Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:5]=1[F:18].[BH4-].[Na+]>>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][C:5]=1[F:18]
Reactant: CC(C)(C)NCC(=O)c1ccc(N)c(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)NCC(O)c1ccc(N)c(F)c1

Procedure:
m.p. of the hydrochloride: 196°-197° C. (decomp.), was prepared from 4'-amino-2-tert.butylamino-3'-fluoro-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([CH2:38][S:39][C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][S:39]([C:40]5[N:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ncccn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ncccn4)cc2)CCN3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.23 g) was dissolved in methylene chloride (7.5 ml), m-chloroperbenzoic acid (68 mg) was added to the mixture at 0° C., and the mixture was stirred for 15 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 189) (90 mg).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5]2)[O:3]C1>C(O)=O>[CH3:11][N:10]([CH3:12])[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1
Reactant: CN(C)C1CCC2(CC1)OCCO2
Solvent: O=CO
Product: CN(C)C1CCC(=O)CC1
Yield: 99.9 %

Procedure:
4.96 gm (26.8 mMol) 4-dimethylamino-1-cyclohexanone ethylene ketal were dissolved in 50 mL formic acid and the solution stirred at reflux for 18 hours. The reaction mixture was then cooled to ambient and the volatiles removed under reduced pressure to give 3.78 gm (100%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([CH2:14][CH:13]([CH2:15][C:16](O)=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.Cl.Cl.[NH2:36][CH:37]1[CH2:43][CH:42]2[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]2)[CH2:38]1>ClCCl.O>[CH3:45][N:44]1[CH:39]2[CH2:40][CH2:41][CH:42]1[CH2:43][CH:37]([NH:36][C:16](=[O:17])[CH2:15][CH:13]1[CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH2:19]3)[CH2:14]1)[CH2:38]2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(CC(=O)O)C2
Reactant: CN1C2CCC1CC(N)C2
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1C2CCC1CC(NC(=O)CC1CC3(CCN(C(=O)OC(C)(C)C)CC3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
1.7 g of [7-(tert-butoxycarbonyl)-7-azaspiro[3.5]non-2-yl]acetic acid was dissolved in 50 ml of dichloromethane. After adding 0.9 ml of triethylamine, the resulting mixture was ice-cooled. After adding 0.95 ml of ethyl chloroformate, the resulting mixture was stirred at room temperature for 30 minutes. Then 1.9 g of 3-amino-8-methyl-8-azabicyclo[3.2.1]octane dihydrochloride and 2.5 ml of triethylamine were added thereto and the resulting mixture was stirred at room temperature for 6 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1 N sodium hydroxide and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained crystals were washed with ether to thereby give 1.25 g of the title compound as white crystals.
Reaction SMILES: [CH:1]1([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([I:18])[CH2:15][CH2:16][CH3:17].C(=O)(O)[O-].[K+]>CO>[I-:18].[CH2:14]([N+:9]1([CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:15][CH2:16][CH3:17]
Reactant: C1CCCC(N2CCCC2)CCC1
Reactant: CCCCI
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CCCC[N+]1(C2CCCCCCC2)CCCC1
Product: [I-]
Reaction time: 96 h
Yield: 90 %

