Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[NH:16][CH:5]([CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]1)[CH2:4][O:3][CH2:2]2.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH:5]12[N:16]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH:1]([CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (0.500 g, 2.2 mmol) in dichloromethane (5 ml) was added triethylamine (0.443 g, 4.4 mmol) at room temperature. The mixture was stirred at room temperature for a few mins, and then benzyl chloroformate (0.751 g, 4.4 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. The mixture was partitioned between dichloromethane and water. The organic phase was dried, and concentrated. The residue was purified by silica gel chromatography to give 9-benzyl 7-tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7,9-dicarboxylate 133b (0.637 g, 80.0%). MS: calc'd (MH+) 363, measured (MH+) 363.
Reaction SMILES: [C:1]1(=[CH:7][C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[C:1]1(=[CH:7][C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C=C1CCCCC1
Yield: 72 %

Procedure:
The ethyl ester from (a) (343 mg, 2.04 mmol) was dissolved in ethanol (5 ml). A 5M aqueous solution of sodium hydroxide (0.82 ml, 4.04 mmol) was added. The solution was stirred at reflux for 3h whereupon a precipitate was formed, and all starting material had disappeared as indicated by tlc. After cooling, the ethanol was removed by evaporation and water (10 ml) was added. The basic solution was extracted with dichloromethane (10 ml) which was discarded. The aqueous layer was acidified with 2M hydrochloric acid and then extracted with ethyl acetate (2×10 ml). The organic layer was dried, filtered and evaporated to leave the title compound (b) (206 mg, 72%) as a sweet-smelling white solid, m.p. 84°-5° C. from ethanol and diethylether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)[CH2:7][Cl:34]
Reactant: COCOc1ccc(F)cc1CO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCOc1ccc(F)cc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
4.15 g of 5-fluoro-2-methoxymethoxybenzyl alcohol [prepared as described in step (b) above] were dissolved in 70 ml of tetrahydrof tiran, and then 6.86 g of carbon tetrachloride and 11.69 g of triphenylphosphine were added to the resulting solution, in that order. The resulting mixture was then stirred at room temperature for 1 hour, and then heated under reflux for 5 hours. At the end of this time, insoluble substances were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 9:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.27 g (yield 71%) of the title compound as an oily substance.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][N:18](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCNC1

Procedure:
A similar procedure starting with 3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)-1-tosylpyrrolidine (19.5 g--see Preparation 6(C)), gave 3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)pyrrolidine, yield 9.5 g, [α]D25 -9.8° (c 1.0, CH2Cl2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]2[C:12]([N+:16]([O-])=O)=[C:13]([CH3:15])[N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]>CO.[Pd]>[NH2:16][C:12]1[N:11]2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]2=[N:14][C:13]=1[CH3:15]
Reactant: CCOC(=O)c1cccc2nc(C)c([N+](=O)[O-])n12
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cccc2nc(C)c(N)n12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of 300 mg of 5-ethoxycarbonyl-2-methyl-3-nitroimidazo[1,2-a]pyridine in 20 ml of methanol was added 10%Pd-C (wet, 90 mg). The mixture was stirred for two hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate and the washing were combined, and the solvent was filtered off. The residue was purified by column chromatography (eluent: ethyl acetate) to afford 184 mg of the object product (69.7%, an orange solid)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27].[C:28](OC(=O)C)(=[O:30])[CH3:29].C(N(CC)CC)C>ClCCl.Cl>[C:28]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:8]1=[O:27])(=[O:30])[CH3:29]
Reactant: O=C1N(C[C@@H]2CCCN2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Yield: 83.7 %

