Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3C=CC=CC=3)[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]([O-])([O-])=O.[K+].[K+].IC(C)C>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:22])[CH3:28])[CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2cc(O[C@H]3CCN(Cc4ccccc4)C3)ccc2[nH]1
Agent: [Pd]
Agent: [K+]
Solvent: CC(C)I
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(O[C@H]3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 18 g (49 mmol) 5-((S)-1-benzyl-pyrrolidin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester, 28.3 ml acetic acid and 2 g Pd/C 10% was hydrogenated with H2 at room temperature during 16 h. The mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 500 ml DMF and 34.1 g (247 mmol) K2CO3 and 42 g (247 mmol) 2-iodopropane was added and the mixture was stirred for 4 h at 50° C. After filtration and evaporation the residue was purified on silica eluting with a gradient formed from DCM/MeOH (2N NH3) 98/2 to 92/8 to yield after evaporation of the product fractions 60% of the title compound as light brown solid. MS (m/e): 317.3 (MH+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][CH:8]=2)[N:3]=1.[SH:14][C:15]1[CH:16]=[C:17]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:14][C:15]3[CH:16]=[C:17]([C:21]4([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccc(I)cc2n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Temperature: 60 °C

Procedure:
2,4-Dichloro-7-iodo-quinoline (3.4 g, 10.5 mmol), 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (5q, 2.3 g, 10.5 mmol), iPr2NEt (3.67 mL, 21.0 mmol), Pd2dba3 (240 mg, 0.26 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (303 mg, 0.52 mmol) were dissolved in 1,4-dioxane (50 mL) and degassed with N2 for 10 minutes. The reaction was heated at 60° C. for 1 hour, and then cooled to room temperature and diluted with EtOAc and saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 5r.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.CN(CCO)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CN(CCO)CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
Experimental Procedure: Triphenylphosphine (77.0 mg, 0.29 mmol) and DIAD (60.0 mg, 0.29 mmol) were dissolved to a 1:1 mixture of THF and toluene (2 mL); then mono-demethylated piperlongumine (40.0 mg, 0.13 mmol) was added. After 10 min, N-methyldiethanolamine (120 mg, 0.06 mmol) was added to the mixture; the reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum. The crude product was purified by preparative TLC(CH2Cl2/MeOH=9/1) to afford the desired product in 78% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=O)(C)(C)C.Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].Cl.CN([CH2:28][CH2:29][CH2:30]N=C=NCC)C.CC[N:38](CC)CC>>[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].[CH2:18]([O:19][C:20]([NH:38][C:14](=[O:16])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]1)=[O:23])[CH2:30][CH2:29][CH3:28]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: COC(=O)CN
Agent: Cl
Product: CCCCOC(=O)NC(=O)C1CCCCN1

