Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C2CCCCCCCCCC2)CCCN=CCCCCC1.[CH3:23][N:24]1[N:33]=[N:32][C:31]2[N:27]([CH:28]=[N:29][C:30]=2[C:34]([NH2:36])=[O:35])[C:25]1=[O:26].IC[C:39]([O:41][CH2:42][CH3:43])=[O:40].Cl>C(#N)C>[C:34]([C:30]1[N:29]=[CH:28][N:27]2[C:25](=[O:26])[N:24]([CH2:23][C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:33]=[N:32][C:31]=12)(=[O:35])[NH2:36]
Reactant: CCOC(=O)CI
Reactant: Cn1nnc2c(C(N)=O)ncn2c1=O
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 8 h
Yield: 13.1 %

Procedure:
1,8-Diazabicycloundec-7-ene (DBU) (32 μL, 0.215 mmol, 1.5 eq.) was added dropwise to a suspension of the hydroxymethyl derivative of Temozolomide (3-(hydroxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide) (30 mg, 0.143 mmol) and ethyl iodoacetate (43 μL, 0.357 mmol, 2.5 eq.) in acetonitrile (700 μL). The resulting green suspension became homogeneous and was stirred overnight. The reaction was acidified with 1 N HCl and the yellow solution was extracted four times with ethyl acetate. The combined organic extracts were washed with water and then dried over MgSO4. The solvent was removed under vacuum and the pale yellow solid was triturated with diethyl ether to remove the excess of ethyl iodoacetate. The precipitate was filtered to give 5 mg of the title compound as a yellow solid (13% crude). 1H NMR (DMSO d6): 8.93 (s, 1H), 7.89 (s, 1H), 7.75 (s, 1H), 5.23 (s, 2H), 4.20-4.23 (q, 2H, J=7.1 Hz), 1.22-1.26 (t, 3H, J=7.1 Hz). LCMS: 97% pure; m/z: 289.4 (M+Na+), 267.5 (MH+).
Reaction SMILES: [NH:1]1CCCCC1.[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].Cl[C:22]([O:24][CH3:25])=[O:23].Cl>CN(C=O)C>[CH3:7][O:8][CH2:9][CH2:10][C@H:11]([NH:1][C:22]([O:24][CH3:25])=[O:23])[C:12]([OH:14])=[O:13]
Reactant: C1CCNCC1
Reactant: COC(=O)Cl
Reactant: COCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC[C@H](NC(=O)OC)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
Piperidine (1.0 mL, 10 mmol) was added to a solution of (S)-2-(9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxybutanoic acid (0.355 g, 1 mmol) in DMF (3 mL), and the mixture was stirred at rt for 3 h. The volatiles were removed and the residue was partitioned between sat. NaHCO3 (aq.) (5 mL) and EtOAc (5 mL). The aqueous layer was further washed with EtOAc and Et2O. To the aqueous solution was added Na2CO3 (212 mg, 2.0 mmol) followed by methyl chloroformate (0.16 mL, 2.0 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was acidified with 1 N HCl (aq.) until pH <7 and then extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified by flash silica chromatography (EtOAc/hexanes, gradient from 20% to 70%) to yield (S)-4-methoxy-2-(methoxycarbonylamino)butanoic acid (Cap-194) (91.5 mg) as viscous colorless oil. LC-MS retention time=0.61 min; m/z 214 [M+Na]+. (Column: PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% Water:10% Methanol: 0.1% TFA. Solvent B=10% Water:90% Methanol: 0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, chloroform-d) δ ppm 7.41 (br. s., 1 H), 5.74-6.02 (m, 1 H), 4.32-4.56 (m, 1 H), 3.70 (s, 3 H), 3.54 (t, J=5.0 Hz, 2 H), 3.34 (s, 3 H), 1.99-2.23 (m, 2 H).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.O.NN.C(OCC)C>C(O)C>[N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCCCNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione (15.0 g, 42.98 mmol) dissolved in ethanol (215 ml) was added hydrazine hydrate (13.4 ml). The solution was stirred for 16 hours at room temperature under a N2 atmosphere. A white precipitate formed. Diethyl ether (215 ml) was added and the mixture was stirred for 10 min then filtered and concentrated. Purification via column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 96:3:1, v/v/v) afforded the product as a brown oil (6.77 g, 74%). 1H NMR (CDCl3) δ 1.57 (m, 9H), 2.05 (m, 2H), 2.75 (m, 6H), 3.78 (t, 1H), 7.06 (dd, 1H, J=7.89, 4.82 Hz), 7.37 (d, 1H, J=7.89 Hz), 8.39 (d, 1H, J=4.82 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:10])=[O:9])=[C:4]([CH2:22][NH2:23])[CH:3]=1.C(N(CC)CC)C.[CH:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:19][O:18][B:17]([OH:20])[C:16]=3[CH:21]=2)(=[O:9])=[O:10])=[C:4]([CH2:22][NH:23][S:34]([CH:31]2[CH2:33][CH2:32]2)(=[O:36])=[O:35])[CH:3]=1
Reactant: NCc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CNS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.9 %