Procedure:
A solution of 1′-[(2S)-pyrrolidin-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.23 g, 0.62 mmol), acetic anhydride (0.09 mL, 0.95 mmol) and triethylamine (0.17 mL, 1.2 mmol) in dichloromethane (4 mL) was stirred at ambient temperature for 40 min. The reaction was diluted with 0.2 M hydrochloric acid (50 mL) and extracted with dichloromethane (3×25 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/diethyl ether (4:1) afforded 1′-{[(2S)-1-acetylpyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.21 g, 84%) as an off-white solid: mp 103-108° C. (hexanes); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.54, 7.53 (d, J=7.8 Hz, 1H), 7.35, 7.34 (dd, J=8.1, 7.7 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5 Hz, 1H), 6.49, 6.46 (s, 1H), 6.42, 6.41 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.68, 4.67 (d, J=9.0 Hz, 1H), 4.54, 4.53 (t, J=8.7 Hz, 2H), 4.49-4.42 (m, 1H), 3.95-3.80 (m, 2H), 3.61-3.54 (m, 1H), 3.46-3.36 (m, 1H), 3.00, 2.99 (t, J=8.6 Hz, 2H), 2.26-1.76 (m, 4H), 2.11-2.08 (s, 3H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ 178.49, 178.47, 170.2, 161.9, 161.8, 161.5, 161.4, 142.6, 142.4, 132.5, 132.3, 129.36, 129.33, 123.8, 123.7, 123.6, 123.5, 120.4, 120.2, 120.0, 119.9, 119.2, 118.7, 110.01, 109.96, 93.4, 93.2, 80.9, 80.8, 72.5, 57.9, 55.0, 54.8, 47.9, 41.5, 41.2, 29.2, 29.1, 28.0, 27.8, 23.9, 22.92, 22.90; MS (ES+) m/z 405.1 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1.[Br-:20].[Br-].[Br-].P>C1(C)C=CC=CC=1>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CO)cc1[N+](=O)[O-]
Reactant: [Br-]
Agent: P
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (15 mL) of 4′-(hydroxymethyl)-2′-nitrobiphenyl-2-carbonitrile (3.62 g) in toluene was added phosphine tribromide (4.63 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate 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 4′-(bromomethyl)-2′-nitrobiphenyl-2-carbonitrile as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)O)c1

Procedure:
Hydrolysis of methyl 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoate following the method used in Example 9 except that LiOH and THF were used instead of K2CO3 and MeOH gave 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoic acid that was used directly in next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([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)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[C:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)[CH2:15][CH2:14]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1cccc(N2CCC(C(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(N2CCC(C(c3ccccc3)c3ccccc3)CC2)c1
Reaction time: 8 h
Yield: 90.5 %

Procedure:
1-(3-nitrophenyl)-4-(diphenylmethyl)piperidine (854 mg) was dissolved in ethanol (60 ml), and 10% palladium/carbon (76 mg) was added thereto, followed by stirring the mixture overnight under hydrogen atmosphere. Palladium/carbon was removed by filtration through Celite and the filtrate was concentrated, followed by purifying the residue by silica gel column chromatography (hexane:ethyl acetate=5:4) to obtain 711 mg of 3-(4-(diphenylmethyl)piperidyl)phenylamine. Yield: 90%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c2ccccc12
Reaction time: 5 h

Procedure:
4-Fluoro-1-nitro-naphthalene (1 g) was dissolved in EtOAc (20 mL) and placed into a hydrogenating flask containing Palladium on activated charcoal (10%, 0.3 g). The reaction mixture was hydrogenated at 50 psi for 5 hr. During the reaction, the pressure of the hydrogen dropped due to the consuming of the hydrogen, and it was brought back to 50 psi a few times. Finally, the reaction stopped when all the starting material was used. The resulting solution was filtered through a pad of celite and washed with EtOAc (20 mL). The clear filtrate was concentrated and dried under vacuum to yield 4-Fluoro-1-aminonaphthalene.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:17])=[C:5]([NH:9]C(=O)OC(C)(C)C)[CH:6]=[CH:7][CH:8]=1)#[CH:2].FC(F)(F)C(O)=O.[Cl:25]CCl>C(O)(C)C.Cl.O1CCOCC1>[ClH:25].[C:1]([C:3]1[C:4]([F:17])=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9])#[CH:2]
Reactant: ClCCl
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cccc(N)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 1,1-dimethylethyl (3-ethynyl-2-fluorophenyl)carbamate (10.5 g, 44.6 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (20 mL). The solution was stirred at room temperature for 1 hr, and was then concentrated in-vacuo. The resultant residue was partition between sodium bicarbonate and ether. The organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford a brown residue. The residue was diluted with isopropanol (10 mL) and 4N HCl in dioxane (8 mL) was added. The recrystallized product was collected by vacuum filtration to afford 3.7 g, 21 mmol (68%) of 3-ethynyl-2-fluoroaniline hydrochloride as a pale brown solid. 1H NMR (400 MHz, d6-DMSO): 7.08-6.91 (m, 3H), 4.45 (s, 1H); MS (EI) for C8H6FN: 136 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-:15].C([N+](C)(C)C)C1C=CC=CC=1.O=O.C>N1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: Fc1ccc2c(c1)Cc1ccccc1-2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ccc(F)cc21

