Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:9][CH2:10][Cl:11]>CC(C)=O>[Br-:9].[Cl:11][CH2:10][N+:1]12[CH2:8][CH2:7][N:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: C1CN2CCN1CC2
Reactant: ClCBr
Solvent: CC(C)=O
Product: ClC[N+]12CCN(CC1)CC2
Product: [Br-]
Temperature: 25 °C

Procedure:
20 ml Of acetone, 4.0 g of 1,4-diazabicyclo[2.2.2]octane, and 20 ml of bromochloromethane, were added to a flask, capped, and stirred at room temperature. Within 45 minutes white precipitate had formed. After 3.5 hours the mixture was cooled to 0-5 C, filtered, washed with three 10 ml portions of cold acetone, and dried under reduced pressure overnight. 2.31 g Of a white solid was obtained.
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)=[CH:12][CH:11]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]([F:33])([F:32])[C:29]([NH2:31])=[O:30].[O-2].[Mg+2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[O:24]1[CH:25]=[CH:26][C:22]([C:13]2[C:14]([O:20][CH3:21])=[C:15]([C:10]([CH2:9][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[N:31][C:29](=[O:30])[C:28]([F:33])([F:32])[F:27])=[O:8])=[CH:11][CH:12]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:23]1
Reactant: COC(=O)c1c(CS(=O)c2ccccc2)ccc(-c2ccoc2)c1OC
Reactant: NC(=O)C(F)(F)F
Agent: [Rh]
Agent: [Mg+2]
Agent: [O-2]
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1c(CS(=O)(=NC(=O)C(F)(F)F)c2ccccc2)ccc(-c2ccoc2)c1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 38.5 %

Procedure:
A mixture of methyl 6-(benzenesulphinylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 216, 0.920 g), trifluoroacetamide (0.56 g), magnesium oxide (0.40 g), iodobenzene diacetate (1.20 g) and rhodium (II) acetate dimer (0.030 g) in DCM (20 mL) was stirred at room temperature for 22 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate and cyclohexane with a gradient of 10-40% to give methyl 3-(furan-3-yl)-2-methoxy-6-{[S-phenyl-N-(trifluoroacetyl)sulphonimidoyl]methyl}benzoate (0.46 g) as a colourless gum.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][N:17](C(=O)C(F)(F)F)[CH2:18][C:19]=2[C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CC#N.O>CO>[C:1]([O:5][CH:6]([C:11]1[C:12]([CH:36]([CH3:38])[CH3:37])=[N:13][C:14]2[C:15]([CH3:35])([CH3:34])[CH2:16][NH:17][CH2:18][C:19]=2[C:20]=1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(C(=O)C(F)(F)F)CC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Yield: 32.8 %

Procedure:
A solution of methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-6-(2,2,2-trifluoroacetyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 4) (0.483 g, 0.897 mmol) and 1N NaOH (4.48 ml) in MeOH (10 mL) was stirred at room temperature overnight (15 h) and then 8 h at reflux. After cooling the product was purified by preparative-HPLC (CH3CN/H2O, 10 mmol NH4OAc) to provide 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (0.126 g, 31% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.37 (2H, d, J=6.7 Hz), 7.31 (2H, d, J=6.7 Hz), 4.67 (1H, s), 3.59 (1H, d, J=16.2 Hz), 3.51-3.57 (1H, m), 3.33 (2H, br. s.), 3.10 (1H, d, J=16.2 Hz), 2.72-2.82 (2H, m), 1.28 (6H, s), 1.19 (3H, d, J=6.4 Hz), 1.07 (3H, d, J=6.7 Hz), 0.87 (9H, s). LCMS (M+H) calcd for C25H34FN2O3: 429.26. found: 429.3.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OC)(OC)OC.CSC.B.CO>O1CCCC1>[CH2:1]([O:8][C@H:9]([CH3:15])[C@H:10]([OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](O)C(=O)O
Agent: B
Agent: COB(OC)OC
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-(benzyloxy)-2-hydroxybutanoic acid (the product of step i) (0.79 g) and trimethyl borate (0.67 mL) in anhydrous tetrahydrofuran (4 mL) at 0° C. was added dropwise borane-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran). The reaction mixture was stirred at room temperature overnight, then further borane-dimethyl sulfide complex (3 mL, 2M in tetrahydrofuran) was added at 0° C. and the reaction mixture stirred at room temperature for a further 2 d. The mixture was cooled to 0° C. and methanol (10 mL) slowly added. When effervescence had ceased, the volatiles were evaporated, further methanol added and the mixture concentrated again to give the subtitle compound as a yellow oil which was used without further purification. Yield: 0.68 g.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[C-:12]#[N:13].[Na+]>CN(C=O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:12]#[N:13])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(CCBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CCC#N)c1

