Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:35]1[C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([C:44]#[N:45])[C:38]=2[CH2:37][CH2:36]1.O>C1COCC1>[CH3:12][O:13]/[CH:14]=[C:35]1\[CH2:36][CH2:37][C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][C:43]\1=2
Reactant: N#Cc1cccc2c1CCC2=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C1\CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxy methyl)triphenylphosphonium chloride (1.47 g, 4.29 mmol) in dry THF (20 mL) at 0° C. for 35 min and a solution of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (450 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0° C. for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via prep-TLC (PE:EtOAc=10:1) to afford (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J=8.3 Hz, 0.4H), 7.42 (d, J=8.3 Hz, 0.6H), 7.30-7.40 (m, 1H), 7.18-7.22 (m, 1H), 6.70 (s, 0.6H), 6.22 (s, 0.4H), 3.72 (s, 3H), 3.15 (t, J=5.7 Hz, 2H), 2.70-2.82 (m, 2H).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:15][CH:14]([NH2:16])[CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O.O>[N+:30]([C:29]1[C:24]([NH:16][CH:14]2[CH2:13][N:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=3)[CH2:15]2)=[N:25][CH:26]=[CH:27][CH:28]=1)([O-:32])=[O:31]
Reactant: NC1CN(c2ccc3ccccc3n2)C1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1NC1CN(c2ccc3ccccc3n2)C1
Yield: 83.3 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-amine hydrochloride (0.90 g, 3.84 mmol) in dry dimethylformamide (15 mL) was added sodium carbonate (1.22 g, 11.5 mmol) and 2-chloro-3-nitro-pyridine (608 mg, 3.84 mmol). The reaction mixture was stirred and heated at reflux for 14 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (20% to 50% ethyl acetate in petroleum ether) to give 3-nitro-N-(1-(quinolin-2-yl)azetidin-3-yl)pyridin-2-amine (1.05 g, 3.20 mmol, 85% yield) as yellow solid.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[CH:14](OCC)=[O:15]>CCOCC.O>[CH:14]([CH:9]([CH2:8][C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:15]
Reactant: CCOC=O
Reactant: COC(=O)CCc1cccnc1
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: COC(=O)C(C=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
To a suspension of 2.1 g (90.8 mmol) of sodium in 55 mL of anhydrous Et2O is added dropwise, at 0° C. under argon, a mixture of 15 g (90.8 mmol) of methyl 3-(pyridin-3-yl)propanoate and 7.3 mL (57.41 mmol) of ethyl formate. The medium is then stirred for 12 hours at room temperature, taken up in 200 mL of water and extracted with 100 mL of Et2O. The aqueous phase is acidified to pH 5 and then extracted with 2×300 mL of EtOAc. The organic phase is then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a DCM/MeOH gradient of 0 to 10% MeOH. 4.8 g of methyl 2-formyl-3-(pyridin-3-yl)propanoate are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([CH:6]1[C:10](O)([CH3:11])[CH:9]=[CH:8][C:7]1=[O:13])[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([OH:28])[CH2:26][CH3:27]>>[CH2:1]([C:6]1[C:7](=[O:13])[CH2:8][CH:9]([O:28][CH2:25][CH2:26][CH3:27])[C:10]=1[CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCO
Reactant: CCCCCC1C(=O)C=CC1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCC1=C(C)C(OCCC)CC1=O
Reaction time: 5 h

Procedure:
Into the same flask as used in Example 1, 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), n-propanol (5 parts) and p-toluenesulfonic acid (1/20 part) were charged, and the mixture was stirred at a temperature of 40° to 70° C. for 5 hours. After completion of the reaction, the mixture was treated in the same manner as in Example 25 to obtain 2-n-pentyl-3-methyl-4-n-propoxy-2-cyclopentenone. Yield, 96%. nD19 1.4792.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH3:3].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[CH2:2][CH3:3]
Reactant: N#C[O-]
Reactant: CCCc1ccc(Cc2cccc(N)c2)n1CCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CCCc1ccc(Cc2cccc(NC(N)=O)c2)n1CCC