Procedure:
To a solution of 60 gms. (0.33 mole) of N-cyclooctyl pyrrolidine in 600 ml. anhydrous methanol, 150 gm. (0.825 mole) of butyl iodide was added. The reaction mixture was refluxed while stirring for four days. Then an additional equivalent of butyl iodide and one equivalent (33 gm., 0.33 mole) of potassium bicarbonate were added and the mixture was stirred at refluxing temperature for an additional 36 hours. The reaction mixture was concentrated at reduced pressure on a rotary evaporator to give an off-white colored solid material. The solids were rinsed several times with chloroform and filtered after each rinse. All the chloroform rinses were combined and concentrated to give a white powder whose NMR data were acceptable for the desired quaternary ammonium iodide salt. The reaction afforded 109 gm. (90% yield) of N-butyl-N-cyclooctylpyrrolidinium iodide. The iodide salt was purified by recrystallization by completely dissolving the iodide salt in acetone, and then precipitating by the addition of ethyl ether to the acetone solution. This procedure gave 98 gms. of white powder with very clean 1H and 13C-NRM spectra.
Reaction SMILES: [C@H:1]1([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5][C@H:4]([C:7]([O-])=[O:8])[CH2:3][CH2:2]1.O.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:8][CH2:7][C@H:4]1[CH2:3][CH2:2][C@H:1]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)[O-])CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](CO)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
The compound obtained in Reference Example 85(2) (mono-methyl trans-cyclohexane-1,4-dicarboxylate, 14.3 g) is dissolved in tetrahydrofuran (78 mL) and 1.0M boran-tetrahydrofuran complex solution in tetrahydrofuran (100 mL) is added dropwise thereto at −50° C. under argon gas atmosphere over a period of 1 hour. The mixture is stirred at −10° C. for 1 hour. To the reaction mixture is added water (160 mL) and a saturated sodium hydrogencarbonate solution (160 mL) under ice-cooling and the mixture is extracted with ethyl acetate (×4). The extract is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=20:1) to give methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (13.25 g, yield; quantitative) as an oil. MS (APCI) m/z; 173 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH:13]([OH:15])[CH3:14])[N:9]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13](=[O:15])[CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1noc(-c2ccc(F)cc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1noc(-c2ccc(F)cc2)n1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a stirred solution of 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanol (0.34 g, 1.92 mmol) in DCM (40 mL) was added Dess-Martin periodinane (2.7 g, 6.5 mmol) at room temperature and the mixture stirred for 3 h. The reaction mixture was filtered and washed with DCM (15 mL). To the filtrate was added NaHCO3 solution (10 mL) and DCM (30 mL). The organic layer was separated, washed with water (20 mL) followed by brine solution (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get crude compound. The crude compound was purified by silica gel column chromatography (100-200 mesh; using 10% methanol in DCM) to obtain 1-(5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl)ethanone as off-white solid (0.25 g, 72% yield). 1H NMR (400 MHz, CDCl3): δ 2.76 (s, 3H), 7.23 (t, 2H), 7.23 (dd, 2H), LC-MS m/z calculated for [M+H]+ 207.17. found 206.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[CH2:33][CH2:32][CH2:31]2>>[CH2:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][CH:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:17]4[CH:16]=[CH:15][N:14]=[C:13]([C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH:18]=4)[CH2:21][CH2:22]3)=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.40 g) and 5-aminoindan (680 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1I.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2)c1
Yield: 103.7 %

Procedure:
2-Iodo-terephthalic acid dimethyl ester (10 g, 31 mmol), phenol (3.23 g, 34 mmol), tetrakis-acetonitrilecopper hexafluorophosphate (2.9 g, 7.8 mmol), and cesium carbonate (10.2 g, 31 mmol) were added to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, a reflux condenser and containing toluene (350 mL). The reaction was refluxed 5 h under nitrogen with stirring. After cooling, EtOAc (200 mL) was added and the mixture was filtered. The filtrate was concentrated to afford the crude title compound (9.2 g) that was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)(=O)C.CCCCCCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Reactant: COc1ccc(CCl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)cc2=O)c1
Temperature: 60 °C
Yield: 22.3 %