Procedure:
The solution of 1-(2-bromoethyl)-3-methoxybenzene (10 g, 46.4 mmol), NaCN (2.73 g, 55.8 mmol) in dry DMF (20 ml) was heated at 90° C. for 6 hours or until all the starting material is consumed, the reaction was cooled, diluted with EtOAc (60 ml) and washed with water (20 ml×3), brine, the organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound as an oil.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C([Cl:28])C=C(C(OO)=O)C=1.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl>CO.C(OCC)C>[ClH:28].[NH2:34][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCC(N)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCC(N)=O

Procedure:
3-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide (3.9 g, 14 mmol) was treated with mCPBA (6.19 g, 26.9 mmol) followed by ammonium hydroxide (50 mL) and p-toluenesulfonyl chloride (4.6 g, 24 mmol) according to the method described in Part D of Example 8. The crude product was dissolved in methanol, and hydrogen chloride (1.25 mL of a 1 M solution in diethyl ether) was added. The resulting solid was isolated by filtration and dried overnight under high vacuum to provide 0.477 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)propanamide hydrochloride as tan needles, mp 242-243° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH:17]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)[CH2:18][C:19]([O-:21])=[O:20])=[O:15])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:31](O)[CH3:32].[CH2:34]([N:41]=[C:42]=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>[Pd].C(OCC)C>[C:35]1([CH2:34][NH:41][C:42]([NH:1][C:4]2[CH:5]=[C:6]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH:17]([C:22]3[CH:30]=[CH:29][C:25]4[O:26][CH2:27][O:28][C:24]=4[CH:23]=3)[CH2:18][C:19]([O:21][CH2:31][CH3:32])=[O:20])=[O:15])=[O:11])[CH:7]=[CH:8][CH:9]=2)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C([O-])CC(NC(=O)CNC(=O)c1cccc([N+](=O)[O-])c1)c1ccc2c(c1)OCO2
Reactant: CCO
Reactant: O=C=NCc1ccccc1
Agent: [Pd]
Solvent: CCOCC
Product: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NCc2ccccc2)c1)c1ccc2c(c1)OCO2
Reaction time: 1.5 h

Procedure:
The compound of Example 120 (2 g, 0.62 mmol) was added to absolute ethanol (60 mL) in a Parr jar. Palladium on carbon 5% (500 mg) was added and the mixture was hydrogenated under 50 psi in a Parr apparatus for a period of 1.5 hours. After complete reaction the palladium catalyst was removed by filtration through a plug of celite. The solvent was removed under reduced pressure and the sample dried in vacuo. Acetonitrile (5 mL) was added to the crude aniline followed by benzyl isocyanate (700 mg, 0.75 mmol). The solution turned to a solid. Diethyl ether was added and the product filtered. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (1.5 g). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:18](=[O:19])[CH:17]2[CH:12]([CH:13]3[CH2:21][CH2:20][CH:16]2[CH2:15][CH2:14]3)[C:11]1=[O:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([Cl:40])[CH:36]=2)[N:31]=1.Cl>CN(C)C=O.ClCCl>[Cl:40][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:10]3[C:18](=[O:19])[CH:17]4[CH:12]([CH:13]5[CH2:21][CH2:20][CH:16]4[CH2:15][CH2:14]5)[C:11]3=[O:22])[CH:5]=1)[CH:39]=[N:38]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CCc1ccc(O)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1C1C(=O)C2C3CCC(CC3)C2C1=O
Temperature: 140 °C

