Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]=[O:13].C(OCC)(=O)C>CN(C=O)C>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[CH:12]=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1cnccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccncc1C=O
Reaction time: 18 h
Yield: 86.9 %

Procedure:
Sodium azide (1.07 g, 16.5 mmol) was added to a mixture of 4-chloro-3-formylpyridine (2.22 g, 15.7 mmol) in DMF (15 mL) and the reaction mixture was stirred for 18 hours. Ethyl acetate was added and the organic layers were washed with water and brine. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in cyclohexane) to afford the title compound as a white solid (2.02 g, 87% yield). 1H NMR (300 MHz, CDCl3): δ 10.35 (s, 1H), 8.99 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 7.20 (d, J=5.6 Hz, 1H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:36])[CH2:30][C:31]1[CH:32]=[N:33][NH:34][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39](I)[CH3:40]>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:11][CH2:10][N:9]1[C:29](=[O:36])[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH2:39][CH3:40])[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cn[nH]c4)[C@@H](Cc4ccccc4)C3)ccc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4cnn(CC)c4)[C@@H](Cc4ccccc4)C3)ccc12
Temperature: 60 °C
Yield: 44.8 %

Procedure:
A solution of (S)-1-(2-benzyl-4-(1-cyclobutyl-3-ethyl-1H-indazol-6-yl)piperazin-1-yl)-2-(1H-pyrazol-4-yl)ethanone (101 mg, 0.21 mmol) in DMF (1 mL) was treated with sodium hydride (10 mg, 0.25 mmol) as a 60% dispersion in mineral oil. Once bubbling subsided, ethyl iodide (18 μL, 0.23 mmol) was added and the mixture was heated to 60° C. for 24 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (5 mL) followed by brine (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The crude residue was purified by silica gel chromatography eluting with a 0-10% MeOH in CH2Cl2 gradient to afford product as a colorless solid (48 mg, 44%). LC/MS 4.03 min, [M+1]+ 511.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][NH:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1.CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[C:30]([NH2:35])[N:29]=1>C(O)C>[Cl:27][C:28]1[CH:33]=[C:32]([N:12]2[CH2:13][CH2:14][O:15][CH:10]([C:8]3[NH:7][C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=3)[CH2:11]2)[N:31]=[C:30]([NH2:35])[N:29]=1
Reactant: COc1ccc2[nH]c(C3CNCCO3)nc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc2[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)nc2c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a suspension of 5-(methyloxy)-2-(2-morpholinyl)-1H-benzimidazole (500 mg, 2.143 mmol) and DIPEA (693 mg, 5.36 mmol) in ethanol (10 mL) stirred at room temperature was added solid 4,6-dichloro-2-pyrimidinamine (352 mg, 2.143 mmol). The reaction mixture was stirred at 85° C. overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The solvent was evaporated in vacuo to give the crude product. The crude product was added to a silica gel column and was eluted with CH2Cl2/CH3OH to afford the title compound (300 mg). LC-MS (ES) m/z=361 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[C:10]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC1CCOCC1
Product: N#Cc1c(N)cccc1OC1CCOCC1

Procedure:
Prepared as in Example 22b from tetrahydro-2H-pyran-4-ol and 2-amino-6-fluorobenzonitrile as a colorless oil (48%). 1H NMR (400 MHz, CDCl3) δ 1.87 (m, 2H), 2.00 (m, 2H), 3.63 (m, 2H), 4.00 (m, 2H), 4.42 (s, 2H), 4.58 (m, 1H), 6.23 (d, J=8.4 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H). MS 219 (MH+).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[NH:20][CH:21]=O)([OH:3])=[O:2].C(O)C>ClC1C=CC=CC=1Cl>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:21]=[N:20][C:11]2[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]1=2)([OH:3])=[O:2]
Reactant: Cn1c(NCCCCCC(=O)O)c(NC=O)c(=O)n(C)c1=O
Solvent: CCO
Solvent: Clc1ccccc1Cl
Product: Cn1c(=O)c2ncn(CCCCCC(=O)O)c2n(C)c1=O
Yield: 65.7 %

Procedure:
9.3 Grams (0.03 mol) of the formamido derivative (IV) was suspended in 500 ml of o-dichlorobenzene and stirred at reflux under an inert atmosphere for 4 hours. It was cooled and the solvent removed on a rotary evaporator attached to a vacuum pump. The crystalline residue was partitioned between 200 ml of ether and 100 ml of 5% aqueous sodium bicarbonate solution. The aqueous phase was separated, washed with 100 ml of ether, and acidified to pH 3.2 with 5N HCl. The precipitate was recrystallized first from aqueous methanol, then from absolute ethanol to give 5.8 g (66% yield) of the xanthine (V) as fine white crystals, mp 177° C.
Reaction SMILES: N[C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[BrH:13].N([O-])=O.[Na+]>O>[Br:13][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)[C@H](N)c1ccccc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@@H](Br)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 40.5 %