Procedure:
To a solution of 3-(4-hydroxy-2-methyl-6-oxo-6H-pyrimidin-1-yl)-4-methyl-benzoic acid methyl ester from Step D (800 mg, 66% purity, 1.93 mmol) in N,N-dimethylformamide (3 mL) was added 4-methoxybenzyl chloride (0.26 mL, 1.93 mmol), potassium carbonate (666 mg, 4.82 mmol) and 18-crown-6 (80 mg). The slurry was heated at 60° C. for two hours. The solution was allowed to cool to ambient temperature and was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided the alkylated product as a white solid (170 mg, 22% yield). MS (M+H): 395
Reaction SMILES: C(O)C.[F:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[N:9][CH:10]=1.[BrH:14].C(O)C.BrBr>C(O)(=O)C>[BrH:14].[Br:14][CH2:12][C:11]([C:7]1[CH:8]=[N:9][CH:10]=[C:5]([F:4])[CH:6]=1)=[O:13]
Reactant: CC(=O)c1cncc(F)c1
Agent: Br
Agent: BrBr
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(CBr)c1cncc(F)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
To an ethanol (5.0 mL) solution of 1-(5-fluoropyridin-3-yl)ethanone (0.50 g), acetic acid (6.0 mL) was added, then a 20 to 30% hydrobromic acid/ethanol solution (1.0 mL) and bromine (0.30 mL) were added under ice cooling, and the resultant was stirred at 70° C. for 45 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (1.30 g) as a faint orange solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1CCCN.[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH:23]2[O:25][CH2:24]2)=[CH:19][CH:18]=1>CO>[NH2:14][C:15](=[O:28])[CH2:16][C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH:23]([OH:25])[CH2:24][NH:1][CH2:5][CH2:4][CH2:9][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)=[CH:19][CH:18]=1
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Reactant: NCCCc1nc2ccccc2[nH]1
Solvent: CO
Product: NC(=O)Cc1ccc(OCC(O)CNCCCn2cnc3ccccc32)cc1

Procedure:
A mixture of 9.8 grams of 1H-benzimidazole-2-propanamine and 12.16 grams of 1-[4-(2-amino-2-oxoethyl)phenoxy]-2,3-epoxypropane in 400 ml of 95% methanol was refluxed for 17 hours. The solvent was then evaporated under reduced pressure and the residue was chromatographed on a silica gel column packed in chloroform and eluted with solutions containing increasing percentages of methanol in chloroform. The fractions eluted with 30% methanol were combined and the solvent evaporated under reduced pressure. The solid residue was triturated with ether and then separated and dried at reduced pressure and room temperature to give N-{3-[4-(2-amino-2-oxoethyl)phenoxy]-2-hydroxypropyl}-1H-benzimidazole-1-propanamine melting at about 92°-96° C. This compound has the following structural formula: ##STR12##
Reaction SMILES: O[CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=2)[C:5](=[O:14])[CH2:4][C:3]1([CH3:16])[CH3:15].FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[I:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH2:2][C:3]([CH3:15])([CH3:16])[CH2:4][C:5]2=[O:14])=[N:8][CH:9]=1
Reactant: CC1(C)CC(=O)N(c2ccc(I)cn2)C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)CC(=O)N(c2ccc(I)cn2)C1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
(275 mg, 828 μmol) (5RS)-5-Hydroxy-1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (Example 13, step 2) was dissolved in CH2Cl2 (2 ml) and trifluoroacetic anhydride (140 μl, 994 μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred for 1 hr at 20-25° C. The solution was evaporated to dryness and the residue was dissolved in trifluoroacetic acid (957 μl, 12.4 mmol, 15 equiv.) and triethylsilane (159 μl, 994 μmol, 1.2 equiv.) was added at room temperature. The mixture was stirred 1 h at room temperature. The reaction mixture was evaporated and extracted with sat. NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodopyridin-2-yl)-4,4-dimethylpyrrolidin-2-one (209 mg, 80% yield) was obtained as a white solid, MS: m/e=317.0 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)=[O:7].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Ag-]=O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])=[O:7]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: CC(C)CCNC(=O)c1ccc2[nH]ccc2c1
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C(=O)NCCC(C)C)cc23)c(OC)c1
Reaction time: 4 h
Yield: 12.9 %

