Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=[O:10])[CH2:8]Br)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7](=[O:10])[CH2:8][O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)OCC(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCC(C)(C)C(=O)COc1ccc(Cl)cc1
Yield: 74.6 %

Procedure:
170 g (0.72 mol) of 4-acetoxy-1-bromo-3,3-dimethylbutan-2-one in 200 ml of acetone were added dropwise, over the course of 100 minutes, to a suspension of 92.1 g (0.72 mol) of 4-chlorophenol and 108 g (0.72 mol) of potassium carbonate in 1,000 ml of acetone. After heating for 15 hours whilst stirring under reflux, the mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water at a time, dried over sodium sulphate and concentrated. The oily residue was distilled. 153 g (72% of theory) of 4-acetoxy-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one of boiling point 140°-145° C./0.2 mm Hg was obtained.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>O1CCCC1>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Reactant: Nc1ccc(CCC(=O)O)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Yield: 55.5 %

Procedure:
A mixture "of 5.51 g (0.025 mole) of 2,6-di-tertiary-butyl-p-benzoquinone, 4.54 g (0.027 mole) of 3-(4-aminophenyl)propionic acid, 50 ml of tetrahydrofuran and 0.25 ml of boron trifluoride etherate was heated on a steam cone under a slow stream of nitrogen for two hours. The resulting solid was triturated with hexane, collected, rinsed with hexane and recrystallized from a mixture of ethyl acetate and hexane to give 5.1 g yellow 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, m.p. 165°-167° C. Analysis: Calculated for C23H29NO3 : % C, 75.2; % H, 8.0; % N, 3.8; Found % C, 74.8; % H, 7.9; % N, 3.7.
Reaction SMILES: [Se](=O)=O.[O:4]1CCOCC1.[O:10]=[C:11]1[NH:15][C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][S:12]1>O>[O:10]=[C:11]1[NH:15][C:14]([C:16](=[O:4])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][S:12]1
Reactant: CCOC(=O)Cc1csc(=O)[nH]1
Reactant: C1COCCO1
Agent: CCOC(=O)Cc1csc(O)n1
Agent: O=[Se]=O
Solvent: O
Product: CCOC(=O)C(=O)c1csc(=O)[nH]1

Procedure:
To a solution prepared by heating a mixture of selenium dioxide (0.33 g.), dioxane (15 ml.) and water (0.3 ml.) at 110° C. with stirring was added ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)acetate, (0.56 g.) without heating, and then the mixture was stirred for 30 minutes at 110° C. After the reaction, the reaction liquid was separated and the residue was washed with a small amount of dioxane. The reaction liquid and the washings were combined together, and the solvents were distilled off. To the residue was added ethyl acetate, and the mixture was washed with water and dried over magnesium sulfate. The solvent was distilled off from the mixture to give a solid of ethyl 2-(2-oxo-2,3-dihydro-1,3-thiazol-4-yl)-glyoxylate, which can be represented as ethyl 2-(2-hydroxy-1,3-thiazol-4-yl)glyoxylate, (0.55 g.)
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([C:14]#[C:15][Si](C)(C)C)=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:26])[CH2:21]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:14]([C:12]1[S:13][C:9]([C:2]2([OH:1])[CH2:7][CH2:6][CH:5]([N:20]3[CH2:23][CH:22]([NH:24][C:25]([CH2:27][NH:28][C:29](=[O:40])[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:31]=4)=[O:26])[CH2:21]3)[CH2:4][CH2:3]2)=[CH:10][N:11]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1ncc(C2(O)CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-trimethylsilanylethynyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1 followed by TBAF work-up.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:19]([O:23][C:24](=[O:44])[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[CH2:34][NH:35][C:36]([C@@H:38]1[CH2:43][O:42][CH2:41][CH2:40][NH:39]1)=[O:37])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C@H:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([N:39]1[CH2:40][CH2:41][O:42][CH2:43][C@H:38]1[C:36](=[O:37])[NH:35][CH2:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:44])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1COCCN1
Reactant: CC(=O)O[C@@H](C(=O)O)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H](C(=O)N1CCOC[C@H]1C(=O)NCc1cc(Cl)ccc1CNC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
To a solution of (R)-2-acetoxy-3,3-dimethylbutanoic acid (0.14 g, 1.04 mmol) in CH2Cl2 (2 mL) was added oxalyl chloride (1.10 mL, 1.30 mmol) at 0° C. under nitrogen atmosphere and the resulting mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated to dryness and the residue was dissolved in CH2Cl2 (4 mL). A solution of (S)-tert-Butyl-4-chloro-2-{(morpholine-3-carboxamido)methyl}benzylcarbamate (0.20 g, 0.52 mmol) and triethylamine (0.70 mL, 2.08 mmol) in CH2Cl2 (2 mL) was added dropwise at 0° C. and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed sequentially with saturated NaHCO3 solution (10 mL) and 1M aqueous HCl (10 mL). The organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 50% EtOAc/hexanes) to afford the title compound as a pale yellow oil (0.2 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].C([NH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25])(=O)C.O>C(O)C>[NH2:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(=O)Nc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C=CC(=O)c2ccccc2)cc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
To a solution of acetophenone (7.2 g) and 4N-sodium hydroxide solution (14 ml) in ethanol (50 ml) was added 4-acetylamino-3-nitrobenzaldehyde (10.4 g) at ambient temperature under stirring and the resultant mixture was stirred at same condition for 2 hours. To the reaction mixture was added water and precipitate was collected by filtration. The precipitate was suspended in water (300 ml) and the resultant mixture was adjusted to pH 4.0 with 10% hydrochloric acid. The precipitate was collected by filtration and washed with brine and dried to give 3-(4-amino-3-nitrophenyl)-1-phenyl-2-propen-1-one (12.7 g).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].Cl[SiH:9]([CH3:11])[CH3:10].C(N(CC)CC)C>CCCCCCC>[CH2:1]([N:4]([SiH:9]([CH3:11])[CH3:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C[SiH](C)Cl
Reactant: C=CCNCC=C
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)[SiH](C)C

