Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[C:9]([C:10]#[N:11])[C:5]=2[CH:4]=[N:3][CH:2]=1.[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[N:21]([C:28]1[C:36]3[CH2:35][O:34]B(O)[C:32]=3[CH:31]=[CH:30][CH:29]=1)[N:20]=[CH:19]2)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1.ClC(Cl)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:12]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([F:26])[CH:25]=1)[C:22](=[O:27])[N:21]([C:28]1[C:36]([CH2:35][OH:34])=[C:32]([N:7]3[C:6]4[N:1]=[CH:2][N:3]=[CH:4][C:5]=4[C:9]([C:10]#[N:11])=[CH:8]3)[CH:31]=[CH:30][CH:29]=1)[N:20]=[CH:19]2)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: N#Cc1c[nH]c2ncncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5cncnc54)c3CO)ncc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
In a 25 mL round-bottomed flask, 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (40.9 mg, 284 μmol, Eq: 1.00), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (100 mg, 284 μmol, Eq: 1.00), copper acetate (34.8 mg) and pyridine (44.9 mg, 45.9 μl, 568 μmol, Eq: 2) were combined with dichloroethane to give a dark blue suspension. The reaction mixture was flushed with nitrogen. The reaction mixture was heated to 80° C. and stirred for 16 hr. The reaction was diluted with sat NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The mixture was separated by flash column using 30-50% EtOAc in hexanes to give the 7-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (42 mg, 31%) as a lyophilized white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[N:17][CH:18]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:70]=[CH:69][C:68]([CH2:71][NH:72][CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])=[CH:67][CH:66]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].C(N(CC)CC)C>CN(C=O)C>[CH2:50]([O:57][C:58]1[CH:82]=[CH:81][C:61]([C:62]([O:64][C:65]2[CH:66]=[CH:67][C:68]([CH2:71][N:72]([CH2:73][C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C:19](=[O:20])[C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)=[CH:69][CH:70]=2)=[O:63])=[CH:60][CH:59]=1)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)nc2)c(C(F)(F)F)c1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CNCC(=O)OC(C)(C)C)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Prepared using General Procedure 6: To a stirred solution of 5-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)picolinic acid INT-15 (20 mg, 0.05 mmol) in DMF (1 mL) was added HATU (22.5 mg, 0.06 mmol). After stirring for 1 h at room temperature, 4-(((2-(tert-butoxy)-2-oxoethyl)amino)methyl)phenyl 4-(heptyloxy)benzoate INT-13 (30.8 mg, 0.06 mmol) was added followed by triethylamine (11.4 mg, 0.11 mmol). The reaction mixture was allowed to stir at room temperature overnight. The final product was isolated by HPLC purification to give 4-((N-(2-(tert-butoxy)-2-oxoethyl)-5-(2-(4-methoxy-2(trifluoromethyl)phenyl)acetamido)picolinamido)methyl)phenyl 4-(heptyloxy)benzoate INT-16. LCMS-ESI (m/z) calculated for C43H48F3N3O8: 792; no m/z observed, tR=4.11 min (Method 7).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:8][CH:7]=1.COCCOC1C=CC(C(O)C2C=CC=CC=2)=CC=1.[BH4-].[Na+].S(Cl)([Cl:43])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH:10]([Cl:43])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COCCOc1ccc(C(=O)c2ccccc2)cc1
Agent: COCCOc1ccc(C(O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCOc1ccc(C(Cl)c2ccccc2)cc1

Procedure:
For the preparation of the compound of Example 27, 4-(2-methoxyethoxy)benzophenone is obtained by reaction of 4-hydroxybenzophenone with 2-methoxyethyl chloride at 100° C. in the presence of sodium hydride in dimethylformamide. Further reaction takes place in accordance with Example 1-5. 4-(2-Methoxyethoxy)benzophenone is reduced to 4-(2-methoxyethoxy)benzhydrol using sodium borohydride. 4-(2-Methoxyethoxy)benzhydrol is reacted with thionyl chloride in chloroform to give 4-(2-methoxyethoxy)benzhydryl chloride. 4-(2-methoxyethoxy)benzhydryl chloride is reacted with piperazine in dimethylformamide in the presence of potassium carbonate to give 1-((4-(2-methoxyethoxy)phenyl)phenylmethyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,4-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.94 (m, 3 H) 1.28-1.39 (m, 2 H) 1.71-1.80 (m, 2 H) 2.47 (s, 3 H) 4.27 (t, 2 H) 6.81 (s, 1 H) 7.73 (d, 1 H) 7.99 (d, 1 H) 8.22 (s, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:4][CH:3]=1.[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O.CC(OC)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][N:9]2[C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(CCc2ccc(F)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1CCc1ccc(F)cc1
Yield: 143.7 %