Procedure:
Silver(I) oxide (4.92 g) was added to a solution of indole (F) (2.05 g) in toluene (15 ml). The mixture was protected from light, stirred, and heated to reflux under an atmosphere of nitrogen for 24 hours. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (2.31 g) in toluene (5 ml) was added, and stirring was continued at 95° C. for 4 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was evaporated to give an amber gum which was purified by flash chromatography on silica gel (862 ml), eluting with 1:99 v/v methanol:chloroform to give (E) (0.47 g, 13%) as a white foam; partial NMR (80 MHz, CDCl3): 0.92[d, 6H, CH(CH3)2], 3.40(q, 2H, NCH2), 3.87(s, 3H, OCH3), 4.09(s, 2H, ArCH2), 6.18(br t, 1H, CONH), 7.98(br s, 1H, H4 -indole), 8.84(br s, 1; H, NH).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[C:18]2[N:19]=[CH:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1)C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O>ClCCl>[C:29]1([S:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:21]2[C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=[C:9]([NH2:8])[C:18]=3[N:19]=[CH:20]2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(CCCCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1ncn2CCCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.2 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 1.78 mmol), triflic acid (2.68 g, 17.83 mmol), and anhydrous dichloromethane (14 mL) under a nitrogen atmosphere. The reaction was judged to be complete after stirring at ambient temperature for 24 hours. The solution was partitioned between chloroform and excess aqueous sodium hydroxide (20%). The layers were separated. The aqueous layer was extracted with chloroform (3×). The organic layers were combined and then concentrated under reduced pressure to afford a light brown solid. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a fine white powder which was recrystallized from acetonitrile to give 1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.32 g, 0.84 mmol) as white needles, m.p. 175-177° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1)=O)(C)(C)C.[F:16][C:17]([F:22])([F:21])[C:18]([OH:20])=[O:19]>>[CH3:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:15].[F:16][C:17]([F:22])([F:21])[C:18]([O-:20])=[O:19]
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: O=C(O)C(F)(F)F
Product: CN1CCNCC1=O
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butoxycabonyl-4-methyl-3-oxopiperazine (3.87 g) was dissolved in trifluoroacetic acid (80 ml), and the mixture stirred at ambient temperature for 2 hours. Solvent was evaporated to give 1-methyl-2-oxopiperazine as a trifluoroacetate salt, with some excess trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30]>CN1CCCC1=O.C(=O)(O)[O-].[Na+]>[C:29]([O:32][CH2:33][C:34]([N:12]1[C:11]2=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][N:10]2[CH2:15][CH2:14][NH:13]1)=[O:35])(=[O:31])[CH3:30]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a mixture of 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (100 mg, 0.339 mmol) and pyridine (54 mg, 0.678 mmol) in N-methyl-2-pyrrolidone (1.5 ml) was added acetoxyacetyl chloride (60 mg, 0.441 mmol) in N-methyl-2-pyrrolidone (0.5 ml) under nitrogen atmosphere with ice cooling. After stirring for 30 minutes, the reaction mixture was diluted with an aqueous saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol; 100/1~20/1) and the obtained amorphous product was crystallized from diisopropyl ether to give 2-acetoxyacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo-[5,1-c][1,2,4]triazine (76 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH:10]([CH2:28][CH3:29])[CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[CH2:34][CH2:35][NH2:36]>>[CH2:28]([CH:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:36][CH2:35][CH2:34][C:33]3[CH:37]=[CH:38][CH:39]=[C:31]([F:30])[CH:32]=3)[N:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:29]
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1cccc(F)c1
Product: CCC1CNCCN1Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1

Procedure:
Intermediate 130 was coupled with 3-fluorophenethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 420. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.25-8.4 (m, 2H) 7.8 (d, 1H) 7.7 (t, 1H) 7.5 (d, 1H) 7.18-7.35 (m, 2H) 7.05-7.15 (m, 2H) 6.9 (m, 1H) 4.72 (d, 1H) 4.1 (d, 1H) 3.92 (br s, 2H) 3.65 (m, 1H) 3.3-3.5 (m, 6H) 3.12 (m, 1H) 3.05 (m, 2H) 2.18 (m, 1H) 1.92 (m, 1H) 1.1 (t, 3H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccc(F)c(F)c2)n1
Yield: 70 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 3,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(3,4-difluorophenyl)-5-fluoropicolinic acid in 70% yield. LC/MS=254.1 (M+H), Rt=0.81 min.