Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][NH:29]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([N:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:26])=[CH:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(CC(=O)N3CCc4ccccc4C3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with 1,2,3,4-tetrahydro-isoquinoline to give 94 mg of {4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C28H33N3O5+H 492.6; found 492.0.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][CH:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])[CH3:27]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 125.6 %

Procedure:
A solution of 4-methoxypropiophenone (24 g, 140 mmol) in tetrahydrofuran (220 mL) was cooled to 0° C. Lithium diisopropylamide, (2M solution in THF) (126 mL, 248 mmol) was added dropwise and warmed to rt for 30 min. The reaction was cooled again to 0° C. and ethyl bromoacetate (18 mL, 161 mmol) was added dropwise and warmed to rt for 30 min and then quenched with aqueous 1M HCl acid at 0° C. The aqueous layer was extracted twice with methylene chloride and the combined organics were washed with brine, dried (Na2SO4), filtered, and concentrated to give 4-(4-methoxyphenyl)-3-methyl-4-oxobutyric acid ethyl ester (44 g), MS m/z 205 (M−45).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CN(C)C=O>[CH3:1][C:2]1[C:3]2[O:9][CH2:18][CH2:17][O:5][C:4]=2[CH:6]=[CH:7][CH:8]=1
Reactant: BrCCBr
Reactant: Cc1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1OCCO2
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
In 300 ml of dry dimethylformamide, was dissolved 30 g of 3-methylcatechol and then 100 g of potassium carbonate was added to the solution. This solution was heated to 120 to 130° C. and 136 g of 1,2-dibromoethane was added dropwise in ten and several portions. After stirring for 30 minutes under the same conditions, the mixture was cooled and solid materials were removed by filtration. To the filtrate, was added diethyl ether, and the mixture was washed successively with a 3% sodium hydroxide aqueous solution, water and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting oily material was purified by silica gel column chromatography to obtain 29.7 g of the titled 5-methyl-1,4-benzodioxane (yield: 82%) .
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[N:21]=[N:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:22]([C:19]2[N:20]=[N:21][C:16]([O:15][CH2:14][C:9]3[N:10]([CH3:13])[N:11]=[N:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:17][CH:18]=2)=[O:24])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 29 %

Procedure:
As described for example 42b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid (67 mg, 0.20 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (25 mg, 29%) which was obtained as a white solid. MS: m/e=414.3 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[C:8](I)=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:19]=2)=[N:11]1)=[O:2].[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[NH:41][N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33].C(=O)(O)[O-].[Na+]>CS(C)=O>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[N:41]([C:8]1[C:3]([CH:1]=[O:2])=[C:4]([N:10]3[CH:14]=[C:13]([C:15]#[N:16])[C:12]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][CH:19]=4)=[N:11]3)[CH:5]=[CH:6][CH:7]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: N#Cc1cn(-c2cccc(I)c2C=O)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c(Nc5ccc(C(=O)N6CCOCC6)cc5)n4)c3C=O)ncc2c1
Reaction time: 1 h
Yield: 40 %

Procedure:
1-(2-Formyl-3-iodophenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (115 mg, 0.218 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (48 mg, 0.218 mmol), cuprous iodide (41.5 mg, 0.218 mmol) and sodium bicarbonate (36.6 mg, 0.436 mmol) were combined in 2 mL of DMSO. The mixture was thoroughly degassed with argon and stirred in an oil bath preheated to 100° C. for 1 hr. The mixture was extracted with dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate and filtered. Solvents were evaporated and the residue was purified by flash column chromatography using methanol in dichloromethane (0% to 5% in 16 minutes, 24 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile as a pale pink solid (54 mg, 40% yield). LC/MS clacd for C34H30FN7O4 (m/e) 619.23, obsd 620.0 (M+H, ES+); 1H NMR (400 MHz, CDCl3) δ ppm 1.43 (s, 9H), 3.56-3.76 (m, 8H), 6.61 br. s., 1H), 7.40 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.52 (dd, J=12.4, 1.8 Hz, 1H), 7.55-7.59 (m, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.78 (t, J=8.1 Hz, 1H), 8.16 (s, 1H), 8.32 (s, 1H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:27][S:26](=[O:29])(=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:8]=2[N:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[N:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1>[OH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[C:8]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[S:26](=[O:29])(=[O:28])[CH2:27][C:7]=3[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:10]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1nn(-c2ccc(C(=O)O)cc2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2ccc(CO)cc2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(ethoxycarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1 (4H)-yl]benzoic acid (21.88 g; 53.05 mmol; 1 eq.) in THF (350 ml) is added triethylamine (14.71 ml; 106.11 mmol; 2 eq.) followed by isobutyl chloroformate (13.83 ml; 106.11 mmol; 2 eq.) at 0° C. under nitrogen. The reaction mixture is stirred at rt for 30 min then cooled at 0° C. Sodium borohydride (10 g; 265.27 mmol; 5 eq.) is added portionwise. After 5 h, THF (100 mL) is added and the reaction mixture is heated at 35° C. for 1 day then at rt for 2 days. Sodium borohydride is added (1 eq) and after 6 h stirring the reaction is quenched by dropwise addition of water at 0° C. over 2 h. The product is extracted with EtOAc, the organic layers washed with HCl 1 m (2×) and brine then dried over MgSO4. After evaporation of the solvent, the residue is taken up in DCM and HCl 1 m. The precipitate formed is filtered off and recrystallized in DCE to afford the title compound as a white solid. 1H NMR (DMSO-d6) δ 8.05-8.02 (m, 1H), 7.68-7.48 (m, 6H), 6.88-6.84 (m, 1H), 5.76 (s, 2H), 4.99 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 3.90 (s, 1H), 1.35 (t, J=7.1 Hz, 3H). HPLC (max plot) 68.2%; Rt 3.02 min. MS (ESI+): 398.9
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[F:34].[N:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42](=O)[O:43]C2C=CC=CC=2)=[CH:37][CH:36]=1>O1CCOCC1>[F:8][C:7]1[CH:6]=[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:29]([F:31])([F:32])[F:30])[C:25]([F:26])([F:27])[F:28])=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[O:10])[CH:4]=[C:3]([F:34])[C:2]=1[NH:1][C:42]([NH:41][C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1)=[O:43]
Reactant: Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 80 °C
Yield: 21.3 %

