Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)C.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1)[NH2:15]
Reactant: NN
Reactant: CCOC1=NCCc2ccccc21
Solvent: CCO
Product: NNC1=NCCc2ccccc21

Procedure:
A solution of 3,4-dihydroisocarbostyril (IV: Y=Y'=Z=Z'=H) (64.3 g.) in dried methylene dichloride was added to a methylene dichloride (250 ml.) solution of triethyloxonium fluoborate, prepared from boron trifluoride etherate (227 g.), epichlorohydrin (74 g.) and absolute ether (600 ml.) After being stirred (for about 16 hr. at 25° C.), the mixture was treated with potassium carbonate solution (50%, 75 ml.) and water (25 ml.), stirred (for 1-1/2 hr.) and filtered. The solid material was washed thoroughly with methylene dichloride and dissolved in hot water. The solution was filtered and extracted three times with chloroform. 1-Ethoxy-3,4-dihydroisoquinoline fluoborate (10.5 g.) obtained in an earlier run was dissolved in potassium carbonate solution and the solution was extracted three times with methylene dichloride. The combined methylene dichloride washing, chloroform extract and methylene dichloride extract were stripped of solvents and distilled under reduced pressure, affording 1-ethoxy-3,4-dihydroisoquinoline (III: Q=C2H5, Y=Y'=Z=Z'=H) (68.4 g., b.p. 110°-137° C./16 mm. Hg), part (10.82 g.) of which was a center cut (b.p. 129°-131° C./16 mm. Hg). B. A solution of 1-ethoxy-3,4-dihydroisoquinoline (2.0 g.) in ethanol (10 ml.) was added dropwise with stirring to a solution (at 80° C.) of hydrazine (95%, 1.83 g.) in ethanol (5 ml.). The solution was concentrated, diluted with chloroform, washed with water, dried and concentrated. The residue (1.6 g.) was crystalized from ether in three crops (0.7 g., 0.5 g., 0.3 g.). Recrystallization of the first crop from ether-pentane afforded 1-hydrazino-3,4-dihydroisoquinoline (V: Y=Y'=Z=Z') (m.p. 55°-57° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O=S(Cl)Cl.CCN(C(C)C)C(C)C.[F:25][C:26]([F:36])([F:35])[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:26]([F:25])([F:35])[F:36])=[CH:29][CH:30]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 5-bromo-6-chloro-nicotinic acid (375 g, 1.586 mol) and DMF (37 mL) in toluene (3.1 L) was treated dropwise with SOCl2 (347 mL, 4.758 mol) at RT and then stirred at 85° C. for 2.5 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (3.1 L), cooled to −25° C., treated firstly with DIPEA (543 mL, 3.172 mol) and then by the dropwise addition of a solution of 4-(trifluoromethoxy)aniline (295 g, 1.665 mol) in THF (3.1 L), After 30 min at 10° C. the solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (4 L), washed with 1N HCl (2×1 L), a sat. solution of NaHCO3 (1 L) and brine (2×200 mL) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the product was crystallized from EtOAc/n-heptane to give the title compound as a beige crystalline solid. UPLC-MS (Condition 3) tR=1.25 min, m/z=393/395/397 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H) 8.73 (d, J=2.20 Hz, 1H) 8.92 (d, J=2.20 Hz, 1H) 10.69 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.CCOC(C)=O.[NH4+].[Cl-]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[CH3:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 27.5 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) in diethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7 g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirred at 25-30° C. for 2 h. After completion of the reaction, the mixture was treated with EtOAc and saturated NH4Cl solution. The separated organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanone product. [M+1]=218.1
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]1[CH2:10][O:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1>CC#N>[C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([OH:9])[CH2:10][NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH2:21][C:20](=[O:23])[NH:19][C:18]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Temperature: 50 °C
Reaction time: 6 h
Yield: 66.1 %