Procedure:
To a stirred solution of 4-amino-2-(aminomethyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)benzenesulfonamide (708 mg, 2.1 mmol) and triethylamine (1 mL, 7 mmol) in 100 mL of DCM was added cyclopropanesulfonyl chloride (0.3 g, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the majority of the solvent was removed under vacuum, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated, the crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a yellow solid (45 mg, yield 5%). MS calcd for (C17H20BN3O6S2): 437.1. MS found (ESI negative): (M−H)−=336.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 9.17 (bs, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.50 (t, J=6.4 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.11 (dd, J=8, 1.6 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 6.40 (dd, J=8.4, 2.4 Hz, 1H), 4.86 (s, 2H), 4.44 (d, J=6.4 Hz, 2H), 2.60 (m, 1H), 0.92 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:8][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cnc(Cl)cc1N
Temperature: 100 °C

Procedure:
Iron (1.0 g) was added to a solution of 10 (500 mg, 2.6 mmol) in glacial acetic acid (10 mL). The reaction mixture was then heated at 100° C. for 20 minutes. The suspension was poured on aqueous NaOH 1M and extracted with ethyl acetate. After drying over Na2SO4, the solvent was then evaporated and 11 was isolated as a colorless solid (370 mg, 2.6 mmol, HPLC Rt=1.3 min, FIA ES+ 143.0).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([O:16]C)[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([OH:16])[C:13]([C:18]#[N:19])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(OC)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(O)c(C#N)c2)cc1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of 4-(3-cyano-4-methoxypyrrole-1-yl)benzoic acid ethyl ester (0.081 g) in dichloromethane (3 mL) was added boron tribromide (0.33 mL, 1 mol/L dichloromethane solution) under ice-cooling, and this mixture was stirred at same temperature for 2 hours. To this reaction mixture was added water, and this mixture was extracted with diethyl ether. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) to give 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g). To a solution of 4-(3-cyano-4-hydroxypyrrole-1-yl)benzoic acid ethyl ester (0.052 g) in N,N-dimethylformamide (4 mL) were added benzylbromide (0.038 g) and cesium carbonate (0.13 g) at room temperature, and this mixture was stirred at 80° C. for 5 hours. To this reaction mixture was added water at room temperature, and the precipitated solid was collected by filtration, and washed with methanol (5 mL) to give the title compound (0.016 g).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25][C@@H:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[S:43]([NH2:46])(=[O:45])=[O:44]>C(Cl)Cl.C(#N)C>[C:11]([O:10][C@H:9]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH:25][C@@H:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[O:7][C@@H:8]1[CH2:14][O:15][S:43]([NH2:46])(=[O:45])=[O:44])(=[O:13])[CH3:12]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](COS(N)(=O)=O)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Temperature: 0 °C
Yield: 48 %

