Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([C:21]1[NH:25][C:24]2[C:26]([C@H:41]3[CH2:45][CH2:44][CH2:43][O:42]3)=[C:27]([F:40])[C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]([OH:39])([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:29][C:23]=2[N:22]=1)[C:9](=[O:20])[N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=NN=N1.CC(N([P:58]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[O:59]CC1C=CC=CC=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:83])C=1>C(Cl)Cl>[CH2:68]([O:67][P:58]([OH:59])([O:42][CH2:41][C:26]1[CH:24]=[CH:23][CH:29]=[CH:28][CH:27]=1)=[O:83])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1.[C:1]([N:8]([C:21]1[NH:25][C:24]2[C:26]([C@H:41]3[CH2:45][CH2:44][CH2:43][O:42]3)=[C:27]([F:40])[C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]([OH:39])([CH3:38])[CH3:37])=[N:34][CH:35]=3)=[CH:29][C:23]=2[N:22]=1)[C:9](=[O:20])[N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CCN(C(=O)OC(C)(C)C)C(=O)N(C(=O)OC(C)(C)C)c1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Agent: c1nnn[nH]1
Solvent: ClCCl
Product: O=P(O)(OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To diBoc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea (28) (1.13 g, 1.797 mmol) and tetrazole (251.8 mg, 3.594 mmol) at 23° C. under N2 was added DCM (30 mL) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (744.7 mg, 724.4 μA, 2.156 mmol). After stirring for 18 h, the reaction was cooled to 0° C. then treated with mCPBA (531.5 mg, 2.156 mmol). The reaction was stirred for 15 min at 0° C., then for 30 min at 23° C. The resulting solution was then partitioned between EtOAc and saturated aqueous sodium bicarbonate (300 mL each), the organic layer separated, then washed with 10% aqueous sodium bisulfite, saturated aqueous sodium bicarbonate and brine (300 mL each), then dried over magnesium sulfate filtered and concentrated. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (80 g silica column) eluting with a 0-80% EtOAc in hexanes linear gradient over 20 column volumes at 60 mL/min flow rate. Desired product fractions were combined and evaporated to give diBoc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (29) (1.03 g, 1.159 mmol, 64.50%) as a clear, glassy oil. ESMS (M+1)=889.5; 1H NMR (300.0 MHz, CDCl3) δ 8.93 (d, J=1.5 Hz, 2H), 8.31 (s, 1H), 8.04 (d, J=6.4 Hz, 1H), 7.36-7.26 (m, 10H), 5.83-5.70 (m, 1H), 5.16-5.05 (m, 4H), 4.24-4.18 (m, 1H), 4.03-3.97 (m, 1H), 3.42-3.36 (m, 2H), 2.43-2.05 (m, 4H), 1.98 (s, 6H), 1.64 (s, 9H), 1.40 (s, 9H) and 1.26 (t, J7.2 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26].CCN(CC)CC>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (1.00 g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 ml, 4.52 mmol) in THF (10 ml) was added Et3N (0.13 ml, 0.90 mmol) at room temperature. After 6 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 104-106° C. (dec.); 1H-NMR (CDCl3) δ1.45 (s, 9H), 2.28 (s, 3H), 3.51 (s, 2H), 6.33 (br, 1H), 6.96 (t, J=7.6 Hz, 1H), 7.08 (br, 1H), 7.16-7.30 (m, 4H), 7.42 (m, 1H), 8.2 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (5° C.) of 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (11 Kg, 38.8 mol, step 7) and Et3N (7.04 L, 50.6 mol) in DCM (55 L) was added methanesulphonyl chloride (2.97 L, 38.4 mol) so that the internal temp <10° C. After stirring for 0.5 h at 5° C. the solution was used below in step 9.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2.O.[OH-].[Na+]>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2[nH]1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
A solution of boron tribromide (32.5 ml, 341 mmol) in methylene chloride (60 ml) was added in portions to a solution of 5-methoxy-2-methylindole (25 g, 155 mmol) in methylene chloride (250 ml) cooled at −45° C. After stirring for 15 minutes at −30° C., the mixture was warmed up to ambient temperature and stirred for 1 hour. Methylene chloride (300 ml) was added in portions and the mixture was cooled to 0° C. Water was added in portions and the mixture was adjusted to pH6 with 4N sodium hydroxide. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the organic layers were combined, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/9 followed by 15/85) to give 5-hydroxy-2-methylindole (21.2 g, 93%).
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:9][C:10]1[C:11]([C:2]#[C:1][C:3]2([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: C#CC1(O)CCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclopentanol (35.8 mg, 0.33 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and CuI (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 5 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(1-hydroxy-cyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 32 mg, 67%).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.CN1CCOCC1.ClC(OCC)=O.Cl.[CH3:25][O:26][NH2:27]>O1CCCC1>[CH3:25][O:26][NH:27][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)Cn1nnnc1S
Reactant: CON
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CONC(=O)Cn1nnnc1S
Reaction time: 1 h

