring at 60° C. for 1 hour and then at 90° C. for 5 hours. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from EtOAc and dried in vacuo to give (2E)-3-[3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinyl]acrylamide (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][NH2:13]>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,4-difluoro-nitrobenzene (13, 5.0 g, 31.4 mmol) taken in dimethyl sulfoxie (30 mL) was added 40% aqueous methylamine in portions. The reaction was stirred at room temperature for 30 minutes. The reaction was diluted with 150 mL of water and the resulting precipitate was filtered and dried under vacuum to obtain solid (5.34 g) in 98% isolated yield.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.ClCCl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=O.[OH:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30]>O>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=1[OH:27])=[O:26]
Reactant: Nc1ccccc1O
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1Cl)Nc1ccccc1O
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a mixture of 1,1′-carbonyl diimidazole (12.45 g, 0.077 mol) and dichloromethane (50 ml) was added 2-chlorophenylacetic acid (12.5 g, 0.073 mol) in portions. The mixture was stirred for 1 h and 2-hydroxyaniline (7.99 g, 0.073 mol) was added in one portion. After stirring overnight, the reaction mixture was diluted with water and filtered to give the title compound (18.3 g after drying).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]([CH2:20][CH3:21])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.I.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](SC)=[NH:31]>C(O)C.C(OCC)(=O)C>[CH2:20]([N:12]([CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][S:6][C:5]2[CH:22]=[CH:23][C:2]([NH:1][C:30]([C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)=[NH:31])=[CH:3][C:4]1=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:21]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(CCN1CCSc2ccc(N)cc21)C(=O)OC(C)(C)C
Agent: I
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CCN1CCSc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of tert-butyl 2-(6-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl(ethyl)carbamate (800 mg, 2.371 mmol) in ethanol (8 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.014 g, 3.56 mmol). The resulting mixture was stirred at room temperature for 3 hours. The mixture was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 1:1 hexanes:ethyl acetate giving the desired product (415 mg, 39.2%). 1H NMR (DMSO-d6) δ 7.70 (d, J=3.0 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.49-7.44 (m, 1H), 7.07 (t, J=4.4 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.35-6.26 (m, 2H), 6.08 (d, J=7.5 Hz, 1H), 3.64-3.49 (m, 2H), 3.45-3.25 (m, 4H), 3.24-3.12 (m, 2H), 3.01-2.85 (m, 2H), 1.39-1.29 (m, 9H), 1.02 (t, J=6.9 Hz, 3H); ESI-MS (m/z, %): 447 (MH+, 100).
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[C:40]1([CH2:46][CH2:47][C:48](Cl)=[O:49])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][N:37]([C:48](=[O:49])[CH2:47][CH2:46][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:36][CH2:35]1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(C(=O)CCc3ccccc3)CC2)cc1F

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and 3-phenylpropionyl chloride (178 μL), respectively, to provide crude 4-(2,5-difluoro-4-methoxyphenyl)-1-(3-phenylpropanoyl)piperazine (348 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(OCC)=O)=[O:5])C>[OH-].[Na+]>[O:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:6][C:4]([OH:5])=[O:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(CCCCCCCOc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCOc1ccccc1
Yield: 85.9 %

Procedure:
A solution of ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.84 g, 5.3 mmol) in 20% NaOH (20 mL) was refluxed for 10 h. The solution was acidified with HCl(pH=2) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with water (2×30 mL), and brine (30 mL), and dried over Na2SO4. After removal of the solvent in vacuo, the residue was heated on an oil bath at 180°-200° C. for 10 min. The crude product was distilled (Kugelrohr) followed by crystallization (hexane) to give the product (1.14 g, 85%), mp 66.5°-67.5° C. (lit.3 68°-69° C.). IR: 3450-2550, 1720 cm-1 ; 1H-NMR: 1.26-1.39 (m, 8H), 1.61 (q, 2H), 1.75 (q, 2H), 2.34 (t, 2H), 3.93 (t, 2H), 6.83-6.96 (m, 3H), 7.28 (t, 2H), 10.8 (bs, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][NH:57][CH3:58])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.CN(C=O)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][N:57]([C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH3:58])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
To a stirred solution of 4-cyanobenzoic acid (322 mg, 2.19 mmol) in CH2Cl2 (10 mL) was added TBTU (702 mg, 2.19 mmol) and N,N-diisopropylethylamine (1.14 mL, 6.54 mmol) and the reaction mixture stirred at RT for 10 min. 4-Methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.19 mmol) in DMF (4 mL) was added and the reaction mixture was stirred at RT for 2 h. The crude material was concentrated in vacuo and purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 100% EtOAc to afford 4-{[(4-cyano-benzoyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester as a orange solid (700 mg, 89%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH2:23][CH2:24][CH3:25])=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32](O)=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C>[F:26][C:27]1[C:28]([F:37])=[C:29]([F:36])[C:30]([F:35])=[C:31]([F:34])[C:32]=1[O:21][C:20]([C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[C:15]([CH2:23][CH2:24][CH3:25])[CH:16]=1)=[O:22]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CCCc1cc(C(=O)O)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
5-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-4-propyl picolinic acid (134 mg, 0.307 mmol) was dissolved in ethyl acetate (6.2 mL). At room temperature, pentafluorophenol (68 mg, 0.368 mmol) and N,N′-dicyclohexylcarbodiimide (76 mg, 0.368 mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (189 mg (yield >99%)) was obtained as a yellow brown crystal.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccn1
Reactant: S=C=Nc1ccccc1
Solvent: c1ccccc1
Product: S=C(NCc1ccccn1)Nc1ccccc1
Yield: 80 %

