Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:53]([O:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:21][CH:22]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1)[CH3:54]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOc1ccccc1OB([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-ethoxyphenyl borate (115 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 14 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(2-ethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 119) (145 mg).
Reaction SMILES: Cl[C:2]([CH3:26])([CH3:25])[C:3]([C:5]1[CH:24]=[CH:23][C:8]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([CH3:21])(Cl)[CH3:19])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][N:27]([C:2]([CH3:26])([CH3:25])[C:3]([C:5]2[CH:24]=[CH:23][C:8]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17](=[O:22])[C:18]([CH3:21])([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH3:19])=[CH:13][CH:12]=3)=[O:10])=[CH:7][CH:6]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: CC(C)(Cl)C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)Cl)cc2)cc1
Reactant: C1COCCN1
Product: CC(C)(C(=O)c1ccc(C(=O)c2ccc(C(=O)C(C)(C)N3CCOCC3)cc2)cc1)N1CCOCC1

Procedure:
78 g of 4,4'-bis-(2-chloro-2-methyl-propanoyl)-benzophenone is boiled with 250 ml of morpholine for 15 hours. The excess morpholine is then distilled off under reduced pressure and the residue is crystallized from ethanol. 4,4'-bis-(2-Morpholino-2-methyl-propanoyl)-benzophenone is obtained; m.p. 145°-147°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]2[C:15](=O)[CH2:16][CH2:17][CH2:18][C:13]=2[O:12][N:11]=1)([O-])=[O:2].Cl.O1CCCC1>[Pd].CO>[NH2:11][C:10]1[C:5]2[C:4]([N+:1]([O-:2])=[C:15]3[C:14]=1[C:13](=[O:12])[CH2:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCCc2onc(-c3ccccc3[N+](=O)[O-])c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1c2c([n+]([O-])c3ccccc13)CCCC2=O
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A mixture of 6,7-dihydro-3-(2-nitrophenyl)-1,2-benzisoxazole-4(5H)-one, (7.0 g), 5% palladium-on-carbon (0.7 g), 5% hydrochloric acid (11 ml), and tetrahydrofuran (200 ml) was hydrogenated at 50 psi. After one hr, methanol (1l) was added, and the mixture was filtered through celite. The flitrate was concentrated, and the concentrate was flash chromatographed (silica, 3-20% methanol/ethyl acetate; 40% methanol/dichloromethane). The appropriate fractions were collected and concentrated. The residue was triturated with methanol/diethyl ether to yield 5.4 g (83%) of product, mp 290° C. (dec).
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8](=[O:20])[C@H:9]([CH3:19])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:21]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:20])[C@H:9]([CH3:19])[N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCN(CCCCCC)C(=O)[C@H](C)Nc1ccccc1C#N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN(CCCCCC)C(=O)[C@H](C)N(c1ccccc1C#N)c1ccccc1[N+](=O)[O-]
Yield: 41.3 %

Procedure:
The crude (2-cyanophenyl)alanine dihexylamide (0.76 g), 2-fluoronitrobenzene (0.30 g) and anhydrous potassium carbonate (0.36 g) in 8 ml of N,N-dimethylformamide were refluxed under heating for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was water and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane-ethyl acetate=5:1) to give 0.42 g of N-(2-nitrophenyl)-(2-cyanophenyl)alanine dihexylamide.
Reaction SMILES: CCN(C(C)C)C(C)C.CC([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23]([OH:25])=O)=[O:16])(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH2:58][N:59]2[C:67]3[C:62](=[C:63]([CH:68]([OH:70])[CH3:69])[CH:64]=[CH:65][CH:66]=3)[C:61]([NH:71][S:72]([C:75]3[S:76][C:77]([Cl:80])=[CH:78][CH:79]=3)(=[O:74])=[O:73])=[N:60]2)[CH:55]=[CH:56][CH:57]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH:15]([OH:16])=[O:14].[Cl:80][C:77]1[S:76][C:75]([S:72]([NH:71][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][C:63]=3[CH:68]([OH:70])[CH3:69])[N:59]([CH2:58][C:54]3[CH:53]=[C:52]([CH2:51][NH:50][C:23]([C@H:18]4[CH2:19][O:20][CH2:21][CH2:22][NH:17]4)=[O:25])[CH:57]=[CH:56][CH:55]=3)[N:60]=2)(=[O:73])=[O:74])=[CH:79][CH:78]=1
Reactant: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@H]2COCCN2)c1
Product: O=CO
Temperature: 25 °C
Yield: 58 %

