Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[CH2:7]2.[CH:14]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[C@@H:24]([NH2:28])[CH2:25][CH2:26][CH3:27])=[N:19][CH:18]=1)([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.CCOC(C)=O>[CH:14]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:29])[C@@H:24]([NH:28][CH:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[CH2:25][CH2:26][CH3:27])=[N:19][CH:18]=1)([CH3:15])[CH3:16]
Reactant: O=C1CCc2c(F)cc(F)cc2C1
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC[C@H](NC1CCc2c(F)cc(F)cc2C1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The 5,7-difluoro-2-tetralone (0.3 mmol) was dissolved in 2.0 mL of anhydrous dichloromethane under N2 at rt. 2-(S)-Amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (0.3 mmol) was then added to the reaction solution, followed by sodium triacetoxy borohydride (0.3 mmol) and acetic acid (0.3 mmol). The reaction was stirred at rt for 16 h. The crude solution was then diluted with 20 mL of EtOAc and washed with 20 mL of aqueous 1N NaOH solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified through flash chromatography to give 2-(S)-(5,7-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide. LC-MS (retention time, M+1): 2.2 min, 408 [M+1].
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C([N:10]([CH2:13][CH3:14])CC)C>C(O)C>[CH:14]1([C:13]2[C:3]([C:2](=[O:7])[CH3:1])=[C:4]([CH3:5])[O:6][N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1]1
Reactant: CCN(CC)CC
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: CC(=O)c1c(C2CCCCC2)noc1C
Temperature: 70 °C
Yield: 67.2 %

Procedure:
To a solution of 2 and 2,4-pentanedione (0.932 ml, 9.08 mmol) in ethanol (10 ml) was added triethylamine (1.26 ml, 9.08 mmol). The resulting mixture was heated at 70° C. overnight. The reaction was partitioned between EtOAc and water and the layers were separated. The organic layer was dried over sodium sulfate then concentrated in vacuo. The crude product was purified by silica column chromatography (5% to 10% EtOAC:hexanes gradient elution) to afford compound 3 (0.633 g, 3.05 mmol) in 37% yield for 2 steps. 1H NMR (CDCl3) δ 0.8-2.0 (m, 10H), 2.5 (s, 3H), 2.7 (s, 3H), 3.2 (m, 1H).
Reaction SMILES: [C:1]1([CH:11]=[C:12]2[CH2:18][CH2:17][C:16](=[O:19])[O:15][C:13]2=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:23]1[CH2:24][CH2:25][N:20]([C:16](=[O:19])[CH2:17][CH2:18][C:12](=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:13]([OH:15])=[O:14])[CH2:21][CH2:22]1
Reactant: O=C1CCC(=Cc2cccc3ccccc23)C(=O)O1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(O)C(=Cc1cccc2ccccc12)CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
7.5 g (30 mmole) of 2-(1-naphthylmethylene)glutaric anhydride (prepared as described above) were dissolved in 70 ml of methylene chloride, and 2.85 ml (33 mmole) of morpholine were added to the resulting solution. The mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was washed with a 5% v/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate and freed from the solvent by evaporation under reduced pressure, to give 10.0 g (30 mmole) of 5-morpholino-2-(1-naphthylmethylene)-5-oxopentanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:37]([CH3:40])=[N:38][N:39]=3)[N:18]=[C:19]([C:21]3[N:22]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:30]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[C:21]1[C:19]1[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:16]2[N:17]([C:37]([CH3:40])=[N:38][N:39]=2)[N:18]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nnc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc2c(NC3CCNCC3)cc(-c3cc4ccccc4n3Cc3ccccc3)nn12
Reaction time: 1 h

Procedure:
4-[6-(1-Benzyl-1H-indol-2-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (13 mg; 0.02 mmol) was dissolved in 1 ml DCM and treated with 300 μl TFA. It was stirred for 1 hour. The solvent was evaporated and the residue taken up in DCM and extracted with aqueous NaHCO3. The organic layer was dried and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(Br)ncc1F
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)ncc1F
Yield: 77 %