Procedure:
The preparation of an azasilacyclobutanes can be illustrated by the following: Diallylamine was reacted with chlorodimethylsilane in heptane in the presence of triethylamine to give diallylaminodimethylsilane as shown by the following equation ##STR24## The silane product was obtained by ambient pressure distillation after removal of triethylamine hydrochloride by filtration. 1-allyl-2,2,3-trimethyl-1-aza-2-silacyclobutane was made by intramolecular hydrosilation of the diallyldimethylsilane. This reaction was carried out at 80° C. in the presence of PtCl2 (PPh3)2 in benzene. The starting material was consumed in four hours to give a product mixture of 83 mole percent of the azasilacyclobutane and 17 mole percent of azasilacyclopentane as illustrated by the following equation ##STR25## Total yield of product was 77 weight percent. The azasilacyclobutane can be reacted with 1,1,3,3-tetramethyldisiloxane in the presence of a platinum catalyst which in turn can be reacted with an alkoxysilane having aliphatic unsaturation as described above to make an azasilacyclobutyl functional alkoxysilane of Formula (A).
Reaction SMILES: [CH2:1]([N:3]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[O:27][C:28]=1[CH3:29]>COCCOC.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:1]([N:3]1[C:7]([C:24]2[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[O:27][C:28]=2[CH3:29])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(C)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCn1nccc1-c1cc(C(=O)OC)oc1C
Temperature: 72 °C
Reaction time: 2 h

Procedure:
To a 100 mL sealed flask was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.2 g, 9.91 mmol), potassium carbonate (2.84 g, 20.54 mmol), methyl 4-bromo-5-methyl-2-furancarboxylate (1.5 g, 6.85 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (0.175 g, 0.34 mmol) in 1,2-dimethoxyethane (6 mL) and H2O (1 mL). After stirring for 2 h at 72° C., the reaction solution was diluted with DCM (50 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [EtOAC/hexanes, 10-30%] to give the product [1.1 g, 68.6%] as an off white solid: LC-MS (ES) m/z 235 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C)C)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:19])[O:3][C:4](=[CH:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](C)(C)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)OC(=O)C(=CC(=O)O)O1
Reaction time: 1 h
Yield: 62 %

Procedure:
The crude (Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with acetic acid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate (500 ml), washed with water, brine and dried (anhydrous magnesium sulfate). Evaporation of the solvent under reduced pressure and trituration of the residual solid with toluene (50 ml) gave 7.70 g (62% yield for 3 steps) of the title Z-isomer as a white crystalline solid. Concentration of the mother liquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers. Z-Isomer; 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer: 1H NMR (400 MHz, CDCl3) δ: 1.80 (s, 3), 6.03 (s, 1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(OC(O)C)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Nc1ccccc1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cncc(Nc2ccccc2)n1