Procedure:
(4-Amino-3,5-difluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.342 mmol, 170 mg) and phenyl pyridin-4-ylcarbamate (0.513 mmol, 110 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (45 mg). MS (ESI) m/z 618.3 [M+H]+
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].Cl[CH2:15][C:16]1[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:15][C:16]2[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[N:3]=1
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CCl
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
Prepared according to Procedure I. A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.5 mmol) in DMF (5 mL) at 0° C. was treated with NaH (60%, 67.4 mg, 1.1 eq) for 30 min before addition of a solution of 3-(chloromethyl)-8-methyl-2-o-tolylquinoline (435 mg, 1 eq) in DMF (2 mL). The mixture was stirred at room temperature over night. The reaction mixture was partitioned between DCM (50 mL) and water (50 mL). The insoluble was filtered and washed with DCM and water. The organic layer from the filtrate was separated, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH, 25/1) to provide a white solid [PI3Kδ IC50=6 nM]. 1H-NMR (DMSO-d6) δ 7.96 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.31 (t, J=7.1 Hz, 1H), 6.94-6.99 (m, 4H), 5.26 (s, 2H), 2.45 (s, 3H), 1.79 (s, 3H). Mass Spectrum (ESI) m/e=507 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:20][O:19][C:17]([C:15]1[O:16][C:12]([CH2:11][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:14]=1)=[O:18]
Reactant: Cc1cc(C)cc(C)c1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c(C)cc(C)cc2C)o1

Procedure:
1,3,5-Trimethylbenzene (6.85 g, 57 mmol), methyl 5-chloromethyl-2-furanoate (2.48 g, 14.2 mmol) and aluminum trichloride (2.46 g, 18 mmol) were refluxed in dichloromethane (30 mL) for 4 h. The reaction was quenched with water, and the two layers were separated. The organic layer was concentrated and passed through a silica gel column. Hexane was used as the mobile phase to elute the product. The 5-(2,4,6-trimethylbenzyl)furan-2-carboxylic acid methyl ester was obtained as a yellow oil (86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:24](COCC[Si](C)(C)C)[C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][C:19]3[N:20]([CH:21]=[N:22][CH:23]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)n1COCC[Si](C)(C)C)cn2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cncn43)[nH]1)cn2C
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
7-(5-Methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.048 g, 0.11 mmol) in DMF (4 mL) was treated with ethylenediamine (0.22 mL, 3.3 mmol) and heated to about 85° C. for about 5 min. The solution was cooled and TBAF (1 M in THF, 0.11 mL, 0.11 mmol) was added. The solution was re-heated to about 85° C. for about 30 min. The mixture was cooled to ambient temperature and another portion of the TBAF (1 M in THF, 0.054 mL, 0.054 mmol) was added and heating was continued for about 1.5 h. The solution was cooled and the material was purified by preparative RP-HPLC (Table 2, Method 1). The product-containing fractions were concentrated to remove MeCN then basified with saturated aqueous NaHCO3 and extracted with EtOAc (2×10 mL). The combined organic solutions were dried over anhydrous MgSO4, filtered, and concentrated. Trituration of the solid with heptane (5 mL) then collection by filtration gave 7-(5-methoxy-1-methyl-1H-indol-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.028 g, 8%): LC/MS (Table 2, Method a) Rt=1.91 min; MS m/z: 318.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6 δ12.18 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.43 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 6.92 (dd, J=8.90, 2.36 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: N=C(NO)c1ccc(Br)cc1F
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C=CONC(=N)c1ccc(Br)cc1F