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A stirred solution of 2 g (7.7 mmol) of 1,5-dipropyl-2-(3'-aminobenzyl)pyrrole in 200 ml of benzene was treated with 1 g (15.3 mmol) of sodium cyanate followed by the dropwise addition, over a 11/2 hour period, of a solution of 1.5 ml (19 mmol) of trifluoroacetic acid in 100 ml of benzene. The reaction mixture was stirred at room temperature for 1 more hour, poured into 300 ml of saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3×300 ml). The combined extracts were washed with water (2×300 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 100 g of silica gel, using hexane-ethyl acetate (55:45) as eluant, thus obtaining 1.85 g (83%) of the title compound, 1,5-dipropyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane. M.P. 123°-126° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].Cl.[NH2:6][C@H:7]([CH:26]([CH3:28])[CH3:27])[C:8]([N:10]1[CH2:15][CH2:14][C@@:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([OH:16])[C:12]([CH3:25])([CH3:24])[CH2:11]1)=[O:9].C1COCC1>C(N(CC)CC)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@:13]2([OH:16])[CH2:14][CH2:15][N:10]([C:8](=[O:9])[C@H:7]([NH:6][C:3]([NH:2][CH3:1])=[O:4])[CH:26]([CH3:28])[CH3:27])[CH2:11][C:12]2([CH3:24])[CH3:25])=[CH:22][CH:21]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction tube was charged with methyl isocyanate (3 μL), (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (20 mg) and THF (2 mL). Triethylamine (7.4 μL) was added and the reaction mixture was shaken overnight at rt. After this time, the resulting solution concentrated and purified by preparative silica gel chromatography (100% EtOAc to 20% MeOH/CH2Cl2) to provide Example 510. MS found: (M+H)+=396.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:9]1=[O:26].[H][H]>CO.[Pt](=O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:15][CH2:14]2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccn(-c3ccccc3F)c2=O)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(c3ccccc3F)C2=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
tert-Butyl 4-(3-(2-fluorophenyl)-2-oxo-2,3-dihydroimidazol-1-yl)piperidine-1-carboxylate (530 mg, 1.5 mmol) was dissolved in methanol (25 mL). Platinum(IV) oxide (28 mg, 123.3 Emoles) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 60 psi of hydrogen gas. Reaction shook at room temperature for 4 hours. More platinum(IV) oxide (28 mg, 123.3 μmol) was added to the mixture. Reaction vessel was placed on a Parr apparatus and charged with 60 psi of hydrogen gas. Reaction shook at room temperature for 18 hours. Mixture was removed from the apparatus and then filtered over celite. The filtrate was concentrated by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as clear colorless oil in 45% yield. MS (M−C4H10O+H)+=290.0.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=O)=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.C(O)(=O)C>[C:10]1([C:8]2[CH:7]=[CH:6][C:3]3[N:4]([CH3:5])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([C:16]#[N:17])=[CH:19][CH:20]=4)=[N:1][C:2]=3[CH:9]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CNc1ccc(-c2ccccc2)cc1N
Reactant: N#Cc1ccc(CC(=O)O)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cn1c(Cc2ccc(C#N)cc2)nc2cc(-c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 24f from 2-amino-4-phenyl-N-methyl-aniline, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran and glacial acetic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:32][CH2:33][CH3:34])[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[C:7](=[O:16])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:2].I[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[CH3:36][C:37]([CH3:40])([CH3:39])[CH2:38][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:16])[N:6]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)[C:5]([CH2:32][CH2:33][CH3:34])=[N:4][C:3]=2[CH2:1][CH3:2])=[CH:14][CH:13]=1
Reactant: CCCc1nc(CC)c(-c2ccc(O)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(-c2ccc(OCC(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
