Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:28][CH2:29][N:30](C)[C:31](=O)OCC1C=CC=CC=1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>[Pd].CO>[CH3:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:28][CH2:29][NH:30][CH3:31]
Reactant: COCCOCCOCCOCCOCCOCCOCCN(CCOC)CCN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCN(CCOC)CCOCCOCCOCCOCCOCCOCCOC
Yield: 95.4 %

Procedure:
Benzyl 23-(2-methoxyethyl)-2,5,8,11,14,17,20-heptaoxa-23-azapentacosan-25-yl(methyl)carbamate 335a (2.58 g, 4.38 mmol) and palladium on carbon (10%, wet, 0.6 g) in methanol (30 mL) were stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered through celite and evaporated to give product as an oil (1.9 g, 99%); MS (ES, m/z): 455 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16](O)=[O:17])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)O)c1
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)NC(C)(C)CO)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid (0.203 mmol, 94.9 mg), HBTU (0.203 mmol, 79.3 mg), diisopropyl ethyl amine (0.34 mmol, 0.0592 mL) in DMF (1 mL) was added 2-amino-2-methyl-propan-1-ol (0.45 mmol, 42.2 mg). It was stirred at room temperature for 20 min. The reaction mixture was partitioned between ethyl acetate (12 mL) and saturated aq. sodium bicarbonate solution (12 mL). The ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×12 mL) and dried over sodium sulfate. The organic solvents were removed in vacuo to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (87.7 mg).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[N:13]1([C:19]2[N:20]=[C:21]3[NH:29][C@H:28]([C:30]([F:33])([F:32])[F:31])[CH2:27][CH2:26][N:22]3[C:23](=[O:25])[CH:24]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:12][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][N:29]2[C:21]3=[N:20][C:19]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:24][C:23](=[O:25])[N:22]3[CH2:26][CH2:27][C@H:28]2[C:30]([F:31])([F:32])[F:33])[CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cccc(CCBr)c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2CCc1cccc(F)c1

Procedure:
296 mg of sodium hydroxide in 2.5 ml of water, 33 mg of tetrabutylammonium hydrogen sulphate and 200 mg of 1-(2-bromoethyl)-3-fluorobenzene are added to a solution of 150 mg of (8S)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one in 2.5 ml of toluene. After one hour under microwave irradiation (power 100 watts on a CEM discover apparatus) at 60° C. and then one hour again at 60° C. and twice six hours at 70° C., the reaction mixture is diluted with ethyl acetate. The resulting mixture is washed with water. The organic phase is separated and then concentrated to dryness under reduced pressure. After purification of the resulting residue by preparative HPLC/MS (method D), 43 mg of (8S)-9-[2-(3-fluorophenyl)ethyl]-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4 H-pyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[N:7][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc2c1cnn2C1CCCC1
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 29.1 %