Procedure:
To a mixture of 2-(2-ethyl-5-hydroxyphenyl)hexahydro-4,7-ethanoindene-1,3-dione (83 mg, 0.28 mmol) and anhydrous potassium carbonate (90 mg, 0.56 mmol) is added a solution of 2,6-dichloroquinoxaline (67 mg, 0.34 mmol) in anhydrous dimethylformamide (2.0 ml), and the mixture is heated at 140° C. for 40 minutes under microwave irradiation. The mixture is acidified with 2M aqueous hydrochloric acid and diluted with dichloromethane then filtered. The organic phase is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to afford 2-[5-(6-chloroquinoxalin-2-yloxy)-2-ethylphenyl]hexahydro-4,7-ethanoindene-1,3-dione.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C@@H:9]12[C:18](=O)[O:17][C:15](=[O:16])[C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14]2.C>C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:15](=[O:16])[C@H:10]3[C@H:9]([CH2:14][CH2:13][CH2:12][CH2:11]3)[C:18]2=[O:17])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CCO
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1c1ccc(O)cc1
Temperature: 170 °C
Yield: 69.5 %

Procedure:
A mixture of 4-aminophenol (5.46 g, 50.0 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (7.71 g, 50.0 mmol) was heated in a round bottom flask at 170° C. for 2 h. After cooling to room temperature the solid material was dissolved in hot ethanol (200 ml), activated charcoal was added and the solution was heated at reflux for 1 h. The solid material was removed by hot filtration. The solvent was partially evaporated. The solids were collected by filtration, washed quickly with a small amount of ethanol and dried in vacuo yielding the title compound (8.52 g, 69%, pink solid).
Reaction SMILES: C([NH:5][S:6]([C:9]1[C:14]([NH:15][CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>CCCCCC>[CH3:16][NH:15][C:14]1[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CNc1cccnc1S(=O)(=O)NC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccnc1S(N)(=O)=O
Yield: 89.5 %

Procedure:
A mixture of 3.50 g of N-tert-butyl-3-methylamino-2-pyridinesulfonamide and 20 ml of trifluoroacetic acid was reacted at about 50° C. for 2 hours. Thereafter, the reaction product was distilled off under a reduced pressure to obtain a residue. Ethyl acetate and n-hexane were added thereto. The resulting crystals were filtered to obtain 2.41 g of 3-methylamino 2-pyridinesulfonamide. This compound had the following NMR values.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=O)[C:8](=[CH:12][CH:13]=1)[C:9]([OH:11])=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>O>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:2]([CH3:1])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:12][CH:13]=1)[C:9](=[O:11])[N:22]([CH2:23][C:24]([OH:26])=[O:25])[C:14]2=[O:16]
Reactant: Cc1cccc(C)c1Oc1ccc(C(=O)O)c(C(=O)O)c1
Reactant: NCC(=O)O
Solvent: O
Product: Cc1cccc(C)c1Oc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Yield: 99 %

