Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][NH:16][CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:20][CH2:19]1>ClCCl>[ClH:4].[ClH:5].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[N:10]3[C:14]([CH2:15][N:16]([C:1](=[O:3])[CH3:2])[CH2:17][C:8]=2[CH:7]=1)=[N:13][N:12]=[C:11]3[CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:22][CH2:23]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
Acetyl chloride (0.1 ml, 1.4 mmol) was added to an ice cooled solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml) and stirred at room temperature for 20 hours. Dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant. The residue was dissolved in dichloromethane (2 ml) and hydrochloric acid (1M in diethyl ether, 2 ml) was added, and the solvents evaporated under reduced pressure to give the title compound as a brown foam (110 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:27])[NH:25][OH:26])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(C)(C)C.C(Cl)[Cl:35]>>[ClH:35].[NH2:7][CH:8]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([NH:25][OH:26])=[O:27])=[CH:20][CH:21]=2)=[CH:13][CH:14]=1
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1
Reactant: ClCCl
Product: CN(C)C(=O)C(N)c1ccc(Oc2ccc(CCC(=O)NO)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The hydroxamate 35 (1.1 g) was dissolved in CH2Cl2 and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temp for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×50 mL), decanted, and dried to yield the desired compound 36 as a white amorphous solid (0.87 g, 92%). 1H NMR (DMSO-d6): 10.44 (s, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 5.48 (d, J=5.2 Hz, 1H), 2.89 (s, 3H), 2.82 (s, 3H), 2.81 (t, J=8.0 Hz, 2H), 2.26 (t, J=8.0 Hz, 2H). LCMS (m/e): Obsd. [M+Na]+ 380, Calcd. 357.4
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.O[CH2:15][C:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1>>[F:11][CH2:15][C:16]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCOC(=O)C1(CO)CCCCO1
Product: CCOC(=O)C1(CF)CCCCO1
Temperature: 70 °C
Yield: 63 %

Procedure:
Neat Deoxo-Fluor® (342 mg, 1.546 mmol) was added to a cold (0° C.) stirred ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (194 mg, 1.031 mmol) and the mixture was heated at 70° C. overnight. The reaction was quenched with ice and neutralized with sat. aq. NaHCO3 and extracted with DCM (2×). The combined organic layers were washed with water, brine and dried (MgSO4), filtered and dried to give a yellow-orange oil which was purified by silica gel FCC (0-5% EtOAc in DCM) to afford ethyl 2-(fluoromethyl)tetrahydro-2H-pyran-2-carboxylate as a colorless oil (125 mg, 63%) which was saponified (LiOH.H2O, MeOH-THF—H2O, sonicate) to afford Cap P-43 as a viscous oil (82 mg, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.66-4.54 (m, 1H), 4.54-4.41 (m, 1H), 4.02-3.84 (m, 2H), 1.98-1.84 (m, 1H), 1.84-1.72 (m, 2H), 1.69-1.52 (m, 4H).
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C@H:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7][NH:6][CH2:5]1.[C:21](Cl)(=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(OCC)(=O)C>C(Cl)Cl>[F:3][C@H:4]1[C@H:9]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH2:8][CH2:7][N:6]([C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:30])[CH2:5]1
Reactant: F[C@@H]1CNCC[C@H]1Oc1cccc2cccnc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3cccnc23)[C@H](F)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a 0° C. solution of 8-((trans)-3-fluoropiperidin-4-yloxy)quinoline dihydrochloride (6.6 g, 26.8 mmol) and TEA (18.7 ml, 134.0 mmol) in 134 mL DCM was added benzyl carbonochloridate (4.4 ml, 29.5 mmol). The reaction mixture was stirred 15 minutes at 0° C., then warmed to ambient temperature and stirred another 16 hours. Water was added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The crude was purified on silica gel (Biotage 40M, loaded with 4:1hexanes:ethyl acetate and 500 mL flushed, then gradient to 1:1 hexanes:ethyl acetate) to give (trans)-benzyl 3-fluoro-4-(quinolin-8-yloxy)piperidine-1-carboxylate (5.2 g, 13.67 mmol, 51.01% yield) as an oil. MS APCI (+) m/z 381 (M+1) detected.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:19])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>CC(CC)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:26][CH:28]2[O:30][CH2:29]2)=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])(=[O:3])[CH3:2]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC1CO1
Yield: 57.8 %