Procedure:
To a stirred solution of methyl 6-bromo-1H-indazole-4-carboxylate (10 g, 39.3 mmol) in acetonitrile (100 mL), was added cesium carbonate (19.2 g, 59.05 mmol) followed by bromocyclopentane (11.93 g, 78.3 mmol). The reaction mass was stirred at 90° C. for 3-4 h. On completion of reaction, acetonitrile was removed under reduced pressure and water added. Extraction was carried out using ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography to obtain methyl 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylate (3.7 g, 29.2%). The regiochemistry of the cyclopentyl group was confirmed by a NOE experiment.
Reaction SMILES: NCC1C=C(C2C=CC=C3C=2CCCN3C(=O)CCCOC2C=CC=C(C)C=2C)C=CC=1.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=C(C=CC=3)CNC(=O)OC(C)(C)C)C=CC=2)CCC1)=O.[CH3:72][C:73]1[C:114]([CH3:115])=[CH:113][CH:112]=[CH:111][C:74]=1[O:75][CH2:76][CH2:77][CH2:78][C:79]([N:81]1[C:90]2[C:85](=[C:86]([C:91]3[N:92]=[N:93][N:94]([CH2:96][C:97]4[CH:98]=[C:99]([NH:103]C(=O)OC(C)(C)C)[CH:100]=[CH:101][CH:102]=4)[N:95]=3)[CH:87]=[CH:88][CH:89]=2)[CH2:84][CH2:83][CH2:82]1)=[O:80]>>[NH2:103][C:99]1[CH:98]=[C:97]([CH:102]=[CH:101][CH:100]=1)[CH2:96][N:94]1[N:93]=[N:92][C:91]([C:86]2[CH:87]=[CH:88][CH:89]=[C:90]3[C:85]=2[CH2:84][CH2:83][CH2:82][N:81]3[C:79](=[O:80])[CH2:78][CH2:77][CH2:76][O:75][C:74]2[CH:111]=[CH:112][CH:113]=[C:114]([CH3:115])[C:73]=2[CH3:72])=[N:95]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn(Cc5cccc(NC(=O)OC(C)(C)C)c5)n4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CN)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4nnn(Cc5cccc(N)c5)n4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-(3-(aminomethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzylcarbamate was replaced with tert-butyl 3-((5-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-2H-tetrazol-2-yl)methyl)phenylcarbamate. LCMS, [M+H]+=497.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]=O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]1[CH:20]=[C:19]([NH2:21])[C:18]([NH2:22])=[CH:17][C:16]=1[CH3:23]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:12]=[N:22][C:18]3[C:19](=[CH:20][C:15]([CH3:14])=[C:16]([CH3:23])[CH:17]=3)[N:21]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=CC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: Cc1cc2ncc(-c3ccc([N+](=O)[O-])cc3)nc2cc1C

Procedure:
0.50 g (3 mmol) 4-nitrophenyl glyoxal was dissolved in 20 ml ethanol. 0.34 g (2.5 mml) 1,2 dimethyl 4,5 diaminobenzene was dissolved in ethanol. The reaction mixture was stirred and refluxed for 1 hour. Product crystallized after cooling, and filtrated washing with ethanol then ether.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].C(Cl)(=O)C1C=CC=CC=1>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: O=C(Cl)c1cccc(F)c1
Solvent: O=C(Cl)c1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccc(F)c2)ncn1Cc1ccccc1
Yield: 78 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-fluorobenzoyl chloride, instead of benzoyl chloride, to obtain 2.63 g of 1-benzyl-4-(3-fluorobenzoylamino)-5-imidazolecarboxamide (yield 78%).
Reaction SMILES: [I:1][C:2]1[C:3]([O:14][CH3:15])=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:21]([O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([N:5]2[CH:6]=[C:2]([I:1])[C:3]([O:14][CH3:15])=[N:4]2)[CH2:12][CH2:11]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COc1nn([C@H]2CC[C@H](O)CC2)cc1I
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1nn([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)cc1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of trans-4-(4-iodo-3-methoxy-1H-pyrazol-1-yl)cyclohexanol (0.359 g, 1.11 mmol), 1H-imidazole (0.228 g, 3.34 mmol), and 4-dimethylaminopyridine (0.0272 g, 0.223 mmol) in anhydrous DCM (10.8 mL) was charged with tert-butyldimethylsilyl chloride (0.336 g, 2.23 mmol) and stirred at rt for 20 min. The reaction was partitioned between CHCl3 and 1M NaHCO3 and separated. The aqueous was re-extracted with CHCl3 (3×) and the combined organic fraction were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a crude colorless oil. The crude material was purified by chromatography on silica gel [eluting with 5% EtOAc in hexanes] resulting in the title compound as a clear colorless oil. 1H NMR (400 MHz, CD3OD): δ=0.09 (d, J=0.51 Hz, 6H), 0.91 (s, 9H), 1.41-1.54 (m, 2H), 1.74-1.87 (m, 2H), 1.93-2.09 (m, 4H), 3.68-3.77 (m, 1H), 3.86 (d, J=0.5 Hz, 3H), 3.96 (tt, J=3.9, 12 Hz, 1H), 7.48 (s, 1H). MS (ES+): m/z 437.17 (100) [MH+]. HPLC: tR=4.98 min (vvnonpolar—5 min, ZQ3).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([NH:19][C:20]1([C:26]([OH:28])=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[NH2:36][C@H:37]([C:42]([NH:44][CH2:45][C:46]([NH2:48])=[O:47])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40]>O1CCCC1.CN(C)C=O>[CH2:9]([O:16][C:17]([NH:19][C:20]1([C:26]([NH:36][C@H:37]([C:42]([NH:44][CH2:45][C:46]([NH2:48])=[O:47])=[O:43])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)NCC(N)=O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1)C(=O)NCC(N)=O
Reaction time: 16 h
Yield: 59 %