Procedure:
A solution of 2,6-dichloropyrazine (1 g, 62 mmol) and aniline (1.25 g, 13.4 mmol) in ethoxyethanol (20 mL) containing DIPEA (2.5 mL, 13.4 mmol) was heated at reflux for 3 days under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (50 mL) and washed successively with H2O (50 mL), 1M HCl (2×50 mL), H2O (50 mL) and brine (50 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with EtOAc-hexane (20:80-50:50) to separate pure product from the lower fractions (230 mg, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:27][O:28][NH:29][CH3:30]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([N:29]([CH3:30])[O:28][CH3:27])=[O:14]
Reactant: CNOC
Reactant: O=C(O)C1OCCc2c(Br)cccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1OCCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid (9.10 g, 35.4 mmol) and CDI (4.14 g, 42.5 mmol) in 200 mL of dry DCM was stirred at r.t. for 30 min and then O,N-dimethyl-hydroxylamine (5.99 g, 42.5 mmol) was added. The result mixture was stirred overnight. The solvents were removed under vacuum, and the residue was purified with silica gel chromatography to give 5-bromo-N-methyl-N-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide. 1H-NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 5.63 (s, 1H), 4.23˜4.28 (m, 1H), 3.87˜3.92 (m, 1H), 3.71 (s, 3H), 3.19 (s, 3H), 2.71˜2.87 (m, 2H).
Reaction SMILES: O[C:2]1([CH2:26][I:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.CCN(S(F)(F)[F:34])CC>ClCCl>[F:34][C:2]1([CH2:26][I:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CI)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CI)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-hydroxy-4-iodomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.01 mmol) with DAST (1.32 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].[CH3:23][N:24]([CH3:30])[C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>O1CCOCC1>[CH3:23][N:24]([CH3:30])[C@H:25]1[CH2:29][CH2:28][N:27]([C:15]2[C:14]([C:9]3[O:10][C:11](=[O:13])[C:12]4[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([O:21][CH3:22])=[CH:6][C:7]=4[N:8]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:26]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Solvent: C1COCCO1
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CC[C@H](N(C)C)C3)oc(=O)c12
Yield: 70 %

Procedure:
A solution of compound S (13.9 g, 46.4 mmol) in anhydrous 1,4-dioxane (232 mL) was treated with (S)-(−)-3-(dimethylamino)-pyrrolidine (7.50 mL, 60.3 mmol) at 100° C. under N2 for 10 minutes. The solution was concentrated, and the residue was purified using a Biotage 40M amine column using a gradient of 20-50% ethyl acetate/hexanes. The fractions containing compound 132 were combined and concentrated by rotary evaporation, dissolved in acetonitrile:water (1:1, 50 mL), and then lyophilized to afford compound 132 as a pale yellow powder (12.81 g, 70% yield). 1H NMR (CDCl3, 400 MHz) d: 8.30 (dd, 1H, J=1.5 Hz), 8.00 (dd, 1H, J=1.5 Hz), 6.95 (d, 1H, J=2.0 Hz), 6.88 (d, 1H, J=3.0 Hz), 6.72 (q, 1H, J=4.5 Hz), 3.92 (s, 3H), 3.66 (q, 1H, J=4.0 Hz), 3.48 (m, 3H), 3.21 (m, 2H), 2.78 (s, 1H), 2.26 (s, 6H), 2.12 (q, 1H, J=6.0 Hz), 1.84 (m, 1H), 1.29 (t, 3H, J=7.0 Hz); 13C NMR (CDCl3, 400 MHz) d: 165.5, 158.8, 158.1, 155.7, 151.1, 151.0, 150.6, 140.3, 117.9, 112.2, 110.6, 107.3, 107.1, 65.4, 55.9, 54.4, 49.1, 44.5, 30.3, 28.6, 15.2; ESMS m/z: 395.1 [M+H+]; Calculated for C22H26N4O3: C, 66.99; H, 6.64; N, 14.20. found: C, 66.81; H, 6.66; N, 14.14.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCCO
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: OCCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 4-aminobutan-1-ol according to general procedure 1 providing the intermediate (150 mg, 82%) as a yellow solid: Rf=0.45 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.7 Hz, 1H), 7.38 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H), 3.40 (t, J=6.9 Hz, 2H), 1.77-1.72 (m, 2H), 1.69-1.64 (m, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]1([CH:15]=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1>O1CCCC1>[C:5]1([CH:15]([OH:16])[CH2:1][CH3:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a flame-dried flask containing 8.0 mL of dry tetrahydrofuran under an argon atmosphere cooled to -78° C. Is added 4.0 mL (3.0 M) of a solution of ethylmagnesium bromide in tetrahydrofuran. The stirrable mixture is treated with a solution of 1.36 g of commercially available 1-naphthaldehyde in 4.0 mL of tetrahydrofuran with a 2 mL rinse. The reaction is stirred at -78° C. for 5 minutes then warmed to room temperature. After 1 hour the mixture is re-cooled to 0° C., carefully quenched with saturated ammonium chloride, and diluted with diethyl ether. The layers are separated; organic phase washed with brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue is flash column chromatographed using 25% ethyl acetate in hexane to give 1.76 g of the title product as a pale pink oil.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:9]=[N:8][CH:7]=1)CCC.Br[C:28]1[N:33]=[C:32]([C:34]([NH:36][CH3:37])=[O:35])[C:31](=[O:38])[N:30]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=2)[C:29]=1[CH3:49]>COCCOC>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([N:10]2[C:6]([C:28]3[N:33]=[C:32]([C:34]([NH:36][CH3:37])=[O:35])[C:31](=[O:38])[N:30]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=4)[C:29]=3[CH3:49])=[CH:7][N:8]=[N:9]2)=[CH:18][CH:17]=1)#[N:16]
Reactant: CNC(=O)c1nc(Br)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1-c1ccc(C#N)cc1
Solvent: COCCOC
Product: CNC(=O)c1nc(-c2cnnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 100 °C
Yield: 40.2 %

