Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].Br[CH:15]([CH3:19])[C:16]([OH:18])=[O:17].Cl>CS(C)=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(Br)C(=O)O
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(C(C)(C)C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled slurry of 9.3 g of sodium hydride-oil dispersion (57%) in 150 ml of dimethyl sulfoxide is added 15.0 g of p-tert-butylphenol in 50 ml of dimethyl sulfoxide and 18.9 g of 2-bromopropionic acid in 50 ml of dimethyl sulfoxide. The mixture is stirred at room temperature for 1/2 hr. and heated on a steam bath overnight. The mixture is diluted with 250 ml of water, acidified with 10 ml of conc. hydrochloric acid and extracted with ether. The ether extracts are dried (MgSO4) and the solvent removed under vacuum. Chromatography over silica gel with dichloromethane as eluent gives the product as white crystals, mp 86°-89° C.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1)=[O:20].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.ClCCl>[CH3:34][C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:19](=[O:20])[NH:16][C:7]2[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:17]=[C:5]3[N:6]=2)=[CH:26][CH:25]=1)([CH3:33])[CH2:28][C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC(C)(C)c1ccc(C(=O)Nc2cc(-c3ccccc3)n3nc(C)cc3n2)cc1
Reaction time: 72 h
Yield: 15.2 %

Procedure:
In a 50 ml pear flask was added 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 200 mg, 0.89 mmol) in pyridine (5 ml) to give a light yellow solution. A solution of methyl 3-(4-(chlorocarbonyl)phenyl)-3-methylbutanoate (230 mg, 0.89 mmol) in dichloromethane (1 ml) was added to the reaction mixture at room temperature, which was then stirred for 72 h. Saturated NaHCO3 was added and pyridine was mostly removed in vacuo. The residue was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 30-40% ethyl acetate/hexanes) to give the titled product (60 mg, 15% yield) as a yellow foam. 1H NMR (CHLOROFORM-d) δ: 8.61 (s, 2H), 8.10-8.15 (m, 8H), 7.87-7.92 (m, 5H), 7.54-7.59 (m, 8H), 7.50-7.54 (m, 5H), 6.28 (s, 2H), 3.54 (s, 8H), 2.68-2.71 (m, 5H), 2.50 (s, 8H), 1.49 (s, 6H); ESI-MS: m/z 443.3 (M+H)+.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[NH:8][CH2:9][CH2:10][C:4]2=[N:3][N:2]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:8]2[C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[N:5]3[CH:1]=[N:2][N:3]=[C:4]3[CH2:10][CH2:9]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)NCCc1nncn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2nncn2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3 mmol of 5,6-dihydro-4H-[1,2,4]-triazolo[4,3-a][1,5]benzodiazepine in 10 ml of dichloromethane under argon is added 5 mmol of triethylamine. To the mixture is added dropwise 3.3 mmol of 4-nitrobenzoyl chloride in 3 ml of dichloromethane. The mixture is stirred at room temperature 3 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed under vacuum. The residue is purified by chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[NH:6][C:7]=2[C:8]([Cl:11])=[CH:9][CH:10]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Br:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[N:6]([CH2:30][CH2:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[C:7]=2[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CN1CCc2[nH]c3c(Cl)ccc(Br)c3c2C1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Br)ccc(Cl)c42)CN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500 mg, 1.67 mmol) in DMF (5 mL), sodium hydride (200 mg, 5.0 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.2 g, 4.2 mmol) was added to the reaction mixture and stirred at the same temperature for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase HPLC to obtain the 9-bromo-6-chloro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.39 (s, 1H), 8.12 (d, 1H), 7.66 (d, 1H), 7.26 (d, 1H), 7.1 (d, 1H), 4.67 (m, 4H), 3.7 (m, 2H), 3.27 (t, 2H), 3.18 (m, 2H), 3.15 (s, 3H), 2.69 (s, 3H).
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.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][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: BrCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCBr
Temperature: 60 °C
Reaction time: 2 h