Procedure:
2-Bromo-5-fluoroisonicotinic acid (500 mg, 2.27 mmol) was dissolved in ethanol (22.7 mL), and the solution was stirred under heat and reflux for 1 hour after adding thionyl chloride (0.829 mL, 11.3 mmol). The solvent was then evaporated under reduced pressure. The residue was extracted with chloroform after adding a sodium hydrogen carbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→4/1) to give ethyl 2 bromo-5-fluoroisonicotinate (434 mg, yield 77%).
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:83][OH:84]>C(Cl)Cl>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([CH2:33][CH2:34][C:35]([CH3:40])([CH3:41])[CH2:36][C:37]([NH:83][OH:84])=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NO)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.3 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (35 mg, 0.050 mmol) in DCM (2 mL) was treated with HATU (28.6 mg, 0.075 mmol), N,N-diisopropylethylamine (0.026 mL, 0.150 mmol), and hydroxylamine (1.8 mg, 0.055 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 10) to afford 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-N-hydroxy-3,3-dimethylpentanamide (1.9 mg, 5% yield). LC/MS m/e 714.5 (M+H)+, 2.23 min (ionization peak, no UV) (method 3). 1H NMR (500 MHz, DMSO-d6) δ 10.29 (2, 1H), 5.20 (d, J=5.5 Hz, 1H), 4.69 (s, 1H), 4.55 (s, 1H), 3.14-3.01 (m, 4H), 2.98-2.84 (m, 4H), 2.65-2.55 (m, 3H), 2.50-2.44 (m, J=5.9 Hz, 1H), 2.40-2.31 (m, J=5.1 Hz, 1H), 1.97-0.76 (m, 28H), 1.65 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.94 (s, 9H), 0.87 (s, 3H), 0.79 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14](O)=[O:15])=[CH:5][CH:4]=1)[CH3:2].CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[CH2:14][OH:15])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2sccc2C(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(-c2sccc2CO)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-ethylphenyl)thiophene-3-carboxylic acid (0.46 g, 1.98 mmol), anhydrous ether (18 mL). This was followed by the addition of a solution of LiAlH4 (1 M in THF, 2.7 mL, 2.7 mmol) in tetrahydrofuran dropwise with stirring at 0° C. The resulting solution was stirred for 2.0 h at 25° C. The reaction progress was monitored by LCMS/TLC (ethyl acetate/petroleum ether=1:6). The reaction was then quenched by the addition of 10 mL of water and 5 mL of 2N HCl. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.46 g (100%) of (2-(4-ethylphenyl)thiophen-3-yl)methanol as a white oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[CH:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:31]3[CH:32]=[CH:33][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)C)cc3)c1)C(C)(C)C2
Yield: 53.5 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (680 mg, 1.67 mmol), 4-isopropylphenylboronic acid (320 mg, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (193 mg, 0.17 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (1.7 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 6-chloro-2-(4′-isopropyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 53.4%) as a white solid: LC/MS m/e calcd for C28H30ClNO2 (M+H)+: 449.01, observed: 448.1.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].[CH2:12](O)[CH3:13].[C:15]1(C)C=CC=C[CH:16]=1.S(=O)(=O)(O)O>O>[CH3:1][C:2]([CH3:11])([CH2:6][CH2:7][C:8]([O:10][CH2:12][CH3:13])=[O:9])[C:3]([O:5][CH2:15][CH3:16])=[O:4]
Reactant: CC(C)(CCC(=O)O)C(=O)O
Reactant: CCO
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)CCC(C)(C)C(=O)OCC
Yield: 90 %

Procedure:
To 0.1 mol 2,2-dimethyl-glutaric acid were added 0.3 mol ethanol, 40 ml toluene, and 0.4 ml concentrated sulfuric acid with stirring. The mixture was heated refluxing, and the water produced was removed by using a water separator until the amount of the water separated reached theoretical value. The mixture was neutralized with saturated sodium carbonate solution and extracted with ethyl acetate. The upper layer solution was separated, washed with saturated saline until being neutral, and dried over anhydrous sodium sulfate. After the solvent was removed, distillation under reduced pressure gave diethyl 2,2-dimethylglutarate as a colorless liquid, and the yield was 90%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[CH2:31]=O.[Na]>C(#N)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([NH:25][CH3:26])=[O:24])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:12]3[CH2:13][CH2:14][N:15]([CH3:31])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1
Reactant: C=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCNCC3)ncc1Cl
Agent: [Na]
Solvent: CC#N
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C)CC3)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[5-Chloro-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was suspended in acetonitrile (5 mL). Aqueous formaldehyde (37%, 325 μL/4 mmol) and sodium cyanoborohydide (210 mg/3.3 mmol) were added sequentially and the reaction stirred at room temperature for two hours. The material was concentrated onto celite and the desired product was isolated by sequential column chromatography on silica gel (eluting with 0→50% methanol/methylene chloride) followed by basic alumina (eluting with 0→40% methanol/methylene chloride). Yield 50 mg/35%. 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.41 (s, 1H), 8.82-8.69 (m, 2H), 8.22 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.56-7.41 (m, 3H), 7.19 (dd, J=7.3, 7.3 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 3.19-2.78 (m, 14H). LC/MS found 436 (M+H). mp 125-130° C. (dec.).
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.Cl[CH2:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[N:14]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:12][C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1ncnc2c1ccn2Cc1nc2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.62 g, 4.1 mmol), 2-(chloromethyl)-1-phenyl-1H-benzo[d]imidazole (1.0 g, 4.1 mmol) and K2CO3 (0.6 g, 4.3 mmol) in DMSO (20 mL) was stirred at room temperature overnight. Then the mixture was added H2O (50 mL) and extracted with EtOAc (20 mL×3). The combine organic layers were concentrated in vacuo to give 4-chloro-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.2 g, yield 80%) as brown solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[O:4][N:3]1[CH2:8][C:9]1[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[CH3:30])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].C(Cl)(Cl)Cl>C1COCC1.CO>[CH3:30][C:22]1[CH:23]=[C:24]([C:27]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:28])[CH:25]=[CH:26][C:21]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][O:13][C:12]2[CH:31]=[CH:32][C:9]([CH2:8][N:3]3[C:2](=[O:1])[NH:6][C:5](=[O:7])[O:4]3)=[CH:10][CH:11]=2)[CH:16]=1
Reactant: C1CCNC1
Reactant: Cc1cc(C(=O)O)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCCC2)ccc1-c1cccc(COc2ccc(Cn3oc(=O)[nH]c3=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
3′-({4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10.8 mg) was dissolved in a THF-methanol [1 ml, 4:1 (v/v)] mixed solution, and the solution was added to pyrrolidine (3.2 mg). DMT-MM (12 mg) was added, followed by overnight stirring at room temperature. Thereafter, chloroform was added to the reaction liquid, and the organic layer was washed with 1 M hydrochloric acid. The organic layer was concentrated, and the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm)) to obtain 2-(4-{[2′-methyl-4′-(pyrrolidin-1-ylcarbonyl)biphenyl-3-yl]methoxy}benzyl)-1,2,4-oxadiazolidine-3,5-dione (8.2 mg).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 41 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N—(N,N-dimethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide; (41% yield); reaction time 25 min; mp 283-285° C. (dec.); IR (CHCl3) 1653; 1H NMR (CDCl3) δ 2.33 (s, 6H), 3.04 (t, 2H, J=7.2), 4.07 (s, 3H), 4.14 (s, 3H), 4.64 (t, 2H, J=7.2), 6.18 (s, 2H), 7.47 (s, 1H), 7.68 (s, 1H), 7.89 (s, 2H), 9.37 (s, 1H); 13C NMR (CDCl3) δ 45.9, 49.2, 56.3, 56.3, 57.9, 101.2, 102.0, 102.3, 107.1, 108.8, 111.7, 114.8, 119.3, 127.6, 140.9, 143.5, 147.3, 147.7, 149.9, 150.3, 154.2, 164.1; HRMS calcd for C23H23N3O5H: 422.1716; found 422.1710.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:17]([NH:8][C:3]2[C:2]([O:22][CH3:21])=[N:7][CH:6]=[CH:5][N:4]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: C[O-]
Reactant: Nc1nccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cccc(S(=O)(=O)Nc2nccnc2OC)c1

