Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][NH:10][CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12].Cl.Cl.Br[CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[O:6][B:5]([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]3[CH:24]=[N:23][CH:22]=[CH:21][N:20]=3)[CH:11]=2)[O:4][C:3]1([CH3:13])[CH3:12]
Reactant: BrCc1cnccn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(Cc3cnccn3)c2)OC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (265 mg, 1.37 mmol), acetonitrile (40 mL), 2-(bromomethyl)pyrazine dihydrochloride (500 mg, 2.03 mmol) and cesium carbonate (2.23 g, 6.84 mmol). The resulting mixture stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluting with 2:1, ethyl acetate/petroleum ether) to afford 2-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl]pyrazine (0.12 g, 31%) as red oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].[Cl-].[NH4+:10]>CO>[N:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH2:2][NH:10][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:4][CH:5]=1
Reactant: [NH4+]
Reactant: C=Cc1ccncc1
Agent: [Cl-]
Solvent: CO
Product: c1cc(CCNCCc2ccncc2)ccn1
Yield: 37 %

Procedure:
A mixture or 4-vinyl pyridine (10.0 g, 95.1 mmol) and ammonium chloride (5.1 g, 95.1 mmol) was heated to reflux in MeOH (90 ml) under argon for 27 h. The resulting precipitate was filtered and the filtrate was concentrated on rotavap. The resulting residue was dissolved in H2O (200 ml) and basified with 2N NaOH to pH 10.5 and extracted with CH2Cl2 (3×100 ml). The Combined organic extracts were dried (anhydrous MgSO4) and concentrated to a yellow oil which was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) to yield the title compound (4.0 g, 18.5%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, 4H), 7.10 (d, 4H), 2.93 (t, 4H), 2.80 (t, 4H), 1.81 (br. 1H); MS (ES) m/e 228.2 [M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(Br)c12
Reaction time: 18 h
Yield: 86 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.21 g, 1.4 mmol) in dry methylene chloride (10 ml) was added N-bromosuccinimide (0.26 g, 1.5 mmol) at ambient temperature. The reaction mixture was stirred for 18 hours, and the resulting solid filtered with methylene chloride washes and dried in vacuo to afford 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine as a tan powder (0.28 g, 88%). GC-MS: 233 (MH+), RT: 4.42 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:24][CH:25]=2)[CH3:12])=[O:9])[C:2]([O:34][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cl)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(Cl)cc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the two steps procedure described in step 2 and 3 of Example 45. Firstly, tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) was reacted with 4-chlorophenol. Next, the crude product was converted to the corresponding carboxylic acid: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.8 Hz), 8.14 (1H, d, J=2.8 Hz), 8.11–8.02 (3H, m), 7.50–7.39 (4H, m), 7.11 (2H, d, J=9.0 Hz), 5.44–5.31 (1H, m), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 431 (M+H)+, 429 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([I:9])[CH:3]=1.[CH:10]1[CH:15]=[CH:14][C:13]([CH:16](Br)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:16]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[I:9])([C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1I
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Clc1ccc(NC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 45 °C
Yield: 95.5 %

Procedure:
To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) in DMF (250 mL) at rt were added α-bromodiphenylmethane (21.5 g, 84.6 mmol) and iPr2NEt (23 mL, 130 mmol) and the reaction mixture was heated at 45° C. overnight. After the volatile was removed under reduced pressure, the residue was dissolved in EtOAc, washed with water (3×) and brine and dried over MgSO4. Purification on SiO2 column chromoatography (hexanes to 5% EtOAc/hexanes) gave the desired Benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as a yellowish solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Fe]>[CH3:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1c([N+](=O)[O-])cc(C)c2ncccc12
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(N)cc(C)c2ncccc12