Procedure:
(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (0.188 g, 0.40 mmol) was stirred in anhydrous methylene chloride (0.6 mL) cooled to 0° C. Triethylamine (0.081 mL, 0.80 mmol) was added followed by the dropwise addition of a 2 N solution of chlorosulfonamide in acetonitrile (0.6 mL). The yellow solution was concentrated after one hour. The residue was purified by column chromatography using 0-5% methanol/methylene chloride concentrated to give the title compound as a yellow solid (0.104 g, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([N+:10]([O-:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:23]OS(OC)(=O)=O.Cl>CN(C=O)C.CCOC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:8]1[CH:7]=[N:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=1)([CH3:20])[CH3:23])[CH3:19]
Reactant: CCOC(=O)C(C)Cl
Reactant: COS(=O)(=O)OC
Reactant: CCOc1cccnc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1cnc([N+](=O)[O-])c(OCC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A solution of 3-ethoxy-2-nitro-pyridine (0.84 g) and ethyl 2-chloropropionate (2.1 g) in DMF (8 mL) was added dropwise to a slurry of sodium hydride (0.6 g, 60% suspension in oil) in DMF (8 mL) while cooling at 0–5° C. The resulting purple-colored solution was stirred at 0–5° C. for one hr., and then at room temperature for two hrs. Dimethylsulfate (0.89 g) was added to the solution and the reaction mixture was shaken overnight. The resulting amber-colored solution was poured onto a mixture of 1N aqueous hydrogen chloride (20 mL), ice water (20 mL), and EtOAc (50 mL), and the phases were separated. The organic phase was washed with 1N aqueous sodium hydroxide, water, and brine. The solvent was evaporated to give an amber-colored oil (933 mg), which was purified by flash chromatography on silica gel, eluting with 1:4 ethyl acetate/hexanes to give 389 mg (28% yield) of a pale yellow oil. AP/MS+=283.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([Cl:15])=[N:7][CH:6]=1)C=C.CCO[C:19]([CH3:21])=O.O.[CH3:23]OCCOCCOC>[Cl-].[Na+].O>[CH2:23]([C:6]1[N:7]=[C:8]([Cl:15])[C:9]2[C:14]([C:5]=1[OH:4])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH2:21]
Reactant: COCCOCCOC
Reactant: CCOC(C)=O
Reactant: C=CCOc1cnc(Cl)c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CCc1nc(Cl)c2ccccc2c1O
Temperature: 180 °C
Yield: 67 %

Procedure:
4-(allyloxy)-1-chloroisoquinoline (1.0 g, 4.55 mmol) was dissolved in diglyme (5 mL) and heated to 180° C. for 1 h. The reaction was cooled down to rt before adding EtOAc and water. Washed EtOAc layer with water then brine solution. The organic layer was then dried and concentrated. The residue was purified by flash chromatography with 20% of EtOAc/hexane to afford 3-allyl-1-chloroisoquinolin-4-ol (670 mg, 67%) as product. MS: MS m/z 220.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.[C:13](O)(=[O:15])C.C(O)(=O)C.IC1C=CC=CC=1.CS(O)(=O)=O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[C:5]2[O:15][CH3:13]
Reactant: CC(=O)O
Reactant: Oc1nccc2cc(F)ccc12
Agent: CS(=O)(=O)O
Solvent: Ic1ccccc1
Solvent: CO
Product: COc1cnc(O)c2ccc(F)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
6-fluoroisoquinolin-1-ol (1 g, 6.13 mmol), iodobenzene diacetate (2.172 g, 6.74 mmol) and MeOH (15 ml) were added to a sealed tube. To the mixture was added methanesulfonic acid (0.477 ml, 7.36 mmol). The threaded stopper was affixed to the vessel and the mixture was heated first to 70° C. for 4 h and then to 130° C. for 3 h. The mixture was concentrated in vacuo to remove half of methanol, then 5 mL of water was added and the solid was collected by filtration and washed thoroughly with 1:1 methanol/water then dried in vacuo to give 6-fluoro-4-methoxyisoquinolin-1-ol (800 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (dd, J=9.0, 5.8 Hz, 1H), 7.49 (dd, J=10.0, 2.5 Hz, 1H), 7.46-7.42 (m, 1H), 6.83 (d, J=6.3 Hz, 1H), 3.81 (s, 3H); MS m/z 194.1 (M++1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]3[O:11][CH:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14][C:15]=3[C:16]([C:18](O)=[O:19])=[CH:17][C:8]=2[N:7]=[C:6]1[CH3:27].[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[OH:32][CH2:31][CH2:30][N:29]([CH3:28])[C:18]([C:16]1[C:15]2[CH2:14][CH2:13][CH:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:11][C:10]=2[C:9]2[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([CH3:27])=[N:7][C:8]=2[CH:17]=1)=[O:19]
Reactant: COCCn1c(C)nc2cc(C(=O)O)c3c(c21)OC(c1ccccc1)CC3
Reactant: CNCCO
Product: COCCn1c(C)nc2cc(C(=O)N(C)CCO)c3c(c21)OC(c1ccccc1)CC3