Procedure:
(R)-methyl 2-amino-2-phenylacetate (5 g, 24.8 mmol, 1 equiv) was dissolved in a mixture of 48% Hydrogen bromide (13 ml, 198 mmol, 8 equiv) and water (19 ml). An aqueous solution of sodium nitrite (5.48 g, 79.36 mmol, 3.2 equiv) was added slowly and the mixture stirred at 0° C. for 1.5 h. The reaction was degassed in vaccuo and extracted with ether. The organic layer was further washed with water and brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, 10% ethyl acetate/hexanes) to afford the (S)-methyl 2-bromo-2-phenylacetate as a light yellow oil (2.3 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H); 5.95 (s, 1H); 7.36-7.42 (m, 3H); 7.532 (d, 2H, J=1.2 Hz); 7.56 (d, 1H, J=2 Hz). MS for C9H9BrO2 m/z 229.98 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4CCN(C(=O)OC(C)(C)C)C4)c3n2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4CCNC4)c3n2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
7-Iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine 0.057 gm, 0.1 mM was placed in an oven dried flask and 1 ml anhydrous THF was added. The flask was chilled in an Acetone-dry ice slurry and evacuated and refilled 3 times with nitrogen. Via syringe 0.061 ml of 2.13M Buli in hexane solution (0.13 mM, 1.3 eq) was added and the now yellow mixture was stirred for 30 seconds then 3-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 0.052 gm, 0.2 mM, 2 eq.) in a minimal amount of THF was added by syringe. The mixture was stirred for 30 minutes, removed from the dry ice-acetone bath and immediately quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted two times with ethyl acetate and the organic extracts dried over magnesium sulfate. After filtering and concentrating, the oil was redissolved in THF and 0.2 ml of 1M Tetrabutylammonium Fluoride in THF added. After 5 minutes the mixture was concentrated and purified on a preparative thin-layer chromatography plate (Ethylacetate/hexane) to give 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. The 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 3 ml of dichloromethane and 0.4 ml trifluoroacetic acid was added and stirred overnight. The solution was concentrated and the solid dried overnight at 2 torr in a 60° C. vacuum oven to give 0.012 gm of Pyrrolidin-3-yl-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone trifluoroacetate salt. (M+H)+=383.
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][CH:17]=[CH:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[Na+].OO>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:20])[CH2:18][CH2:19]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COC(C(c2ccccc2)c2ccccc2)CC1
Reactant: [OH-]
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Into a solution of 0.5M 9-BBN-THF complex (24 ml, 12 mmol) in dry THF (20 ml) was added in a drop wise manner 2-diphenyl-3,4-dihydro-2H-pyran 10 (1 g, 4 mmol) dissolved in dry THF (10 ml). The mixture was kept under stirring at room temperature. After the completion of initial addition reaction, the intermediate reaction mixture was oxidized with 5.3 ml 3N sodium hydroxide and 3 ml of 30% hydrogen peroxide. The reaction was continued at 55° C. for 1 hr to insure the completion of oxidation. After the mixture was diluted with sat. aqueous NaHCO3, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×40 ml). The combined extract was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (Hexane/Ethyl Acetate 7:3) to furnish trans-6-diphenyltetrahydropyran-3-ol 11 (1 g, 93.5%) as a liquid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])(=[O:17])C.[NH4+]>C(O)(=O)C>[Cl:14][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2](=[O:17])[C:11]=1[C:12]#[N:13]
Reactant: N#Cc1c(Cl)nc2ccccc2c1Cl
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)c2ccccc2[nH]c1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
2,4-dichloroquinoline-3-carbonitrile (Example 72a) (0.95 g, 4.26 mmol) and ammonium acetate (0.36 g, 4.67 mmol) were heated in acetic acid (20 mL) at 140° C. for 4 hours, then cooled to room temperature. The reaction was poured into ice water (400 mL), and the resultant precipitate was collected by filtration to give 4-chloro-2-oxo-1,2-dihydroquinoline-3-carbonitrile (0.668 g, 77%) as a light yellow solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ7.42 (m, 2H), 7.79 (m, 1H), 7.96 (d, J=8.4 Hz, 1H), 12.72 (s, 1H). MS 205 (MH+)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[C:15]([N:17]=[CH:18][O-])#[N:16]>C(#N)C>[C:15]([NH:17][CH:18]=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][C:9]([CH2:11][N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1)#[N:16]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: N#CN=C[O-]
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCN=CNC#N)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.6 g of 5-[[(2-aminoethyl)thio]methyl]N,N-dimethylfuranmethanamine (prepared according to Belgian Pat. No. 857,388, hereby incorporated by reference) in 35 ml of acetonitrile are added dropwise 2.56 g of N-cyano-formimidate in 15 ml of acetonitrile, under cooling at 0° C. The mixture is maintained under stirring for 30 minutes and the acetonitrile is removed by vacuum evaporation. A solid residue is formed, which is crystallized from ethyl acetate. 2.1 g are obtained of N-cyano-N'-[2-[[[5-[(dimethyl-amino)methyl]-2-furanyl]methyl]thio]ethyl]formamidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Br:14])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CN([CH:27]=[O:28])C>C1COCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH:27]=[O:28])[C:8]=1[Br:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(F)c(C=O)c1Br
Reaction time: 1.25 h
Yield: 62 %

