Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[O:6])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(NC(=O)c2ccc(OC)c(N)c2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(NC(=S)Nc3cc(Cl)cc(Cl)c3)c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 79.6 %

Procedure:
A mixture of 3-amino-4-methoxy-N-(4-methoxyphenyl)-benzamide from Example 3 (0.681 g, 2.50 mmol) in ethyl acetate (80 mL) was heated briefly to 60° C. then filtered to clarity and mixed with 3,5-dichlorophenyl isothiocyanate (0.511 g, 2.50 mmol). The reaction was allowed to stand for 3 days at room temperature then concentrated to two-thirds volume and allowed to stand overnight. Filtration afforded the product (0.948 g); m.p. 175-182° C.
Reaction SMILES: [CH2:1]1[C:5]2([O:10][CH2:9][CH2:8][CH2:7][O:6]2)[CH2:4][C@@H:3]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:29]=[C:30]([C@@H:33]6[CH2:37][CH2:36][CH2:35][N:34]6[C:38]([C@@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[CH:41]([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=5)=[CH:24][CH:23]=4)=[CH:18][CH:17]=3)[N:15]=2)[NH:2]1.[CH3:49][O:50][C:51]([NH:53][C@H:54]([C:58](O)=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:52].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:42][CH:41]([CH3:43])[C@H:40]([NH:44][C:45](=[O:48])[O:46][CH3:47])[C:38]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:30]1[NH:31][CH:32]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([C:19]3[CH:18]=[CH:17][C:16]([C:14]4[N:15]=[C:11]([C@@H:3]5[CH2:4][C:5]6([O:10][CH2:9][CH2:8][CH2:7][O:6]6)[CH2:1][N:2]5[C:58](=[O:59])[C@@H:54]([NH:53][C:51]([O:50][CH3:49])=[O:52])[CH:55]([CH3:57])[CH3:56])[NH:12][CH:13]=4)=[CH:21][CH:20]=3)=[CH:23][CH:24]=2)[N:29]=1)=[O:39]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5C(=O)[C@@H](NC(=O)OC)C(C)C)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Yield: 55.8 %

Procedure:
Methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[(3S)-2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (47 mg, yield: 53%) was prepared from methyl [(1S)-1-({(2S)-2-[4-(4′-{2-[(3S)-6,10-dioxa-2-azaspiro[4.5]dec-3-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Intermediate 19) (68 mg, 0.104 mmol), N-[(methyloxy)carbonyl]-L-valine (18.2 mg, 0.104) and HATU (40 mg, 0.104 mmol), following the similar procedure outlined in Example 5. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.20-11.06 (m, 2H) 7.35-8.02 (m, 8H) 7.22 (d, J=7.78 Hz, 2H) 4.97-5.89 (m, 4H) 3.22-4.58 (m, 15H) 2.83-3.20 (m, 1H) 2.58-2.83 (m, 1H) 2.29-2.58 (m, 1H) 1.57-2.31 (m, 8H) 0.64-1.22 (m, 12H). HRMS: (M+H)+ calcd: 811.4143. found: 811.4142.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:26])([CH2:23][NH:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[O:15].C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:38]=1[C:39](Cl)=[O:40]>O1CCCC1>[C:18]([O-:26])(=[O:40])[CH3:23].[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:23][N:24]([C:39]([C:38]1[C:37]([Cl:36])=[CH:45][CH:44]=[CH:43][C:42]=1[Cl:46])=[O:40])[CH3:25])([OH:26])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: CNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)[O-]
Product: CN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(Cl)cccc1Cl
Reaction time: 0.33 h
Yield: 135.2 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{3,3,3-trifluoro-2-hydroxy-2-[(methylamino)methyl]propyl}-1H-pyrazole-4-carboxamide (56 mg, 0.15 mmol) in anhydrous tetrahydrofuran (2 ml) cooled in ice was added diisopropylethylamine (0.052 ml, 0.3 mmol) followed by 2,6-dichlorobenzoyl chloride (0.023 ml, 0.164 mmol). After 20 minutes, the mixture was removed from the ice and left at 21° C. for 19 hours. The mixture was blown down, the residue was dissolved in dichloromethane (3 ml) and washed with 2M hydrochloric acid (1 ml) and water (1 ml). It was again blown down and purified on a 5 g SPE cartridge, eluting with dichloromethane and then mixtures of cyclohexane/ethyl:acetate (10:1), (5:1), (3:1) and finally (2:1) to give the title compound (55.6 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([CH2:13][CH2:12]2)[CH2:10][CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19]COCC>CCOCC.CO.[Si](C=[N+]=[N-])(C)(C)C>[CH2:12]1[C:11]2([CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]2)[CH2:13]1
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C1CC2(CCN1C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 199.9 %