Procedure:
The title compound was prepared as a white solid in quantitative yield from 1-(2-methoxyethyl)-2-methyl-8-phenyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxylic acid (200 mg, 0.55 mmol, Step 12 of Example 1) and 2-(methylamino)ethanol (45 mg, 0.60 mmol) by the same manner in Step 13 of Example 1.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N+]([C:18]1[CH:19]=[C:20]([C:26]#[N:27])[C:21](=[CH:24][CH:25]=1)[C:22]#[N:23])([O-])=O.[C:28](=[O:31])([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:26]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][C:21]=1[C:22]#[N:23])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:31][C:28]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]#[N:27])[CH:19]=1)#[N:27]
Reactant: O=C([O-])[O-]
Reactant: OCCCCCCCCCCCCO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(OCCCCCCCCCCCCOc2ccc(C#N)c(C#N)c2)cc1C#N

Procedure:
A mixture of 1,12-dodecanediol (20.4 g, 0.10 mol), 4-nitrophthalonitrile (35 g, 0.20 mol), anhydrous potassium carbonate (69 g, 0.50 mol) and 180 ml of dimethyl sulfoxide was heated at 70°-75° C. for 6 hours under a nitrogen atmosphere. The potassium carbonate was added in three portions. After cooling, the content was slowly poured into 500 ml of cold dilute (2 N) hydrochloric acid. The aqueous solution was extracted with four, 100 ml portions of chloroform. The combined extract was washed several times with water, charcoaled, dried over anhydrous sodium sulfate and concentrated to afford 42 g of crude product. Recrystallization from ethanol-water yielded 24.4 g (54%), m.p. 104°-107° C. of 1,12-bis(3,4-dicyanophenoxy) dodecane.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]1[CH2:12][C:13]([O-:15])=O.N1C2C(=O)CCCC=2C=CC=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:13](=[O:15])[CH2:12][CH:3]3[C:2]([C:11]4[CH:10]=[N:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:35]2)=[CH:30][CH:29]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C([O-])CC1C=CC2=C(CNCC2)C1=O
Agent: O=C1CCCc2cccnc21
Product: O=C1CC2CCc3ccncc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from methyl 5,6,7,8, -tetrahydro-8-oxoisoquinoline-7-acetate (prepared from 5,6-dihydroquinoline-8(7H)-one (Boyd et al, J. Chem. Soc., Perkin Trans. I (1992)31) according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2([NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[N:27]5[C@@:28]([CH2:41][C:42]6[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=6)([CH3:40])[C:29](=[O:39])[N:30]([C:31]6[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=6)[C:26]5=[N:25][CH:24]=4)=[O:22])[CH2:19][CH2:18]3)=[O:16])[CH2:13][CH2:12]2)[CH:6]=1.CCN(C(C)C)[CH:53]([CH3:55])[CH3:54].BrCCCBr>CC(N(C)C)=O.CCOC(C)=O>[N:3]1([CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]3([NH:14][C:15]([C:17]4([NH:20][C:21]([C:23]5[N:27]6[C@@:28]([CH2:41][C:42]7[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=7)([CH3:40])[C:29](=[O:39])[N:30]([C:31]7[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=7)[C:26]6=[N:25][CH:24]=5)=[O:22])[CH2:18][CH2:19]4)=[O:16])[CH2:12][CH2:13]3)[CH:6]=2)[CH2:55][CH2:53][CH2:54]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Reactant: CCN(C(C)C)C(C)C
Agent: BrCCCBr
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN6CCC6)ccn5)CC4)CC3)n21
Temperature: 100 °C
Yield: 13 %

Procedure:
To the solution of (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide dihydrochloric acid salt (60 mg, 0.081 mmol) in dry DMA (5 mL) was added DIPEA (0.071 mL, 0.405 mmol) followed by 1,3-dibromopropane (0.0415 mL, 0.405 mmol). The reaction mixture was heated in the microwave at 100° C. for 2×10 min. Diluted with EtOAc (50 mL). Washed with saturated NaHCO3 (2×25 mL). Layers were separated. The organic layer was dried, filtered, and concentrated. The resultant crude product was purified by prep-TLC using 5% MeOH/DCM as the eluent. The prep TLC plate looked messy, presumably due to the significant existence of DMA. The product fraction was collected and redissolved in EtOAc (50 mL), washed with water (3×15 mL), dried, filtered, and concentrated. The crude product was purified by prep-TLC using 5% MeOH/DCM as the eluent to afford 7.5 mg of the title compound as a light yellow solid, m/z 709.8 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1.Cl[CH2:23][CH:24]([OH:27])[CH2:25][OH:26].O>C1(C)C=CC=CC=1>[OH:27][CH:24]([CH2:25][OH:26])[CH2:23][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: OCC(O)CCl
Reactant: O=C1Nc2ccc(O)cc2C1=Cc1c[nH]c2ncccc12
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2ccc(OCC(O)CO)cc2C1=Cc1c[nH]c2ncccc12
Yield: 70 %