Procedure:
Dimethyl 2-(4-fluorophenethyl)piperidine-1,4-dicarboxylate (3.18 g, 9.83 mmol) was dissolved in acetonitrile (35 mL) and water (0.7 mL) and lithium bromide (6.83 g, 78.67 mmol) was added. Triethylamine (5.45 mL, 39.34 mmol) was added and the resulting suspension was heated under reflux for 5 h. MTBE and water were added, the phases separated and the organic layer was extracted with water. The combined aqueous layers were acidified to pH 1 with 3.8 M HCl and extracted with MTBE. The combined organic layers were washed with water, dried with Na2SO4 and evaporated. Crude 2-(4-fluorophenethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.37 g) was isolated. MS m/z 310 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:20]1([Mg]Br)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O1CCCC1>>[CH:20]1([CH:8]([C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=3)[O:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Yield: 76 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furaldehyde (1.21 g) and 1N cyclohexylmagnesium bromide-tetrahydrofuran solution (6.8 mL) to give the title compound (1.21 g, 76%) as a yellow crystal.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=[C:16]([C:25](O)=[O:26])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1)#[N:2].ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[O:54]=[C:52]1[CH2:53][N:49]([C:25]([C:16]2[CH:15]=[C:14]([C:5]3[CH:4]=[C:3]([CH:8]=[C:7]([O:9][C:10]([F:11])([F:13])[F:12])[CH:6]=3)[C:1]#[N:2])[N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:17]=2)=[O:26])[CH2:50][NH:51]1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: N#Cc1cc(OC(F)(F)F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2cccnc2)c1

Procedure:
98 mg (0.26 mmol) of the compound of Example 58A is reacted analogously to the synthesis of the compound of Example 1 with 35 mg (0.29 mmol) of 4-imidazolinone-hydrochloride. 80 mg (69% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O-]S([O-])(=O)=O.[Mg+2].[H-]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:41]3[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20](=[O:29])[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(C=O)ccc21
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3[nH]c2=O)cc2cc(CN3CCN(S(C)(=O)=O)CC3)ccc21
Reaction time: 3 h

Procedure:
To a stirred solution of the aldehyde (1-9, 2.01 g, 5.15 mmol, 1 equiv) and N-methanesulfonylpiperazine acetic acid salt (4.62 g, 20.60 mmol, 4 equiv) in dichloroethane (400 mL) was added at ambient temperature acetic acid (1.2 mL). The reaction mixture was treated with sodium triacetoxyborohydride and stirred for 3 hours. The reaction stopped at 76% of conversion and treated with MgSO4 and additional 1 g of the hydride. After further stirring for 1 hour the reaction was complete. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was once again washed with saturated aqueous NaHCO3, and then with brine, separated, dried with (Na2SO4) and concentrated in vacuo. The crude solid was dissolved in dimethylformamide and treated with the activated carbon. The filtrate solution (celite) was concentrated to syrup which was quickly trituated with methanol (100 mL). The resulting solid was collected by filtration, redissolved in dimethylformamide, concentrated to syrup, trituated with methanol (100 mL), collected by filtration and vacuum-dried to give 5-(4-Methanesulfonyl-piperazin-1-ylmethyl)-2-(2-oxo-1,2-dihydro-quinolin-3-yl)-indole-1-carboxylic acid tert-butyl ester (1-10) as a white powder; 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.06 (s, 1H), 8.04 (d, 1H, J=8.5 Hz), 7.74 (d, 1H, J=8.0 Hz), 7.55 (s, 1H), 7.53 (dt, 1H, J=8.0, 1.5 Hz), 7.35 (d, 1H, J=8.5 Hz), 7.30 (dd, 1H, J=8.5, 1.5 Hz), 7.22 (t, 1H, J=7.5 Hz), 6.76 (s, 1H), 3.62 (s, 2H), 3.16 (m, 4H), 2.87 (s, 3H), 2.48 (m, 4H), 1.35 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CN(C)C=O.CCOCC.O>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[N:11]2)=[CH:21][CH:22]=1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1ccc(Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(-c3ccc(Cl)cc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.5 %

Procedure:
To a stirred suspension of 1.1 g of sodium hydride (50% oil dispersion) in 40 ml of dimethylformamide was added, dropwise, under nitrogen, 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. The reaction was stirred at ambient temperature for 45 min, and 2.9 ml of 4-fluorochlorobenzene was added. The temperature was increased to 120° and the reaction proceeded at this temperature for 24 hr. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was heated (steam bath) with 3N hydrochloric acid and the salt was collected. The salt was immediately recrystallized from water. The wet salt was treated with ammonium hydroxide and the base was extracted into dichloromethane. Evaporation of the dichloromethane in vacuo gave an oil. The oil solidified on standing. The solid was dissolved in ether and 1.4 g of fumaric acid was added. Recrystallization from 2-propanol gave 3.9 g (47.5%) of product, mp 176°-178° C.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:45]=[CH:46][CH:47]=4)[O:39][CH2:40][C:41]([O:43]C)=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:45]=[CH:46][CH:47]=4)[O:39][CH2:40][C:41]([OH:43])=[O:42])[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(OCC(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(OCC(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a mixture of methyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenoxy}acetate (0.25 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added dilute hydrochloric acid to acidify the solution, and the precipitated crystals were collected by filtration to give {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenoxy}acetic acid as colorless crystals (0.18 g, yield 72%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 166-168° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Br:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([Br:29])=[CH:31][CH:32]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1nc(CCCOc1ccccc1)n2CCCNC(=O)c1ccc(Br)cc1
Yield: 60.6 %

