Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].[C:15]([CH2:19][CH2:20][CH:21]([CH3:25])[C:22](Cl)=[O:23])([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[C:22](=[O:23])[CH:21]([CH3:25])[CH2:20][CH2:19][C:15]([O:17][CH3:18])=[O:16])=[O:4]
Reactant: COC(=O)C1CCc2ccccc2N1
Reactant: COC(=O)CCC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCC(C)C(=O)N1c2ccccc2CCC1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1.0 g of 1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester (Ber. 61,2377), 0.87 g of 4-carbomethoxy-2-methylbutanoyl chloride, 1.44 g of powdered potassium carbonate and 20 ml of methylene chloride is stirred at room temperature overnight. It is cooled with ice, and 50 ml of water are added. The organic layer is separated, washed with N-hydrochloric acid and water, dried and evaporated, to yield the 1-(4-carbomethoxy-2-methylbutanoyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid methyl ester, showing NMR-peaks at 0.85, 1.25, 3.35, 3.65 and 3.75 ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>O1CCCC1.ClCCl>[Cl:1][CH2:2][C:3]1[S:28][C:7]([C:9]2[C:17]3[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=2)=[N:6][N:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cccc2c(-c3nnc(CCl)s3)cn(CC3CCCCC3)c12
Yield: 352.5 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (prepared as described in Example 37; 50 mg, 0.139 mmol) in tetrahydrofuran (0.5 ml) was added phosphorus pentasulfide (62 mg, 0.139 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 5 minutes. The reaction was repeated twice on a 0.7 mmol scale. The combined reaction mixture was poured into a separating funnel and diluted with dichloromethane (60 ml). The organics were washed with 5% aqueous sodium carbonate (2×30 ml), brine (30 ml), dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography to afford 3-(5-chloromethyl-[1,3,4]thiadiazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (186 mg, 0.49 mmol).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[CH3:19][NH:20][CH2:21][C:22]#[CH:23]>>[CH3:19][N:20]([CH2:21][C:22]#[CH:23])[C:13]([C:11]1[S:12][C:8]([C:5]2[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=2)=[CH:9][CH:10]=1)=[O:15]
Reactant: C#CCNC
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: C#CCN(C)C(=O)c1ccc(-c2noc(C(F)(F)F)c2C)s1

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-methyl propargylamine by the method described in Example 2 method B. Colorless solid (128 mg, 98%). 1H NMR (CDCl3) 2.37 (d, J=1.8, 3H), 3.28 (br s, 3H), 4.34 (br s, 2H), 7.48 (d, J=3.5, 1H), 7.51 (br d, 1H). 19F NMR −63.13. LC/MS 6.36 min, [M+1]+ 329.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[CH2:5]([NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7]>>[CH2:5]([N:9]([CH:1]=[CH:2][CH3:3])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CNCC(C)C
Reactant: CCC=O
Product: CC=CN(CC(C)C)CC(C)C
Yield: 29 %