Procedure:
LiClO4 (7.20 g, 3 eq.) was added to a solution of tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (commercial; 4.25 g, 22.6 mmol) in MeCN (70 mL). 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 3.70 g, 1 eq.) was then added and the mixture was stirred at 50° C. for 6 h. The solvent was removed under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000/25/2) to afford the title intermediate as a pale brown foam (5.25 g, 66% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[Br:28][CH2:29][C:30](Cl)=[O:31]>C(Cl)Cl>[Br:28][CH2:29][C:30]([O:10][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[CH2:8][C:7]1[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=1[Cl:1])=[O:31]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(Cl)CBr
Solvent: ClCCl
Product: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (500 mg, 1.2 mmol) was dissolved in DCM (15 ml), and TEA (180 mg, 1.8 mmol) and 2-bromoacetyl chloride (243 mg, 1.55 mmol) were added. The mixture was stirred at RT for 2 hours, then was diluted with DCM (50 ml) and washed with HCl 1N (2×). The organic phase was dried over Na2SO4 and evaporated under vacuum, obtaining a crude (550 mg) containing the title compound (MS/ESI+ 541.17 [MH]+) which was employed in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C(Cl)Cl.CO>[Pd].CO>[NH2:1][C:4]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A mixture of 2-nitro-4-(trifluoromethyl)benzoic acid (646 g, 2.75 mol) and 10% palladium on carbon (50% in water, 71 g) in MeOH (3.6 L) was allowed to stir at rt under an atmosphere of H2 (15 psi). After 3 h, TLC (DCM:MeOH 10:1) showed no remaining starting material. The mixture was filtered and the filtrate was concentrated to give 2-amino-4-(trifluoromethyl)benzoic acid (520 g, 92%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([CH2:16][C:17](=O)[CH3:18])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(Cl)Cl.O>C(O)(=O)C>[CH3:18][C:17]1[CH:16]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]2[N:4]=[C:5]([NH2:7])[N:6]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Nc1n[nH]c(N)n1
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)n2nc(N)nc2n1
Yield: 100 %

Procedure:
A mixture of 7.0 g (71 mmol) 3,5-diamino-1,2,4-triazole and 12.0 g (74 mmol) benzoylacetone in 100 ml of glacial acetic acid was heated at reflux 2 hours. After cooling, methylene chloride (200 ml) was added followed by the addition of excess water. The organic layer was separated, washed with water, brine, dried over magensium sulfate and evaporated in vacuo to give a solid residue to which ethyl acetate was added. Filtering gave 16.0 g of crude 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-amine (m.p. 246°-250° C.) which was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C.O>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:17]2[CH2:18][CH2:19][C:11]3[C:10]([NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=4)=[N:15][CH:14]=[N:13][C:12]=3[CH2:16]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 170 °C
Yield: 57.4 %

Procedure:
A mixture of N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.250 g, 0.85 mmol), 2,3-dichloropyridine (0.251 g, 1.69 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.27 mmol) in a mixture of 1,4-dioxane (2 mL) and N,N-dimethylacetamide (0.2 mL) was heated in a sealed tube via microwave (Emerys Optimizer model, Personal Chemistry) for 10 hr at 170° C. The mixture was allowed to cool to room temperature and poured into water (60 mL). The mixture was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated to leave an oil. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to obtain 198 mg of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH2:11][CH2:12][O:13][CH2:14][CH2:15]Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: ClCCOCCCl
Solvent: Cc1ccccc1
Product: COc1cccc(N2CCOCC2)c1
Yield: 77.1 %