Procedure:
N-Phenyl-N'-2-pyridinylmethylthiourea is prepared by heating 19.8 g (0.147 m) phenylisothiocyanate and 13.2 g (0.122 m) 2-aminomethylpyridine in 500 ml benzene for 3 hr. The solid (22.8 g, 77% yield) which is collected with a melting point of 98°-9° C. and is analytically pure.
Reaction SMILES: C(OC([C:6]1[O:7][C:8]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:9]=2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)C.[Cl-].[Na+].O>CS(C)=O>[CH2:14]([O:13][C:11]([C:10]1[C:9]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:8]=2[O:7][CH:6]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1oc2cc(OC)ccc2c1C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1coc2cc(OC)ccc12
Temperature: 170 °C
Reaction time: 2 h

Procedure:
6-Methoxy-benzofuran-2,3-dicarboxylic acid diethyl ester (24) (27 g, 92 mmol) is dissolved in 200 ml of a DMSO and the mixture is heated to 170° C. Then sodium chloride (10.7 g, 184 mmol) and water (3.3 ml) are added and the mixture is stirred for 2 h at 160° C. (temperature of reaction mixture). Then the mixture is allowed to cool down and evaporated at high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate. Evaporation gave an brown solid, which is further purified by Flash-chromatography (silica gel, ethyl acetate/hexanes 3:7).
Reaction SMILES: N1(C([O-])=O)CCCCC1.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]2[O:21][C:20]([NH:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:19][N:18]=2)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=1.[NH2:40][C:41]1[CH:49]=[CH:48][C:44]2[N:45]=[CH:46][S:47][C:43]=2[CH:42]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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].O>[S:47]1[C:43]2[CH:42]=[C:41]([NH:40][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]5[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]5)=[N:19][N:18]=4)=[C:13]([NH:36][CH:37]([CH3:39])[CH3:38])[CH:12]=3)[CH:49]=[CH:48][C:44]=2[N:45]=[CH:46]1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Reactant: Nc1ccc2ncsc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(NC2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 110 °C

Procedure:
Synthesis of tert-butyl 445-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate: To a solution of tert-butyl 4-((5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate (45) (400 mg, 0.9 mmol) in dioxane (10 mL):H2O (2 mL), 6-amino benzothiazole (1.3 mmol, 1.5 equiv.), xanthphos (0.4 mmol, 0.5 equiv.) and Na2CO3 (2.7 mmol, 3 equiv.) were added and degassed for 10 min. To the reaction mixture Pd2(dba)3 (0.4 mmol, 0.5 equiv.) was added and degassed again for 10 min. It was then heated at 110° C. for overnight. The reaction mass was cooled and filtered through small pad of celite. The filtrate obtained was concentrated to provide crude material. The crude material was purified by column chromatography through silica gel and MeOH:DCM as eluent. The material obtained was further purified by prep. HPLC to afford tert-butyl 4-((5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)amino)piperidine-1-carboxylate. 1H NMR: 400 MHz, CD3OD: δ 1.34 (d, J=6.00 Hz, 6H), 1.48 (s, 9H), 1.58-1.60 (m, 2H), 1.96-2.06 (m, 4H), 3.29-3.34 (2H, merged with the water peak), 3.61-3.64 (m, 1H), 3.78-3.82 (m, 1H), 4.00-4.04 (m, 2H), 6.16 (s, 1H), 7.53-7.58 (m, 2H), 7.97 (d, J=8.80 Hz, 1H), 8.37 (s, 1H), 8.43 (d, J=2.00 Hz, 1H), 9.08 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.028 min; LCMS (ES-API), m/z 551.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.276 min; Purity: 98.8%.