Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CCC(C)=O>[CH3:19][C@@H:13]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC[C@@H](C)Oc1ccccc1F
Reaction time: 14 h
Yield: 74.6 %

Procedure:
A reaction vessel was charged with 10 g of 2-fluorophenol, 25 g of (S)-1-methylhexyl tosylate, 20 g of potassium carbonate and 160 ml of MEK, and the mixture was refluxed with stirring for 14 hours (the disappearance of the starting materials was confirmed by TLC). The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with water and dried over Glauber's salt, and the solvents were distilled off. The residue was distilled under reduced pressure to obtain 14 g (74.5%) of (R) -2- (1-methylhexyl) oxyfluorobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:19]([O:31][CH3:32])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[C:19]([O:31][CH3:32])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccnc3)c(OC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cccnc3)c(OC)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridylmethoxy)benzyl]-1H-pyrazole-4-yl]propionate (527 mg), 1 N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N hydrochloric acid (2.5 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (381 mg, yield: 77%) was obtained. This was recrystallized from ethanol-hexane. Melting point: 124–125° C.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:17][C@H:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C[O-]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
8-Bromo-2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.1 g, 18.48 mmol) was dissolved in anhydrous methanol (70 ml) and a solution of sodium methoxide (25%) in methanol (8 ml) was added dropwise under an atmosphere of nitrogen. The solution was heated to reflux at 90° C. for 4 hours under an atmosphere of nitrogen. Additional sodium methoxide in methanol (25% solution, 3 ml) was added and the reaction was stirred at 60° C. for a further 16 hours. An additional portion of sodium methoxide in methanol (25% solution, 5 ml) was added and the reaction was stirred at 90° C. for a further 7 hours. The solvent was removed on the rotary evaporator and the crude product was partitioned between EtOAc (75 ml) and saturated ammonium chloride solution (75 ml). The organic layer was washed with brine (75 ml). The solvent was removed on the rotary evaporator to yield the title compound as a pale orange foam (6 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][NH:23][CH3:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([N:23]([CH2:22][C:21]([O:20][CH3:19])=[O:25])[CH3:24])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCC(=O)OC
Reactant: N#Cc1ccn(Cc2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)C(=O)c1c(C#N)ccn1Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A solution of 1-benzyl-3-cyano-1H-pyrrole-2-carboxylic acid (7.3 g, 32.4 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was treated with sarcosine methyl ester hydrochloride (12 g, 86 mmol) and DIPEA (30 mL, 172 mmol), followed by HATU (26 g, 68.4 mmol). The mixture was stirred at 40° C. for 1 hour. The mixture was cooled to room temperature, brine was added and the resultant was extracted with ethyl acetate. The combined extracts were washed with HCl (1M), followed by brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-3-cyano-N-methyl-1H-pyrrole-2-carboxamido)acetate (9.2 g, 29.6 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.31-7.38 (m, 3H). 7.20-7.26 (m, 2H) 6.73-6.78 (m, 1H) 6.40-6.46 (m, 1H) 5.17-5.26 (s, 2H) 4.16-4.26 (s, 2H) 3.71-3.80 (s, 3H) 3.06-3.15 (s, 3H); LCMS (m/z) ES+=312 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:14])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2sc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2sc(Br)cc12

Procedure:
6-Bromo-3H-thieno[2,3-d]pyrimidin-4-one (11.64 g, 0.05 mol) was added portion-wise to phosphoryl chloride (220 ml) and the resulting mixture was heated under reflux for 6 hours. The excess phosphoryl chloride was then removed in vacuo. The resulting residue was dissolved in dichloromethane (250 ml) and washed with water (2×100 ml), followed by saturated sodium hydrogen carbonate solution (100 ml). The organic layer was then dried (MgSO4) and the solvent was removed in vacuo to give 6-bromo-4-chlorothieno[2,3-d]pyrimidine (9.06 g) as a yellow solid, which was used without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O[CH2:23][C:24]2([CH3:27])[CH2:26][O:25]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[CH3:23][C:24]1([CH2:27][S:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][N:10]=2)[CH2:26][O:25]1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)CO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CSc2nnnn2-c2ccccc2)CO1
Temperature: 60 °C
Reaction time: 6 h
Yield: 39 %