Procedure:
First, N-(4-bromobutyl)phthalimide is synthesized from a mixture of 30 mmol potassium phthalimide and 100 mmol 1,4 dibromobutane in 50 ml DMF. The solution is stirred for 2 hours at 60° C., and the DMF and 1,4-dibromobutane is evaporated off in vacuo. The remaining residue is extracted with CHCl3 and H2O. The resulting white compound is recrystallized from ethyl alcohol. See Chem. Pharm. Bull. 32:3428 (1984). ##STR2##
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1>ClCCl>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:8](=[O:11])[CH:9]=[CH2:10])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Add triethylamine (0.82 mL; 2.0 equiv; 5.86 mmoles) followed by 2-propenoyl chloride (0.24 mL; 1.0 equiv; 2.93 mmoles) dropwise to a 0° C. solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.781 g; 1.0 equiv; 2.93 mmoles) in dichloromethane (29 mL). Stir the solution for 16 hours at ambient temperature, then dilute with dichloromethane, wash with brine, dry over sodium sulfate, filter, and concentrate to an orange oil. Purify the crude product by column chromatography to afford 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]prop-2-en-1-one (0.66 g; 70%): MS (m/z): 321 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:4]=2[O:3]1.[CH:21](O)=[O:22]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH:19][CH:21]=[O:22])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: O=CO
Reactant: CC1(C)N=C(n2ccccc2=O)c2cc(N)ccc2O1
Solvent: c1ccncc1
Product: CC1(C)N=C(n2ccccc2=O)c2cc(NC=O)ccc2O1

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-2H-1,3-benzoxazine in 15 ml of formic acid and 1 ml of pyridine is boiled for 16 hours and evaporated. Customary work-up gives 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-formamido-2H-1,3-benzoxazine.
Reaction SMILES: NC(N)=O.[NH2:5][C:6]1[C:7]([OH:17])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([Cl:12])=[CH:10][CH:11]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:7]=1[OH:17])=[O:34])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1ccccc1OCc1ccccc1
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Agent: NC(N)=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2OCc2ccccc2)c1O
Yield: 26.3 %

Procedure:
Following the general procedure for urea formation outlined in example 12, 3-amino-6-chloro-2-hydroxybenzenesulfonamide (52 mg, 0.23 mmol) and 2-benzyloxyphenylisocyanate (40 mg, 0.17 mmol) were coupled to form the desired urea (20 mg, 26%). EI-MS (m/z) 446.2, 448.3, 450.2 (M−).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH2:25])(=[O:22])=[O:21])[CH3:19]>>[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)(=[O:22])=[O:21])[CH3:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: CCS(=O)(=O)c1ccc(O)cc1N
Product: CCS(=O)(=O)c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-ethylsulfonyl-5-hydroxyaniline (46 mg, 0.231 mmol) similar to Example 180. The reaction mixture was evaporated under vacuum to give a residue. The residue was precipitated using acetone to give the product as a yellow solid (30 mg, 46%). 1H NMR (DMSO-d6): 9.45 (s, 1H), 8.71 (m, 3H), 7.84 (brs, 1H), 7.0 (brd, 1H), 6.08 (brd, 1H), 3.0 (q, 2H), 1.0 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:7]=1)#[N:9]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(C#N)nc(N)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-cyano-6-methylpyrimidine, 0.2 g, was mixed with 2-carbomethoxybenzenesulfonyl isocyanate, 0.7 g, in 8 ml of dry methylene chloride. After five minutes a thick precipitate formed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate stripped to give 0.3 g of the title compound as a solid, m.p. 208°-213° C. (dec). NMR (CF3CO2D): δ2.95 (s, 3H), 4.05 (s, 3H), 7.85 (s, 1H), 7.88-8.15 (m), 8.25-8.65 (m).
Reaction SMILES: [CH2:1]1[CH2:6][NH:5][CH2:4][C:3]2[C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:2]1=2.C(N(CC)CC)C.Cl[CH2:24][C:25](=[O:27])[CH3:26]>>[O:27]=[C:25]([CH3:26])[CH2:24][N:5]1[CH2:6][CH2:1][C:2]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7](=[O:15])[C:3]=2[CH2:4]1
Reactant: O=c1oc2ccccc2c2c1CNCC2
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Product: CC(=O)CN1CCc2c(c(=O)oc3ccccc23)C1

Procedure:
Prepared by the method described for example 26 from 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (5.14 g, 0.025 moles), triethylamine (3.8 g, 0.027 moles), and 1-chloro-2-propanone (2.5 g, 0.027 moles). Recrystallization from ethanol gave the produce (3.8 g) mp 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[O:12][CH2:11][C:10]([C:16]([OH:18])=[O:17])=[CH:9][C:8]=3[C:7]=2[CH:19]=1>C(O)C.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[O:12][CH2:11][CH:10]([C:16]([OH:18])=[O:17])[CH2:9][C:8]=3[C:7]=2[CH:19]=1
Reactant: COc1ccc2ccc3c(c2c1)C=C(C(=O)O)CO3
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc2ccc3c(c2c1)CC(C(=O)O)CO3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The unsaturated acid obtained in Step A (750 mg:2.9 mmol) is solubilised in a mixture of ethanol/dimethylformamide (20 ml:3 ml) in the reactor of a Parr apparatus. After addition of the catalyst, 10% palladium-on-carbon (75 mg; 10% by weight), the whole is stirred at ambient temperature at a pressure of 45 psi for 4 hours. The solvents are removed; the residual oil is then precipitated and washed with diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[I:11][C:12]1[CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]([NH2:21])=[CH:14][CH:13]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:21][C:15]2[CH:14]=[CH:13][C:12]([I:11])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(I)cc1C(=O)O
Temperature: 25 °C