Procedure:
A solution of m-anisidine (11.2 mL, 0.1 mol), chloroethyl ether (11.7 mL, 0.1 mol), and diisopropylethylarine (35 mL, 0.2 mol) in toluene (100 mL) was stirred at reflux for 72 h. The precipitate was removed by filtration and washed with toluene (100 mL). The combined toluene solutions were concentrated in vacuo and purified by distillation (120–130° C., 0.2 Torr) to afford the intermediate 4-(3-methoxyphenyl)-morpholine (14.9 g, 77%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=1)[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=1)[C:16]#[N:17])=[O:11]
Reactant: N#Cc1ccnc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1ccnc(C=O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a cooled solution of oxalyl chloride (13.2 mL, 150 mmol) in anhydrous DCM (86 mL) under nitrogen atmosphere at −78° C. was added DMSO (21.2 mL dropwise over 20 minutes. The mixture was stirred for 15 minutes at (−78° C.) before 2-hydroxymethyl-isonicotinonitrile (4.0 g, 30 mmol) dissolved in anhydrous DCM (60 mL) was added dropwise to the reaction mixture over 5 minutes. The reaction was stirred for 2 hrs at −78° C. maintaining a nitrogen atmosphere. A white solid precipitate formed and the temperature was raised to (−55° C.) and triethylamine (6.15 mL, 450 mmol) was added dropwise for over 15 minutes, cooling bath was removed allowing the mixture to warm to room temperature over 2 hrs. The mixture was diluted with DCM (400 mL) and washed with brine (2×50 mL). The aqueous phase was extracted with DCM (3×50 mL). The combined organic layers were combined and concentrated in vacuo. A buff white solid was isolated that was used without any further purification. Single peak in LC-MS analysis, (yield taken to be quantitative), m/z (LC-MS, ESP), RT=2.53 mins, (M+H)=133.0.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K]>CN(C=O)C.CCOCC>[CH2:2]([N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCCN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-1-butene (8-3, 20 g, 148 mmol) in DMF (150 mL) was added potassium phthalimide (8-4, 25 g, 133 mmol) and the mixture stirred for 18 hours at 70° C. After cooling to RT, the mixture was diluted with ether, washed with water and brine, dried over MgSO4, and concentrated to give 8-5 as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].OS(O)(=O)=O.[CH3:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=CC=1O>O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[C:17]([CH3:16])[C:22]([OH:23])=[CH:21][CH:20]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1c(O)cccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To ethyl 4-chloro-3-oxobutanoate (5.77 mL) was added conc.H2SO4 (15.03 mL) at 0° C. Then to the mixture was added 2-methylbenzene-1,3-diol (5.0 g) in several portions at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was warmed to room temperature for 1.5 h. The reaction mixture was poured into water under stirring at 0° C. The precipitate was collected by filtration and washed with water to give the title compound (8.58 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[Cl:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: ClCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCCl)c2)OC1(C)C
Temperature: 62 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (560 mg, 2.89 mmol), 1-Bromo-2-chloro-ethane (0.36 mL, 4.39 mmol), and cesium carbonate (2.81 g, 8.67 mmol) in acetonitrile (20 mL) stirred at 62° C. for 4 hrs. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (664 mg, 90%). 1H NMR (300 MHz, CDCl3): δ 7.84 (s, 1H), 7.79 (s, 1H), 4.45 (t, 2H), 3.90 (t, 2H), 1.34 (s, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([N+:16]([O-])=O)=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl.O>CCO>[NH2:16][C:9]1[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2c(Cl)cc(C(F)(F)F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(C(F)(F)F)cc(Cl)c2[nH]c(=O)c(=O)[nH]c12
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A mixture of 5-chloro-8-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.08 mmol), SnCl2.2 H2O (97 mg, 0.34 mmol) and EtOH (3 mL) was heated at 75° C. with stirring for 12 h. Work-up as above gave 21 mg (93%) of the title compound as a yellow powder. Mp >360° C. 1H NMR (DMSO-d6) 11.441 (s, 1H), 11.324 (s, 1H), 7.241 (s, 1H), 5.916 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)C1C=CC=CC=1.[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[CH2:5][CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1CCNCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 91 %

Procedure:
22.2 g (0.2 mol) of 4-aminomethylpiperidine was dissolved in 250 ml of toluene and 21.2 g (0.2 mol) of benzaldehyde was added thereto. The reaction mixture was refluxed for 3 hours with Dean-stack to remove water, and then cooled down to 0° C. 34.2 g (0.2 mol) of benzylchloroformate was added slowly thereto while stirring. The mixture was stirred at room temperature for 3 hours and 220 ml of 1N aqueous KHSO4 solution was added thereto. The mixture was extracted three times with 200 ml of diethylether, and the aqueous layer was basified with 1N aqueous sodium hydroxide solution. The aqueous solution was saturated with sodium chloride. The aqueous layer was extracted three times with 100 ml of dichloromethane, dried over anhydrous magnesium sulfate and distilled under reduced pressure to give 38 g (Yield 91%, Molecular weight 248) of the title compound.
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[OH2:6]>>[O:6]=[CH:2][C@@H:1]([C@H:2]([C@@H:1]([C@@H:2]([CH2:1][OH:4])[OH:6])[OH:4])[OH:6])[OH:4]
Reactant: CC(=O)[O-]
Reactant: O
Agent: [Na+]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
The substrate used for the assay is a maltodextrin (Maltrin-100 available from the Grain Processing Company, Muscatine, Iowa). 0.1 ml of the enzyme solution was mixed with 0.6 ml of a 5% maltodextrin solution, 0.1 ml of 500 mM sodium acetate solution (pH 5) and water is added to make a total volume of 1 ml. After the mixture is incubated at 60° C. for 30 minutes, the reaction is terminated by immersing the mixture in a boiling water bath for 10 to 20 minutes. Glucose is then determined by the glucose-oxidase method using a glucose analyzer (Yellow Springs Instrument Company, Yellow Springs, Ohio). One glucoamylase unit is defined as the amount of enzyme required to produce 1 gram of glucose in 1 hour under the assay conditions.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Cl.[Br:12]Br>C(O)(=O)C>[Br:12][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1C
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccccc1C(=O)CBr
Reaction time: 3 h
Yield: 96 %