Procedure:
1-(tertButoxycarbonyl)-2-piperidinecarboxylic acid (11.46 g, 1.2 eq), glycine methyl ester hydrochloride (9.42 g), 1-(dimethylaminopropyl)-3-(ethyl)carbodiimide hydrochloride (8.00 g, 1.0 eq) and Et3N (16.3 mL) were reacted as described in Example 1 to give 5.6 g of the title compound as a colorless crystalline-solid: mp 118.5-119.5° C. (EtOAc/isooctane 1:31; 1H-NMR (CDCl3) σ 6.60 (br s, 1H, CONH), 4.81 (m, 1H), 3.82-4.35 (complex m, 4H), 3.76 (s, 3H, OMe), 2.89 (m, 1H), 2.32 (m, 1H), 1.33-1.72 (complex m, 4H), 1.49 (s, 9H, tBu); Anal (calcd for C14H24N2O5): C 55.99, H 8.05, N 9.33. Found: C 56.00, H 8.09, N 9.36.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:36][CH2:35][CH2:34][N:33]([CH3:38])[CH3:32])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccccc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(=O)c1cnc2c(OCCCN(C)C)cccc2c1Nc1ccccc1C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (3.20 g, 10 mmol) and potassium t-butoxide (3.05 g, 25 mmol) were dissolved in dimethyl formamide (30 ml), warmed to 80° and 3-dimethylaminopropyl chloride hydrochloride (1.90 g, 12 mmol) added. The mixture was stirred for 1 hour at 80° then a further portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) added. After a further 2 hours at 80° the mixture was poured into water, extracted with ether and the ether extracts dried and evaporated. Chromatography (silica gel, 5% methanolic ammmonia in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-methylphenylamino)-8-(3-dimethylaminopropoxy)quinoline (1.80 g, 88%), m.p. 109°-110°.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[Si:35]([O:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47]Br)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O>[Si:35]([O:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CBr)c1
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 20 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (164 mg) and potassium carbonate (115 mg) in N,N-dimethylformamide (5 mL) was added 3-tert-butyldimethylsilyloxymethylbenzyl bromide (197 mg) at room temperature, and the mixture was stirred for 20 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1–5/1) to give 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of the obtained 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole in tetrahydrofuran (2 mL) was added tetra-(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 0.065 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (22 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([CH2:35]O)[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)C.O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([O:6][CH2:35][C:22]1([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:26][CH2:27]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: Nc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc([N+](=O)[O-])c2N)(c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a suspension of 2-amino-5-chloro-3-nitrobenzoic acid (500 mg, 2.3 mmol), tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (714 mg, 2.3 mmol), and dimethylaminopyridine (282 mg, 2.3 mmol) in dichloromethane (6.6 mL) was added 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (664 mg, 3.46 mmol) in one portion. The suspension was stirred overnight. The reaction was poured into water and diluted with diethyl ether. The ethereal was washed with water, then saturated sodium bicarbonate, then water. The ethereal was washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→30% ethyl acetate/n-hexane) gave 0.88 g (75%) as a yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.31 (d, J=2.4 Hz, 1H), 8.27 (bs, 2H), 7.87 (d, J=2.8 Hz, 1H), 7.36 (dd, J=8.9, 5.2 Hz, 2H), 7.09 (dd, J=8.9, 8.6 Hz, 2H), 4.25 (s, 2H), 3.81 (m, 2H), 3.06 (m, 2H), 2.25 (m, 2H), 1.86 (m, 2H), 1.43 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 165.5, 161.8 (d, J=248 Hz), 154.9, 145.8, 138.6, 136.8, 133.5, 131.6, 128.8 (d, J=7.7 Hz), 118.9, 115.8 (d, J=21 Hz), 115.4, 79.8, 73.2, 40.8, 39.9, 32.2, 28.5.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][C:8]1([C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2=[N:17][CH:18]=[CH:19][N:9]12)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([O-:32])=[O:31].[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:8]2([CH2:7][C:6]([OH:27])=[O:5])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[NH+:17][CH:18]=[CH:19][N:9]23)=[CH:21][CH:22]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Solvent: ClCCl
Product: O=C(O)CC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl[5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]acetate (3.22 g) in CH2Cl2 (10 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was concentrated after stirring at room temperature for 6 h. The viscous material was dissolved in MeCN-water and lyophilized to a sticky solid. This material when dissolved and concentrated from toluene (3×) afforded the title compound as a white solid. Mass. found (M+H)+, 371.0.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[CH:24][C:23]=1[O:35][CH3:36]>>[CH3:36][O:35][C:23]1[CH:24]=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:26]=[CH:27][C:22]=1[O:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2OC)cc1)c1ccccc1
Yield: 47.62 %

Procedure:
Compound 94 was synthesized from (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.12 g, 0.446 mmol) and ethyl 3-(4-hydroxy-3-methoxyphenyl)propanoate (0.1 g, 0.446 mmol) by following the procedure described in scheme 16 (0.06 g, yield: 47.62%); Purity: 98.66%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18][CH2:19]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:11]1([CH2:17][CH2:18][CH2:19][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A mixture of 68.1 g (0.5 mole) of 4'-hydroxyacetophenone, 100.3 g (0.5 mole) of 3-phenylpropyl bromide, 69.0 g (0.5 mole) of potassium carbonate and 500 ml of anhydrous acetone is refluxed with stirring for 8 hours. After adding 1 liter of water the product is extracted into ether, the extract is washed with water and 2 N sodium carbonate solution and dried over anhydrous sodium sulfate and the solvent is evaporated. The resulting oil (125.8 g) begins to crystallize and yields after two recrystallizations from ether-hexane and ether, respectively, 73.9 g (58% yield) of the desired product, M.P. 80°-81°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[C:25](O)=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:26])[CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: Fc1cnc(NCC2CCNCC2)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of 5-fluoro-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (1.00 g, 4.76 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (T. Riley et al., J. Med. Chem., 15, 1187, 1972) (0.77 g, 4.76 mmol), EDC (1.37 g, 7.13 mmol) and HOBt (0.96 g, 7.13 mmol) in DMF (10 mL) was stirred at rt for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with aqueous saturated NaHCO3 (50 mL), water (5×50 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (90 g), eluting with 10:1–15:89–75 CH2Cl2:2-propanol:hexane to give the title compound. M.S. (M+1): 355.
Reaction SMILES: Cl.[CH2:2]([NH2:4])C.C(N(CC)CC)C.Br[C:13]1[N:17]([C@H:18]2[O:30][C@@H:29]([CH2:31][O:32]C(=O)C)[C@H:24]([O:25]C(=O)C)[C@@H:19]2[O:20]C(=O)C)[C:16]2[CH:36]=[C:37]([Cl:41])[C:38]([Cl:40])=[CH:39][C:15]=2[N:14]=1.C(O)C>CN(C=O)C>[Cl:40][C:38]1[C:37]([Cl:41])=[CH:36][C:16]2[N:17]([C@H:18]3[O:30][C@@H:29]([CH2:31][OH:32])[C@H:24]([OH:25])[C@@H:19]3[OH:20])[C:13]([NH:4][CH3:2])=[N:14][C:15]=2[CH:39]=1
Reactant: CCN
Reactant: CC(=O)OC[C@@H]1O[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCO
Product: CNc1nc2cc(Cl)c(Cl)cc2n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Ethylamine hydrochloride (3.7 g, 46 mmol), triethylamine (7 mL), and 2-bromo-5,6-dichloro-1-(2,3,5-tri-O-acetyl-beta-L-ribofuranosyl)-1H-benzimidazole (0.60 g, 1.1 mmol) were combined with absolute ethanol (20 mL) and stirred at 80° C. for 24 h. The reaction mixture was separated between saturated sodium bicarbonate (2×50 mL) and ethyl acetate (200 mL). The organics were dried with sodium sulfate, concentrated, and purified on a silica gel column (2.5×18 cm, 230-400 mesh) with 1:20 methanol:dichloromethane. The main product off the column was a white solid (0.30 g, 0.96 mmol, 87%) m.p. 155-157° C.; [a]20D=(−) 20.6 (c=0.5 DMF).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].Br[CH2:19][CH2:20][OH:21]>CN(C=O)C.CCOC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:17][CH2:19][CH2:20][OH:21]
Reactant: OCCBr
Reactant: COc1ccc(O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(OCCO)cc1OC
Temperature: 120 °C
Yield: 60 %

