Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([NH2:44])=[O:43]>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:41][C:42]([NH2:44])=[O:43])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in THF (3 mL) was added potassium carbonate (174 mg, 1.26 mmol) and 2-bromoacetamide (63 mg, 0.46 mmol) and the reaction mixture was stirred at RT for 18 hours. The volatiles were evaporated in vacuo and the residue partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The organic layer was washed with water followed by brine, dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-5% MeOH in DCM) to give 319 isolated as a cream solid after freeze drying from methanol and water (40 mg, 22%). LCMS: RT=3.03 min, [M+H]+=425. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.05 (1H, s), 7.20 (1H, dd, J=8.24, 1.83 Hz), 7.08 (1H, s), 7.00 (2H, d, J=1.87 Hz), 5.83-5.73 (1H, m), 4.34-4.28 (2H, m), 3.69-3.62 (2H, m), 3.63-3.52 (1H, m), 3.41-3.35 (2H, m), 3.21-3.14 (2H, m), 2.99 (2H, s), 1.50 (6H, d, J=6.59 Hz)
Reaction SMILES: Cl[C:2]([O:4][C:5]([CH3:7])=[CH2:6])=[O:3].[F:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:28]([CH3:29])=[N:27][C:20]3[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=3[CH:18]=2)=[CH:12][C:10]=1[NH2:11]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:28]([CH3:29])=[N:27][C:20]3[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=3[CH:18]=2)=[CH:12][C:10]=1[NH:11][C:2](=[O:3])[O:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)OC(=O)Cl
Reactant: CSc1ncc2cc(-c3cc(N)c(F)cc3C)c(C)nc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Add isopropenyl chloroformate (146 mg, 1.207 mmol) to a bi-phasic mixture of 2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)aniline (345 mg, 1.097 mmol) in EtOAc (15 mL) and saturated NaHCO3 (20 mL) and stir at RT for 2 h. Add EtOAc, separate the layers, wash the organic layer with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as an amorphous solid (434 mg, 99%). MS (m/z): 399.1 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([CH3:9])=O)C.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(O)CCC>[CH3:9][C:7]1[C:6]([CH2:5][C:4]([OH:3])=[O:18])=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccccc1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCCCO
Product: Cc1nn(-c2ccccc2)c(-c2ccccc2)c1CC(=O)O
Yield: 93.9 %

Procedure:
3.0 grams 3-benzoyl-levulinic acid-ethyl ester, 1.3 gram phenyl-hydrazine, 0.15 milliliter 2N aqueous hydrochloric acid and 25 milliliters n-butanol were mixed and the mixture heated to boiling temperature under reflux for 1.5 hour. The reaction mixture was evaporated in vacuo and benzene added to the residue. The benzene solution was adjusted to a pH of 4 and extracted with water. The benzene was evaporated from the solution, and 15 milliliters ethanol and 20 milliliters 1N aqueous sodium hydroxide were added to the residue and the mixture heated to the boiling temperature. The mixture was then worked up and the free acid recovered in accordance with the procedure set out in Example (1b). 3.3 grams 3-methyl-1,5-diphenyl-pyrazol-4-acetic acid, melting at 159°-161° C., were obtained representing a yield of 93%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:16]C)([O-:3])=[O:2].[OH-].[Na+]>>[N+:1]([C:4]1[CH:9]=[C:8]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:16])([O-:3])=[O:2]
Reactant: COc1ccc(S(=O)(=O)CCO)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1O

Procedure:
The synthesis of 2-amino-4-(beta-sulfatoethylsulfonyl)-phenol is somewhat difficult in that it requires several reaction steps involving a high investment for equipment. In its preparation, it is necessary to start from 2-nitro-4-(beta-hydroxyethylsulfonyl)-anisole which is dealkylated by heating with aqueous sodium hydroxide solution to give 2-nitro-4-(beta-hydroxyethylsulfonyl)-phenol. The resulting phenol is then reduced to give 2-amino-4-(beta-hydroxyethyl-sulfonyl)-phenol which, in turn, must be sulfated in accordance with the disclosure of U.S. Pat. Nos. 3,364,194 or 4,334,076.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[C@@H:11]1([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1>N1C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7]([CH:16]([OH:17])[C@H:15]2[O:18][C@@H:11]([N:19]3[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]3=[O:21])[CH2:12][C@@H:13]2[OH:14])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)C(O)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 16.6 %