Procedure:
To an ice cooled solution of 6-(tert-butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (racemic mixture) (D1) (500 mg, 0.78 mmol) in Et2O/MeOH (10/5 ml), TMSCHN2 2M sol in Et2O (1.5 ml, 2.94 mmol) was added and the resulting mixture was stirred 2 hrs at 0° C. then 18 hrs at RT. After solvent evaporation the crude residue was loaded onto SPE-Si cartridge (10 g) eluting with DCM. Collected fractions after solvent evaporation afforded the title compound (D4) (420 mg) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]Br>C(O)(=O)C>[Br:13][C:9]1[C:10]([OH:12])=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)cc1F
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(O)cc1F
Temperature: 45 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
To a solution of 66.43A (2.03 g, 11.9 mmol) in acetic acid (65 mL) was added a pre-mixed solution of bromine (0.67 mL, 13.1 mmol) in acetic acid (10 mL). The mixture was stirred at 45° C. and monitored with TLC and LC-MS. After 18 hours, the reaction mixture was concentrated under reduced pressure. Brine was added to the residue, and the mixture was extracted three times with EtOAc. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to provide 66.43B as a white solid (2.12 g, 71% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, d, J=7.4 Hz), 6.82 (1H, d, J=11.3 Hz), 6.04 (1H, s), 3.92 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][N:5]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]=1[C:7](=[O:9])[NH2:8].CN(C)[CH:21]=[O:22]>>[CH2:13]([O:12][CH2:11][CH2:10][N:5]1[C:6]2[C:7](=[O:9])[NH:8][C:21](=[O:22])[NH:1][C:2]=2[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4]1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCOCCn1nc(C(=O)OC)c(N)c1C(N)=O
Product: CCOCCn1nc(C(=O)OC)c2[nH]c(=O)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the amide of Step 4 (570 mg, 3.38 mmol) in N,N-dimethylformamide (30 mL) was treated with N,N′-carbonyldiimidazole (658 mg, 4.06 mmol) and the reaction mixture stirred at room temperature for 1 hour and then at 90° C. for 18 hours. The reaction mixture was concentrated in vacuo and the crude product suspended in acetone and sonicated for 30 minutes. The solid product was filtered off and dried in vacuo to yield the title product.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: ClCCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
1-[2-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-4,5-dimethyl-phenyl]-ethanone (compound 314) (150 mg), 1-bromo-3-chloropropane (210 mg), and potassium carbonate (307 mg) were suspended in N,N-dimethylformamide (6 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (174 mg, 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[NH:11][C:10]=1[C:25]([OH:27])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:28]([O:35][CH2:36][CH2:37][NH:38][CH:39]([CH3:41])[CH3:40])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:28]([O:35][CH2:36][CH2:37][N:38]([CH:39]([CH3:41])[CH3:40])[C:25]([C:10]1[NH:11][C:12]([CH2:16][C:17]2[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[N:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2c(Cl)cccc2Cl)nc(=O)c1OCc1ccccc1
Reaction time: 0.67 h
Yield: 56.9 %

Procedure:
5-(Benzyloxy)-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (62) (0.2 g, 494 μmol, Eq: 1.00) and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-2-amine (118 mg, 543 μmol, Eq: 1.1) were dissolved in pyridine (3 ml) and cooled in an ice/NaCl bath. POCl3 (227 mg, 138 μl, 1.48 mmol, Eq: 3) was added dropwise. After the addition was complete, stirring of the reaction mixture was continued at 0° C. for approx. 40 minutes. The reaction mixture was quenched with ice and extracted twice with ethyl acetate. The organic layers were washed with NaHCO3, were combined, dried over Na2SO4, filtered and concentrated. The remaining oil was purified by SiO2 flash chromatography (24 g SiO2, hexanes/ethyl acetate 0-50% ethyl acetate). Product containing fractions were combined and concentrated. The remaining oil was treated with hexanes and concentrated again to afford 5-benzyloxy-2-(2,6-dichlorobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (63) (0.17 g, 281 μmol, 57.0% yield) as a white solid.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:7].[CH3:16][O:17][C:18](=[O:23])[C:19](OC)=[O:20]>C1C=CC=CC=1>[OH:20][C:19](=[CH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[O:7])[C:18]([O:17][CH3:16])=[O:23]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(O)=CC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
To a well stirred suspension of freshly prepared sodium ethylate (820 mg, 12 mmol) in dry benzene (10 mL), 3,4-dichloroacetophenone (1.89 g, 10 mmol) and dimethyloxalate (1.18 g, 10 mmol) dissolved in dry benzene (20 mL), were added dropwise on cooling at +5° C., and under dry nitrogen atmosphere. The resulting dark red suspension was stirred at room temperature over 4 hours. The reaction mixture was then poured into ice/2N HCl (1:1 w/w), stirred for 5 minutes and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated in vacuo to afford a pale yellow solid, which was recrystallized from acetonitrile to yield the pure ester (2.4 g, 86%),colorless needles, mp. 122-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH2:16][CH2:17][CH2:18][CH:19]=O>CCOC(C)=O.CCCCCC>[N+:10](/[C:9](/[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[CH:19]/[CH2:18][CH2:17][CH2:16][CH:15]=[O:14])([O-:12])=[O:11]
Reactant: COC(CCCC=O)OC
Reactant: Cc1ccc(CC[N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(C/C(=C\CCCC=O)[N+](=O)[O-])cc1
Yield: 34.9 %