Procedure:
4-(2,6-Dimethyl-phenoxy)-phthalic acid and an equimolar amount of glycine were ground thoroughly together in a mortar. The mixture was then heated at 220 to 240° C. in an oil-bath in vacuo until the formation of water ceased (ca. 30 min) to give the title compound as a dark glass (yield: 99%); MS-(−)-ion: M−1=324.5.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nc2ccccc2n1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 2-chlorobenzimidazole (100 g, 0.65 mol) in 500 ml of dimethylformamide (DMF) was added dropwise to a stirred suspension of 60% sodium hydride-mineral oil dispersion (28 g, 0.70 mol) in 500 ml of DMF. Mild intermittent cooling was required. After the addition was completed the mixture was stirred an additional 15 min and benzylbromide (82.6 g, 0.49 mol) was added dropwise with mild intermittent cooling. The reaction mixture was stirred an additional 1.5 h and 1 L of water was added. The mixture was extracted with benzene. The extract was dried (Na2SO4), concentrated and the residue crystallized from isopropyl ether to obtain 110 g (93%), mp 102°-105° C.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]COCC.[Br:13][C:14]1[C:15]([CH3:22])=[C:16]([C:19]([OH:21])=[O:20])[S:17][CH:18]=1.C(O)(=O)C>CO.O1CCCC1>[CH3:8][O:20][C:19]([C:16]1[S:17][CH:18]=[C:14]([Br:13])[C:15]=1[CH3:22])=[O:21]
Reactant: Cc1c(Br)csc1C(=O)O
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
The (trimethylsilyl)diazomethane solution in ether (2.0 M, 41.2 mL, 82.3 mmol) was added dropwise to a solution of 4-bromo-3-methyl-thiophene-2-carboxylic acid (13.0 g, 58.8 mmol, purchased from Oakwood Products) in methanol (50 mL) and tetrahydrofuran (50 mL) at ambient temperature. After the reaction mixture was stirred at ambient temperature for 30 min, acetic acid was added to decompose the excess (trimethylsilyl)diazomethane until the yellow color disappeared. Most of the solvent was evaporated and ethyl acetate was added. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to produce 12.8 g of a white solid. 1H NMR (CDCl3, 200 MHz): δ=7.40 (s, 1H), 3.87 (s, 3H), and 2.54 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[C@H:3]1[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.C(Cl)(Cl)=O.C(#N)C.[C:36](=[O:38])=[O:37].[C:39]1([CH3:45])[CH:44]=CC=C[CH:40]=1>C1C=CC=CC=1>[C:39]([O:37][C:36]([NH:1][C@H:2]1[C:5](=[O:6])[N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[O:16][CH3:17])[C@H:3]1[C:18]([O:20][CH3:21])=[O:19])=[O:38])([CH3:45])([CH3:44])[CH3:40]
Reactant: COC(=O)[C@H]1[C@@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: Cc1ccccc1
Reactant: O=C=O
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1[C@@H](NC(=O)OC(C)(C)C)C(=O)N1Cc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.5 g (18.8 mmole) of methyl cis-3-amino-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate in 100 ml of dry toluene was cooled to -78° and 2.5 ml (18.8 mmole) of triethylamine was added followed by rapid addition of 35 ml (42 mmole) of a 12% solution of phosgene in benzene. The mixture was stirred 15 min at -78°, 3 hours at -45° (acetonitrile-dry ice), then warmed to room temperature and concentrated to half volume in vacuo. To the resulting solution was added 50 ml of t-butanol and the mixture was stirred at room temperature overnight. The solvents were removed in vacuo and the residue diluted with ethyl acetate and filtered. The filtrate was transferred to a separatory funnel and washed with 5% aqueous sodium bicarbonate, 5% hydrochloric acid and brine, dried (MgSO4) and evaporated to dryness. Recrystallization of the crude, crystalline product from ether gave methyl cis-3-t-butoxycarbonylamino-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, m.p. 134°-135°.
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[CH2:32][CH3:33]>>[CH2:32]([C:31]1[CH:30]=[CH:29][N:26]=[C:24]([NH:23][C:13]2[CH:14]=[CH:15][C:16]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:11]([O:10][CH3:9])[CH:12]=2)[N:25]=1)[CH3:33]
Reactant: CCC(=O)C=CN(C)C
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCc1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (149 mg, 0.4 mmol) and 1-dimethylamino-pent-1-en-3-one using (64 mg, 0.5 mmol) using in analogous manner the procedure described in example 139. Obtained as a white solid (18 mg, 16%). MS ISP (m/e): 310.2 [(M+H)+]. NMR (CDCl3, 300 MHz): δ (ppm)=8.33 (d, 1H), 7.81 (d, 1H), 7.63 (s, 1H), 7.25 (s, 1H), 7.15 (d, 1H), 7.07 (dd, 1H), 6.87 (s, 1H), 6.67 (d, 1H), 3.87 (s, 3H), 2.71 (q, 2H), 2.30 (s, 3H), 1.33 (t, 3H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([O:7][CH3:8])=[O:6])[CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([N:1]1[CH2:4][CH:3]([C:5]([O:7][CH3:8])=[O:6])[CH2:2]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CNC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
To a solution of methyl azetidine-3-carboxylate (5.0 g, 33.1 mmol) and DIEA (10.7 g, 82.8 mmol) in DMF (50 mL) was added dropwise bromomethyl benzene (5.7 g, 33.1 mmol) at 0° C. over 10 min. After stirring for 2 hr at rt, the mixture was poured to water (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated and purified by chromatography column on silica (EA/PE=1/4) to give the product (3.5 g, 51.6%) as a light yellow oil. 1H NMR (DMSO-d6) δ 7.34-7.20 (m, 5H), 3.62 (s, 3H), 3.53 (s, 2H), 3.41-3.35 (m, 1H), 3.29-3.31 (m, 2H), 3.19-3.22 (m, 2H). MS (ESI, m/e) [M+1]+ 206.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[C:13]([C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1)([CH3:15])=[CH2:14]
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cccc(C2OCCO2)c1
Temperature: 90 °C
Yield: 66.3 %