Procedure:
DIPEA (0.059 mL, 0.336 mmol) was added to a stirring solution of (3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (19.41 mg, 0.084 mmol) in DCM (1 mL). HATU (35.1 mg, 0.092 mmol) was then added followed by N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(1-hydroxyethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 77) (44 mg, 0.084 mmol) and stirred for an hour at room temp. The mixture was treated with 4M hydrogen chloride in dioxane (0.5 mL, 2 mmol) and the reaction stirred at room temperature for 0.5 h. The reaction mixture was passed through an SCX-2 cartridge, washed with methanol and then eluted using 2M ammonia in methanol. The appropriate ammoniacal fractions were concentrated under reduced pressure and the residue was dissolved in DMSO-Methanol (1:1) (1 mL) and purified by MDAP (Method A) to give the title compound (31.2 mg, 58%). LCMS (System C) RT=2.04 min, ES+ve m/z 590/592 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH2:10][CH2:9][N:8]2[C:4](=[N:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=32)[C:3]=1[C:15]([O:17]CC)=O.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]([C:3]2[C:4]3=[N:5][C:6]4[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=4[N:8]3[CH2:9][CH2:10][C:2]=2[OH:1])=[O:17])=[CH:22][CH:23]=1
Reactant: Nc1ccncc1
Reactant: CCOC(=O)C1=C(O)CCn2c1nc1ccccc12
Product: O=C(Nc1ccncc1)C1=C(O)CCn2c1nc1ccccc12

Procedure:
The pyridobenzimidazo derivative VII (4.0 g, 15.5 mmol) and 4-aminopyridine (2.82 g, 30.0 mmol) were combined in xylenes (200 mL) and heated at reflux for 6 h in a flask fitted with a Dean Stark trap. The resulting solid was isolated from the cooled reaction mixture and recrystallized from a mixture of methylene chloride and EtOH to give the title compound as a crystalline solid: mp 274-276° C.; MS: 307 (MH+).
Reaction SMILES: C(N(CC)CC)C.C([O:10][C:11]([C:13]1[N:14]([CH2:27][C:28]2([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29]2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=2)=O)C.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:10]=[C:11]1[C:13]2=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:15]=3[N:14]2[CH2:27][C:28]2([CH2:29][CH2:30][CH2:31]2)[CH2:32][NH:33]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCC1)CNC3=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
Triethylamine (23.3 mL, 167.5 mmol) is added to a mixture of crude 1-(1-aminomethyl-cyclobutylmethyl)-1H-indole-2,6-dicarboxylic acid diethyl ester from the preceding step and K2CO3 (23.16 g, 167.5 mmol) in ethanol (1.2 L). The reaction mixture is heated at 80° C. for 2 h then is cooled down to room temperature and stirred for another 16 h. The solid K2CO3 is removed by filtration and the filtrate is concentrated to afford the crude compound which is purified by flash column chromatography using 3% methanol in CH2Cl2 to afford the title compound (7 g, 40% for 3 steps) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH3:11])=[C:7]([OH:9])[CH:8]=1.C(=O)([O-])O.[Na+].[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([CH3:21])[CH3:20])#[N:18]>O1CCCC1>[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH3:11])=[C:7]([OH:9])[CH:8]=1)=[O:26])([CH3:21])[CH3:20])#[N:18]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: CCc1ccc(N)cc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a two-layer solution of 5-amino-2-ethylphenol hydrochloride (2.2 g, 12.6 mmol) in tetrahydrofuran (20 mL)/1N aqueous sodium hydrogen carbonate solution (38 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 12 hr. The aqueous layer was separated, and extracted with ethyl acetate (80 mL). The combined organic layer was washed with water (40 mL) and saturated brine (40 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (45 mL)/hexane (25 mL) was added to the obtained residue, and the obtained solid was collected by filtration to give the title compound (3.48 g, 90%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:13])[CH2:11]Br)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[OH-].[Na+].CCOCC.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([OH:13])[CH2:11][NH:24][CH:21]([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(O)CBr)cc1Cl
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: CSc1ccc(C(O)CNC(C)C)cc1Cl
Reaction time: 0.17 h