Procedure:
To a solution of 2-bromo-4-fluoro-benzoic acid tert-butyl ester (10.0 g, 36 mmol) in THF (100 mL) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M solution, 20 mL, 36 mmol) dropwise. The reaction mixture was stirred for 1.25 hours before adding DMF (10 mL) then stirred for a further 10 minutes before quenching with acetic acid (3 mL). The products were partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil which crystallized on standing. The crude product was triturated in cyclohexane to give the title compound as a yellow solid (6.8 g, 62%). 1H NMR (CDCl3, 400 MHz) 10.38 (1H, s), 7.80-7.73 (1H, m), 7.17 (1H, t, J=9.09 Hz), 1.62 (9H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14](N3CCOCC3)[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([O-])(O)=[O:32].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14]([OH:32])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])O
Reactant: COc1cc(C2CC(N3CCOCC3)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C2CC(O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Yield: 80 %

Procedure:
The [4-(3-bromo-4,5-dimethoxy-phenyl)-2-morpholin-4-yl-chroman-7-yl]-dimethyl-amine was hydrolyzed to the lactol by heating 160 mg of crude solid in a mixture of acetic acid (2 ml) and water (2.4 ml) at 50° C. for 20 min. The reaction mixture was slowly added to saturated NaHCO3. It was extracted with dichloromethane (100 ml) and washed with brine (10 ml). The extract was dried over sodium sulphate and the solvent was evaporated. The crude product was passed through a bond-elute (hexane:ethyl acetate=9:1 and 4:1), yielding the title compound (110 mg; 80%). 1H NMR (CD3OD): 6.96 and 6.91 (two broad signals, 1H), 6.82 and 6.80 (two broad signals, 1H), 6.58 and 6.51 (d each, J=8.6 Hz, 1H), 6.28-6.34 (m, 1H), 6.23 and 6.22 (d each, J=2.1 Hz, 1H), 5.47 (broad signal) and 5.37 (d, J=8.9 Hz) (1H), 4.11-4.17 (m, 1H), 3.795, 3.793, 3.785 and 3.782 (s each, 6H), 2.871 and 2.868 (s each, 6H), 1.87-2.15 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13](COCC[Si](C)(C)C)[C:12]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:11][C:10]=2[C:38](O)=[O:39])=[CH:5][CH:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH:79]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]1)([CH3:81])[CH3:80]>C(Cl)Cl>[CH:79]([N:82]1[CH2:87][CH2:86][N:85]([C:38]([C:10]2[N:11]=[C:12]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[C:33]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:26][CH2:27]3)[NH:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:42])[F:1])=[CH:4][CH:5]=2)=[O:39])[CH2:84][CH2:83]1)([CH3:81])[CH3:80]
Reactant: CC(C)N1CCNCC1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc(C(=O)O)c1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A mixture of 5-(4-(trifluoromethyl)phenyl)-2-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid from step (e) above (200. mg, 0.325 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (216 mg, 0.488 mmol, Aldrich), DIEA (0.17 mL, 0.98 mmol, Aldrich), and 1-isopropylpiperazine (62 mg, 0.49 mmol, Aldrich) in DCM (2 mL) was stirred at RT for 70 h. The solvents were removed and the residue was purified on silica gel using ISCO Combiflash® system with DCM/2M methanolic ammonia gradient to give the title compound, which was used in the next step. MS (ESI, positive ion) m/z: 726 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([OH:36])=O)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:68][C:69]1[CH:82]=[CH:81][C:72]([CH2:73][S:74][CH2:75][C@H:76]([C:78]([OH:80])=[O:79])[NH2:77])=[CH:71][CH:70]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:77][C@@H:76]([C:78]([OH:80])=[O:79])[CH2:75][S:74][CH2:73][C:72]3[CH:81]=[CH:82][C:69]([CH3:68])=[CH:70][CH:71]=3)=[O:36])=[O:31])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CSC[C@@H](N)C(=O)O)cc1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(CSC[C@@H](NC(=O)CNC(=O)COc2ccc([C@@H]3[C@@H](SCC(O)c4ccc(F)cc4)C(=O)N3c3ccc(F)cc3)cc2)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine, (19.9 