Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]([OH:17])([CH3:16])[CH3:15])(=O)=O)=CC=1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[CH:21][C:20]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:12][CH2:13][C:14]([CH3:16])([OH:17])[CH3:15])=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
A mixed solution of 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (4.24 g) synthesized in accordance with the method described in [WO 2009/067613 pamphlet, Example 308], 4-bromo-3,5-dimethylphenol (3.0 g), and potassium carbonate (3.09 g) in N,N-dimethylformamide (15 mL) was stirred at 80° C. for 3 hours. To the reaction mixture, ethyl acetate (200 mL) and water (100 mL) were added and the mixture was extracted with ethyl acetate. The organic phase was successively washed with water (50 mL) and brine (50 mL) and then dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=80:20 to 70:30). From the eluted solution, the solvent was distilled off under reduced pressure to give the title compound (3.9 g).
Reaction SMILES: [CH3:1]N(C=O)C.[H-].[Na+].[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[CH3:27])=[O:18])=[CH:9]1.CI>C1COCC1>[CH3:1][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[CH3:27])=[O:18])=[CH:9]1
Reactant: CN1CCCCC1COC(=O)c1c[nH]c2ccccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1CCCCC1COC(=O)c1cn(C)c2ccccc12
Reaction time: 0.25 h

Procedure:
To a DMF (10 ml) suspension of 60% sodium hydride (0.09 g, 2.3 mmol) was dropwise added a DMF (5 ml) solution of (1-methyl-2-piperidyl)methyl 1H-indole-3-carboxylate (0.50 g, 1.8 mmol) at room temperature over a period of 5 min. Onto the reaction mixture stirred for 15 min. was poured a THF (5 ml) solution of methyl iodide (0.29 g, 2.0 mmol). After stirring overnight, a reaction solution was poured onto water followed by extraction with EtOAc. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product thus produced was purified by column chromatography on silica gel (20 g, CHCl3) to give 0.43 g of the title compound as a colorless oil.
Reaction SMILES: [ClH:1].CO.[Cl:4][C:5]1[C:6]([C:54]([F:57])([F:56])[F:55])=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][C@@H:22]3[C@H:26]4[O:27]C(C)(C)[O:29][C@H:25]4[C@H:24]([N:32]4[C:36]5[N:37]=[CH:38][N:39]=[C:40]([NH:41][CH:42]6[CH2:44][CH2:43]6)[C:35]=5[CH:34]=[CH:33]4)[CH2:23]3)[CH:18]([CH3:20])[CH3:19])[N:10](COCC[Si](C)(C)C)[C:9]=2[CH:53]=1>>[NH3:10].[ClH:4].[ClH:1].[ClH:4].[Cl:4][C:5]1[C:6]([C:54]([F:57])([F:55])[F:56])=[CH:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:21][C@H:22]3[CH2:23][C@@H:24]([N:32]4[C:36]5[N:37]=[CH:38][N:39]=[C:40]([NH:41][CH:42]6[CH2:43][CH2:44]6)[C:35]=5[CH:34]=[CH:33]4)[C@H:25]([OH:29])[C@@H:26]3[OH:27])[CH:18]([CH3:20])[CH3:19])[NH:10][C:9]=2[CH:53]=1
Reactant: CC(C)N(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CC(C)N(CCCCc1nc2cc(C(F)(F)F)c(Cl)cc2[nH]1)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@H](O)[C@@H]1O
Product: N
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of 12N aq. HCl:MeOH (1:1, 3 ml) was added to 7-[(3aS,4R,6R,6aR)-6-[({4-[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]butyl}(propan-2-yl)amino)methyl]-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine at 0° C., stirred at 40° C. for 4 hrs. Upon completion, the reaction mixture was concentrated in vacuo. The residue was dissolve in DCM (100 ml) and MeOH (1 ml). This was washed with sat. NaHCO3 (2×50 ml), dried over Na2SO4, filtered and evaporated. Purification by prep.TLC, eluting with MeOH:DCM (1:9) and then 7N NH3 in MeOH:DCM (5:95) gave the desired product. This was then dissolved in MeOH (1 ml). To this was added HCl (4M in dioxane, 5 eq), shaken for 5 mins and evaporated to dryness. This was then re-dissolved in Water (1 ml) and MeOH (3 drops) and lyophilised to give an off white solid (100 mg, 55%); MS (ESI+) for C30H37ClF3N7O2 m/z 620 [M+H]+: HPLC purity>95% (ret. time, 1.35 min): 1H NMR (500 MHz, MeOD) δ ppm 8.31 (1H, s), 8.16 (1H, s), 8.01 (1H, br. s.), 7.59 (1H, d, J=3.31 Hz), 6.91 (1H, br. s.), 5.08 (1H, br. s.), 4.30 (1H, t, J=5.91 Hz), 4.16 (1H, br. s.), 3.85 (1H, br. s.), 3.38-3.59 (2H, m), 2.85 (1H, br. s.), 2.52 (2H, br. s.), 1.93-2.21 (4H, m), 1.86 (1H, s), 1.32-1.52 (6H, m), 1.00-1.24 (2H, m), 0.73-1.00 (2H, m).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:9][CH2:8]1>CCOCC.[Cl-].[Cl-].[Cl-].[Ti+3]>[C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:11][CH2:12]1
Reactant: Cc1ccccc1N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccccc1N1CCN(Cc2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
To a suspension of 4-(o-tolyl)-1-(p-nitrobenzyl)piperazine (3.11 g, 0.01 M) in 30 ml of ether is added dropwise 30 ml of titanium trichloride (20% aqueous solution). The resulting mixture is stirred at room temperature for one hour. This is then quenched into cold water, made strongly basic with aqueous 10% ammonium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and concentrated to an oil. This is purified by column chromatography on silica gel to afford 1.3 g (46%) of 1-(o-tolyl)-4-[(4-aminophenyl)methyl]piperazine as an oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1[CH:11]=[C:12]([C:42]2[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:18](=[O:41])[N:19]([C@H:30]2[CH2:33][C@@H:32]([O:34][CH:35]([CH3:40])[C:36]([OH:39])([CH3:38])[CH3:37])[CH2:31]2)[C:20]2[N:21]([N:26]=[C:27]([CH3:29])[N:28]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]>CS(C)=O.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[NH:3][C:4](=[O:7])[O:5][N:49]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:18](=[O:41])[N:19]([C@H:30]2[CH2:33][C@@H:32]([O:34][CH:35]([CH3:40])[C:36]([OH:39])([CH3:37])[CH3:38])[CH2:31]2)[C:20]2[N:21]([N:26]=[C:27]([CH3:29])[N:28]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OC(C)C(C)(C)O)C2)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2C[C@@H](OC(C)C(C)(C)O)C2)c2nc(C)nn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (806 mg), sodium hydrogen carbonate (1.29 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C. for 30 min, a solution of 3′-fluoro-4′-({4-[cis-3-(2-hydroxy-1,2-dimethylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (430 mg) in dimethyl sulfoxide (2 mL) was added, and the mixture was stirred at 90° C. for 16 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 dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (150 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (141 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution 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 chromatography [eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (542 mg, 81%).
Reaction SMILES: N1CCCCC1.[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([CH2:28][C:29]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35])=[O:30])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[CH:28]/[C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([OH:36])=[O:35])=[O:30])=[CH:17][C:16]=1[O:23][CH3:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OCc1ccccc1