Procedure:
p-Toluoyl chloride (6.78 mL, 51.25 mmol) was added dropwise (to keep the temperature of the mixture below 5° C.) to a cooled (ice/water bath) stirred suspension of thymidine (12.112 g, 50 mmol) in anhydrous pyridine (50 mL) under an argon atmosphere. After complete addition, the bath was removed and the mixture was allowed to warm to room temperature. After 16.5 h, thin layer chromatography (using EtOAc as eluant) showed that no starting material was remaining. The mixture was poured into ice (50 g), and after the ice melted, a white precipitate was collected by filtration. The aqueous filtrate was extracted with CH2Cl2 (3×50 mL) and the combined organic extracts were washed with 1M HCl (3×50 mL), saturated aqueous NaHCO3 (3×50 mL) and water (3×50 mL). The CH2Cl2 solution was dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to give a pale yellow foam (3.00 g). The solid material was combined, and recrystallized in ca. 2 g batches from CH2Cl2 (300 mL). After each filtration, the volume of the filtrate was reduced to 100 mL and cooled. A white solid crystallizing from solution was collected by filtration. This filtrate was used as the solvent for the next crystallization. This was done multiple times. The insoluble solids removed after each crystallization were combined and recrystallized as above.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(NC(C)C)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]4[CH2:26][CH2:27][CH2:28][C:29]4=[O:30])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Cc1nnc2ccc(-c3cccc(N4CCCC4=O)c3)nn12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 2 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 400 ml of dichloromethane was added 1.7 ml of diisopropylamine and 1 ml of 4-chlorobutyryl chloride. This solution was stirred for 12 hours, then poured onto 200 ml of saturated aqueous sodium bicarbonate and extracted with 150 ml portions of dichloromethane. The combined extracts were dried and concentrated in vacuo. The residue was dissolved in 200 ml of dimethylformamide and 2.0 g of potassium carbonate was added. This solution was heated to 80° C. for 12 hours, then poured onto 200 ml of water and extracted with 150 ml portions of dichloromethane. The combined extracts were dried, concentrated in vacuo and chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing the desired product were combined, concentrated in vacuo and the solid recrystallized from dichloromethane-hexane to give 1.67 g of white crystals, mp 235°-237° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[N:20][CH:21]=1)=[O:5]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(C(F)(F)F)ccc2F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.98 mL, 19.72 mmol) in dichloromethane (22.3 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (3.0 g, 19.72 mmol), pyridine (4.80 mL, 59.16 mmol) and dichloromethane (89.4 mL) at 0° C. The mixture was removed from the ice bath after 1.5 hours and was stirred at room temperature for 0.5 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration rinsing with hexanes to yield methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (5.16 g, 76%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.38 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (dd, J=6.1, 2.4 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.09-7.98 (m, 1H), 7.67 (t, J=9.2 Hz, 1H), 3.88 (s, 3H) ppm. ESI-MS m/z calc. 342.06. found 343.2 (M+1)+; Retention time: 1.54 minutes (3 minutes run).
Reaction SMILES: O[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2nccn2c(O)c1-c1c(F)cccc1Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc2nccn2c(Cl)c1-c1c(F)cccc1Cl

Procedure:
A mixture of 0.16 g of 5-hydroxy-6-(2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyrimidine, 0.20 g of N,N-diethylaniline and 2 ml of phosphorus oxychloride was refluxed under heating for 26 hours. The reaction mixture was concentrated, and dichloromethane and aqueous saturated sodium bicarbonate solution were added to the residue. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel chromatography to give 45mg of 5-chloro-6-(2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyrimidine.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O)[C:3]([NH2:5])=[NH:4].O.NN>C(O)C>[NH:2]([C:6]1[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13])[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)Nc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1cccc(OCCCN)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a partial suspension of N-[3-(3-guanidinophenoxy)propyl]phthalimide hydrochloride (1.0 g; 2.95 mmoles) in 10 ml of 95% aqueous ethanol was added 0.27 ml of hydrazine hydrate. The mixture was stirred at ambient temperature for 17 hours and evaporated under reduced pressure to give the title compound. The product was used without further purification in Step E.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])[CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C.CO>[NH2:12][C:11]1[CH:13]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=[CH:9][C:10]=1[NH2:14]
Reactant: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cc1N
Reaction time: 8 h