Procedure:
Prepared according to the general procedure B from 1-methyl-4-(2-nitroethyl)benzene 112f (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.38 g, 35% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:11]([CH:13]=O)=O.O>C(O)C.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[N:8][CH:11]=[CH:13][N:9]=[C:4]2[C:3]=1[CH3:10]
Reactant: Cc1c(Br)cnc(N)c1N
Reactant: O=CC=O
Solvent: O
Solvent: CCO
Product: Cc1c(Br)cnc2nccnc12
Temperature: 25 °C

Procedure:
5-bromo-4-methylpyridine-2,3-diamine (0.21 g, 1 mmol) was dissolved in a mixture of EtOH—H2O; to this was added aqueous glyoxal 40% (0.2 ml, 4 mmol) and the resulting mixture was refluxed for 1 h. Upon cooling to room temperature, water was then added. The product was separated, filtered and washed with excess water yielded 7-bromo-8-methylpyrido[2,3-b]pyrazine as a sufficiently enough pure material (0.21 g) for the next step.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1CCC(N=C=NC2CCCCC2)CC1>CCOC(C)=O>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[F:17])=[O:15])=[O:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 16 h
Yield: 93.9 %

Procedure:
To a solution of N-Boc-6-aminohexanoic acid (4.78 g, 20.8 mmol) and pentafluorophenol (3.68 g, 20 mmol) in 50 mL of EtOAc was added DCC (4.12 g, 20 mmol). This was allowed to stir for 16 h, and was then filtered and the filtrate evaporated in vacuo to a syrup. On standing, this crystallized to give 7.46 g (94%) of the ester. Rerystallization from isopropanol/1% acetic acid gave 6.26 g of white needles, mp 81°-83° C. 1H NMR (CDCl3) δ 1.4-1.6 (m, 15H, Boc CH3 and internal CH2), 1.8 (m, 2H, C2CH2CO2), 2.67 (5, J=7.3 Hz, 2H, CH2CO2), 3.1 (m, 2H, NHCH2), 4.5 (b, 1H, NH). 13C NMR (CDCl3) δ 24.38 (C4), 26.00 (C3), 28.39 (Boc CH3), 29.70 (C5), 33.20 (C2), 40.28 (C6), 79 (Boc C), 156 (Boc C=0), 169 (C1). Anal. Calcd for C17H20NO4F5 : C, 51.4; H, 5.1; N, 3.5. Found: C, 51.5; H, 5.0; N, 3.4.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[C:23]([Cl:31])[C:22]=1[NH2:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[CH2:13]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([Cl:31])[C:22]=2[N:32]=[C:1]1[OH:2])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1ccccc1
Temperature: 50 °C
Yield: 62.4 %

Procedure:
1,1′-Carbonyldiimidazole (2.9 g, 18 mmol) was added to a solution of N4-benzyl-2-chloroquinoline-3,4-diamine (5.0 g, 18 mmol) in tetrahydrofuran (THF) (50 mL), and the reaction was heated at 50° C. for three days. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (1.5 g, 9.2 mmol) was added. The reaction was stirred for several hours at 80° C., and additional 1,1′-carbonyldiimidazole (2.9 g, 18 mmol) was added. The reaction was stirred for one hour at 80° C. and overnight at 50° C. A solid was present and was isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 3.48 g of 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a fluffy, white solid. Diethyl ether was added to the filtrate, and the resulting mixture was stirred for 20 minutes. A solid was present and was isolated by filtration and dried under vacuum to provide 0.95 g of 1-benzyl-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a fluffy, beige solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:12])[CH3:11].[Cl:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:24][N:23]=[C:22]2[N:32]([CH2:41][C:42](O)=[O:43])[N:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]=12.Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][N:32]2[C:22]3=[N:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]([Cl:19])=[C:21]3[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:33]2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and 1-acetylpiperazine (38 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h then 1-acetylpiperazine (10 mg, 0.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.15 mmol) were added. After a further 3.5 h the reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 66 as a white solid (32.2 mg).