Procedure:
To a solution cooled at -28° C. to -35° C. of 5-mercapto-1H-tetrazole-1-acetic acid (0.8 g) in tetrahydrofuran (40 ml) are added N-methylmorpholine (1.26 ml) and ethyl chloroformate (0.62 ml). After stirring for 1 hour, a solution of methoxyamine hydrochloride (0.34 g) and N-methylmorpholine (0.71 ml) in tetrahydrofuran (11 ml) is added to the mixture at -50° C. After 2 hours' stirring at about -30° C., the mixture is concentrated under reduced pressure, and the resultant mixture is diluted with water (50 ml) and ethyl acetate (50 ml). The mixture is acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract solution is dried over magnesium sulfate and concentrated to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester. mp. 165°-167° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:3]([CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[C:4](=[O:9])[CH:5]=[C:6]([CH3:8])[N:7]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cc1cc(=O)[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(C)n1
Yield: 28 %

Procedure:
The title compound (0.8 g, 30%) was prepared from 2,4-dimethyl-1,6-dihydro-6-pyrimidone (1.3 g. 10.48 mmol) and 4-[2-bromoethoxy]benzaldehyde (2.4 g, 10.48 mmol) in the presence of a base K2CO3 (2.89 g, 20.96 mmol) by a similar procedure as described in preparation 1.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[CH:1]1([C:4]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (784 mmoles) in ca. 750 ml. of 2:1 ether-hexane during 1 hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice--4 N hydrochloric acid. The ethereal phases are combined and washed with brine, soeium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, b.p. 102°-104° C. (80 mm), pmr spectrum (CDCl3):δ2.55 (triplet--CH2CO--).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].N1C=CC=CC=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C=CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere, to a cold (0° C.), stirring solution of 3-buten-1-ol (2.16 g, 30.0 mmol), pyridine (9 mL), and methylene chloride (30 mL) was added tert-butyldimethylsilyl chloride (4.53 g, 30.1 mmol) purchased from Aldrich Chemical Company. The ice-bath was removed and the mixture was allowed to stir 1 h at room temperature. The mixture, containing a white precipitate, was poured into water (60 mL) and shaken. The methylene chloride layer was separated from the aqueous layer, and the aqueous layer extracted with methylene chloride (30 mL). The two resulting organic extracts were combined, washed twice with water, dried (Na2SO4), filtered, and evaporated to give 8.94 g of crude product. Vacuum distillation afforded several fractions, the fraction with bp 80°-82° C. at 35 mm Hg was collected to give 3.14 g (56.3%) of product as an oil. 1H NMR (CDCl3): δ 5.86-5.73 (m, 1H), 5.08-4.98 (m, 2H), 3.64 (t, 2H), 2.29-2.22 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]([C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)[OH:5]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: O=Cc1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br

Procedure:
To a solution of 2-bromobenzaldehyde (3.15 mL, 27.0 mmol) and THF (135 mL) at 0° C. was added (4-chlorophenyl)magnesium bromide solution (29.7 mL, 1M in THF, 29.7 mmol). The reaction was stirred at 0° C. for 30 min before addition of a saturated solution of ammonium chloride. The layers were separated and the aqueous extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage to afford (2-bromophenyl)(4-chlorophenyl)methanol. To a solution of DCM (100 mL) and oxalyl chloride (2.471 mL, 28.2 mmol) at −78° C. was added DMSO (3.34 mL, 47.0 mmol) and the reaction stirred at −78° C. for 15 min. After 15 min a solution of (2-bromophenyl)(4-chlorophenyl)methanol in DCM (25 mL) was added dropwise and stirred for 15 min at −78° C. before addition of Et3N (9.84 mL, 70.6 mmol). The cold bath was removed and the reaction was warmed to room temperature. To this solution was added water and the layers separated. The aqueous was extracted with DCM and the combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (2-bromophenyl)(4-chlorophenyl)methanone. LC/MS m/z 295 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:12]([CH3:21])=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][C:16]=2[CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 125 °C
Reaction time: 20 h
Yield: 6 %