Procedure:
2-Fluorofluorene (824.7 g, 4.48 mol) was dissolved in pyridine (4 L) and stirred. A 40% solution of Triton B (100 mL of benzyltrimethylammonium hydroxide 40% in pyridine according to a general procedure of U. Sprinzak, J. Amer. Chem. Soc. 80 (1958) 5449) was added and oxygen was bubbled into the vigorously stirred solution. This exothermic reaction was run for 20 hours whereupon an additional portion of the Triton B solution (50 mL) was added with continued stirring and oxygen addition for an additional 24 hours. The resulting dark green reaction mixture was treated with Norite (100 g, neutralized charcoal), stirred for 30 minutes and filtered through a Celite pad (diatomaceous earth filter aid). The filter pad was then washed with pyridine (1 L). The combined filtrates were concentrated to a small volume in vacuo with heat. A 5% solution of hydrochloric acid in water (1 L) was added and the pyridine was azeotrophed in vacuo with heat. This process was repeated until a total of 6-8 L of water were evaporated. The granular product was filtered and washed with water (4 L) and air dried. The yellow-orange product was distilled through a large bore short path distillation apparatus (bp 167°-170° C.; 1.5 mm Hg) to yield into a chilled receiving flask the bright yellow 2-fluoro-9-fluorenone (600 g) with a m.p. 113°-115° C. and m/e+. 198 for C13H7FO.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[C:12](Br)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]2[O:10][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C=O)cc2O1

Procedure:
One equivalent of 3,4-dihydroxybenzaldehyde, 1.1 equivalents of diethyl dibromomalonate and powdered potassium carbonate is stirred in acetonitrile at room temperature for 18 hours. The reaction mixture is filtered, evaporated in vacuo and distilled to give diethyl 5-formyl-1,3-benzodioxole-2,2-dicarboxylate. 1H NMR(CDCl3): δ 9.9(s,1H,CHO); 7.5(m,2H, aromatic H) ; 7.1(d, 1H,aromatic H); 4.45(q,4H,CH2); 1.8(t,6H,CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[N:3]=1.Br[CH2:22][C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=2)[N:3]2[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:1]=[C:2]2[CH:7]=1
Reactant: N#Cc1ccc(NCCNc2nc(N)cc(Cl)n2)nc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Temperature: 100 °C

Procedure:
480 mg (1.66 mmol) of 6-({2-[(4-amino-6-chloropyrimidin-2-yl)amino]ethyl}amino)pyridine-3-carbonitrile and 538 mg (2.49 mmol) of ethyl bromopyruvate are dissolved in 8 ml of DMF and heated at 100° C. for 16 h. After the reaction is complete, the crude mixture is purified by preparative HPLC. 190 mg (27% of theory) of the product are obtained as a solid.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:10][CH:9]=1)=[O:7].[BH4-].[Na+]>C(OC(=O)C)C>[NH2:3][C:4]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:5]=1[CH:6]([OH:7])[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(C(O)c2cc(Cl)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.4 %

Procedure:
To a methanol (40 ml) solution of 2-amino-4′-(2-tert-butoxycarbonylaminoethyl)-5-chlorobenzophenone (2.0 g) was added sodium borohydride (0.5 g). The mixture was stirred for 30 minutes at room temperature, to which was added acetic acid ethyl ester (100 ml). The mixture was washed with water and, then, dried over anhydrous MgSO4, followed by distilling off the solvent. The residue was purified by means of a silica gel column chromatography to give the object 2-amino-5-chloro-α-[4-(2-tert-butoxycarbonylaminoethyl)phenyl]benzyl alcohol (2.2 g) as a colorless oily product.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2([CH2:23][CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:22])[CH:19]=3)[CH2:14]2)=[CH:11][N:10]=[C:9]1S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH2:1]([N:8]1[C:12]([C:13]2([CH2:23][CH3:24])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:22])[CH:19]=3)[CH2:14]2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(c2cnc(S)n2Cc2ccccc2)Cc2ccc(F)cc2C1
Agent: [Ni]
Solvent: CCO
Product: CCC1(c2cncn2Cc2ccccc2)Cc2ccc(F)cc2C1
Temperature: 40 °C
Reaction time: 10 h
Yield: 33.2 %