Procedure:
A mixture of 1-phenyl-5-mercapto-1H-tetrazole (3.5 g, 19.64 mmol), (2-methyl-2-oxiranylmethyl) toluene-4-sulfonate (5 g, 20.64 mmol), potassium carbonate (3 g, 21.71 mmol), and sodium iodide (4.5 g, 30.02 mmol) in DMF (30 ml) was stirred at 60° C. for 6 hours. The reaction mixture was was poured into water, and extracted with ethyl acetate twice. The extracts were combined, washed with 5% sodium hydroxide aqueous solution and then with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford 5-(2-methyl-2-oxiranylmethylsulfanyl)-1-phenyl-1H-tetrazole (1.9 g, yield 39%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[H-].[Na+].Cl[CH2:26][S:27][CH3:28]>CN(C)C=O>[CH3:26][S:27][CH2:28][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
To a solution of 100 mg (0.35 mmol) of 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one in 0.5 ml of dimethylformamide were added 17 mg (0.42 mmol, 1.2 equiv.) of a 60% sodium hydride suspension in mineral oil. After stirring for 1 h at room temperature, 40 uL (50 mg, 0.52 mmol, 1.5 equiv.) of chloromethyl methylsulfide were added and the suspension was stirred for another 16 h at room temperature. After workup with methylene chloride/water, the crude material was purified by flash chromatography (SiO2, gradient ethyl acetate to ethyl acetate:methanol 90:10 v/v) to yield 32 mg of the title compound as a light yellow solid, MS: 350.2 (M+H+).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH:16]=[O:17]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:8][O:17]2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: C[S+](C)C
Reactant: COc1ccc(C=O)cc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 3-fluoro-4-methoxybenzaldehyde (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether (4×50 mL), dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:24][O:25][C:26]1[C:27](=[O:50])[C:28]([CH3:49])=[C:29]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:45]C(=O)C)=[C:40]([CH:44]=2)[C:41](O)=[O:42])[C:30](=[O:34])[C:31]=1[O:32][CH3:33]>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:36]([CH2:35][C:29]3[C:30](=[O:34])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[C:27](=[O:50])[C:28]=3[CH3:49])[CH:37]=[CH:38][C:39]=2[OH:45])=[CH:3][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccncc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccncc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.3 %

Procedure:
4-Aminopyridine (0.282 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.123 mmol, 12%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: CN(C)CCNCc1ccccc1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(CCN(C)C)Cc3ccccc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with N'-benzyl-N,N-dimethyl-ethane-1,2-diamine to give 98 mg of {4-[benzyl-(2-dimethylamino-ethyl)-carbamoyl]-6,8-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C29H38H4O5+H 523.6; found 523.0.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][C@@H:30]2[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40]>>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][C@@H:30]5[CH2:34][CH2:33][N:32]([CH2:35][CH3:36])[CH2:31]5)=[O:28])=[CH:25][C:24]=4[O:39][CH3:40])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CC[C@@H](NC(=O)c2ccc(N)c(OC)c2)C1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CCN1CC[C@@H](NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CC3)C(=O)N4C)c(OC)c2)C1

Procedure:
The title compound was prepared by an analogous method to the preparation of Example 350, utilising, 2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 75 mg, 0.24 mmol), and 4-amino-N-[(3R)-1-ethylpyrrolidin-3-yl]-3-methoxy-benzamide (Intermediate 245; 70 mg, 0.26 mmol) heating by microwave irradiation at 160° C. for 1 hour, as an off-white foam (50 mg, 39%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]1[C:14]2[N:15]([CH3:19])[C:16](=O)[NH:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[N:15]([CH3:19])[C:14]2[C:9]([N:4]3[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]3[CH2:1][CH3:2])=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]=1
Reactant: CCC1CCCCN1c1cccc2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCC1CCCCN1c1cccc2nc(Cl)n(C)c12
Yield: 89.8 %