Procedure:
Piperidine (0.20 mL, 2.1 mmol) was added to a suspension of 4-benzyloxy-3-methoxybenzaldehyde (0.50 g, 2.1 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.42 g, 1.9 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH providing (E)-2-[[3-(4-benzyloxy-3-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic (0.48 g, 63%) as a yellow crystalline solid; mp 197-199° C.; δH (400 MHz, DMSO-d6) 3.84 (s, 3H, OCH3), 5.13 (s, 2H, OCH2), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 7.07 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.22 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.31-7.46 (m, 6H, H2′, Ph), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.28 (s, 1H, NH), 13.60 (br s, 1H, CO2H); do (100 MHz, DMSO-d6) 55.7, 69.8, 110.7, 113.1, 116.6, 120.0, 120.3, 122.5, 122.7, 127.5, 127.8, 127.9, 128.4, 131.1, 134.0, 136.8, 141.1, 141.6, 149.3, 149.6, 164.2, 169.5; HRMS (ESI) calculated for C24H21NO5 [M−H]− 402.1336. found 402.1342; vmax 697, 1133, 1233, 1516, 1599, 1673, 1697, 3035 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:19])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)(=[O:29])=[O:28])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCCC2N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COc1cccc2c1CCCC2NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (199 mg, 0.72 mmol) and biphenyl-4-sulfonyl chloride (217 mg, 0.86 mmol) in dry tetrahydrofuran (10 mL) was added diisopropylethylamine (186 mg, 1.44 mmol) at 0° C. The reaction mixture was stirred at room temperature for 12 hours, and then concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, and evaporated in vacuo. Column chromatography (silica gel, 100-200 mesh, 10-15% ethyl acetate in hexane) gave [5-(biphenyl-4-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester. MS cald. for C28H31NO5S 493, obsd. 494 [(M+H)+].
Reaction SMILES: [CH:1]([C:3]1[O:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)=[O:2].C1(C)C=CC(S([CH2:19][N+:20]#[C-:21])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC.C(OCC)(=O)C>CO>[OH:8][CH2:7][C:6]1[O:9][C:3]([C:1]2[O:2][CH:21]=[N:20][CH:19]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCc1ccc(-c2cnco2)o1
Yield: 66.2 %

