Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[F:10].[N:11]([O-])=O.[Na+].[OH-].[Na+]>CC(O)=O>[Br:1][C:2]1[C:3]([F:10])=[C:4]2[C:5](=[CH:7][CH:8]=1)[NH:6][N:11]=[CH:9]2
Reactant: O=N[O-]
Reactant: Cc1c(N)ccc(Br)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1c(Br)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
To a solution of 4-bromo-3-fluoro-2-methylaniline (20 g, 98.0 mmol) in CH3CO2H (600 mL) was added NaNO2 (8.1 g, 118 mmol) at 10° C. The resulting mixture was stirred at room temperature for 4 hours. Upon completion, aqueous NaOH (50%) was added to the reaction mixture until pH was ˜7-8. The mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜40% EtOAc in petroleum ether) affording the title compound (16 g). 1H NMR (300 MHz, DMSO-d6): δ 13.58 (br, 1H), 8.22 (s, 1H), 7.53 (t, 1H), 7.38 (d, 1H).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl-:12]>>[Cl:12][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: OC1CCCc2ncccc21
Reactant: [Cl-]
Product: ClC1CCCc2ncccc21

Procedure:
5-Hydroxy-5,6,7,8-tetrahydroquinoline from step 1 above was converted to the chloride using the procedure as given in step 2 of Example 3. The crude 5-chloro-5,6,7,8-tetrahydroquinoline was purified by pressurized silica gel column chromatography using 7:3 EtOAc:hexane as eluant. 5-Chloro-5,6,7,8-tetrahydroquinoline was obtained as a pale yellow oil (TLC Rf = 0.40 (8:2 EtOAc:hexane)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH:27]=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:33]2[O:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(/C=C/C=C/C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1cc(CCCCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadien-1-al was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]pentyl]-2,4-oxazolidinedione. The product was recrystallized from dichloromethane-ether to give colorless prisms, m.p.114-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH:19]=O)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(OP([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(OCC)=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:18]=[C:17]([CH:19]=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:16]=[CH:15][N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc(C=O)ccn2)cc(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C=Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1
Reaction time: 3 h

Procedure:
2-(3,4,5-Trimethoxyphenyl)pyridine-4-carboaldehyde (507 mg) and ethyl diethylphosphonoacetate (570 μL) were dissolved in tert-butanol (16 mL), and to the solution potassium carbonate (438 mg) was added. The mixture was stirred for 3 hours under reflux and concentrated under reduced pressure. The residue was dissolved in chloroform, and the solution was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=2[F:28])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18]2[C:19]([F:28])=[C:20]([F:27])[C:21]([F:26])=[C:22]([F:25])[C:23]=2[F:24])[N:17]=1)=[O:9]
Reactant: Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)cs1
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)cs1)c1cc(Cl)ccc1O
Yield: 23.8 %

Procedure:
Using 5-chlorosalicylic acid and 2-amino-4-(2,3,4,5,6-pentafluorophenyl)-thiazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][NH2:12])[CH:8]=[CH:7][CH:6]=[CH:5]2.O[CH:14]1[O:18][C:17](=O)[CH2:16][CH:15]1[CH2:20][CH2:21][CH3:22]>ClCCCl.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:14][CH:15]([CH2:20][CH2:21][CH3:22])[CH2:16][C:17]1=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: NCc1c(F)cc2ccccn12
Reactant: CCCC1CC(=O)OC1O
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCC1CC(=O)N(Cc2c(F)cc3ccccn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of 1-(2-fluoroindolizin-3-yl)methanamine x263 (0.38 g, 2.3 mmol) and 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.33 g, 2.3 mmol) in DCE (12 ml) is kept at room temperature for 2 h, then STAB (0.74 g, 3.5 mmol) is added, and the mixture is stirred overnight. The reaction mixture is kept under stirring at 50° C. for 2 h, cooled to room temperature, and diluted with dichloromethane (10 ml). The mixture is washed with a 20% K2CO3 solution (2×15 ml), and the aqueous layer is washed with brine (25 ml), dried over anhydrous Na2SO4 and evaporated. The residue (0.60 g) is purified by chromatography on silica gel (gradient: chloroform to chloroform/methanol 50/1) to isolate a product of approximately 80% purity (0.162 g). This product is purified by chromatography on silicagel (hexane/ethyl acetate 5/2) to afford pure 1-[(2-fluoroindolizin-3-yl)methyl]-4-propylpyrrolidin-2-one 264 (0.126 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(Cl)Cl>N(CC)CC.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.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:34]#[C:33][CH2:32][OH:35])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (264 mg), PdCl2(PPh3)2 (17.3 mg), and CuI (4.7 mg) in 9.6 mL Et2NH is added propargyl alcohol (0.029 mL, 0.492 mmol). Distilled CH2Cl2 (14 mL) is added to help solublize the reactants. The reaction is stirred at room temperature overnight, then condensed to remove the solvents. The crude product is adsorbed onto silica and chromatographed (eluent 1% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 3% MeOH in CH2Cl2 (2L)). Product-containing fractions are combined and condensed to afford 148.2 mg (63%) of the desired product as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16](S(C)(=O)=O)=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31].[CH2:32]([OH:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2=[N:15][C:16]([O:34][CH2:33][CH2:32][OH:35])=[N:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])=[C:13]2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: OCCO
Product: Cc1cc(F)ccc1-c1nc(OCCO)nc2c1CNC(=O)N2c1c(F)cccc1F