Procedure:
2-(4-Chlorophenylaminocarbonylamino)-5-iodobenzoic acid was prepared by adding a solution of 4-chlorophenyl isocyanate (15.4 g) in ethyl acetate (60 ml) dropwise, at room temperature, to a stirred suspension of 5-iodoanthranilic acid (26.3 g) in ethyl acetate (150 ml). The mixture was heated at reflux for 1 hour, cooled to ambient temperature and the solid removed by filtration, to give 34 g of the substituted benzoic acid. This (34 g) was added to absolute alcohol (250 ml) saturated with hydrogen chloride gas and heated at reflux for 40 minutes. When cool, the solid was filtered and washed with absolute alcohol (50 ml) to give 27.1 g of 3-(4-chlorophenyl)-6-iodoquinazoline-2,4(1H,3H)-dione, mp 324°-6° C. This product (26.9 g) was added slowly to a mixture of pyridine (25 ml) and phosphoryl chloride (250 ml). The mixture was heated at reflux for 6 hours, when a solution developed. When cool, excess phosphoryl chloride and pyridine were removed by distillation in vacuo. The residue was cautiously added to ice water (500 ml) and the solid filtered. This solid was extracted with dichloromethane (100 ml), the extract concentrated in vacuo and chromatographed on silica using dichloromethane to give 9.7 g of 2-chloro-3-(4-chlorophenyl)-6-iodoquinazolin-4(3H)-one, mp 178°-180° C. This was then treated with 1,2,4-triazole and potassium carbonate in a similar manner to Example 1 to give 3-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-6-iodoquinazolin-4(3H)-one, mp 206°-208° C. (Compound 2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:17])[CH3:16]>C(#N)C>[C:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:17])[CH3:16]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a solution of 10.0 g (57.8 mmol) of 4-bromophenol in 100 mL of acetonitrile was added 9.6 g (69.5 mmol) of potassium carbonate. A white slurry was obtained to which was added 8.6 mL (121.0 mmol) of acetyl chloride and the resultant reaction mixture was stirred at ambient temperature for 17.5 hours. The reaction mixture was filtered, washed with ethyl acetate and the filtrate was concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a clear, nearly colorless oil.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33](B(O)O)[CH:32]=1>>[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1cnc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cnc2ccccc2c1
Yield: 24 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and quinolin-3-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a yellow solid (24% yield); 1H-NMR (d6-DMSO) 0.97 (9H, s), 3.78 (2H, t), 4.18 (3H, t), 6.69 (1H, s), 7.55-7.59 (1H, m), 7.66-7.70 (1H, m), 7.92-8.00 (2H, m), 8.08 (1H, d), 8.77 (1H, d); 13C-NMR (CDCl3) 27.7, 41.7, 66.9, 126.8, 127.4, 128.7, 129.2, 133.6, 148.8; MS ES(+) 313.0 (M++1); HRMS m/z calcd for C18H20N2O3+H+ 313.1552 [M+H+]. Found 313.1556. IR λmax=1697, 1636 cm−1.
Reaction SMILES: [CH2:1]([CH:4]1[CH:7]([O:8]C(=O)C)[NH:6][C:5]1=O)[CH2:2][CH3:3].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1>[CH2:1]([CH:4]1[CH:5]([S:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[NH:6][C:7]1=[O:8])[CH2:2][CH3:3]
Reactant: CCCC1C(=O)NC1OC(C)=O
Reactant: O=[N+]([O-])c1ccc(S)cc1
Solvent: c1ccccc1
Product: CCCC1C(=O)NC1Sc1ccc([N+](=O)[O-])cc1

Procedure:
3-Propyl-4-acetoxy azetidinone, 171 mg, is refluxed with 200 mg p-nitrophenyl thiol in 10 ml benzene for 6 hours. The solution is washed 3x with aqueous Na2CO3, dried with MgSO4, filtered and evaporated. The residue is chromatographed on silica gel, eluting with 10:1 CHCl3 -EtOAc, affording 3-propyl-4-p-nitrophenylthioazetidin-2-one.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:8]1=[O:17])[CH3:5])[CH3:2].C([Li])CCC.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCCCCC.C(=O)(O)[O-].[Na+]>[C:23]([N:9]1[C@H:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[C:8]1=[O:17])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(C)O[C@@H]1C(=O)N[C@@H]1c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1c1ccccc1
Temperature: -78 °C
Yield: 101.7 %