Procedure:
By the method outlined in Example 1 (reaction performed at room temperature) using 3-chloro-2-aminopyrazine (0.83 g), 3-methoxybenzenesulfonyl chloride (1.44 g). The crude adduct was reacted with a solution of sodium methoxide (10 mL of a 25% solution in methanol) in methanol (20 mL) to afford the sub-titled compound (1.41 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][NH2:15])[C:7]=2[CH:6]=[CH:5][CH:4]=1.BrC1C=CC(S(O[CH2:27][C@@H:28]2[O:42][C:32]3=[C:33]4[C:38](=[CH:39][CH:40]=[C:31]3[O:30][CH2:29]2)[N:37]=[C:36]([CH3:41])[CH:35]=[CH:34]4)(=O)=O)=CC=1>CS(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][NH:15][CH2:27][CH:28]3[O:42][C:32]4=[C:33]5[C:38](=[CH:39][CH:40]=[C:31]4[O:30][CH2:29]3)[N:37]=[C:36]([CH3:41])[CH:35]=[CH:34]5)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(CCCN)coc12
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc2c(CCCNCC3COc4ccc5nc(C)ccc5c4O3)coc12
Temperature: 50 °C

Procedure:
To a stirred solution of 3-(7-methoxy-benzofuran-3-yl)-propylamine (770 mg, 3.75 mmol) in 5 mL of anhydrous DMSO was added [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (563 mg, 1.25 mmol). The reaction mixture was heated to 50° C. overnight. The reaction was diluted with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Flash chromatography on SiO2 (5% MeOH/CH2Cl2) afforded 120 mg (23%) of the (S)-enantiomer of the title compound as a yellow oil. The fumarate salt was prepared, yielding 132 mg of a beige solid, m.p. 155-160° C.; MS (ESI) m/z 419 [M+H]+.
Reaction SMILES: [OH-:1].[K+].Cl[CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.[CH3:19]O>>[CH3:19][O:1][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: O=C(c1ccccc1)c1ccc(CCl)cc1
Reactant: CO
Agent: [K+]
Product: COCc1ccc(C(=O)c2ccccc2)cc1
Yield: 88.5 %

Procedure:
To 4 liters of absolute methyl alcohol was added 300 grams (4.5 moles) of 85% potassium hydroxide pellets with mechanical stirring. The amount of 618 grams (2.7 moles) of 4-(chloromethyl)benzophenone was added to the resulting warm solution. The reaction mixture was refluxed for three hours, filtered with suction, and concentrated. Water was added and the lower oily layer was separated and distilled to provide 530 grams (88.5% yield) of 4-(methoxymethyl)benzophenone as an almost colorless liquid (b.p. 140° C., 0.20 mm Hg). The infrared spectrum revealed a carbonyl band at 1660 cm-1. Ultraviolet analysis revealed λ max (ε) at 256 nanometers (18,380).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O[CH:11]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Product: COc1ccc(OC(CCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-{3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 515.6 (M+H)+.