Procedure:
The product of Example 3 (0.0658 g, 0.147 mmol) was suspended in ethylene glycol (1 mL) and stirred under argon. NaH, dry, 95%, (8.0 mg, 0.32 mmol) was added. After 30 min the solvent was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O (2×), satd aq NaCl (1×), dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product. Flash chromatography on silica gel eluted with 0-10% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 172-175° C., LC MS m/z=431 (MH+) Rt=1.7 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][N:7]=1)=[O:11]
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cn1
Yield: 84 %

Procedure:
A solution of 5-(trifluoromethyl)-pyridine-2-carboxylic acid (CAN 80194-69-0, 3 g, 15.7 mmol) and sulfurous dichloride (0.1 mL) in methanol (30 mL) was stirred under reflux conditions overnight. Removal of the solvent provided the crude title compound which was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to obtain the title compound (2.7 g, 84%) as white solid; MS (EI): m/e=206.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: ClCCN1CCCC1
Reactant: COC(=O)c1cc(N)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)ccc1OCCN1CCCC1
Temperature: 60 °C
Yield: 12.6 %

Procedure:
A suspension of 5-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6.0 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.2 g, 7.1 mmol) and cesium carbonate (5.0 g, 15 mmol) in DMF (40 mL) was heated at 60° C. for 17 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% MeOH/DCM) to afford the title compound (0.2 g, 13%) as a light brown solid. MS (ES+): m/z 265 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CCNC(c2cccc(C(C)(C)C)c2)C1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(c2cccc(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
Methyl 2-(3-tert-butylphenyl)piperidine-4-carboxylate (2.56 g, 9.30 mmol) was dissolved in DCM (100 mL) and DIPEA (2.429 mL, 13.94 mmol) added followed by methyl carbonochloridate (0.9 mL, 11.43 mmol) at 0° C. The solution was stirred at room temperature for 1 h. The reaction mixture was washed with 1 M aq HCl (pH 4) followed by brine, satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield dimethyl 2-(3-tert-butylphenyl)piperidine-1,4-dicarboxylate (3.17 g, quant.) as a brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][C@@H:3]([NH:2][C:23](=[O:26])[CH:24]=[CH2:25])[CH3:22])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: C[C@H](N)COc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: C=CC(=O)N[C@@H](C)COc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To an ice-cooled mixture of 107c (390 mg, 1.0 mmol) and TEA (0.53 ml, 3.0 mmol) in DCM (20 mL) was added acryloyl chloride (0.23 ml, 2.0 mmol) dropwise. The reaction mixture was stirred at rt for 2 h and quenched with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to give 107d (284 mg, 70%) as brown solid. MS-ESI: [M+H]+ 409.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][S:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:15][CH2:16][S:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CN(CCSSC(C)(C)C)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Ethyl 2-((tert-butoxycarbonyl)(2-(tert-butyldisulfanyl)ethyl)amino)acetate (Compound 6e-A, 320 mg, 0.91 mmol) was dissolved in methanol (80 ml), an aqueous potassium hydroxide solution (0.18 mol/l, 30.3 ml) was added and the mixture was stirred at room temperature for 2 hours. Methanol in the reaction solution was removed by concentration under reduced pressure, and the aqueous layer was washed with diethyl ether and then adjusted to pH 3 with a 1 mol/1 aqueous hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (268.1 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.[OH-].[Na+]>[OH:22][C:17]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH3:11])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1C1(O)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
4-Bromo-3-methyl-benzoic acid (4.00 g, 18.6 mmol) was dissolved in tetrahydrofuran (80 mL) and the solution was cooled to −78° C. n-Butyllithium (16.4 mL of 2.5 M in hexanes, 40.9 mmol) was added dropwise over 20 min while maintaining the internal temperature below −65° C. resulting in a thin, light yellow slurry. The reaction mixture was allowed to stir for 30 min at −78° C. Cyclopentanone (1.57 g, 1.65 mL, 18.6 mmol) was then added in a dropwise manner. The mixture was stirred at −78° C. for 30 min, warmed to room temperature and stirred for 2 h. The reaction mixture was then diluted with 1 M NaOH (100 mL) and washed with diethyl ether. The organic layer was discarded and the aqueous layer was acidified with 4 M HCl to <pH 3. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was filtered through silica gel eluting with 0-10% methanol/dichloromethane, and all product containing fraction concentrated in vacuo. The resulting solid was slurried in dichloromethane and filtered to provide 4-(1-hydroxycyclopentyl)-3-methylbenzoic acid (1.10 g, 26%) as a white solid. ESI-MS m/z calc. 220.10994. Found 221.5 (M+1)+; Retention time: 1.16 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.67 (dd, J=8.1, 1.7 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 4.77 (s, 1H), 2.54 (s, 3H), 2.07-1.98 (m, 2H), 1.98-1.89 (m, 2H), 1.87-1.77 (m, 2H), 1.72-1.59 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([OH:21])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([Cl:24])=[O:21])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
combining 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid and thionyl chloride to form 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole4-carboxylic acid chloride;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O:20]CC)=O)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.[NH2:24][NH2:25]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([NH:24][NH2:25])=[O:20])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: CCOC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Solvent: O
Solvent: CCO
Product: NNC(=O)CCN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Yield: 19.2 %

