Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1>>[N:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccncc1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccncc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.011 gm (0.062 mMol) 4-pyridinecarbonyl chloride, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(F)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
550 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 10A; 1.5 mmol, 1 equivalent) were dissolved in 64 ml of THF and 12 ml of methanol, 7.5 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT overnight. 8 ml of 1 N aqueous hydrochloric acid were then added, and the mixture was concentrated under reduced pressure. The solid formed was filtered off and washed with water. This gave 429 mg of the title compound (80% of theory).
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])([O-])=[O:7].[K+].[CH2:11]([O:13][C:14](=[O:30])[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH3:28])[C:18](=[O:29])[CH2:17]1)[CH3:12]>ClCCl>[CH2:11]([O:13][C:14](=[O:30])[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([N+:6]([O-:9])=[O:7])[CH:26]=[CH:27][C:20]=2[N:19]([CH3:28])[C:18](=[O:29])[CH2:17]1)[CH3:12]
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccccc2C1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
To conc H2SO4 (14 ml), kept in an ice bath, KNO3 (2 g, 20 mmol) was added in portions whereby the temperature rose to 10° C. (see also R. I. Fryer et al., J. Heterocyclic Chem. 1991, 28, 1203-1208). To this mixture was added a solution of (1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (5 g, 18 mmol) in dichloromethane (16 ml) whereby the temperature was kept between 20-25° C. After stirring for 90 min the mixture was carefully poured onto ice water and extracted with dichloromethane. The organic extracts were washed with aqueous sat. NaHCO3 followed by water, dried over Na2SO4 and the solvents evaporated. Upon addition of EtOH to the oily residue a precipitate was formed which was collected by filtration to give (1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (4 g): mp. 129-130° C.; MS (EI): 321 (M)+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[N:16][OH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-])=O.[H-].[Na+].O>COCCOCCOC>[O:17]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:16]1
Reactant: CCOC(=O)C(=NO)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)c1noc2ccccc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
20 g of 3A was dissolved in 100 ml of diglyme and the solution was added dropwise to a vigorously stirred mixture of 2.5 g of sodium hydride and 100 ml of diglyme, under nitrogen at room temperature. The mixture was heated slowly to and held at 150° C. for 6 hours, then cooled, mixed with 200 ml of water and extracted with ether. The extract was dried and stripped of solvent. The residue was distilled in a Kugelrohr apparatus (60° C./0.05 Torr); the resulting residue was dissolved in warm petroleum ether, the solution was chilled to 0° C., and the solid phase was collected and dried, to give ethyl 3-benzisoxazolylcarboxylate (3B), as a white solid, m.p.: 53°-55° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31](OCC)=[O:32])=[C:25]([F:36])[C:24]=2[F:37])=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:19]=[C:18]([CH3:20])[S:17][C:16]=2[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH2:31][OH:32])=[C:25]([F:36])[C:24]=2[F:37])=[CH:13][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C)cc2-c2ccc(CC)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2cc(C)sc2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-ethylphenyl)-5-methylthiophen-2-yl)methoxy)-2,3-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J=7.0 Hz, 2H), 7.24 (d, J=7.1 Hz, 2H), 6.78 (s, 1H), 6.72 (m, J=5.8 Hz, 1H), 6.62 (m, J=7.2 Hz, 1H), 5.11 (s, 2H), 3.72 (t, J=8.1 Hz, 2H), 2.72 (m, J=5.2 Hz, 2H), 2.65 (m, J=7.5 Hz, 2H), 2.49 (s, 3H), 1.82 (m, J=5.8 Hz, 2H), 1.70 (br, s, 1H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:18])[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=[O:13])=[O:9])=[O:4].COC(CC(C)C([N:27]1CCC[C@H]1C(O)=O)=O)=O>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:18])[C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([NH2:27])=[O:13])=[O:9])=[O:4]
Reactant: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CC(C)C(=O)N1CCC[C@H]1C(=O)O
Product: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
By substituting the 1-(4-methoxycarbonyl-2-methylbutanoyl)-L-proline of Example 24 for the 1-(3-methoxycarbonyl-2-methylpropanoyl)-L-proline in the procedure of Example 50, 1-(4-methoxycarbonyl-2-methylbutanoyl)-L-prolineamide is obtained.
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[F:14][C:15]([F:34])([F:33])[C:16]([NH:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][CH2:31][CH3:32])=[CH:17][C:18]([OH:20])=O>CCCCCC>[F:28][C:26]1[CH:25]=[CH:24][C:23]([O:29][CH2:30][CH2:31][CH3:32])=[C:22]2[C:27]=1[C:18](=[O:20])[CH:17]=[C:16]([C:15]([F:14])([F:34])[F:33])[NH:21]2
Reactant: CCCOc1ccc(F)cc1NC(=CC(=O)O)C(F)(F)F
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCOc1ccc(F)c2c(=O)cc(C(F)(F)F)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
Diphenyl ether (15 ml) was added to ethyl ester of 4,4,4-trifluoro-3-(5-fluoro-2-propoxyphenylamino)buta-2-enoic acid (19.7 g, 59.0 mmol), and the mixture was stirred for 1.5 hours while heating under reflux. The reaction mixture was cooled to room temperature, n-hexane was added, and the precipitate was collected by filtration. The substance remaining on the filter was washed with n-hexane, and dried to thereby obtain 16.2 g of powdery white 5-fluoro-8-propoxy-2-trifluoromethyl-1H-quinolin-4-one (yield: 94%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCCc2c(OCc3ccccc3)cccc21
Yield: 87.6 %