Procedure:
To a solution of 5-hydroxy-3-[(7-azaindol-3-yl)methylene]-2-oxindole (2.773 g, 10 mmol) in toluene (100 ml) was added portionwise under nitrogen NaH 80% (0.300 g, 10 mmol). After the salification was complete 3-chloro-1,2-propane-diol (1.547 g, 14 mmol) was added and the mixture heated to reflux for 5 h. After cooling water was added, the organic phase washed and evaporated to dryness. The residue was submitted to flash chromatography using CHCl3 --MeOH mixtures as eluant to give pure title compound in about 70% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:19])[N:12]=1.[CH2:20]([O:22][C:23]([N:25]=[C:26]=S)=[O:24])[CH3:21].C(N=C=NC(C)C)(C)C>C(#N)C.C(N(CC)CC)C>[NH2:19][C:13]1[N:12]=[C:11]([S:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:16]=[C:15]2[C:14]=1[N:18]=[C:26]([NH:25][C:23](=[O:24])[O:22][CH2:20][CH3:21])[NH:17]2
Reactant: CCOC(=O)N=C=S
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Agent: CC(C)N=C=NC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)Nc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of the product of example 5, step (c) (10.5 g) in acetonitrile (50 ml) and triethylamine (17 ml) was added to an ice cold stirred solution of ethoxycarbonylisothiocyanate (3 ml) in acetonitrile (50 ml). This mixture was then stirred at room temperature for 20 min. Diisopropylcarbodiimide (4.5 ml) was then added and the reaction mixture was stirred at reflux for 2 hr and allowed to cool. The reaction mixture was evaporated to dryness and purified by flash chromatography on silica gel (ethyl acetate:dichloromethane, 1:1) to yield the sub-titled compound as a yellow solid (3.0 g).
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=O)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C1C=NC2N(O)N=NC=2C=1.[NH2:53][C:54]1[CH:55]=[C:56]([S:60]([OH:63])(=[O:62])=[O:61])[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl.FC(F)(F)C(O)=O.C(N(CC)CC)C>[NH2:8][C@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][C:12]([NH:53][C:54]1[CH:55]=[C:56]([S:60]([OH:63])(=[O:61])=[O:62])[CH:57]=[CH:58][CH:59]=1)=[O:14]
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)CCC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OME, 130 mg (0.5 mmol), 190 mg (0.5 mmol) of 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 70 mg (0.5 mmol) of 7-aza-1-hydroxybenzotriazole (HOAt) and 87 mg (0.5 mmol) of 3-aminobenzenesulfonic acid were suspended in 2.0 ml of methylene chloride, and 0.5 ml of triethylamine was added to the suspension. The mixture was stirred at room temperature overnight. After the solvent was removed by distillation, the purification step A was applied to give the intermediate. The crude product was dissolved in 4.0 ml of trifluoroacetic acid (TFA) and stirred at room temperature for an hour. After the solvent was removed by distillation, the purification step A was applied to give 7.4 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[O:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].[H][H].O1C=C[CH:16]=[CH:15]1>C(O)C.[Pt]>[CH2:15]([O:10][CH2:9][C:8]1[O:11][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[CH:6][CH:7]=1)[CH3:16]
Reactant: CCOCc1ccc(C=O)o1
Reactant: [H][H]
Reactant: c1ccoc1
Agent: [Pt]
Solvent: CCO
Product: CCOCc1ccc(COCC)o1
Yield: 80 %

Procedure:
In a 7.5 ml batch reactor, 0.06 mmol 5-(ethoxymethyl)furfural (EMF) in 1 mL ethanol and 5 bars of hydrogen was reacted with 3 mol % of a Pt/C catalyst for 4 days at room temperature. The starting material was completely converted in 100% selectivity to 5-(ethoxymethyl)-2-hydroxymethyl)furan. Subsequently, the mixture was heated to 75° C. for 1 day without hydrogen. The 5-(ethoxymethyl)-2-hydroxymethyl)furan was fully converted and 2,5-bis(ethoxymethyl)furan was obtained in 80% yield. 20% Side products are ring opened levulinate derivatives. The experiment was successfully repeated on a 20 gram scale.