Procedure:
5,8-Dimethyl-6-aminoguinoline. To a solution of 5,8-dimethyl-6-nitroquinoline (1.41 g) in ethanol (17.4 mL) under argon is added iron (Fe) (1.21 g) and glacial acetic acid (2.56 g). The mixture is refluxed for two hours. More Fe (1.23 g) and glacial acetic acid (2.49 g) are added to the reaction, which is allowed to reflux for an additional hour. The reaction is poured into a beaker of ice and adjusted to pH 10 by careful addition of a saturated solution of potassium carbonate. The product is extracted with methylene chloride and the organic layer is dried over sodium sulfate, filtered, and rotary evaporated to give 5,8-dimethyl-6-aminoquinoline.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])=[O:34])[C:15]1=[O:41].NN.O>CCO>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:35][CH2:36][CH2:37][O:38][CH2:39][CH3:40])=[O:34])[C:15]1=[O:41]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.155 g, 0.277 mmol) in EtOH (6.5 mL) under nitrogen was treated with hydrazine (0.218 mL, 6.92 mmol) for 7 h@50° C. The reaction was then cooled to ambient temperature and stirred overnight. After heating an additional 6.5 h@50° C. the resulting solution was poured into water (75 mL), refrigerated and the resulting suspension was filtered and washed with cold 3:1 water:EtOH. The solid was then thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (t, J=7.1 Hz, 3 H), 2.8 (t, J=7.2 Hz, 2 H), 3.5 (q, J=6.9 Hz, 2 H), 3.5 (s, 4 H), 4.2 (s, 2 H), 4.2 (t, J=7.1 Hz, 2 H), 7.1 (t, J=8.8 Hz, 2 H), 7.4 (dd, J=8.7, 5.4 Hz, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES+ MS: 429 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.[N:27]1([CH2:33][C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:26]=[C:9]1[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH:11]=[CH:12][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:35])[CH2:33][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1
Reactant: O=C(O)CN1CCCCC1
Product: O=C(CN1CCCCC1)Nc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1

Procedure:
1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with piperidin-1-ylacetic acid as described in example 217. The product with the molecular weight of 468.56 (C28H28N4O3); MS (ESI): 469 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Br)[CH:13]=[CH2:14]>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:14][CH:13]=[CH2:12]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1 mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 30 min at −78° C. The reaction was quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%). 1H NMR (CDCl3): 2.27 (m, 2H), 2.51 (m, 1H), 2.74 (m, 1H), 3.22 (m, 1H), 3.58 (m, 1H), 5.16 (m, 2H), 5.53 (m, 1H), 7.23 (m, 1H), 7.39 (m, 4H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[Li]CCCC.CN([CH:23]=[O:24])C>C1C=CC=CC=1>[CH3:14][O:13][C:3]1[C:4]([CH3:12])=[C:5]([CH3:11])[C:6]([O:9][CH3:10])=[C:7]([CH3:8])[C:2]=1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: COc1c(C)c(C)c(OC)c(Br)c1C
Agent: [Li]CCCC
Solvent: c1ccccc1
Product: COc1c(C)c(C)c(OC)c(C=O)c1C
Reaction time: 0.03 h
Yield: 112 %