Procedure:
7 g of 1-(3-chloro-4-methylthiophenyl)-2-bromoethanol (0.025 mol) in 50 cc of ethanol are treated with 1.4 g of sodium hydroxide (0.035 mol). The product is stirred for 10 minutes, then diluted with water. One extracts with ether and dries on magnesium sulfate. The solvent is evaporated under vacuum and the residual oil is treated with 100 cc of EtOH and 5.9 g of isopropylamine (0.1 mol). The product is brought to 50° overnight with stirring. The solvent and excess of isopropylamine are evaporated under vacuum. The residual oil crystallises after some time (melting point of 111°-112°C after recrystallisation from cyclohexane). The free base is dissolved in ether; by passing dry gaseous HCl, 4.88 g of 1-(3-chloro-4-methylthiophenyl)-2-isopropylaminoethanol hydrochloride are obtained which are recrystallised from a methanol-ether mixture. Melting point: 139°-141°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[CH2:21]2>>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:21]2=[CH:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([O:2][CH3:1])=[CH:10][CH:9]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: COc1ccc(C=O)cc1-c1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1-c1ccccc1

Procedure:
4-Methoxy-3-phenylbenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.3 g of 5-fluoro-3-(6-methoxybiphenyl-3-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cccc(CCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cccc(CCCBr)c1
Reaction time: 12 h
Yield: 84.4 %

Procedure:
Compound 15-1 (1.88 g) was dissolved in methylene chloride (50 ml), triphenylphosphine (3.64 g) and N-bromosuccinimide (2.46 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 12 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:1) to give the object product (2.25 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:7])[CH2:5][OH:6].[Br:8][C:9]1[N:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:16]([C:19]#[N:20])=[C:17](Cl)[C:12]2=[N:11][CH:10]=1>O>[Br:8][C:9]1[N:13]2[CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:16]([C:19]#[N:20])=[C:17]([O:6][CH2:5][CH:4]([CH3:7])[CH3:3])[C:12]2=[N:11][CH:10]=1
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc2c1Cl
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
NaH (60% in mineral oil, 149 mg, 3.7 mmol) was carefully added to 2-methyl-1-propanol (10 mL) at 0° C. (ice bath). The mixture was stirred at RT for 10 min before 3-bromo-8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (500 mg, 1.25 mmol) was added in one portion. The reaction mixture was heated at 70° C. and stirred for 1 h, then cooled to RT and poured into water (100 mL). The formed slurry was extracted successively with DCM (2×50 mL) and AcOEt (50 mL), and the combined organic fractions were dried over Na2SO41 filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95.5→100% TBME) to yield the title compound (348 mg, 0.79 mmol, 63%). MS: 438 [M+1]+; HPLC: AtRet=3.36; TLC: RF 0.81 (hexane/TBME 1:1).
Reaction SMILES: CNC[CH2:4][C:5]1([CH2:20][CH:21]=[CH2:22])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[CH2:23]([N:25](CC)CC)C.Cl[C:31]([O:33][CH2:34]C)=[O:32].O>C1COCC1>[CH2:20]([C:5]1([CH2:4][CH2:34][O:33][C:31](=[O:32])[NH:25][CH3:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH:21]=[CH2:22]
Reactant: CCOC(=O)Cl
Reactant: C=CCC1(CCNC)c2ccccc2CCc2ccccc21
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CCC1(CCOC(=O)NC)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolved 10,11-dihydro-N-methyl-5-(2-propenyl)-5H-dibenzo[a,d]cycloheptene-5-ethanamine (0.50 g, 1.72 mmol) in 20 mL of dry THF. Added triethylamine (0.29 mL, 0.21 g, 2.06 mmol) and ethyl chloroformate (0.18 mL, 0.20 g, 1.88 mmol). Stirred at room temperature for 5 hours. Added 50 mL of water, and extracted with dichloromethane. Dried combined organic extracts with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with dichloromethane. Combined appropriate fractions, and evaporated to give 0.50 g (81% yield) of ethyl N-[2-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]ethyl-N-methylcarbamate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:35]=[CH:36][C:37]2[O:41][CH:40]=[CH:39][C:38]=2[CH:42]=1)=[NH:33]>CN(C=O)C.C([O-])(O)=O.[Na+]>[O:41]1[C:37]2[CH:36]=[CH:35][C:34]([C:32]3[N:31]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:33]=3)=[CH:42][C:38]=2[CH:39]=[CH:40]1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1ccc2occc2c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4occc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
Prepared using General Procedure 2. A flask containing 3-cyano-4-isopropoxybenzoic acid (147.7 mg, 0.72 mmol), HOBt (143 mg, 0.94 mmol) and EDC (180 mg, 0.94 mmol) in DMF (2.0 mL) was stirred for 0.5 h at room temperature under an atmosphere of N2. A solution of N-hydroxybenzofuran-5-carboximidamide INT-68 (218 mg, 0.79 mmol) in DMF (2.0 mL) was added to the mixture. After 1 h at room temperature, the mixture was stirred at 85° C. overnight. The reaction mixture was diluted with NaHCO3 and extracted with EA. The combined organic extracts were dried over Na2SO4, and concentrated. The resulting crude material was chromatographed (EA/hexanes) to provide 110 mg (44%) of 5-(3-(benzofuran-5-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 69 as a white solid. LCMS-ESI (m/z) calculated for C20H15N3O3: 345.4; found 346.1 [M+H]+, tR=2.77 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J=4.5, 1.9 Hz, 2H), 8.35 (dd, J=8.9, 2.2 Hz, 1H), 8.12 (dd, J=8.6, 1.7 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.88 (dd, J=2.2, 0.8 Hz, 1H), 4.80 (s, 1H), 1.48 (d, J=6.1 Hz, 61-1).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].CO[CH2:36][CH2:37][NH2:38].[C:39](O)(=O)C>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:4])[N:38]([CH2:37][CH2:36][CH3:39])[CH:32]=[CH:31][N:6]3[CH:7]=2)=[O:30])=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: COCCN
Reactant: CC(=O)O
Solvent: ClCCl
Product: CCCn1ccn2cc(C(=O)NCc3ccc(F)cc3)c(=O)c(OCc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a solution of the compound 16 (400 mg, 0.884 mmol) in methylene chloride (12 ml) were added 2-methoxyethylamine (77 ul, 0.884 mmol) and acetic acid (18 ul), and the mixture was stirred at room temperature for 5 minutes. Thereafter, the reaction was performed at 140° C. for 30 minutes in a microwave reaction apparatus. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and fractions eluting with toluene-acetone were concentrated under reduced pressure to obtain 9-benzyloxy-2-(2-methyl-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide 17-1 (226 mg, 54%) as a yellow solid.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.C(=O)([O-])[O-:22].[K+].[K+].O>CN(C)C=O>[OH:22][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[O:7][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: C1CCC2OC2C1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OC2CCCCC2O)cc1C(F)(F)F
Yield: 49.9 %