Procedure:
A solution of ethyl 3-[4-(3-nitrophenyl)piperazino]propanoate D6 (3.00 g, 9.76 mmol) and hydrazine monohydrate (2.93 g, 2.85 mL, 58.56 mmol) in ethanol (30 mL) was refluxed for 24 hrs. The solvent was evaporated under reduced pressure, brine was added to the residue and the product was extracted several times with dichloromethane. The combined organic phases were dried over MgSO4 and the solvent was evaporated under reduced pressure to afford 3.00 g crude product as an orange semi-solid. Purification by flash chromatography (Silica gel 60 Å, 45 μm, 10% methanol in dichloromethane) afforded 0.55 g (19%) 3-[4-(3-nitrophenyl)piperazino]propanohydrazide D7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH2:17]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([CH:31]=O)[CH:21]=1)[CH2:18][CH3:19]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:31][C:22]2[CH:21]=[C:20]([CH2:17][CH2:18][CH3:19])[N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=2)[CH2:12][CH2:13]1
Reactant: CCCc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: CCCc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1
Yield: 59.3 %

Procedure:
Compound 63 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-propyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:8][CH:9]=1.N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([CH:15]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:6][C:7]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:40](=[O:42])[CH3:41])=[N:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCCCNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a methylene chloride solution (5.0 ml) of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]propane-1,3-diamine dihydrochloride (47 mg, 0.084 mmol) were added pyridine (17 μl, 0.34 mmol) and acetic anhydride (9.5 μl, 0.10 mmol). The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture was purified by silica gel chromatography (ethyl acetate:methanol=10:1) to give the title compound (35 mg, 79%). The compound was crystallized in ether to afford a white solid (27 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][N:3]=1.ClC1C=CC=[C:18]([C:22]([O:24]O)=[O:23])C=1>ClCCl>[C:22]([O:24][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[CH:4][N:3]=1)(=[O:23])[CH3:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.1 g of t-butyl 6-methylnicotinate in 100 ml of dichloromethane, 9.8 g of m-chloroperbenzoic acid is added slowly, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is washed successively with 10% sodium carbonate solution and water, dried over magnesium sulfate, and concentrated. The residue is slowly added to 7.1 g of acetic anhydride at 100°-120° C., and the mixture is refluxed with stirring for 1 hour. After cooling, the remaining acetic anhydride is decomposed with ethanol, and the mixture is concentrated. The residue is neutralized with saturated aqueous potassium bicarbonate and extracted with three 50-ml portions of chloroform. The combined extracts are dried over magnesium sulfate and concentrated to give crude 5-t-butoxycarbonyl-2-pyridylmethanol acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][C:8]([F:23])=[CH:7][N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40]Br)[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:2]=3[Cl:1])=[N:6][CH:7]=[C:8]([F:23])[CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:36]
Reactant: O=C(c1cc(F)cnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)CCBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCN(C(=O)c2cc(F)cnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-5-fluoro-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (25.1 mg, 0.06 mmol, 1.0 equiv; Example 147) in anhydrous DMF (1 mL) was added lithium aluminium hydride (2.3 mg, 0.06 mmol, 1.0 equiv; [CAS RN 16853-85-3]) and the reaction mixture stirred at rt. After 30 min, 3-bromo-propionic acid ethyl ester (13.0 mg, 10 μL, 0.072 mmol, 1.2 equiv; [CAS RN 539-74-2]) was added and the reaction mixture heated by microwave irradiation to 150° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 2.4 mg (8%) of the title compound as a light brown oil. MS (ISP): 518.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[H-].[Na+].[C:17]([CH2:19]P(=O)(OCC)OCC)#[N:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=[CH:19][C:17]#[N:18]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc2ccccc2c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1C=CC#N

Procedure:
Starting from 5 g (26.85 mmol) of 2-methoxynaphthaldehyde in 30 ml of anhydrous THF in the presence of 1.3 g (1.2 eq) of NaH (60% in oil) in 15 ml of anhydrous THF and 6.5 ml (1.2 eq) of diethyl cyanomethylphosphonate, the title product is obtained in the form of a white solid.