Procedure:
1-Bromo-2,5-dimethoxy-3,4,6-trimethylbenzene from Step 1 (5 g, 19.3 mmol, 1 equiv.) was dissolved in benzene (2×20 mL) and the solvent removed in vacuo to remove residual water. The dry solid was dissolved in toluene (100 mL) and the resulting solution cooled in an ice-water bath. To the colorless solution was added n-BuLi (1.6 M in hexanes, 16 mL, 26.9 mmol, 1.4 equiv.) dropwise over 1 min. After 2 min stirring, the resulting aryllithium species was quenched with DMF (7 mL, 90 mmol, 4.5 equiv.). Following an additional 30 min, excess base was quenched with 1 M aqueous citric acid (20 mL), and the mixture diluted in ethyl acetate (100 mL). The organics were removed, rinsed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4.5 g 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde as an orange solid, which was used without further purification. 1H NMR (CDCl3, 400 MHz) 10.5 (s, 1H), 3.79 (s, 3H), 3.63 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N:30]([CH2:33][CH2:34][CH3:35])=[C:31]=[O:32].[N-]=C=O.O>N1C=CC=CC=1>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:31]([NH:30][CH2:33][CH2:34][CH3:35])=[O:32])[N:12]=[N:13]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: CCCN=C=O
Agent: [N-]=C=O
Solvent: O
Solvent: c1ccncc1
Product: CCCNC(=O)Nc1n[nH]c2ccc(-c3cn(Cc4ccccc4)nn3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 64A (75 mg, 0.19 mmol) in pyridine (2 mL) was added 1-isocyanatopropane (16 mg, 0.19 mmol) and the reaction mixture was stirred at ambient temperature for about 3 hours. Additional isocyanate (0.1 mL) was added and the mixture was heated at about 80° C. for about 16 hours. The reaction mixture was cooled to ambient temperature and water (5 mL) was added. The resulting precipitate was collected by filtration then treated with hydrochloric acid (4 N solution in dioxane, 3 mL) and stirred at room temperature for about 4.5 hours. Diethyl ether (5 mL) was added and the precipitate collected by filtration. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.31-7.48 (m, 5H), 5.65 (s, 2H), 3.18 (dd, J=6.6, 12.7 Hz, 2H), 1.51 (dd, J=7.1, 14.3 Hz, 2H), 0.91 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:25].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:10][CH:9]1[CH2:21][CH2:22][O:23][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC1CN(c2ccccc2C)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred, 0° C. solution of 1-t-butyloxycarbonyl-2-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 1 above (0.38 g; 1.2 mmol) and iodomethane (0.20 mL; 3.4 mmol) in dry THF (20 mL) was added NaH (60 mg of a 60% suspension in mineral oil; 1.5 mmol). The reaction was stirred at 0° C. for 15 min and then at ambient temperature for 18 h. The reaction was quenched by adding several drops of MeOH and the solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The organic phase was separated and washed with water and brine. The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The title compound was obtained as a gum (1H-NMR: consistent with structure; TLC: silica gel, 1:3 EtOAc:hexanes: single component, Rf =0.62; FABMS: M+H @ m/e=335; HPLC: >99%, retention time 11.7 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:30]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: Fc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccc(F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-fluorophenyl)pyrrolidine oxalate (15.3 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.2 mg). Calcd for C20H16ClFN2O2: 370.0884, found 370.0890.
Reaction SMILES: [C-:1]#[N:2].[K+].[N:4]([CH:7]([CH2:12][CH2:13]I)[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6].O>CS(C)=O>[N:4]([CH:7]([CH2:12][CH2:13][C:1]#[N:2])[C:8]([O:10][CH3:11])=[O:9])=[N+:5]=[N-:6]
Reactant: COC(=O)C(CCI)N=[N+]=[N-]
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(CCC#N)N=[N+]=[N-]
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
To a cold (10°) suspension of potassium cyanide (1.5 g, 23 mmol) in dry DMSO (25 ml) was added methyl 2-azido-4-iodobutyrate (4.0 g, 15 mmol) and the mixture stirred at 10° C. for 10 min and at room temperature for 45 min. The reaction mixture was poured into cold water (200 ml) and the solution was extracted with chloroform (4×80 ml). The chloroform extract was washed with water (4×50 ml), dried and evaporated to give a syrup (2.0 g) which on tlc (silica, 10% ether-benzene) showed a major spot of Rf 0.4 and some impurities (Rf 0, 0.67, and 1.0). The product was purified by chromatography on a silica column (20 cm×2.9 cm 1-D) using 10% ether in benzene as eluent to give 1.1 g (44%) of title compound as a syrup; ir (neat) νmax : 2100, 1745 cm-1 ; 1Hmr (CDCl3) δ:2.17 (m, 2H, --CH2 --), 2.5 (m, 2H, CH2CN), 3.83 (s, 3H, OCH3) and 4.13 ppm (q, J=9, 6 Hz, 1H, CHN3). Anal. calcl for C6H8N4O2 : C 42.84, H 4.89, N 33.31; found: C 42.76, H 4.72, N 33.16.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[CH2:19][C:20]([NH2:22])=[O:21].B(Br)(Br)Br.C(Cl)Cl.Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[C:6]2[CH2:19][C:20]([NH2:22])=[O:21]
Reactant: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NC(=O)Cc1cn(Cc2ccccc2)c2ccc(O)cc12
Yield: 89.9 %