Procedure:
To a solution of 4.86 g of 5-hydroxy-1-tetralone in 50 ml of acetonitrile, 5.13 g of benzyl bromide and 6.22 g of potassium carbonate were added and the mixture was heated at reflux for 4 hours. The insoluble matter was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 6.62 g of the desired compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:12]([C:13](=[CH:25][N:26]([CH3:28])[CH3:27])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19])=[CH:10][C:9]2[C:4](=[C:5]([F:22])[C:6]([F:21])=[C:7]([F:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)c(F)c2nc1Cl
Reaction time: 2 h

Procedure:
A suspension of 26.7 g of ethyl 3-(2-chloro-6,7,8-trifluoro-3-quinolyl)-3-oxopropionate in 270 cm3 of ethyl acetate and 32 cm3 of N,N-dimethylformamide dimethyl acetal is heated at a temperature close to 75° C., with stirring, for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The dry extract is taken up in 175 cm3 of diisopropyl ether, drained and washed with twice 85 cm3 of the same solvent. 19.32 g of ethyl 2-(2-chloro-6,7,8-trifluoro quinoline-3-carbonyl)-3-dimethylaminoacrylate are obtained in the form of an orange solid melting at 118° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCC>[F:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:2]([O:1][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]#[CH:4])=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: C#CC(O)COc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamidee and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. The organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[C:19]([CH3:25])=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[C:19]([CH3:25])=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: Cc1c(N)cccc1O
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(N)cccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 57.5 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (800 mg, 2.44 mmol), 3-amino-2-methylphenol (380 mg, 2.93 mmol), potassium carbonate (843 mg, 6.10 mmol) and N,N-dimethylformamide (6.0 mL) as starting materials and in the same manner as in Example 91, the title compound (454 mg, 58%) was obtained as a blackish brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[N:16](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([NH2:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C=O
Reactant: O=C(O)CCc1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a mixture of 3-(4-nitrophenyl)propionic acid (13.45 g), N,N-dimethylformamide (0.1 mL) and tetrahydrofuran (300 mL) was added dropwise oxalyl chloride (10.5 g) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. and concentrated. The obtained residue was dissolved in tetrahydrofuran (50 mL) and added dropwise to a mixture of 25% aqueous ammonia (100 mL) and tetrahydrofuran (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 3-(4-nitrophenyl)propanamide as colorless crystals (11.80 g, yield 88%). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br>CN1C(=O)CCC1.CCOCC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
A mixture of NaH (3.1 g, 76 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with the mixture of 2-(4-methoxyphenyl)acetonitrile (4.5 g, 31 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (7.1 g, 31 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+Na=240. The mixture was carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.2 g of the product as a pale yellow oil. MS (m/z)=240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([C:36]([F:37])([F:38])[F:39])=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C(F)(F)F)cc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 36.8 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2-fluoro-4-(trifluoromethyl)aniline (0.064 g, 0.357 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.11 (s, 2H), 7.31 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.81 (d, J=11.4 Hz, 1H), 8.46 (s, 2H), 8.70 (t, J=8.4 Hz, 1H), 10.23 (s, 1H), 11.03 (br s, 1H), 11.60 (br s, 1H); MS [M+H]+: 552.33.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.[CH3:21][C:22]([C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:27]4[CH:28]=[CH:29][C:24]([C:22](=[O:23])[CH3:21])=[CH:25][CH:26]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 25.2 %