mg, 0.037 mmol) in DMF (2.0 ml) was added N-methylmorpholine (15 μl, 0.14 mmol). TBTU (14.4 mg, 0.045 mmol) was added and the mixture was stirred at 30° C. for 45 minutes. S-(4-methylbenzyl)-D-cysteine (10.5 mg, 0.047 mmol) was added and the mixture was stirred at 30° C. for 1 hour. The formation of the ketone of the title compound was confirmed. M/z: 748.02 (M+1). Methanol (2 ml) and sodium borohydride (14.7 mg, 0.39 mmol) were added the mixture was stirred for 30 minutes. Ammonium acetate (20 mg) was added and the methanol was removed under reduced pressure. The remaining DMF-solution was purified with preparative HPLC on a C8 column, UV-detection 240/260 nm. A gradient from 20 to 50% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The combined organic phases were concentrated and the residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained as a white solid (8.7 mg, 31.5%). H-NMR (400 MHz, DMSO-d6): 2.24 (s, 3H), 2.60-2.68 (m, 1H), 2.72-2.79 (m, 1H), 2.86-2.94 (m, 2H), 3.68 (s, 2H), 3.82 (d, 2H), 4.25 (d, 0.5H), 4.27 (d, 0.5H), 4.39-4.46 (m, 1H), 4.52 (s, 2H), 4.67-4.77 (m, 1H), 5.03 (d, 0.5H), 5.06 (d, 0.5H), 5.60-5.67 (bs, 1H), 6.98 (d, 2H), 7.05-7.18 (m, 8H), 7.20-7.25 (m, 2H), 4.30-4.39 (m, 4H), 8.23-8.32 (m, 2H), 12.80-12.95 (bs, 1H). M/z: 748.04 (M−1).
Reaction SMILES: [CH2:1]([C:7]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:8]=1[O:9][CH2:10][CH:11]([OH:33])[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH2:54](Br)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C)C=O>[CH2:1]([C:7]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:34][C:8]=1[O:9][CH2:10][CH:11]([O:33][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:12][O:13][C:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
A 13.8 g portion of 1-(2-hexyl-5-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol in 40 ml of dimethylformamide was added dropwise to a suspension of 14.5 g of prewashed 50% sodium hydride in 40 ml of dimethylformamide and the mixture was stirred 15 minutes. A 4.45 g portion of benzyl bromide was added and the mixture was stirred an additional 3 hours. This mixture was quenched slowly with water and then extracted several times with ether. The ether extracts were combined, washed with water, brine, dried and evaporated, giving 15 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Cc1ccccc1)Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Yield: 15 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-phenylacetyl chloride to afford the title compound (11 mg, 15%). 1H-NMR (δ, ppm, DMSO-d6): 3.62 (s, 2H, CH2), 6.45 (d, 1H, HPy,5, J=6.0 Hz), 6.83 (d, 1H, Harom, J=8.0 Hz), 7.22-7.47 (m, 8H, Harom), 7.78 (d, 1H, HPy,6, J=6.0 Hz), 10.28 (s, 1H, NHamide), 11.15 (s, 1H, NHPy3), 11.37 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C20H17N4O3: 361.1301; found: 361.1299.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[NH2:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1O>CN(C)C=O>[N+:11]([C:9]1[CH:10]=[CH:5][C:2]([C:1]2[O:3][C:6]3[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:5]=3[N:4]=2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1

Procedure:
About 60 grams (0.3 mole) of the 4-nitrophenylchloroxime is mixed with 340 milliliters of ethanol, 60 grams (0.39 moles) of 2-amino-4-nitrophenol and 60 milliliters of dimethylformamide. The mixture is heated to reflux for about 6.5 hours, filtered, washed with methanol and air dried. Approximately 55 grams of 2-(p-nitrophenyl)-5-nitrobenzoxazole are obtained.