Procedure:
A solution of 375 mg (1.23 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 3) and 5 mL of 1M BBr3 /methylene chloride in 75 mL of methylene chloride was stirred for 1.25 hours, and poured into 1N HCl. The methylene chloride layer was separated, washed with brine and dried (Na2SO4). The solvent was removed at reduced pressure to give as residue 310 mg (90% yield) of 5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([OH:14])=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1.I[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>>[CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([O:14][CH2:21][CH2:22][CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:15]=1
Reactant: Cc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Product: Cc1nc2cnc3cc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)C

Procedure:
The general method described in Part L of Example 2 was used to treat 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol with tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate. After chromatographic purification, tert-butyl 4-(2-{[2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)piperidine-1-carboxylate was isolated as a viscous, orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:46](Cl)(=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50]>>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:17][CH:16]=2)[C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])[CH:3]=2)[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCC(=O)Cl
Reactant: CCCCc1nn(-c2cccc(N)c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCCC(=O)Nc1cccc(-n2nc(CCCC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)c4ccccc4Cl)cc3)c2=O)c1
Yield: 67 %

Procedure:
This material was prepared from 2-(3-aminophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 66, Step E), sodium hydride, and valeryl chloride according to the procedure of Example 62. The crude product was flash chromatographed over silica gel to afford the title compound in 67% yield as a cream-colored solid, mp 102°-105° C., homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 700 (M+1)+.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].Cl>C(O)C.O>[OH:5][CH:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[CH3:4]
Reactant: CC(=O)c1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(O)c1cccc2ccccc12
Reaction time: 2 h

Procedure:
Sodium borohydride (2.1 g) was added to a solution of 1-acetylnaphthalene (18.86 g) in ethanol (200 ml) at room temperature and the mixture was stirred at the same temperature for 2 hours. The mixture was diluted with water (50 ml), acidified to pH 3 with 1N hydrochloric acid and concentrated to about 70 ml. The concentrate was extracted with ethyl acetate (100 ml×2). The extract was dried over magnesium sulfate and evaporated to give 1-(1-hydroxyethyl)naphthalene as an oil which was used in a next reaction without further purification. Hydrogen bromide was bubbled into a solution of 1-(1-hydroxyethyl)naphthalene (18.96 g) in ether (180 ml) for 2 hours under ice-bath cooling. The reaction mixture was washed with water (50 ml×2), 2.5% sodium bicarbonate (50 ml×2) and water (50 ml×2), dried over magnesium sulfate and evaporated to give 1-(1-bromoethyl)naphthalene (22.63 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:5]([CH3:15])=[CH:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC(O[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O>>[CH3:15][C:5]1[N:4]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:3](=[O:21])[C:2]([NH:1][C:17]([O:19][CH2:20][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:18])=[C:7]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: COC(=O)Cn1c(C)cc(Sc2ccccc2)c(N)c1=O
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cn1c(C)cc(Sc2ccccc2)c(NC(=O)OCCc2ccccc2)c1=O

Procedure:
1.7 g (5.6 mmol) of methyl 3-amino-6-methyl-2-oxo-4-(phenylthio)-1,2-dihydropyridine-1-acetate are treated with 1.2 ml (8.4 mmol) of phenylmethyl chloroformate under the conditions described in Example 3.