Procedure:
A degassed solution of 2-(3-bromo-phenyl)-[1,3]dioxolane (3.46 ml, 22.6 mmol) in dimethoxyethane (60 ml) was added into a tube which has been charged with a mixture of 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.8 g, 22.6 mmol) and an aqueous solution of sodium carbonate (1M, 20 ml); tetrakis(triphenylphosphine)palladium(0) (0.266 g) is then added, the tube is sealed and heated to 90° C. overnight. After cooling of the reaction mixture, water (20 ml) was added, the aqueous layer separated and extracted with dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using cyclohexane as the eluent. There were obtained 2.85 g (68% of theory) of the 2-(3-isopropenyl-phenyl)-[1,3]dioxolane.
Reaction SMILES: CC(C)([O:4][C:5]([NH:7][C@H:8]([C:13]([NH:15][CH:16]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:17]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[OH:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])C.CC(C[C@H](NC(O[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O)C(O)=O)C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:46]1([CH2:45][O:4][C:5]([NH:7][C@H:8]([C:13]([NH:15][C@@H:16]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH:17]([P:19]([O:23][CH3:24])([O:21][CH3:22])=[O:20])[OH:18])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COP(=O)(OC)C(O)C(CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(O)[C@H](CC1CCCCC1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
The title E compound of Example 1 (749.3 mg, 2.5 mmol) was added to a solution of N-α-CBZ-L-Leucine (548.5 mg, 2.07 mmol) in dimethylformamide (10 mL) and cooled to 0° C. Hydroxybenzotriazole hydrate (348.3 mg, 2.27 mmol), triethylamine (432.7 μl, 3.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (436.4 mg, 2.27 mmol) were added sequentially. After 16 hours at 25° C., pH 4.01 buffer solution was added and the reaction mixture was stirred for 10 minutes. The resulting precipitate was filtered, washed sequentially with pH 4.01 buffer (3×50 mL) and water (3×50 mL) and dried over sodium sulfate yielding 804 mg of crude material. Flash chromatographic purification afforded 546.4 mg of the title compound as a white solid, m.p. 151° C., [α]D -56.2° (c=1.04, CH3OH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: BrCc1cccc(CBr)c1
Reactant: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1cccc(CBr)c1)OCC
Temperature: 150 °C
Yield: 72.3 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (10.02 g, 37.95 mmol) in DMF (20 mL) was added triethyl phosphite (3.15 g, 3.3 mL, 19.98 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with diethyl ether (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 30-100% ethyl acetate in hexanes to give 4.64 g (76%) 60 as a colorless oil. LCMS: m/z for C12H18BrO3P++H observed 321.0 and 323.0 at 2.29 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.