Procedure:
K2CO3 (1.07 g, 7.78 mmol) was added to a solution of 3,4,dimethoxyphenol (1.0 g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.81 g, 6.48 mmol) was added, and the mixture was heated overnight at 120° C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4×20 ml), dried over MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 60% yield. B. Synthesis of 4-(2-bromo-ethoxy)-1,2-dimethoxy benzene
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:28])([CH3:27])[CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:16]=3)[NH:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:27][C:9]1([CH3:28])[C:8]2[C:13](=[CH:14][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)[NH:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:10]1
Reactant: COC(=O)c1ccc2c(c1)NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2cc(C(=O)O)ccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester (380.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (330.0 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: [Cl:1][CH:2]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.C(O)=O>ClC1C=CC=CC=1>[Cl:1][CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: CCCC(O)C(Cl)C(=O)OCC
Reaction time: 3 h

Procedure:
Ethyl 2-chloro-3-oxohexanoate (194 mg), chlorobenzene (3 ml), RuCl[(S,S)-TsDPEN](p-cymene) complex (1 mol %) and triethylamine (5 equivalents) were mixed, and formic acid (3 equivalents) was gradually added thereto. The reaction was carried out at 40° C. for 3 hours. The reaction mixture was analyzed. As a result, the conversion ratio was 100%, and the isomer ratio of (2S,3R):(2S,3S):(2R,3R):(2R,3S) is 63.7:24.9:4.1:7.3.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[CH:25].CCOC(C)=O.CO>CN(C=O)C.[Cu](I)I.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>[Cl:1][C:2]1[C:3]([C:25]#[C:24][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:5]2[N:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=2[CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(I)c(Cl)cc21
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(C#Cc3ccccc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 4 mL vial equipped with a stirring bar was charged with copper iodide (2.0 mg, 10 mol %), and Pd(PPh3)2Cl2 (3.5 mg, 5 mol %). A solution of 6-chloro-5-iodo-2-methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (Intermediate 5, 49.0 mg, 0.100 mmol) in DMF (0.5 mL) was added to the vial, followed by a solution of ethynyl-benzene (20.0 mg, 0.200 mmol) in DMF (0.5 mL) and TEA (98 uL, 0.70 mmol). The resulting suspension was stirred at rt for 10 min, during which time it gradually turned brown. The solvent was then removed in vacuo to give brown oily solid, which was suspended in 1:1 EtOAc/MeOH (3 mL) and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The resulting solution was evaporated to dryness in vacuo to give light yellow oil. LR-MS (API-ES): calculated C22H25ClN2O3SSi 460.1, m/e (M+H)+ not observed, 433.0, 403 (Rt 3.83 min).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22](O)=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=[N:44][C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC1C=NC=CC=1>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH:44][C:39]5[CH:38]=[N:43][CH:42]=[CH:41][CH:40]=5)=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:27])([F:26])[F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(N4CCOCC4)cc3C(F)(F)F)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cccc2[nH]c(-c3ccc(N4CCOCC4)cc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.2 %

Procedure:
A mixture of 2-(4-morpholino-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (20; 157 mg, 0.40 mmol), HATU (304 mg, 0.80 mmol), DIEA (207 mg, 1.60 mmol) and 3-aminopyridine (173; 37 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature for 12 h. Water (20 mL) was added and stirred for 30 min. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to give 2-(4-morpholino-2-(trifluoromethyl)phenyl)-N-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 430) (64 mg, 34%) as a pale yellow solid. MS (ESI) calcd for C24H20F3N5O2: 467.16; found: 468 [M+H].