Procedure:
Methyl 3-(5-acetamido-2-hydroxybenzoyl)propionate (0.75 g, 0.0028 mole), anhydrous potassium carbonate (0.39 g, 0.0028 mole), epibromohydrin (0.78 g, 0.00565 mole) and dry ethyl methyl ketone (20 ml) were stirred and heated under reflux for 16 hours. The cooled mixture was filtered and evaporated under reduced pressure to an oil which was purified by elution from a silica column with chloroformmethanol to give methyl 3-[5-acetamido-2-(2,3-epoxypropoxy)benzoyl]propionate (0.52 g, 57%, m.p. 84°-87°).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[CH2:19]>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:18]=[CH:19][C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C=Cc1ccccn1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Product: C(=Cc1ccccn1)c1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Yield: 24 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine] (150 mg, 0.5 mmol) was treated with 2-vinylpyridine (0.070 mL, 0.65 mmol) in the same way as described in example 16. Purification by flash chromatography through silica gel (eluting with ammoniated ether/methanol, 95:5 to 9:1), followed by recrystallization from acetonitrile produced the title compound (37 mg, 0.12 mmol, 23%): electrospray MS (m/z, relative intensity) 320 ([MH]+, 100).
Reaction SMILES: CCCCC[C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/C=C\CCCC(O)=O)[C@@H](O)C[C@H:10]1[OH:24].C(OC(Cl)=O)C(C)C.C([N:36](CC)CC)C>>[OH:25][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH2:36])=[O:24])=[CH:13][CH:14]=1
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: CC(C)COC(=O)Cl
Product: NC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.738 g. of PGF2α, 0.347 ml. of triethylamine, 0.326 ml. of isobutylchloroformate, and 0.433 g. of p-hydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-acetone (3:7). The residue obtained by concentration of selected fractions, 0.455 g., is crystallized from acetone diluted with an equal volume of acetonitrile as the title compound, white, free-flowing crystals, m.p. 129.5°-130.8° C., having Rf 0.32 (TLC on silica gel in ethyl acetate-acetone (3:7)).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCOC(C)=O.[CH3:25][C:26]([O:29][C:30]([NH:32][C@@H:33]([CH2:39][CH3:40])/[CH:34]=[CH:35]/[C:36]([OH:38])=O)=[O:31])([CH3:28])[CH3:27].[NH:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42]1.CCN(CC)CC>C(Cl)Cl>[N:41]1([C:36](=[O:38])/[CH:35]=[CH:34]/[C@@H:33]([NH:32][C:30](=[O:31])[O:29][C:26]([CH3:25])([CH3:27])[CH3:28])[CH2:39][CH3:40])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42]1
Reactant: CC[C@@H](/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCN2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of 50 wt % ®T3P in EtOAc (22.00 mL, 37.0 mmol) was added dropwise via addition funnel to a solution of (2E,4S)-4-({[(1,1-dimethylethyl)oxy]carbonyl}-amino)-2-hexenoic acid (5.65 g, 24.64 mmol), 2,3-dihydro-1H-indole (2.76 mL, 24.64 mmol), and Et3N (11 mL, 79 mmol) in CH2Cl2 (90 mL) at 0° C. (bath temp). The ice bath was removed, and the reaction was stirred at RT. After 30 min, the reaction was quenched by dropwise addition of saturated aq. NaHCO3 (50 mL). The layers were separated, and the reaction was washed with 10% citric acid (1×50 mL). The organic layer was concentrated under a stream of nitrogen, and the residue was purified by flash column chromatography, giving 7.21 g (89%) of the title compound. LC-MS m/z 331 (M+H)+, 1.05 (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:21])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=O)=[N:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[OH:31].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>O.CN(C=O)C>[OH:31][C:25]1[CH:26]=[C:27]([OH:30])[CH:28]=[CH:29][C:24]=1[NH:23][C:18]([C:15]1[N:16]=[CH:17][C:12]([O:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:21])=[CH:13][CH:14]=1)=[O:20]
Reactant: C[C@@H](COc1ccc(C(=O)O)nc1)NC(=O)OC(C)(C)C
Reactant: Nc1ccc(O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](COc1ccc(C(=O)Nc2ccc(O)cc2O)nc1)NC(=O)OC(C)(C)C