Procedure:
Scheme 10 shows the synthesis of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2-fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3-dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O>COCCOC>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2=NC2c2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: COCCOC
Product: Fc1cccc(-c2cc3ccc(C(F)(F)F)cn3n2)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of 2-[3-(3-fluorophenyl)-2H-azirin-2-yl]-5-trifluoromethylpyridine (2.2 g, 7.85 mmol) in DME (10 ml) was added FeCl2 (10 mg, 0.079 mmol). The solution was warmed to 75° C. and stirred for 2 hours. The reaction was cooled to room temperature and added to H2O (180 ml). The resultant suspension was cooled to 0° C. and stirred for 30 min. The solid was isolated by filtration and partially dried via airflow. Recrystallization of the crude product in IPA afforded 1.34 g (60%) of the title compound as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([NH2:9])[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:1]1([C:4]2[N:8]=[C:7]([NH:9][C:17](=[O:18])[CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(C2CC2)no1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C(Nc1nc(C2CC2)no1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 163° C. and MS: m/e=219 (M+) was prepared in accordance with the general method of example 44a from 3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966), 1430-1432) and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Brc1ncnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ncnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 12.62 mmol) in 50 mL N,N-dimethylformamide at 0° C. was added 95% sodium hydride (0.351 g, 13.89 mmol). The mixture was stirred at 0° C. for 30 minutes, benzenesulfonyl chloride (1.772 mL, 13.89 mmol) was added, and the mixture was stirred at 0° C. for an additional 2 hours. The mixture was quenched with 20 mL saturated ammonium chloride and diluted with water (100 mL). The resulting suspension was stirred for 5 minutes, filtered, and dried under-vacuum to give the title compound. MS (ESI+) m/z 340.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Cl[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:14]([OH:15])[N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Product: COc1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-methoxythiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[N:10]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[Cl:16][C:11]1[CH:12]=[C:13]([Cl:15])[N:14]=[C:9]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)nc(NC2CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a solution of cyclohexanamine (1.1 mL, 9.57 mmol) in ethyl acetate (10 mL) was added 2,4,6-trichloropyrimidine (1.0 mL, 8.70 mmol) dropwise at 0° C. followed by dropwise addition of diisopropylethylamine (1.8 mL, 10.4 mmol). The reaction was warmed to ambient temperature and stirred for 3 h. Additional cyclohexanamine (0.3 mL) and diisopropylethylamine (0.5 mL) were added. After 4 h, the mixture was diluted with ethyl acetate and washed with 20% brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting oil was purified by flash chromatography on silica gel eluting with a gradient of 92:8 to 85:15 hexane/ethyl acetate to give 0.740 g (35%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:14](=O)[CH:15]([CH3:17])[CH3:16].[BH3-]C#N.[Na+]>>[CH2:14]([N:8]1[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C=O
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CN1CCOc2cc([N+](=O)[O-])ccc21
Yield: 100.6 %

Procedure:
This compound was prepared by General Method 3 (EXAMPLE 1) from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (550 mg, 3.0 mmol), isobutyraldehyde (1.65 g, 22.8 mmol) and NaBH3CN (959 mg, 15 mmol) to afford 713 mg (99%) of 3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine, an yellow solid. Data for 3,4-dihydro-4-isobutyl-7-nitro-2H-1,4-benzoxazine: Rf 0.75 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, 1H, J=9.0, 2.6), 7.66 (d, 1H, J=2.6), 6.55 (d, 1H, J=9.2), 4.21 (t, 2H, J=4.5), 3.52 (t, 2H, J=4.6), 3.16 (d, 2H, J=7.4), 3.12 (hept, 1H, J=6.9), 0.97 (d, 6H, J=6.7).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[C:27]([CH2:37][CH2:38][CH3:39])[C:26]=1[OH:40])(=[O:24])[CH3:23].Cl>CN(C)C=O>[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][CH2:33][CH2:34][CH2:35][S:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:27]([CH2:37][CH2:38][CH3:39])[C:26]=1[OH:40])(=[O:24])[CH3:23]
Reactant: CCCc1c(SCCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)c1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(SCCCCSc2nc3ccc(C(=O)OCC)cc3[nH]2)ccc(C(C)=O)c1O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A mixture of ethyl 2-mercaptobenzimidazole-5-carboxylate (1.29 g), anhydrous potassium carbonate (960 mg) in N,N-dimethylformamide (20 ml) was stirred at 60-70 ° C. for 30 minutes. To this mixture was added a solution of 4-(4-acetyl-3-hydroxy-2-propylphenylthio)butylbromide (2.00 g) in N,N-dimethylformamide (10 ml) dropwise during 10 minutes and stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice-water, made acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane-ethyl acetate 10:1), to give the title compound (2.53 g, 89.8%) as pale yellow oil.