Procedure:
300 mg of 5-formylfurfuryl alcohol see Japanese Laid-Open Patent Publication No. 154758/1979 was dissolved in 10 ml of methanol, and 502 mg of p-toluenesulfonylmethyl isocyanide and 329 mg of potassium carbonate were added. The mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a mixture of water and ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate. The desiccant was separated by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography Wakogel C-200, 45 g; eluting solvent: hexane/ethyl acetate=3/2→1/1] to give 260 mg (yield 66%) of the captioned compound as a pale yellow crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(O)[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-]>ClCCl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(O)(C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(C(C(=O)O)c2ccccc2)cc1

Procedure:
1.49 g (5 mmol) of tert-butyl 2-(4-methyl-phenyl)-2-phenyl-2-hydroxy-acetate are stirred at room temperature in 60 ml of dichloromethane for 3 h with 6.3 ml (40 mmol) of triethylsilane and 12.6 ml (60 mmol) of trifluoroacetic acid. The mixture is diluted with 60 ml of water, adjusted to a pH of 2-3 with saturated aqueous bicarbonate solution and shaken. After removal of the organic phase, the aqueous phase is extracted twice more with dichloromethane. The combined organic phases are dried over sodium sulphate, filtered and concentrated. The product is chromatographed on silica gel 60 using 40-60 petroleum ether/ethyl acetate (6:4).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C1(N)CCCCC1>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cc(F)ccc1F
Solvent: NC1CCCCC1
Solvent: CC(=O)O
Product: CC(=Cc1cc(F)ccc1F)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 2,5-difluorobenzaldehyde (25.0 g, 0.176 mol), nitroethane (26.41 g, 0.352 mol) and cyclohexylamine (17.45 g, 0.176 mol) in 150 mL of acetic acid was stirred at 80° C. overnight. After cooling to rt the solvent was evaporated, the residue was purified by column chromatography (silica-gel, CH2Cl2/acetone=19/1 v/v) to give a yellow solid product, 28.5 g, 81.3% yield. MS: 197.6 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 7.94 (s, 1H), 7.46-7.43 (m, 1H), 7.41-7.35 (m, 2H), 2.31 (s, 3H).
Reaction SMILES: [CH:1]1([N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.CCN(CC)CC.[N:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36][C:37](O)=[O:38])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl.[Pd]>[CH:1]1([N:5]2[CH:9]=[C:8]([NH:10][C:37](=[O:38])[CH2:36][C:32]3[CH:31]=[C:30]4[C:35](=[CH:34][CH:33]=3)[N:26]=[CH:27][CH:28]=[CH:29]4)[N:7]=[CH:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cn(C2CCC2)cn1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc2ncccc2c1)Nc1cn(C2CCC2)cn1
Temperature: -10 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a Parr hydrogenation bottle was added 1-cyclobutyl-4-nitro-1H-imidazole (Preparation 1, 150 mg, 0.9 mmol) and ethyl acetate (10 mL), followed by 10% Pd on carbon (250 mg). The reaction mixture was placed on a Parr hydrogenation apparatus and was reacted for 6 h under 50 psi H2 at 23° C. The contents of the bottle were filtered through a short pad of celite and were rinsed with dry methylene chloride (25 mL) into a flame-dried flask under nitrogen. Et3N (626 uL, 4.5 mmol) was added and the reaction solution was cooled to −10° C. 6-Quinolylacetic acid (168 mg, 0.9 mmol) and tripropylphosphonic anhydride (530 uL, 1.7 M solution in ethyl acetate) were then added and the mixture was stirred at −10° C. for 2 h. The solution was diluted with methylene chloride (50 mL) and washed with water (2×). The aqueous layer was extracted with methylene chloride (3×) and the organic layers were combined and washed with brine (1×). The solvent was removed in vacuo, the residue was adsorbed onto silica gel and chromatographed using the Biotage Flash 12 system with SIM attachment (40:1 methylene chloride—methanol) to afford 130 mg (47% yield) of N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide (the title compound); 1H NMR (300 MHz, CDCl3) δ9.48 (s, 1H), 8.87 (dd, J=1.6, 4.3 Hz, 1H), 8.11 (m, 2H), 7.76 (d, J=1.8 Hz, 1H), 7.67 (dd, J=2.0, 8.7 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.38 (m, 1H), 7.25 (d, J=1.6 Hz, 1H), 4.5 (m, 1H), 3.90 (s, 2H), 2.4 (m, 2H), 2.3 (m, 2H), 1.85 (m, 2H); MS (AP/Cl): 307.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Li+].[CH2:18]([C@H:20]1[O:22][CH2:21]1)[Cl:19]>>[Cl:19][CH2:18][C@@H:20]([OH:22])[CH2:21][N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Br-]
Agent: [Li+]
Product: O[C@H](CCl)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
Dibenzylamine (39.4 g, 0.20 mol) and lithium bromide (1.7 g, 20 mmol) were added to (S)-epichlorohydrin (185 g, 2 mol). The mixture was stirred at room temperature (25° C.) for 2 hours, Filtered, and the solvent was evaporated to provide 53 g of colorless Oil in 90% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]=2[CH2:8]1.[OH-].[Na+].CO>O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]=2[CH2:8]1
Reactant: CCOC(=O)c1ccc2c(c1)CCC(Cc1ncc[nH]1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCC(Cc1ncc[nH]1)C2
Yield: 54.8 %