Procedure:
4 ml of isobutyl chloroformate were added dropwise to 7.9 g of 1-benzyloxycarbonylaminocyclohexane-1-carboxylic acid and 4 ml of triethylamine in 75 ml of tetrahydrofuran at -10° C., while stirring, 5.6 g of L-leucyl-glycinamide in 50 ml of dimethylformamide were added to the resulting solution of the asymmetric acid anhydride after 15 minutes, and the mixture was stirred for 1 hour at -10° C. and then for 16 hours at room temperature, after which it was evaporated down under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed successively with 10% strength aqueous citric acid solution, sodium carbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. 7.5 g of 1-benzyloxycarbonylaminocyclohex-1-yl-carbonyl-L-leucyl-glycinamide were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([NH2:17])[CH:11]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[S-:18][C:19]#[N:20].[Na+].C(O)(=O)C.BrBr>O>[NH2:17][C:12]1[C:13]([F:16])=[CH:14][C:15]([S:18][C:19]#[N:20])=[C:10]([C:8](=[O:9])[C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:11]=1
Reactant: Cc1cccnc1C(=O)c1ccc(F)c(N)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccnc1C(=O)c1cc(N)c(F)cc1SC#N
Yield: 36.6 %

Procedure:
To a mixture of 3-amino-4-fluorophenyl 3-methyl-2-pyridyl ketone(4.20 g, 0.171 mol), sodium thiocyanate (4.19 g, 0.0517 mol) and glacial acetic acid is added a solution of bromine in acetic acid (2M, 12 ml, 0.0240 mol) over a one hour period. The resultant mixture is stirred one hour at room temperature and poured into cold water. The precipitate is filtered and dried to afford the title compound as a green solid (5.43 g, >100%) which is identified by NMR and mass spectral analysis.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH2:13](I)[CH2:14][CH3:15].O>CN(C=O)C>[CH3:3][C:4]1[C:11]([O:12][CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CCCI
Reactant: Cc1c(O)cccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccc(C=O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Sodium hydride (1.15 g, 50% in oil) was added to a stirred solution of 2-methyl-3-hydroxybenzaldehyde (3.00 g) in dry DMF (30 ml). The mixture was stirred for 1 h at room temperature under nitrogen, then n-propyl iodide (4.49 g) was added portionwise over 20 min, followed by stirring for 1 h. The mixture was poured into water and extracted with diethyl ether, and the combined extracts dried (MgSO4) and evaporated to dryness. Purification by chromatography (SiO2 ; hexane/ethyl acetate) gave 2-methyl-3-n-propyloxybenzaldehyde (1.38 g).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>ClC(Cl)C>[C:1]([O:4][CH:5]([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:18](=[O:20])[CH3:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)Cc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)OC(C)Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-Acetoxy-1-phenylpropane (5.2 g) in acetyl chloride (20 ml) was added dropwise to a stirred solution of aluminium chloride (16.0 g) and acetyl chloride (4.2 ml) in dichloroethane (150 ml). The mixture was stirred at ambient temperature for 72 hours, poured on to ice (500 g) and the organic phase was separated. The organic phase and washings were washed with sodium bicarbonate solution, dried (MgSO4) and evaporated to an oil. Chromatography of the oil on alumina, eluting with ether/petrol gave the title compound (4.5 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22]O)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:24])[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:50]4[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]4)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:24])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(-c2nc(-c3ccc(CO)nc3)no2)ccc1CC(C)C
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(C)c4)n3)cn2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.19 g, 0.58 mmol) that was obtained in Example 28 (28a), carbon tetrabromide (0.39 g, 1.2 mmol), triphenylphosphine (0.30 g, 1.2 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.13 mg, 0.87 mmol), and N,N-diisopropylethylamine (0.30 ml, 1.7 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1 or 3:1) as the eluent to afford the title compound (0.15 g) in a yield of 60% as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH3:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH3:20])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:30])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
A solution of N-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (0.98 g, 3.45 mmol) in 35 mL of CH2Cl2 was treated with MCPBA (77% max., 1.10 g, 4.48 mmol). After stirring for 3 h, the reaction was quenched with 2% Na2CO3 solution and extracted into CH2Cl2. The organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (0.93 g) as a light-orange solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:2][CH:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)c1ccc(OC)cc1)C(C)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (1 g) was suspended in dry methylene chloride (30 ml) and dissolution was effected with addition of triethylamine (1.69 ml). After adding 4-methoxybenzoyl chloride (0.91 ml) dropwise under cooling, the reaction mixture was allowed to warm up to room temperature and to react for 20 minutes. The mixture was treated with water and extracted with methylene chloride. The extract was washed with water, 1N-HCl, 4% aqueous sodium bicarbonate and saturated aqueous NaCl, dried (anhydrous Na2SO4) and concentrated. The residue was dissolved in developing solvent (benzene:ethyl acetate=4:1) and applied on a silica gel column. The first fraction (unpurities) was discarded and the following fraction was pooled and concentrated to give ethyl 2-(4-methoxybenzamido)-3-oxobutanoate (1.28 g, 83%) as white solid, m.p. 67°-69° C.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]([CH2:2][CH:3]([CH3:5])[CH3:4])[S:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1
Reactant: CC(C)CBr
Reactant: C[C@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN([C@@H](C)c1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 12 %