Procedure:
A mixture of 7-(2-ethyl-1-piperidinyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.77 mmol) and phosphorus oxychloride (3.55 g, 23.1 mol) was refluxed for 12 h with stirring and concentrated to dryness under vacuum. The residue was purified by column chromatography eluting with a 10% acetone/hexanes mixture to afford 192 mg (90%) of the title compound.
Reaction SMILES: [NH3:1].[NH2-].[Na+].[CH3:4][CH2:5][CH2:6][CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>CN(C)C1C=CC=CC=1>[CH3:12][CH2:11][CH2:10][CH2:9][CH:8]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5][CH3:4].[NH2:1][C:15]1[CH:14]=[C:13]([CH:8]([CH2:7][CH2:6][CH2:5][CH3:4])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:18]=[CH:17][N:16]=1
Reactant: N
Reactant: [H][H]
Agent: CCCCC(CCCC)c1ccncc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CCCCC(CCCC)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
Liquid ammonia, containing one mole of freshly prepared sodamide, was replaced with 500 cc of N,N-dimethylaniline. The mixture was heated to 150° C. and 102.5 g (0.5 moles) of 4-(5-nonyl)pyridine was rapidly added through a dropping funnel. This mixture was heated to 175° C. at which point a fast evolution of hydrogen gas began. The reaction mixture was kept at 175°-180° C. for 4.5 hours and then allowed to cool over night with little hydrogen gas evolution during the last hour of the heating period. The cooled mixture was then hydrolyzed with 200 cc of water and the organic phase was separated and distilled to give 8.7 g of unreacted 4-(5-nonyl)pyridine and 39.2 g of 2-amino-4-(5-nonyl)pyridine, with most of the aminopyridine product boiling at 162°-164° C. and 2 mm Hg. Also obtained from such distilling was 18.6 g of 4,4'-di-(5-nonyl)-2,2'-bipyridyl, such 2,2' -bipyridyl product boiling at 237°-250° C. and 1 mm Hg. Based on the recovered 4-(5-nonyl)pyridine, yields were calculated for the amino product of 38.9% and for the 2,2'-bipyridyl product of 19.9%. Upon subsequent testing, the 2,2'-bipyridyl product performed effectively as a metal chelating agent and exhibited significant and valuable fungicidal properties.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.[C:27]([O:30][CH2:31][C:32](Cl)=O)(=[O:29])[CH3:28]>C1COCC1.O>[C:27]([O:30][CH2:31][C:32]1[O:1][N:2]=[C:3]([N:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:8][CH2:9]2)[N:17]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)OCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
1,1-Dimethylethyl 4-[(hydroxyamino)(imino)methyl]piperazine-1-carboxylate (3.58 g, 14.6 mmol) was suspended in THF (50 mL) followed by the addition of diisopropylethylamine (3.0 mL, 17.5 mmol) and the mixture was cooled to 0° C. Acetoxyacetyl chloride (1.6 mL, 14.6 mmol) was added by syringe and the mixture was allowed to stir an additional 30 minutes at 0° C. The resulting homogeneous solution was allowed to warm to room temperature then concentrated in vacuo to afford a white solid residue. The material was suspended in water (50 ml) and the solid product was collected by filtration, washed with additional water then hexanes and dried in vacuo. The intermediate O-acyl derivative was then suspended in THF (50 mL) followed by addition of TBAF (1.0M in THF, 3.5 mL) and the mixture was stirred for 30 minutes at room temperature. The homogeneous solution obtained was concentrated in vacuo and the residue partitioned with ethyl ether and water. The organic layer was washed twice with additional water then with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration and concentration gave 1,1-dimethylethyl 4-{5-[(acetoxy)methyl]-1,2,4-oxadiazol-3-yl}piperazine-1-carboxylate (3.6 g, 76% yield) as a colorless crystalline solid. 1H-NMR (400 MHz, CDCl3): 5.14 (s, 2H), 3.51 (tr, 4H), 3.42 (tr, 4H), 2.18 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH3:2].[CH2:8]=[O:9]>ClCCl>[CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2]
Reactant: C=O
Reactant: CCn1cncn1
Solvent: ClCCl
Product: CCn1ncnc1CO
Temperature: 170 °C
Yield: 63.2 %

Procedure:
A mixture of 18a (0.5 g, 5.1 mmol) and paraformaldehyde (0.8 g) were heated at 170° C. for 2 hr under microwave irradiation in a 10-mL tube. The mixture was cooled to room temperature and diluted with dichloromethane (10 mL). The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Two runs (total of 10.3 mmol) were combined and the crude product was purified on an Analogix automated column chromatography system (24 g column, 0-4% MeOH/dichloromethane) to give 410 mg of 26a as a white solid.
Reaction SMILES: I[CH2:2][C:3]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:64][C:65]1[CH:77]=[CH:76][C:75]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68](=[O:78])[C:67]=2[CH:66]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:46]([O:45][CH2:44][C:3]([CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:2][O:64][C:65]1[CH:77]=[CH:76][C:75]2[C:74]3[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=3)[C:68](=[O:78])[C:67]=2[CH:66]=1)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCCCCCCCOCC(CI)(COCCCCCCCCCCCCCCCCCC)COCCCCCCCCCCCCCCCCCC
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc2c(c1)C(=O)c1ccccc1-2
Temperature: 130 °C
Yield: 92.2 %

Procedure:
1-(3-Iodo-2,2-bis-octadecanoxymethyl-propoxy)octadecane (500 mg, 102 μmol) and 2-hydroxy-9-fluorenone (30 mg, 152 μmol) were dissolved in DMF (2 ml), potassium carbonate (21 mg, 152 μmol) was added, and the mixture was stirred at 130° C. After completion of the reaction, 0.5N hydrochloric acid (6 ml) was added, the precipitate was filtered, and the precipitate was washed with acetonitrile and water to give 2-(3-octadecyloxy-2,2-bis-octadecyloxymethyl-propoxy)-9-fluorenone (101 mg, 94 μmol).
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[C:9]([C@:11]2([O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]2[O:14]C(=O)C)[OH:12])[CH:8]=[C:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=2)[C:6]=1[CH3:44])#[N:4].Cl>CO.C1COCC1>[C:3]([C:5]1[CH:10]=[C:9]([C@:11]2([O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]2[OH:14])[OH:12])[CH:8]=[C:7]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([CH2:42][CH3:43])=[CH:40][CH:41]=2)[C:6]=1[CH3:44])#[N:4]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(C#N)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(C#N)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (1.7 mL, 4 mol/L) is added to 1-cyano-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene (0.85 g) dissolved in methanol (6 mL) and THF (3 mL). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1:0->8:1).