Procedure:
To a solution of 2.35 g (10 mmol) of cis-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one in 40 mL of THF at -78° C. was added 6.1 mL (10.07 mmol) of a 1.65M solution of n-butyllithium in hexane. The mixture was stirred for 10 rain at -78° C. and a solution of 1.42 g (10.1 mmol) of benzoyl chloride in 10 mL of THF was added. The mixture was stirred at -78° C. for 1 h and diluted with 70 mL of saturated aqueous sodium bicarbonate and extracted with three 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were dried over sodium sulfate and concentrated to give 3.45 g of an oil. Chromatography of the oil on silica gel eluted with ethyl acetate/hexane gave 3.22 g (95%) of cis-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (2) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:10]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>[Cl:10][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[S:9][CH:8]=1
Reactant: Cc1nc2ccsc2s1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: Cc1nc2c(Cl)csc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 218.1 %

Procedure:
To a solution of 1.18 g (7.2 mmol) of 2-methylthieno[3.2-d]thiazole (from Step 1) in 35 ml of CH2Cl2 was added 670 mg (2.9 mmol) of trichloroisocyanuric acid at 0° C. The reaction was stirred at 0° C. for 30 min., then at r.t. for 2 h.; 60 mg (0.26 mmol) of trichloroisocyanuric acid was again added, and the reaction was stirred at r.t. for another hour. The product was partitioned between CH2Cl2 and aqueous NaHCO3. Chromatographic purification on silica gel using hexane/EtOAc=5:1 afforded 1.2 g (90%) of the title product. 1H NMR (CDCl3) 7.28(s, 1H), 2.82(s, 3H).
Reaction SMILES: [OH-].[Li+].[CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([O:29][CH:30]([CH3:32])[CH3:31])[C:25]=1[O:26][CH2:27][CH3:28])[C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[C:15]([F:22])[CH:14]=1)=[O:11])([CH3:5])[CH3:4]>C1COCC1>[CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:23]=[C:24]([O:29][CH:30]([CH3:31])[CH3:32])[C:25]=1[O:26][CH2:27][CH3:28])[C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:22])[CH:14]=1)=[O:11])([CH3:5])[CH3:4]
Reactant: CCOc1c(OC(C)C)cc(C(=O)Nc2ccc(C(=O)[O-])c(F)c2)cc1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1c(OC(C)C)cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc1OC(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.7 %

Procedure:
2 M Lithium hydroxide (554 μL, 1.11 mmol) was added to a solution of 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoate (3) (320 mg, 0.740 mmol) in THF (5 mL) and the mixture was stirred at RT for 20 h. The mixture was partitioned between 1M HCl (5 mL) and DCM (10 mL) and the phases were separated. The organic solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-20% IPA in isohexane) to afford 4-(3,5-diisopropoxy-4-ethoxybenzamido)-2-fluorobenzoic acid (AAA-064) as a white solid (176 mg, 56%): m/z 420 [M+H]+ (ES+), 418 [M−H]− (ES−). 1H-NMR (400 MHz, DMSO-d6) δ: 13.03 (1H, br s), 10.45 (1H, s), 7.88 (1H, t), 7.81 (1H, dd), 7.61 (1H, dd), 7.22 (2H, s), 4.65 (2H, sep), 4.00 (2H, q), 1.29 (12H, d), 1.26 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C:22](=[O:30])[CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][CH2:18][CH2:19][OH:20])[CH2:13]1)[CH:6]=[CH:5]2.[C:31]([O:35][C:36](=O)[O:37]C(C)(C)C)([CH3:34])([CH3:33])[CH3:32]>ClCCl.CO>[CH3:32][C:31]([O:35][C:36](=[O:37])[N:17]([CH:14]1[CH2:15][CH2:16][N:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[C:3]=3[NH:21][C:22](=[O:30])[CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:8]=2)[CH2:13]1)[CH2:18][CH2:19][OH:20])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-[(2-hydroxyethyl)amino]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 36) (1 g) in dichloromethane (5 mL) and methanol (2 mL) was added di-tert-butyl-carbonate (1 g). The mixture was stirred at room temperature for 18 hours and absorbed onto silica. Purification (SiO2, methanol:dichloromethane 5:95 as eluant) gave the title compound as a solid (400 mg).