Procedure:
Diisopropyl azodicarboxylate (1.9 M solution in toluene, 9.52 mL) was added to a mixture of methyl 5-hydroxypyridine-2-carboxylate (5.00 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (8.58 g), triphenylphosphine (12.9 g), and THF (50 mL) at 0° C. dropwise. The mixture was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg) as a mixture with impurities. A mixture of methyl 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylate (810 mg, a mixture with impurities), THF (8 mL), methanol (8 mL), and 1 M sodium hydroxide (8 mL) was stirred at room temperature for 4 hr. The mixture was neutralized with 1 M hydrochloric acid at 0° C., and brine was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg) as a mixture with impurities. A mixture of 5-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)pyridine-2-carboxylic acid (765 mg, a mixture with impurities), 4-aminobenzene-1,3-diol hydrochloride (417 mg), HATU (982 mg), N,N-diisopropylethylamine (0.902 ml), and DMF (7 mL) was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (442 mg) as a pale yellow oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[N:8][CH:9]=[C:10]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=1.[OH-].[Na+]>O.S(=O)(=O)(O)O>[N:31]1[C:32]2[CH:23]([CH2:22][CH2:21][CH2:20][N:19]3[C:7]4=[N:8][CH:9]=[C:10]([CH2:12][C:13]5[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=5)[CH:11]=[C:6]4[N:5]=[N:1]3)[CH2:24][CH2:25][CH2:26][C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=N[O-]
Reactant: Nc1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1cncc(Cc2cnc3c(c2)nnn3CCCC2CCCc3cccnc32)c1
Temperature: 4 °C
Yield: 106.7 %

Procedure:
Sodium nitrite (1.3 g) in water (60 ml) was added over 25 minutes to a solution of 3-amino-2-[3-(5,6,7,8-tetrahydroquinol-8-yl)propylamino]-5-(pyrid-3-ylmethyl)-pyridine (5.5 g) in molar sulphuric acid (250 ml) stirred at 4° C. The reaction mixture was stirred at 4° C. for 50 minutes, then allowed to warm to room temperature, basified with 10 molar sodium hydroxide solution to pH 13 and extracted with chloroform (3 x 150 ml). The chloroform extracts were combined, dried over magnesium sulphate, and the solvent removed to give a brown oil (6.04 g). The oil was chromatographed on silica in 5% MeOH/chloroform to give the title compound as an oil (3.61 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:14])[CH3:13])[CH:5]=[C:6](F)[C:7]=1[N+:8]([O-:10])=[O:9].[OH-].[Na+].CS(C)=[O:19].Cl>O>[CH3:13][N:12]([CH3:14])[C:4]1[CH:3]=[C:2]([F:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:19])[CH:5]=1
Reactant: CN(C)c1cc(F)c([N+](=O)[O-])c(F)c1
Reactant: CS(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1cc(O)c([N+](=O)[O-])c(F)c1
Reaction time: 2 h

Procedure:
(3,5-Difluoro-4-nitro-phenyl)-dimethyl-amine (0.630 g, 3.12 mmol) and 19.1 M of Sodium hydroxide in Water (0.400 mL) in Water (4 mL) and Dimethyl sulfoxide (8 mL) was heated to 70° C. Additional DMSO (8 mL) was added to solubilize the mixture. After 2 h, the solution was cooled then rendered acidic with 12.0 M of Hydrogen Chloride in Water (0.80 mL). The yellow precipitate was collected, using water to aid in the transfer and to rinse the solids. 5-Dimethylamino-3-fluoro-2-nitro-phenol was isolated as yellow solids (598 mg, 96%). 1H-NMR (DMSO): 11.10 (s, 1H), 6.29 (d, 1H, J=15.6 Hz), 6.02 (s, 1H), 3.01 (s, 6H); 19F-NMR (DMSO): −118.
Reaction SMILES: ON1C(=O)CCC1=O.[C:9]([O:13]C(=O)CC)(=[O:12])[CH2:10][CH3:11].[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]>C(OCC)(=O)C>[C:9]([O-:13])(=[O:12])[CH2:10][CH3:11].[CH2:18]([NH+:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:19]
Reactant: CCN(CC)CC
Reactant: CCC(=O)OC(=O)CC
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Product: CCC(=O)[O-]
Product: CC[NH+](CC)CC
Temperature: 25 °C

Procedure:
N-hydroxysuccinimide (32.06 g) was suspended in ethyl acetate (150 ml). Propionic anhydride (37 ml) and triethylamine (39 ml) were added alternately in small portions. A solution formed and the vessel became warm as the reaction progressed. After cooling to room temperature, several milliliters of saturated saline were added, resulting in the precipitation of a thick crystalline mass (triethylammonium propionate). The solid was filtered and washed with ethyl acetate. The combined filtrate was washed with saturated saline (3×) and water (1×). Evaporation of the organic layer left a residue of oil, which crystallized upon scratching with a glass rod and trituration with petroleum ether to give 45.36 g of product (95.2% yield). Mp. 44°-46° C., analysis (C7H9NO4); calc. 49.62% C, 5.30% H, 8.18% N; found 49.29% C, 5.20% H, 8.19% N.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[CH:7]=[C:6]([C:13]([OH:15])=[O:14])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CCC(=O)c2cc(C(=O)O)ccc21
Reaction time: 16 h