Procedure:
A mixture of 2.31 g of ethyl 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate, 0.49 g of sodium hydroxide, 60 ml of methanol and 20 ml of water was heated under reflux for 4 hours. Methanol was distilled off in vacuo and 50 ml of water was added to the residue. Chloroform was added to the mixture and the aqueous layer was separated. The aqueous solution was adjusted to pH 6 with 2 normal hydrochloric acid. The precipitate formed was collected by filtration and washed with water to give 1.14 g of 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid as a colorless powder with m.p. 224°-226° C.
Reaction SMILES: C([NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1)(=O)C1C=CC=CC=1.[ClH:23]>C(O)(=O)C>[ClH:23].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1nccc2cc(C(=O)O)ccc12
Temperature: 100 °C

Procedure:
A mixture of 445 mg [1-(benzoylamino)-6-isoquinolinyl]carboxylic acid, 10 mL of acetic acid and 20 mL of 4N hydrochloric acid was heated at 100° C. for one day. The reaction mixture was concentrated and coevaporated with 0.5N hydrochloric acid. The resulting residue was triturated with diethyl ether to yield 341 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][N:33]([CH2:35][CH2:36]Cl)[CH3:34]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][C:17]([N:20]([CH2:36][CH2:35][N:33]([CH3:34])[CH3:32])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:16][CH:15]=3)=[CH:8]2)=[CH:28][CH:29]=1
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCN(C(=O)OC(C)(C)C)c1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53.6 %

Procedure:
According to Scheme 19 Step 4: tert-Butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenylcarbamate (0.34 mmol 0.14 g) was dissolved in dry THF (4 mL) and the resulting solution was cooled at 0° C. Then, NaH (60% mineral oil; 1.02 mmol, 40.8 mg) was added, the mixture was stirred at 0° C. for 10 minutes, warmed at room temperature and stirred for 30 minutes. After, N,N-dimethylaminoethyl chloride (0.69 mmol) and KI (0.34 mmol, 57.0 mg) were added and the reaction mixture was heated at 90° C. for 16 hours. The resulting suspension was taken up in CH2Cl2, washed with water, washed with brine, filtered off and the filtrate washed with CH2Cl2. The organic solvent was separated, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified in a manifold (vac.) using a Sep-Pak silica cartridge (CH2Cl2/MeOH(NH3)sat. 95/5). The product fractions were collected and the solvent was evaporated to yield tert-butyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl(2-(dimethylamino)ethyl)carbamate (87.9 mg)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:16]([O-])=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]>[Pd].CO>[NH2:16][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COCCOc1ccc([N+](=O)[O-])c(C(=O)OC)c1
Agent: [Pd]
Solvent: CO
Product: COCCOc1ccc(N)c(C(=O)OC)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To methyl 5-(2-methoxyethoxy)-2-nitrobenzoate (1.08 g, 4.2 mmol) under argon was added 10% Palladium on carbon and MeOH (20 mL). The flask was flushed with H2(g) and stirred under H2 (1 atm) for 30 minutes. The mixture was filtered through Celite and concentrated in vacuo to give methyl 2-amino-5-(2-methoxyethoxyl)benzoate (964 mg, 4.2 mmol, 100%). LC-MS (ESI) m/z 226 (M+H)+.