Procedure:
To a solution of 5-morpholino-2-nitroaniline (0.50 g, 2.2 mmol) in 4:1 ethyl acetate/methanol (25 ml) was added 5% palladium on carbon (0.11 g) and the reaction mixture stirred under an atmosphere of hydrogen overnight. The reaction mixture was then filtered through celite, the filtered solid washed with methanol, and the combined filtrate and washings concentrated in vacuo to give the crude 2-amino-4-morpholinoaniline which was used immediately for the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:8]1[C:7]2[CH:12]=[CH:13][C:4]([CH3:3])=[CH:5][C:6]=2[O:10][C:9]1=[O:11]
Reactant: Cc1ccc2[nH]c(=O)oc2c1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)oc2cc(C)ccc21

Procedure:
The product is produced as described in example 1 from 3.6 g. of NaH (of 80% suspension in mineral oil), 19.9 g. of 6-methylbenzoxazolin-2-one (produced in usual manners by subjecting 2-amino-5-methyl-phenol-hydrochloride to reaction with phosgene), 240 cc. of DMF, 28.4 g. of 8-bromo caprylic acid methyl ester and 3.6 g. NaJ.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CCCO)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-hydroxyphenyl)-1-propanol (3 g, 19.7 mmol) in acetone (30 mL) is added potassium carbonate (4.08 g, 29.5 mmol) and methyl bromoacetate (2.8 mL, 29.3 mmol) and the reaction is heated at reflux for 15 h. The reaction mixture is allowed to cool to RT, filtered, and the solvent removed in vacuo. The residue is purified by chromatography (SiO2, EtOAc:iso-hexane, 2:3) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.14 (2H, d), 6.85 (2H, d), 4.64 (2H, s), 3.82 (3H, s), 3.69 (2H, t), 2.68 (2H, t), 1.82 (2H, m).
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][C:15]=3[F:28])[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.17 g), 2-bromo-1-(4-methoxyphenyl)ethanone (0.64 g) and N,N-dimethylformamide (20 mL) was added 60% sodium hydride (0.11 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.9 g, 69%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:23][C:24]([OH:26])=[O:25])[C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-p-tolyl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]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.[CH3:19][Mg+].[Br-].[OH-].[Na+]>CCOCC>[CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
To 1-benzhydryl-azetidin-3-one (1.0 g, 4.2 mmol) in ether (100 mL) at 0° C. was added CH3MgBr (1.5 mL, 3M in ether). The mixture was warmed to rt over 1 h and 1N NaOH (3 mL) was added. The organic layer was concentrated providing the title compound (1.1 g). MS (ESI): mass calcd. for C17H19NO, 253.2; m/z found, 254.2 [M+H]+. 1H NMR (CDCl3): 7.42-7.11 (m, 10H), 4.32 (s, 1H), 3.14 (d, J=8.5 Hz, 2H), 2.96 (d, J=8.5 Hz, 2H), 1.43 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:17]N(CN(C)C)C>FC(F)(F)C(O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[C:13](=[CH2:17])[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: CN(C)CN(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=C1CCc2nc3ccccc3c(N)c2C1=O