Procedure:
1-Bromo-2-methylpropane (34.7 g, 255.0 mmol) was added into a solution of (S)—N-(1-(4-bromophenyl)ethyl)(phenyl)methanesulfonamide (30.0 g, 85.0 mmol) and K2CO3 (35.2 g, 255.0 mmol) in CH3CN (500 mL) dropwise at 0° C. The mixture was then stirred at reflux for 48 h before it was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo to remove the solvent. The residue was dissolved with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified on silica gel chromatography (petroleum ether:ethyl acetate=10:1) to provide (S)—N-(1-(4-bromophenyl)ethyl)-N-isobutyl(phenyl)methanesulfonamide (4.2 g, 12% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.71 (d, 3H), 0.77 (d, 3H), 1.48 (d, 3H), 1.60-1.66 (m, 1H), 2.77-2.83 (m, 2H), 4.11-4.22 (m, 2H), 4.94-4.96 (m, 2H), 7.24-7.48 (m, 9H); >99% ee value (Chiral-HPLC, 214 nm).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>O>[CH2:12]([NH:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:13]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Product: CCNS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of 26 g of paratoluene sulfochloride in 200 cm3 of water is cooled to 0° C. With stirring there are slowly added 100 cm3 of a 40% aqueous solution of ethylamine in water. At the end of the addition the reaction mixture is again stirred for two hours at 0° C., then for two hours at ambient temperature. The solid in suspension is filtered, washed several times with water, then dried under reduced pressure. 24 g of N-ethyl(4-methyl phenyl) sulfonamide are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Br:14])[N:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[C:23]([Cl:29])[CH:22]=1)(=[O:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O.O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]([C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Br:14])[N:6]=2)[C:1](=[O:3])[CH3:2])=[C:23]([Cl:29])[CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1nc(Br)ccc1[N+](=O)[O-]
Reactant: CC(=O)Oc1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(CN(C(C)=O)c2nc(Br)ccc2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a solution of 2-acetamido-6-bromo-3-nitropyridine (203 mg) in N,N-dimethylformamide (2.34 ml) was added sodium hydride (60%, 34.3 mg) under ice-cooling, and the mixture was stirred for 1 hr. 4-Acetoxy-2-chlorobenzylbromide (288 mg) was added, and the mixture was stirred for 30 min under ice-cooling and at room temperature for 1 hr. Ethyl acetate (350 ml) and water (700 ml) were added to the reaction mixture under ice-cooling, and the mixture was partitioned. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash silica gel column chromatography and eluted with hexane/ethyl acetate=4/1-3/1. The eluate was concentrated under reduced pressure to give 2-[N-(4-acetoxy-2-chlorobenzyl)acetamido]-6-bromo-3-nitropyridine as an oil (256 mg).