Procedure:
Following a procedure similar to that described in Example 64(i), but using propionaldehyde and diisobutylamine as starting materials, the title compound was obtained as a colorless oily substance (yield 29%), boiling at 63-66° C./10 mmHg
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:21]([O:23][C:24](=[O:33])[CH:25]=[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[NH2:27])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH:8]([C:24]([O:23][CH2:21][CH3:22])=[O:33])[C:6]([CH3:5])=[N:27][C:26]=1[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:33])[CH3:22]
Reactant: CCOC(=O)CC(=O)C=Cc1cccc2ccccc12
Reactant: CCOC(=O)C=C(N)N1CCCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCCC2)N=C(C)C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Boiling a solution of 13.4 g of naphth-1-ylmethylideneacetoacetic acid ethyl ester and 9.2 g of 3-pyrrolidino-3-aminoacrylic acid ethyl ester in 100 ml of ethanol for 2 hours yields 2-pyrrolidino-6-methyl-4-naphth-1-yl-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121°C (ethanol). Yield: 52% of theory.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:4][O:5][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:32][C:33]([F:56])([F:55])[CH2:34][CH2:35][C@@H:36](OS(C(F)(F)F)(=O)=O)[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C1COCC1>[CH3:1][C:2]1[C:3]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:36]([CH2:35][CH2:34][C:33]([F:32])([F:55])[F:56])[C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=[N:4][O:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Reactant: Cc1conc1CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1conc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl 2-(4-methylisoxazol-3-yl)acetate (25 mg, 0.127 mmol) (S7C) in a 10 mL round bottomed flask at room temperature was added THF (Ratio: 4.00, Volume: 0.8 mL). The solution was colorless. The solution was stirred at −78° C. 10 min. Next, 0.5 M KHMDS in toluene (0.317 mL, 0.158 mmol) was added slowly. The color of the solution turned to light orange. The mixture was stirred at −78° C. for 10 min and then placed in a room temperature water bath. After 10 minutes, the reaction mixture was put into a −78° C. bath for 20 min. (R)-Benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate, Intermediate S5D (65.0 mg, 0.165 mmol) in THF (Ratio: 1.000, Volume: 0.2 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 4 h. The reaction was quenched with saturated aqueous NH4Cl at −78° C. The mixture was placed in a room temperature water bath and diluted with brine. After 5 minutes, the mixture was extracted with EtOAc. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated to give a crude material as Intermediate S7D.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH:14]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][Cl:36])[CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[ClH:36].[ClH:36].[CH:14]([N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])[CH2:31][CH2:32]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=C1C(=O)N(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
A mixture of isatin (1.32 g) and 50% sodium hydride (0.44 g) in N,N-dimethylformamide (13 ml) was stirred for 10 minutes at ambient temperature. To the mixture was added a solution of 4-benzhydryl-1-(3-chloropropyl)piperazine (3.04 g) in N,N-dimethylformamide (6 ml) and the mixture was stirred for 2.5 hours at 50° to 60° C. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. To the residue dissolved in ethanol (30 ml) was added 29% ethanolic hydrogen chloride (6 ml), followed by an addition of diethyl ether (20 ml). The resulting precipitate was filtered and recrystallized from a mixture of methanol and diethyl ether to give crystals of 1-[3-(4-benzhydryl-1-piperazinyl)propyl]isatin dihydrochloride (1.31 g), mp. 245° to 248° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:21])([F:20])[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=O)=[CH:4][C:3]=1[CH3:22].S(C)C.N#N.C([O-])(O)=O.[Na+]>C1COCC1.CO>[F:20][C:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[C:3]([CH3:22])[CH:4]=1)([F:21])[CH2:12][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cc1cc(C(F)(F)C(=O)N2CCOCC2)cc([N+](=O)[O-])c1N
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)CN2CCOCC2)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.9 %

Procedure:
To a solution of 2-(4-amino-3-methyl-5-nitro-phenyl)-2,2-difluoro-1-morpholin-4-yl-ethanone (945 mg, 3 mmol) in anhydrous THF (15 mL) was added BH3.S(CH3)2 (1 mL, 790 mg, 10.4 mmol) dropwise and slowly under N2 at 0° C. The mixture was stirred under N2 at the room temperature for 19 h and then refluxed under N2 for 1.5 h. After being cooled to 0° C., MeOH (2 mL) was added dropwise and slowly. The reaction mixture was poured into 20% aqueous NaHCO3 solution (150 mL) and extracted with EtOAc (3×50 mL). The organic extract was washed with brine (2×10 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography (2:3 hexanes/EtOAc) to afford the title compound (740 mg, 82%). 1H NMR (CDCl3) δ 2.29 (s, 3H), 2.56-2.61 (4H), 2.93 (t, J=12 Hz, 2H, CH2CF2), 3.62-3.63 (4H), 6.34 (br s, 2H NH), 7.44 (s, 1H), 8.25 (s, 1H). (s, 1H). ESI-MS m/z 302 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](O)(=O)[C:12]1C(=CC=C[CH:20]=1)C(O)=O.[BH4-].[Na+].[OH-].[Na+]>O.CC(C)=O>[CH:12]([NH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])([CH3:20])[CH3:11]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C#N)c(NC(C)C)c1
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 264 g. of 2-amino-4methylbenzonitrile, 504 g. of phthalic acid and 2.32 liters of reagent grade acetone is added 80 g. of sodium borohydride portionwise over 40 minutes at a temperature of 18°-30° C. The resulting solution is stirred for 30 minutes during which the temperature rises from 29°-30° C. to 35° C. and then dropped to 34° C. The resulting solution is then heated from 34° C. to 53° C. over a period of 30 minutes and their maintained at 55° C. for one hour. The mixture is cooled to 37° C., 500 ml. of water added followed by addition of 417 g. of 50% aqueous sodium hydroxide, after which the temperature is allowed to rise to 56° C. to maintain the solution. An additional 92 ml. of water is added and the acetone and aqueous salt layers separated at 45°-50° C. The acetone layer is concentrated in vacuo to obtain a brown oil and salt solution which is diluted with 800 ml. of heptane and the aqueous and heptane layers separated. The heptane layer is dried, filtered and cooled to 10° C. to obtain the major portion of the desired 2-isopropylamino-4-methylbenzonitrile, m.p. 55°-57° C. Additional product is also recovered from the mother liquor and phthalic acid is recovered to a high degree from aqueous salt layer above referred after dilution with a total of 4.5 liters of water, filtering and acidifying with sulfuric acid (other aqueous alkaline solutions obtained in the work up being combined with said aqueous salt layer).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(/[CH:15]=[CH:16]/[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(/[CH:16]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(/C=C/c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(/C=C/c1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.04 g (5 mmol) of (E)-chalcone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.44 g of the desired product (yield 97%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]([F:28])([F:27])[F:26])(=O)OC.O.[NH2:31][NH2:32]>>[F:26][C:25]([F:28])([F:27])[O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[CH:16]=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:32][N:31]=1
Reactant: O=C1C(=O)C2CCC1C2
Reactant: COP(=O)(CC(=O)c1ccccc1OC(F)(F)F)OC
Reactant: NN
Solvent: O
Product: FC(F)(F)Oc1ccccc1-c1cc2c(nn1)C1CCC2C1