Procedure:
In 25 ml of trifluoroacetic acid cooled in ice was dissolved 5.00 g 9-amino-3,4-dihydroacridin-1(2H)-one. To the solution was added dropwise 6.70 ml (2.09 eq) of bisdimethylaminomethane over 5 minutes and thereafter the mixture was maintained at 90°-100° C. for 5 hours during which the starting material was converted to a mixture of intermediate and exo-methylene products. The reaction mixture was poured into ice/NaOH to make it basic and the precipitate was extracted with several portions of 5:1 dichloromethane/MeOH. The combined extracts were evaporated to a residue. The residue was refluxed in toluene for 5 hours during which the intermediate was converted to the end product. The reaction mixture was evaporated to a residue which was purified by chromatography on silica gel (EtOAc) to yield about 2 g of a solid. This was recrystallized from dichloromethane/EtOAc to yield 1.79 g (34%) of product as a solid, melting point 192°-193° C.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[C@@H:13]12[C:22](=[O:23])[O:21][C:19](=[O:20])[C@@H:14]1[CH2:15][CH2:16][CH2:17][CH2:18]2.S(=O)(=O)(O)O>CCOCC>[F:12][C:7]1[CH:6]=[C:5]([C:22]([C@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:19]([OH:21])=[O:20])=[O:23])[CH:10]=[C:9]([F:11])[CH:8]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: O=C(c1cc(F)cc(F)c1)[C@H]1CCCC[C@H]1C(=O)O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A dry three-neck, round-bottom flask, equipped with a reflux condenser, was charged with magnesium turnings (1.89 g, 78 mmol) and iodine (0.131 g, 0.518 mmol). The apparatus was capped tightly with septa and purged with N2, and then anhydrous diethyl ether (80 mL) was added by cannula. The reaction mixture was stirred for 2 h, during which time the iodine was consumed. The flask was cooled with an ice bath, and then 1-bromo-3,5-difluorobenzene (10 g, 51.8 mmol) was injected in portions with stirring. The ice bath was removed, and the reaction mixture was stirred for 1 h, during which time an exotherm was evident, and much of the Mg was consumed. The supernatant solution of the Grignard reagent was slowly transferred by cannula to a stirred solution of cis-1,2-cyclohexanedicarboxylic anhydride (7.98 g, 51.8 mmol) in anhydrous ether (120 mL), maintained at −78° C. under N2. The resulting solution was stirred at −78° C. for 1 h, and then allowed to warm to 20° C. over 18 h. The reaction mixture was poured into 1M sulfuric acid (150 mL) and extracted with 200 mL hexanes. The organic layer was washed with sat. NaCl, dried over MgSO4, filtered, and evaporated to give cis-2-(3,5-difluorophenylcarbonyl)-cyclohexanecarboxylic acid, as an oil, which was used immediately in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Br[C:18]1[N:22]2[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:29])[CH3:28])=[N:26][C:21]2=[N:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[N:22]3[N:23]=[CH:24][C:25]([C:27]([OH:30])([CH3:28])[CH3:29])=[N:26][C:21]3=[N:20][CH:19]=2)=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4ccncc4)c3)cnc2n1

Procedure:
4-Fluoro-3-(pyridin-4-yl)benzeneboronic acid was coupled with 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 80% yield by a similar procedure to that described in Example 3, step f, to afford the title compound as a yellow solid: mp 233-237° C. (CH2Cl2-EtOAc-MeOH); 1H NMR (400 MHz, DMSO-d6) δ 1.57 (6H, s), 5.78 (1H, s), 7.60 (1H, dd, J 11.0, 8.6 Hz), 7.68-7.70 (2H, m), 8.27 (1H, m), 8.35 (1H, dd, J 7.4, 2.3 Hz), 8.53 (1H, s), 8.73 (2H, m), 9.04 (1H, s); MS (ES+) m/z 350 [M+H]+. Anal. Found: C, 64.87; H, 4.58; N, 19.79%. Required for C19H16FN5O.0.1H2O: C, 64.98; H, 4.65; N, 19.94%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[H-].[Na+].O([CH2:22][C:23]([F:26])([F:25])[F:24])S(C(F)(F)F)(=O)=O.O>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A stirred solution of 3-fluoro-4-nitrophenol (200 mg, 1.3 mmol) in dimethylformamide (3 ml) at 0° C. under argon was treated portionwise with sodium hydride (60 mg of 60% oil dispersion, 1.5 mmol) and maintained for 20 minutes. The mixture was treated with trifluoroethyl triflate (325 mg, 1.4 mmol), then allowed to warm to room temperature and stir overnight. The yellow solution was treated with water (40 ml) and brine (5 ml) and extracted with ethyl acetate. The extract was washed with water, dried (Na2SO4) and concentrated under vacuum to leave the title compound as a yellow oil (280 mg, 92%).