A mixture of 4′-{[4-ethyl-5-(4-hydroxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.52 g), 1-iodo-2,2-dimethylpropane (0.29 g), cesium carbonate (0.45 g) and dimethylformamide (10 mL) were stirred at 80° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.37 g, 62%).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH:4]([OH:7])[CH2:5][OH:6].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(CC)CC>C(Cl)Cl>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:6][CH2:5][CH:4]([OH:7])[CH2:3][N:2]([CH3:8])[CH3:1])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CN(C)CC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(O)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(dimethylamino)propane-1,2-diol (934 mg, 7.84 mmol) in CH2Cl2 (8 mL) were added Bu2SnO (42 mg, 0.16 mmol), tosyl chloride (1.49 g, 7.84 mmol), and Et3N (1.10 mL, 7.92 mmol). The reaction mixture was stirred at rt for 2 hrs. The mixture was quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layers were dried over MgSO4 and concentrated to afford 3-dimethylamino-2-hydroxypropyl 4-methylbenzenesulfonate; [m/z (APCI+) 274.10 (M+H)+]. The residue was dissolved in THF (10 mL), then DBU (2.56 mL, 16.6 mmol) and 4-nitro-1H-pyrazole (602 mg, 5.32 mmol) were added and the resulting mixture was stirred at rt for 30 min. The mixture was then quenched with water (30 mL) and extracted with EtOAc (two×30 mL). The combined organic layer were dried over MgSO4 and concentrated to give the title compound as a pale yellow oil (526 mg, 46° A yield) which was used without purification. m/z (APCI+) for C8H14N4O3 215.10 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH:4]([NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1)[C:5](O)=[O:6].Cl.[CH2:31]([O:38][C:39](=[O:45])[CH2:40][CH:41]([OH:44])[CH2:42][NH2:43])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[CH2:31]([O:38][C:39](=[O:45])[CH2:40][CH:41]([OH:44])[CH2:42][NH:43][C:5](=[O:6])[CH:4]([NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])=[O:19])=[CH:13][CH:12]=1)[CH2:3][CH:2]([CH3:29])[CH3:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCC(O)CC(=O)OCc1ccccc1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)C(=O)NCC(O)CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
To a stirred solution of 4-methyl-2-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-pentanoic acid (3.6 g), 4-amino-3-hydroxy-butyric acid benzyl ester hydrochloride (1.6 g), triethylamine (1 ml) and HOBT (1.06 g) in DMF (50 ml) at room temperature was added EDCl (1.63 g). After stirring 16 h the mixture was poured into 1500 ml ice-water and stirred for 20 min. The resulting ppt was filtered and dried to give a creme colored solid. Recrystallization from EtOAc gave 2.1 g of the title compound as a white solid. MS [M+1]+ 589.2; 1H nmr (400 MHz, DMSO-d6) δ0.73-0.81 (m, 6H), 1.37-1.49 (m, 3H), 2.19 (s, 3H), 2.20-2.28 (m, 1H), 2.46-2.49 (m, 1H), 2.99-3.09 (m, 2H), 3.33 (q, J=13.8 Hz, 2H), 3.90 (m, 1H), 4.19-4.23 (m, 1H), 5.05 (m , 2H), 6.88 (t, 1H), 7.06-7.12 (m, 4H), 7.26-7.34 (m, 6H), 7.75 (d, J=8.1 Hz, 1H), 7.92 (dt, 1H), 8.06 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 9.13 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13](Br)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:19][NH2:20])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(OCc2ccccc2)ccnc1Br
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(OCc2ccccc2)ccnc1NN
Temperature: 150 °C
Yield: 95.3 %

Procedure:
To a solution of intermediate compound D2 (1.2 g, 4.15 mmol) in THF (12 ml), was added hydrazine monohydrate (0.416 g, 8.301 mmol). The reaction mixture was subjected to microwave heating at 150° C. for 1 min. After cooling, additional hydrazine monohydrate (1 eq) was added to the resulting mixture, which was then subjected to microwave heating at 150° C. for 0.5 min. After cooling, the reaction mixture was concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield intermediate compound D3 (0.95 g, 95%).