Procedure:
yellow gum. MS (EI): 306.2 (M+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-Oxo-2-(2-trifluoromethoxy-phenyl)-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[BrH:10].O>C1C=CC=CC=1>[Br:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: OCCCCCCCO
Reactant: Br
Solvent: O
Solvent: c1ccccc1
Product: OCCCCCCCBr
Reaction time: 16 h
Yield: 62 %

Procedure:
Heptane-1,7-diol (36.0 g, 272 mmol; Alfa Aesar) and aq. 48% HBr (38 mL, 0.9 equiv.) were heated under reflux in benzene (400 mL) with water removal using a Dean-Stark apparatus. After 16 h, all volatiles were removed in vacuo and the residue was purified by SiO2 column chromatography using a gradient of 10-30% EtOAc/hexanes as eluent to give 7-bromoheptan-1-ol (26.22 g, 62%) as a colorless oil. TLC: 50% EtOAc/hexanes, Rf≈0.40; 1H NMR (400 MHz, CDCl3) δ 3.61 (t, 2H, J=7.1 Hz), 3.39 (t, 2H, J=6.8 Hz), 1.80-1.88 (m, 2H), 1.52-1.58 (m, 2H), 1.30-1.46 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](OC2C=CC=CC=2)=[N:17][C:18]#[N:19])=[CH:11][CH:10]=1.CCOCC.CO.C(Cl)(Cl)Cl>C=C>[C:18]([N:17]=[C:16]([O:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[NH:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][CH:3]=1)#[N:19]
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1ccc(Cl)nc1
Agent: C=C
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N#CN=C(Nc1ccc(Cl)nc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
A stirred mixture of 5-amino-2-chloropyridine (1.3 g, 0.01 mol) and diphenylcyanocarbonimidate (2.4 g, 0.01 mol) in 15 ml of ethylene glycoldimethyl ether (DME), under nitrogen, was kept at 60° C. for 24 hours and at 85° C. for 6 hours when it was allowed to cool to room temperature. The solvent was removed in vacuo and the residue was heated to a melt at 120° C., under nitrogen, for 1 hour to complete the reaction as shown by TLC (5% MeOH/CHCl3). This was allowed to cool and was triturated with Et2O to give a solid that was collected by filtration. The solid was washed with Et2O to give 2.61 g of the titled product.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28](C3SC=CC=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].S(Cl)(=O)(=O)[NH2:38]>>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([NH2:38])(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3]
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Reactant: NS(=O)(=O)Cl
Agent: Cl
Product: N#Cc1ccc2c(c1)CN(S(N)(=O)=O)[C@H](Cc1ccccc1)CN2