Procedure:
2′-Methylacetophenone (25.0 g, 186 mMole) was dissolved in glacial acetic acid (250 ml) and concentrated HCl (250 uL) was added followed by a dropwise addition of bromine (9.6 ml, 186 mMole) over 15 minutes. The mixture was stirred 3 hours and then concentrated under reduced pressure. The residue was taken up in ethyl ether and washed with saturated NaHCO3 solution. The ether layer was dried over Na2SO4, filtered, and concentrated to yield 38.0 g, (96%) of crude 2-bromo-2′-methylacetophenone which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33]>O1CCCC1.C(N(CC)CC)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.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:33]#[C:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)palladium (55 mg, 0.047 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, then evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[C:22](=O)[N:21]([CH3:24])[C:19](=O)[CH2:18]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1.C(OCC)(=O)C>[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:21]([CH3:24])[CH2:22]1
Reactant: CN1C(=O)CC(c2c[nH]c3ccc(Br)cc23)C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC(c2c[nH]c3ccc(Br)cc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a stirred mixture of lithium aluminum hydride (1.10 g, 29.0 mmol, 2.2 eq) in anhydrous tetrahydrofuran (60 mL) at 0° C. was added 3 -(5-bromoindol-3-yl)-N-methylsuccinimide (4.00 g, 13.02 mmol) portionwise cautiously. The resulting reaction mixture was heated at reflux under nitrogen for 2 hours. The reaction mixture was then cooled, and sodium sulfate decahydrate (approximately 20 g) was added slowly and cautiously, followed by the addition of water (approximately 2 mL) and ethyl acetate (200 mL). The resulting mixture was stirred at room temperature under nitrogen for 2 hours, and then filtered through Celite®. The filtrate was evaporated under reduced pressure to afford the title compound (2.64 g, 9.46 mmol, 73%) as an off-white solid: mp, 163.0°-164.0° C.; TLC Rf =0.30 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 1H NMR (DMSO-d6) δ 11.0 (br m, NH), 7.74 (d, J=1.3 Hz, 1 H), 7.29 (d, J=8.8 Hz, 1 H), 7.20 (br s, 1 H), 7.15 (dd, J=1.7 and 8.6 Hz, 1 H), 3.55-3.45 (m, 1 H), 2.88 (t, J=8.2 Hz, 1 H), 2.62-2.42 (m, 3 H), 2.29 (s, 3 H), 2.28-2.21 (m, 1 H), 1.90-1.80 (m, 1 H); 13C NMR (DMSO-d6) d 135.4,128.2,123.4, 122.9,121.1, 118.3, 113.5,110.8, 62.6, 56.0, 42.1, 34.4, 32.2; HMRS calculated for C13H,5 BrN2 278.0415, found 278.0355.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)C(=O)C2=CC=CC=C12.NN.Cl>CO>[NH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: NN
Solvent: CO
Product: COC(=O)c1ccc(OCCN)cc1

Procedure:
19-2 (1.59 g, 4.89 mmol) was suspended in 25 mL MeOH. Upon addition of hydrazine (2.0 mL, 64 mmol) the reaction became homogeneous. After 20 h a heavy precipitate had formed. The pH was adjusted to 1 by addition of 6N HCl, MeOH evaporated, and the solid suspended in 1N HCl. After filtering through Celite, the filtrate was washed with CH2Cl2, the pH was adjusted to 12 with 6N NaOH. The aqueous layer was extracted with fresh CH2Cl2. This organic phase was dried (Na2SO4) and concentrated providing 19-3 as a white solid.