Reaction SMILES: [CH2:1]([N:7]1[C:12](=O)[CH:11]2[CH:9]([C:10]2([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:14][CH2:15][CH3:16])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O1CCCC1.B.CO>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:14][CH2:15][CH3:16])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1C(=O)C2C(C1=O)C2(CCC)c1cccc([N+](=O)[O-])c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(CCC)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a stirred solution of 3-hexyl-6-(3-nitrophenyl)-6-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione (Preparation 64, 0.28 g, 0.78 mmol) in tetrahydrofuran (3 ml), under nitrogen, was added borane tetrahydrofuran complex (1M in tetrahydrofuran, 1.7 ml, 1.7 mmol) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was cooled to room temperature, methanol (1.5 ml) was added and then the reaction mixture was heated under reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in methanol (14 ml) and refluxed for 5 h. The reaction mixture was concentrated in vacuo, methanol (14 ml) was added and the reaction mixture was refluxed for a further 3 h before concentrating in vacuo. The crude residue was purified by chromatography on a Biotage Flash12™ cartridge packed with silica gel (8 g), eluting with hexane:ethyl acetate (4:1) to give the title compound as a yellow oil (0.2 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C(OO)(=[O:28])C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:20])[CH3:21])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N+:9]([O-:28])[C:10]=2[CH:11]=1
Reactant: CC(=O)OO
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOCc1nc2c[n+]([O-])c3cc(Br)ccc3c2n1CCCOC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A slurry of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (6.6 g, 16.2 mmol) in ethyl acetate (55 mL) was heated to 50° C. Peroxyacetic acid (5.12 mL, 24.4 mmol, of 32% in dilute acetic acid) was added dropwise over a period of 2 minutes. The reaction was allowed to stir at 50° C. for 2 hours. Additional peroxyacetic acid (1 mL) was added and the reaction mixture was stirred for an additional 2 hours. A solution of sodium metabisulfite (4.01 g, 21.1 mmol) in water (8 mL) was added. Following the addition of the sodium metabisulfite, the pH of the reaction mixture was adjusted to pH 10 with aqueous saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by flash chromatography (150 g of silica gel eluting with a gradient of 1-12% CMA in chloroform) to provide 5.49 g of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline-5-oxide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:5]3[CH:6]=[C:2]([NH:1][C:52](=[O:53])[CH2:51][O:50][CH3:49])[N:3]=[CH:4]3)=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc(N)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Nc1cn(CCOc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a suspension of 1-(4-(2-(4-amino-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate I) (50 mg, 0.095 mmol) in DCM (2.0 mL) was added DIPEA (33 μl, 0.191 mmol) and 2-methoxyacetyl chloride (10 μl, 0.105 mmol). The mixture was stirred at RT overnight and then partitioned between saturated aq NaHCO3 solution (5.0 mL) and DCM (2.0 mL). The layers were separated through a phase separator cartridge and the organics were collected and evaporated under reduced pressure. The resulting residue was subjected to SCX capture and release and column chromatography (12 g), eluting with 0 to 10% MeOH in EtOAc. Trituration with EtOAc (5.0 mL) gave N-(1-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-1-yloxy)ethyl)-1H-imidazol-4-yl)-2-methoxyacetamide (Example 24) as a white solid (8 mg, 14%): m/z 596 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9H, s), 2.38 (3H, s), 3.29 (3H, s), 3.93 (2H, s), 4.37 (2H, t), 4.47 (2H, t), 6.34 (1H, s), 6.93 (1H, d), 7.34 (2H, m), 7.41-7.45 (3H, m), 7.48-7.62 (4H, m), 7.88 (1H, d), 8.13-8.15 (1H, dd), 8.54 (1H, s), 8.75 (1H, s), 9.84 (1H, s).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:18]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccccc1-c1cccc2ccccc12
Yield: 79.9 %

Procedure:
Into a 200-mL eggplant type flask were introduced 6.45 g (34.9 mmol) of 2-bromobenzaldehyde, 5.0 g (29.1 mmol) of 1-naphthylboronic acid, 0.15 g of tetrakis(triphenylphosphine)palladium, 60 mL of tetrahydrofuran, 10 g (73 mmol) of potassium carbonate, and 20 mL of water. This reaction mixture was heated with refluxing overnight. After washing with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and drying with anhydrous magnesium sulfate, the extract was concentrated to obtain yellow crystals. These crystals were purified by silica gel chromatography (solvent: hexane/toluene) to obtain 5.4 g of 2-(1-naphthyl)benzaldehyde (yield, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:24]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:28]=[C:27]([CH:26]=[C:23]([CH3:24])[CH:22]=1)[CH2:29][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1cc(C)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCc2cc(C)cc(C)c2)c1
Reaction time: 16 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (3 g, 16.6 mmol) in DMF (20 ml) was added potassium carbonate (2.99 g, 21.6 mmol) at room temperature followed by drop wise addition of 3,5-Dimethylbenzyl bromide (3.30 g, 16.6 mmol). The reaction mixture was stirred for 16 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.