Procedure:
To a solution of methyl-5,5-dimethyl-5,6-dihydro-naphthalen-8(7H)-one-2-carboxylate (Compound E2, 1.05 g, 4.5 mmol) in 10 mL of ethanol and THF (10 mL) was added sodiumhydroxide 9 mL (1M solution). The solution was stirred for 16 h and thereafter acidified with 10% HCl. The mixture was extracted with ethyl acetate, the combined organic layer was washed with water and brine, and dried over MgSO4. The solvent was distilled off under reduced pressure to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19][C:20]#[C:21][CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])(C)(C)C.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:18][O:17][C:15]([CH2:14][CH:9]1[CH2:10][CH2:11][CH:12]([OH:13])[C:8]1([C:6]([O:5][CH3:1])=[O:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23])=[O:16]
Reactant: CCC#CCC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC#CCC1(C(=O)OC)C(O)CCC1CC(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 5 q quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (compound (2-a)) and 1.35 g of sodium borohydride are dissolved in 200 ml of methanol, and the solution is refluxed in a nitrogen atmosphere for one hour. The reaction mixture is cooled to room temperature, and about 30 ml of acetic acid is added to the mixture. The resulting mixture is stirred for 30 minutes and thereafter concentrated in a vacuum. The residue is dissolved in a mixture of benzene and ethyl acetate, and the solution is purified with a silica gel column. After removing the solvent from the product, the product is distilled in a vacuum, affording 3-methoxycarbonylmethyl-2-methoxycarbonyl-2-(2-pentynyl)-cyclopentanol (compound (1-a), R1 =R2 +CH3) in a yield of 92.5%, b.p. 70-75° C./0.005 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:22][S:23]([O:11][CH2:10][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:21][CH:20]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)OCC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 30.4 parts of β-[2-(4-bromophenoxy)ethyl]-2,4-dichlorobenzeneethanol, 11.5 parts of methanesulfonyl chloride, 100 parts of pyridine and 70 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed successively with a diluted hydrochloric acid solution and twice with water, dried, filtered and evaporated, yielding 34 parts of 4-(4-bromophenoxy)-2-(2,4-dichlorophenyl)butyl methanesulfonate as a residue.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C(N(CC)CC)C.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:7](=[O:12])[C:6](=[O:13])[N:5]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)CCn1c(=O)c(=O)[nH]c2cnc(Cl)nc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCn1c(=O)c(=O)n(-c2ccccc2)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 17.2 %

Procedure:
To a stirred solution of 2-chloro-8-(3-methylbutyl)-5,8-dihydropteridine-6,7-dione (500 mg, 1.86 mmol), triethylamine (1.88 g, 18.61 mmol) in dichloromethane (20 mL) was added copper acetate (678 mg, 3.73 mmol), phenyl boronic acid (455 mg, 3.73 mmol) and molecular sieves (4 Å, 2 g). The resulting mixture was and stirred at rt for 60 h with an air balloon. The reaction mixture was then diluted with dichloromethane (20 mL) and filtered through celite to remove insoluble material. The bulk of solvent from filtration was then removed under reduced pressure to give a crude residue, which was purified by a silica gel column chromatography (eluent: 40% ethyl acetate in hexanes) to provided the desired compound (110 mg). 1H NMR (CDCl3, 300 MHz) δ 1.05 (d, J=6.8 Hz, 6H), 1.60-1.79 (m, 3H), 4.38-4.42 (m, 2H), 7.21-7.38 (m, 3H), 7.48-7.65 (m, 2H), 7.79 (s, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[O:16][C:3]=12.O=P(Cl)(Cl)[Cl:24]>>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[O:16][C:3]3[C:4](=[N:5][C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:7][C:2]=3[Cl:24])[C:14]=2[CH:20]=1
Reactant: Oc1cc(-c2ccccc2)nc2c1oc1ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccc2)nc2c1oc1ccc(Br)cc12
Yield: 71.01 %

Procedure:
4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (8.7 g, 25.72 mmol) was added to POCl3 (100 mL) The mixture was refluxed for 4 hours. TLC showed the reaction completed. POCl3 was evaporated under reduced pressure. The residue was poured into ice-water under stirring. The yellow solids precipitated out were collected by filtration to give 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6) (6.52 g, 71.01% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:20][Cl:21]>O1CCOCC1>[Cl-:21].[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26])[CH2:20][N+:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: COc1cc(CCl)cc(OC)c1OC
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CC[N+](Cc1cc(OC)c(OC)c(OC)c1)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethoxy-3,4-dihydroisoquinoline and 3,4,5-trimethoxybenzyl chloride in dioxan. Melting point: 187°-189° C. (Decomp.)