Procedure:
Cyclohexene oxide (13.11 g, 133.6 mmol), 4-fluoro-2-(trifluoromethyl)benzonitrile (5.00 g, 26.72 mmol), and potassium carbonate (5.539 g, 40.08 mmol) in DMF (dimethylformamide) (50 mL) were heated to 95° C. for 14 hours. The reaction was then allowed to cool. The reaction was added to water (300 mL) and then extracted with ethyl acetate (200 mL) three times. The combined extracts were washed with water (300 mL), 0.5M NaOH (300 mL), water (300 mL), and a 15% sodium chloride solution (300 mL). The organic phase was dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on silica, eluting with a 2:1 solution of hexane:ethyl acetate. This yielded the desired product, 4-(2-hydroxy-cyclohexyloxy)-2-trifluoromethyl-benzonitrile (3.8 g, 50% yield).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1Br.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(C(C)C)CC)(C)C>C(O)C>[Br:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[C:20](=[O:25])[CH2:21]1
Reactant: CN1CCNCC1=O
Reactant: O=c1c(Br)c(Br)cnn1Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCN(c2cnn(Cc3ccc(F)cc3)c(=O)c2Br)CC1=O
Temperature: 100 °C

Procedure:
A mixture of 4,5-dibromo-2-(4-fluorobenzyl)pyridazin-3(2H)-one (0.8 g, 2.21 mmol), 1-methylpiperazin-2-one (0.33, 2.87 mmol; see Example 7, Step 3), and diisopropylethyl-amine (0.34 g, 3.32 mmol) in absolute ethanol (3 mL) was heated in a sealed tube in an oil bath at 100° C. overnight. The mixture was concentrated under vacuum. The residue was partitioned between ethyl acetate and brine. The organic extract was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with hexanes and ethyl acetate gradient to give titled material.