Procedure:
The title compound was prepared from Compound A of Example 23 and sulfamyl chloride following the procedure of Compound B of Example 37.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:31][CH3:32])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[CH2:31]([C:20]1[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:8][C:34](=[O:35])[O:36][CH2:37][CH3:38])[C:18]=2[N:19]=1)[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1nc2ccccc2c2c1nc(CC)n2CCCCNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Triethylamine (3.86 mL, 10 eq) was added to a chilled (ice/water bath) suspension of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (1.0 g, 1 eq) in N,N-dimethylformamide (DMF) (10 mL). Ethyl chloroformate (1.5 g, 5 eq) was added dropwise to give a clear solution. The reaction mixture was allowed to come to ambient temperature with stirring for 2 hours. Additional triethylamine (3.86 mL, 10 eq) and ethyl chloroformate (3.86 mL, 10 eq) were added and the reaction mixture was stirred overnight. The reaction mixture was poured onto crushed ice and then extracted with dichloromethane (50 mL). The organic layer was washed sequentially with water (2×50 mL), 4% sodium carbonate (50 mL), water (50 mL), and brine (50 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a linear gradient of 0-25% CMA in chloroform, 2500 mL) followed by recrystallization from acetonitrile to provide 0.815 g of ethyl 2-ethyl-1-{4-[(methylsulfonyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-ylcarbamate as a white crystalline solid, mp 185-187° C. Anal calcd for C20H27N5O4S: C, 55.41; H, 6.28; N, 16.15. Found: C, 55.30; H, 6.29; N, 16.24.
Reaction SMILES: [OH-:1].[K+].O.[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][C@H:11]([CH2:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:12](N)=[O:13]>C(O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][C@H:11]([CH2:15][C@@H:16]([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([OH:1])=[O:13]
Reactant: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(N)=O
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCC[C@H](C)C[C@@H](OC1CCCCO1)C(=O)O
Yield: 59.8 %

Procedure:
In an egg-plant type flask were charged 7.66 g of 85% potassium hydroxide, 3 ml of water, 60 ml of ethanol, and 3.0 g of the compound obtained in Step 6, and the mixture was refluxed for 10 hours. Ethanol was removed by distillation under reduced pressure, and 30 ml of water was added to the residue. The mixture was adjusted to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, and the solvent was removed by distillation under reduced pressure to obtain 2.6 g of a crude product. Purification by silica gel column chromatography gave 1.8 g (59.77%) of the titled compound.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>O1CCCC1.C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH2:17][C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A 20% sodium ethoxide-ethanol solution (17 g) was added to tetrahydrofuran (100 ml), and the mixture was cooled to 0° C. It took 60 minutes to dropwise add a solution of 2′,4′-dichloroacetophenone (9.45 g) and diethyl oxalate (7.30 g) in tetrahydrofuran (100 ml) to the mixture. After the completion of the dropping, the mixture was allowed to warm to a room temperature and stirred for 2 hours. To the mixture, 2-N hydrochloric acid (200 ml) and chloroform (200 ml) were added. The organic layer was collected by separation and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Thus, the title compound (11.3 g, 78%) as a light-brown oily substance was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[N:12]1([C:11]2[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:3][C:4]3[C:9]([N:10]=2)=[CH:8][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 2-oxo-3-(piperidin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate (180 mg, 0.63 mmol) in dichloromethane (50 mL) was added pyridine (220 mg, 2.8 mmol) and then Tf2O (393 mg, 1.4 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as yellow oil (290 mg, crude).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:36]=[CH:35][C:32](C=O)=[CH:31][CH:30]=1>C(O)C>[OH:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:36]=[CH:35][C:32]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(C2CNCCN2CCO)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C3CNCCN3CCO)cc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A one liter three necked flask fitted with a dropping funnel, mechanical stirrer, and condenser is charged with 34.35 g of 4-nitrophenylacetic acid. Piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition period, 44.46 g of 4-[N-(2-hydroxyethyl)piperazinyl]benzaldehyde is added. The mixture is heated at 100° C. for three hours, and at 130° C. for three hours. After cooling, the resultant semi-solid mass is ground up in ethanol in a blender, then filtered, washed with water, and vacuum dried. The crude solid is recrystallized from chlorobenzene: m.p. 221°-224° C.