Procedure:
Using the general method of Example 189, 1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin4-amine (2.0 g, 5.32 mmol) was reacted with 4-bromobenzoyl chloride (880 mg, 5.86 mmol) to provide 1.8 g of N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl} 4-bromobenzamide as a light yellow solid, m.p. 186.2-186.7° C. Analysis: Calculated for C29H28BrN5O2: % C, 62.37; % H, 5.05; % N, 12.54; Found: % C, 62.18; % H, 5.16; % N, 12.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-])=O)[CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:6].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[NH:18][C:16]1[CH:15]=[CH:14][C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[O:6])=[C:3]([O:2][CH3:1])[CH:17]=1
Reactant: COc1cc(Nc2ccccc2[N+](=O)[O-])ccc1C(=O)c1ccccc1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(Nc2ccccc2N)ccc1C(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxy-2′-methyl-4-(2-nitrophenylamino)benzophenone (Compound 255, 1.02 g, 2.8 mmol) in methanol (10 ml) was added, under argon, ammonium formiate (0.80 g, 13 mmol) and 10% palladium on carbon (0.16 g). The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through Celite® and evaporated in vacuo. The residue was treated with water (50 ml) and extracted with methylene chloride (2×50 ml). The organic phase was dried (MgSO4), filtered and evaporated in vacuo to afford the crude product which was further purified by chromatography using ethyl acetate/pentane 1:1 as eluant.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: c1cncc(CN2CCNCC2)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-[(3-pyridyl)-methyl]-piperazine (0.097 g, 0.55 mmol) followed by diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.160 g, 82%); 1H-NMR (500 MHz, DMSO-d6) 3.05 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2), 7.02 (s, 2H, NH2), 7.36 (dd, J=7.80, 4.75 Hz, 1H, pyridyl 5-H), 7.74 (dt, J=7.80, 1.70 Hz, 1H, pyridyl 4-H), 8.16 (s, 1H, 6-H), 8.47 (dd, J=4.75, 1.60 Hz, 1H, pyridyl 6-H), 8.50 (d, J=1.65 Hz, 1H, pyridyl 2-H);
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCCCCCCCCCCCCCCOCCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCCOCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To 13.1 g (31.8 mmol) of 30 was added 128 mL of a 1 M solution of TBAF in THF and the reaction was stirred for 16 h at room temperature. The reaction mixture was then quenched with saturated solution of aq. NH4Cl and THF was evaporated under reduced pressure. The aq. solution was then diluted with 200 mL of water and the product was extracted with Et2O (3×), the combined organic layers were then washed with brine (1×), dried over MgSO4 and the solvent was removed under reduced pressure. The crude was then purified by combiflash using hexane/ethyl acetate as eluent to furnish 7.1 g of target product 31 in 75% yield as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH3:10]
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(F)cc1Cl
Reaction time: 8 h
Yield: 101.6 %

Procedure:
To a stirred mixture of 2-chloro-4-fluorobenzenethiol (65 g, 0.403 mol) and potassium carbonate (54 g, 0.39 mol) in DMF (450 mL) was added drop wise CH3I (24.96 mL, 0.442 mol) at room temperature and the mixture was stirred overnight. The reaction mixture was diluted with water (200 mL) and extracted with ethyl ether (150 mL×3), the combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give (2-chloro-4-fluorophenyl)(methyl)sulfane (70 g, 98%) as a yellow liquid. To a solution of (2-chloro-4-fluorophenyl)(methyl)sulfane (66 g, 0.37 mol) in dichloromethane (1600 mL) was added 3-chloroperoxybenzoic acid (85% purity, 157 g, 0.77 mol) in portions, and the mixture was stirred at room temperature for 2 h. The mixture was washed with aq. saturated sodium sulfite solution (600 mL). The organic phase was separated and sequentially washed with aq. sodium bicarbonate solution (250 mL×2) and water (250 mL), dried over Na2SO4 and evaporated under reduced pressure to give a yellow solid. The crude product was re-crystallized from ether (200 mL) to give the title compound (33.1 g, 43%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:31](O)(=[O:42])[CH2:32][NH:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:34]([NH:33][CH2:32][C:31]([N:14]([CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][CH:29]=2)[CH2:8][CH2:9]1)[CH2:15][CH:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:42])(=[O:35])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: Clc1ccc(CN2CCC(CNCC(c3ccccc3)c3ccccc3)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCC(=O)N(CC1CCN(Cc2ccc(Cl)cc2)CC1)CC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (0.084 mmol) in CH2Cl2 was treated with hippuric acid (1.1 equiv.), HBTU (1.1 equiv.), HOBt (1.1 equiv.). The reaction mixture was stirred at 40° C. for 24 h. General workup and preparative TLC (SiO2) afforded 4-{N-(N-benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl}-1-(4-chlorobenzyl)piperidine (Compound No. 524) (8.5 mg, 17%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 580 (M++H, C36H38ClN3O2).