Procedure:
4-(5-Tributylstannanyl-[1,2,3]triazol-1-yl)-benzonitrile (0.15 g, 0.32 mmol), 6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (SM2, 0.054 g, 0.14 mmol), Pd(PBut3)2 (10 mg) and DME (2 ml) were placed in a tube for microwave synthesis. The mixture was degassed with argon and heated in a synthesis microwave heater (CEM) at 100° C. (max 150 W) for 10 minutes. The solvent was removed in vacuo giving a crude product which was purified on silica and then further purified on preparative HPLC. The pure fractions were freeze-dried giving 27 mg (41%) of the title compound.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH3:22])=[N:19][C:18]=2[CH:23]=1.IC>C1COCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[S:21][C:20]([CH2:22][CH3:1])=[N:19][C:18]=2[CH:23]=1
Reactant: CC(C)NC(C)C
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Br)ccc2s1
Reaction time: 0.33 h

Procedure:
A 0° C. solution of diisopropylamine (340 μL, 2.41 mmol) in THF (3 mL) was treated with 2.5M n-butyllithium in hexanes (0.88 mL), stirred for 20 minutes, added to a −78° C. solution of 5-bromo-2-methyl-1,3-benzothiazole (250 mg, 1.10 mmol) in THF (3 mL), stirred for 30 minutes, treated with iodomethane (340 μL, 5.50 mmol), and stirred for 1 hour. The mixture was diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% hexanes/dichloromethane to provide the desired product. MS (DCI) m/e 242 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26]C(C)(C)[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([C:27]([OH:28])=[O:26])=[C:23]([OH:24])[CH:31]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)OC(C)(C)OC2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(C(=O)O)c(O)c1
Yield: 76.3 %

Procedure:
To a solution of 7-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (613 mg, 1.2 mmol) in THF (18 mL) was added a suspension of lithium hydroxide monohydrate (1.47 g, 35.1 mmol) in water (5.0 mL). The resulting mixture was refluxed for 48 hrs. The reaction mixture was diluted with Et2O (60 mL) and washed with an aqueous solution of HCl (3×15 mL, 1N) and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure to give 443 mg (78%) of the title compound as a yellow powder. HPLC, Rt: 6.2 min (purity: 97.7%). LC/MS, M−(ESI): 482.2. 1H NMR (CDCl3) δ: 10.59 (s, 1H), 7.66 (d, J=9 Hz, 1H), 7.45 (m, 4H), 7.13 (m, 4H), 6.21 (m, 1H), 6.14 (m, 1H), 4.58 (s, 2H), 3.40 (m, 2H), 2.60 (t, J=7.5 Hz, 2H), 1.72-1.51 (m, 2H), 1.42-1.20 (m, 10H), 0.95-0.82 (m, 6H).