Procedure:
7.5 ml of Raney-Nickel prepared according to Vogel, Practical Organic Chemistry, 5th Edition, 1999, Longman, U.K. p. 450–451, was mixed with 20 ml of ethanol under nitrogen atmosphere in a round-bottomed flask equipped with a thermometer and a stirring bar. 500 mg of 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole-2-thiol was dissolved in 10 ml of ethanol and added to the mixture. The reaction mixture was stirred at 40° C. for about 10 hours and then the temperature was raised to 60° C. for 2 hours followed by cooling to room temperature. The mixture was filtered and the filter (Celite™) was washed with ethanol. The ethanol solution was evaporated to dryness to obtain 151 mg of a crude product. After chromatographic purification using methylene chloride, methylene chloride:methanol (10:1) and methylene chloride:methanol (1:1) as eluents 1-benzyl-5-(2-ethyl-5-fluoro-indan-2-yl)-imidazole was obtained. The purity was measured by HPLC: 83%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C)C=O>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)NC(C)C
Reaction time: 15 h
Yield: 45.6 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (1.04 g, 3.31 mmol) in 30 mL of CH2Cl2 and 5 mL of N,N-dimethylformamide was placed under an atmosphere of nitrogen and slowly treated with isopropyl isocyanate (0.320 mL, 3.31 mmol). After 15 h, the reaction mixture was concentrated under reduced pressure to yield a yellow/orange foam. The foam was purified by chromatography (SiO2, 30% (80:18:2 CHCl3:MeOH: conc. ammonium hydroxide (NH4OH)) in CHCl3) to give an off-white solid. The solid was triturated with diethyl ether (Et2O) and collected by vacuum filtration to yield 1-(3-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]amino}propyl)-3-isopropylurea (0.603 g) as an off-white solid. mp 174–177° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.46–7.41 (m, 1H), 7.26–7.22 (m, 1H), 6.96 (t, J=5.5 Hz, 1H), 6.60 (s, 2H), 5.72 (t, J=5.5 Hz, 1H), 5.59 (d, J=7.7 Hz, 1H), 4.75 (s, 2H), 3.70–3.58 (m, 3H), 3.19–3.08 (m, 4H), 1.72–1.63 (m, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.99 (d, J=6.5 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 157.8, 152.3, 149.5, 145.3, 132.4, 127.4, 126.1, 124.2, 121.2, 114.7, 65.9, 63.1, 50.2, 41.2, 37.4, 28.9, 23.6, 15.4; MS (APCI) m/z 400 (M+H)+; Anal. Calcd for C20H29N7O2: C, 60.13; H, 7.32; N, 24.54; Found: C, 59.94; H, 7.58; N, 24.45.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7](I)[N:6]=1)=[O:4].[CH3:25][Sn](C)(C)C.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([CH3:25])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(I)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 120 °C
Yield: 28.2 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-5-iodo-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (86 mg, 0.197 mmol), tetramethyltin (0.14 mL, 0.99 mmol) and PdCl2(PPh3)2 (28 mg, 0.039 mmol) in DMF (4 mL) was heated at 120° C. for 2 h under N2 atmosphere. After cooling to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1 M HCl was added until pH about 2-3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 18 mg of the title compound as a white solid. MS: (+) m/z 325.28 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][CH:4]=1.[C-:11]#[N:12].[Na+]>O>[Cl:10][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:11]#[N:12])=[N:8][C:7]=1[Cl:9]
Reactant: Clc1ccc(CBr)nc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(Cl)c(Cl)n1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
To a solution of 6-(bromomethyl)-2,3-dichloropyridine (Preparation 60, 2.90 g, 3.13 mmol) in IMS (20 mL) and water (15 mL) was added NaCN (552 mg, 11.3 mmol). The reaction was heated to 100° C. for 1 hour before cooling to room temperature and quenching with saturated aqueous NaHCO3 solution (50 mL). The mixture was extracted with DCM (3×50 mL) and the organic layers combined, dried over MgSO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-100% MeCN in water with 0.1% formic acid to afford the title compound (341 mg, 15% over two steps).