Procedure:
To a solution of 4-methoxyphenol (6.70 g, 53.9 mmol) and 4-chloro-3,5-dimethyl nitrobenzene (10 g, 53.9 mmol) in N-methylpyrrolidinone (50 mL) at room temperature was added potassium carbonate (8.19 g, 59.3 mmol). The reaction mixture was heated to 125° C. and stirred for 20 hours. The solution was cooled to room temperature, diluted with water (500 mL), and extracted with methylene chloride (3 times 300 mL). The combined organic extracts were washed with potassium hydroxide (0.1N, 3 times 500 mL), water (500 mL), brine (500 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in a mixture of ether (20 mL) and petroleum ether (30 mL) and the title compound was crystalized as a brown solid (6.84 g). The mother liquor was concentrated and purified by column chromatography (20% methylene chloride in hexane to 27.5% methylene chloride in hexane) to give an additional product (0.88 g) and the unreacted starting material (3.4 g). 1H NMR (400 MHz, CDCl3) δ7.97 (s, 2H), 6.78 (d, 2H), 6.64 (d, 2H), 3.74 (s, 3H), 2.18 (s, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#CCc1cccc(O)c1
Temperature: 25 °C
Yield: 54.7 %

Procedure:
To a solution of (3-methoxyphenyl)acetonitrile (150 g, 1.03 mol) in CH2Cl2 (1000 mL) was added BBr3 (774 g, 3.09 mol) dropwise at −70° C. The mixture was stirred and warmed to room temperature slowly. Water (300 mL) was added at 0° C. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by column (Petroleum Ether/EtOAc 10:1) to give (3-hydroxyphenyl)acetonitrile (75.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:6][C:7]1[N:8]=[N:9][C:10]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:11][CH:12]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2ccnc2)nn1
Yield: 83.1 %

Procedure:
A mixture of imidazole (0.613 g, 8 mmol) and 3,6-dichloropyridazine (1.55 g, 10 mmol), K2CO3 (4.15 g) and DMF (15 mL) was heated at 70–80° C. overnight. After removal of DMF in vacuo, the residual solid was dissolved in CH2Cl2 (50 mL), washed with 1N Na2CO3 aq. solution, and dried (MgSO4). Separation using column chromatography (CH2Cl2/methanol 100:1) afforded 3-chloro-6-(imidazol-1-yl)pyridazine (1.2 g) as a white solid.
Reaction SMILES: CS(C)=O.O=C1CCC(=O)N1OC(=O)CCC(NC[CH:20]1[O:24][C:23]2[CH:25]=[CH:26][C:27]([CH2:29][CH:30]([N:32](CC)[C:33](=O)[C:34](F)(F)F)[CH3:31])=[CH:28][C:22]=2[O:21]1)=O.N[C@H](C(O)=O)CCCCN>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>[CH3:34][CH2:33][NH:32][CH:30]([CH2:29][C:27]1[CH:26]=[CH:25][C:23]2[O:24][CH2:20][O:21][C:22]=2[CH:28]=1)[CH3:31]
Reactant: CCN(C(=O)C(F)(F)F)C(C)Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2
Agent: NCCCC[C@H](N)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCNC(C)Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 188 mg of keyhole limpet hemocyanin (KLH) in 5.5 ml of 50 mM potassium phosphate (pH 7.5) was cooled in an ice-bath. To the solution were added 6 mL of dimethylsulfoxide dropwise, and the reaction temperature was maintained below room temperature. Then a solution of 54 mg (0.10 mmol) of 2L in 1.2 mL of DMF was added to the protein solution dropwise. The mixture was allowed to stir at room temperature 18 hours. The resulting conjugate was placed in a dialysis tube (10,000 MW cut-off) and was dialyzed in 1 L of 70% DMSO in 50 mM potassium phosphate (pH 7.5, 3 changes, at least 3 hours each), 1 L of 50% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 30% DMSO in 50 mM potassium phosphate (at least 3 hours), 1 L of 10% DMSO in 50 mM potassium phosphate (at least 3 hours) at room temperature. The trifluoroacetamido group of the conjugate was deprotected by dialysis of the resulting conjugate against 10% ammonium hydroxide for 3 days (1 L each for approximately 24 hours each), followed by 6 changes with 50 mM potassium phosphate (pH 7.5) at 4° C. (1 L each for at least 6 hours each). The protein concentration was determined to be 2.1 mg/mL using BioRad Coomassie blue protein assay (Bradford, M., Anal. Biochem. 72:248, 1976). A total of 34 mL of the conjugate was obtained. The extent of available lysine modification was determined to be 60% by the TNBS method (Habeeb AFSA, Anal. Biochem. 14:328-34, 1988).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([NH:20][C@H:21]([C:23]([OH:25])=O)[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[NH2:26][CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:20]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:21]([C:23]([NH:26][CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:25])[CH3:22]
Reactant: NCC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
One equivalent of EDC [1-(3-dimethylaminopropyl)3-ethylcarbodiimide.hydrochloride] (1 g, 5.3 mmol, Aldrich) is added into a cold stirred solution of 1 g (5.3 mmol) Boc Alanine (Sigma), 1.07 g of (5.3 mmol) of Gly-OBzl (Sigma), 0.71 g of HOBT (Aldrich), and 0.5 ml of NMM in 50 ml DCM. The reaction mixture is stirred at 0° C. for 3 h and at ambient temperature for 22 h. The precipitate is filtered out and the filtrate is diluted with 100 ml of ethyl acetate. The organic layer is washed with 10% aqueous citric acid, water, saturated NaHCO3, water, and saturated brine. The organic layer is dried over anhydrous Na2SO4 and the solid is decanted from the mixture. The organic solvent is evaporated and the residue is recrystallized using petroleum ether to give a colorless solid of Boc-Ala-Gly-OBzl (11). 1H-NMR (CDCl3): 1.35 (3H,d, J=6 Hz), 1.42 (9H, s), 4.05 (2H, d, J=5 Hz), 4.25 (1H, m), 5.15 (2H, s), 5.28 (1H, d, J=5 Hz), 7.02 (1H, br), 7.33 (5H, s). FABMS: 337 (M+1).
Reaction SMILES: [Cl:1]Cl.[C:3]1(=[O:13])[NH:7][C:6](=[O:8])[C:5]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:4]12.[Na]>C(Cl)Cl>[Cl:1][N:7]1[C:3](=[O:13])[C:4]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:5]2[C:6]1=[O:8]
Reactant: ClCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Na]
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To 170 ml. of methylene chloride saturated with chlorine and maintained at 0° C. were added 8.3 grams (49 mmoles) of sodium phthalimide. The resulting mixture was warmed to 20° C. and was stirred for 1.5 hours. The resulting precipitated sodium chloride was removed by filtration, and the filtrate was evaporated to dryness to afford 8.0 grams (90% yield) of N-chlorophthalimide.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1OC1C.N1C2C(=CC=CC=2)C=CC=1.[Cl:26]Cl>C(Cl)Cl>[Cl:26][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: CC1CO1
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Product: O=C1c2ccccc2C(=O)N1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 150 ml. of methylene chloride were added 7.35 g. (0.05 mole) of phthalimide and 17.5 ml. (5 equiv.) of propylene oxide. The resulting mixture was cooled to 0° C., 0.13 g. (0.001 mole; 0.02 equiv.) of quinoline was added, and the mixture was saturated with chlorine. The phthalimide began to dissolve within 30 minutes, and after one hour it was nearly all dissolved. Analysis of the sample by TLC at 1.25 hours showed only a trace of starting material. The mixture was subjected to partial vacuum to remove excess chlorine, and a small amount of amylene was added. The resulting mixture then was evaporated to obtain crystalline N-chlorophthalimide. The product was filtered and vacuum dried overnight to give 8.2 g. (90.4%) of product. Analysis: (1) Percent Cl+ : Theory: 19.6; Found: 19.3. (2) Percent total chlorine: 19.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([O:31][CH3:32])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=1)#[CH:17]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[C:6]([C:17]#[C:16][C:18]2[CH:19]=[CH:20][C:21]([O:31][CH3:32])=[C:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1ccc(OC)c(NC(=O)C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 83.1 %

Procedure:
To an oven-dried flask under N2 was added 2,4-dichloropyrimidine (860 mg, 5.76 mmol), anhydrous degassed TH F (100 mL), dichlorobis(triphenylphosphine)-palladium(II) (81 mg, 0.12 mmol), copper(I) iodide (13 mg, 0.07 mmol), and triethylamine (1.26 g, 13 mmol). After heating the reaction at 60° C. for 30 min, N-[5-ethynyl-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (560 mg, 2.30 mmol) was added dropwise as a solution in THF (10 mL) and the resulting mixture was allowed to heat overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M+H)+=356.