Procedure:
To a solution of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (70 mg, 0.25 mmol) in DMF (2.5 mL) was added 4-fluoroacetophenone (35 mg, 0.25 mmol) and potassium carbonate (69.1 mg, 0.5 mmol) and the resulting mixture heated at 120° C. overnight. The resulting mixture was then poured into HCl (1 N, 200 mL) and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient afforded the title compound (25 mg, 25%) which was obtained as a white solid. MS: m/e=398.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)=[CH:4][CH:3]=1.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH2:14][C:11]1[C:12](=[O:13])[N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]=[C:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:10]=1)[CH3:33]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Reactant: CNC
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 60.8 %

Procedure:
Following the procedure of Example 7, 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 60.8%).
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([SH:7])[S:4][N:3]=1.Br[CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13]>C(C(C)=O)C>[F:15][C:11](=[C:12]([F:14])[F:13])[CH2:10][CH2:9][S:1][C:2]1[N:6]=[C:5]([S:7][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[S:4][N:3]=1
Reactant: Sc1nsc(S)n1
Reactant: FC(F)=C(F)CCBr
Solvent: CCC(C)=O
Product: FC(F)=C(F)CCSc1nsc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1.0 gram (0.004 mole) of the dipotassium salt of 3,5-dimercapto-1,2,4-thiadiazole in 35 ml of methyl ethyl ketone was stirred and 1.7 grams (0.009 mole) of 4-bromo-1,1,2-trifluoro-1-butene was added. The reaction mixture was heated under reflux for two hours then allowed to cool to ambient temperature where it stirred for 18 hours. The reaction mixture was concentrated under reduced pressure lo a residue. The residue was stirred in 25 ml of water and the mixture was extracted with two 25 ml portions of toluene. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 1.1 grams of 3,5-di-(3,4,4-trifluoro-3-butenylthio)-1,2,4-thiadiazole as a liquid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:28](=[O:29])[N:27]([CH3:30])[C:11]3[N:12]([CH3:26])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH2:24][OH:25])[S:22][CH:23]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.I[CH2:32][CH3:33]>>[CH2:32]([O:25][CH2:24][C:21]1[S:22][CH:23]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:26])[C:11]2[N:27]([CH3:30])[C:28](=[O:29])[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=2)[N:20]=1)[CH3:33]
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Reactant: CCI
Product: CCOCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as in Example 10 above, using 3-(4-fluorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, compound from Example 63 and iodoethane.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].F[C:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[C:12]([C@@H:18]2[O:23][CH2:22][C@H:21]3[CH2:24][NH:25][CH2:26][CH2:27][N:20]3[CH2:19]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:3][O:4][C:9]1[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[C:12]([C@@H:18]2[O:23][CH2:22][C@H:21]3[CH2:24][NH:25][CH2:26][CH2:27][N:20]3[CH2:19]2)=[CH:11][CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([C@H]2CN3CCNC[C@@H]3CO2)c(C)c1C#N
Temperature: 150 °C

Procedure:
A microwave vial was charged with 6-fluoro-2-methyl-3-[(3S,9aR)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile trifluoroacetate (110 mg, 0.290 mmol), sodium carbonate (30 mg, 0.290 mmol), and methanol (2 mL). The mixture was heated to 150° C. in a microwave apparatus for 2 h, then cooled to ambient temperature, filtered and concentrated to provide the title compound which was used without further purification. LC-MS (IE, m/z): 288 [M+1]+.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[NH2:15][C@H:16]([C:18]([N:20]1[C:26](=[O:27])[CH:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[C:22]2[C:33]([NH2:37])=[CH:34][CH:35]=[CH:36][C:21]1=2)=[O:19])[CH3:17]>>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6]([NH:15][C@H:16]([C:18]([N:20]1[C:26](=[O:27])[CH:25]([CH3:28])[C:24]2[CH:29]=[CH:30][CH:31]=[CH:32][C:23]=2[C:22]2[C:33]([NH2:37])=[CH:34][CH:35]=[CH:36][C:21]1=2)=[O:19])[CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CC(=O)N(CC(=O)O)c1ccccc1
Product: CC(=O)N(CC(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21)c1ccccc1

Procedure:
Following one or more of the general procedures outlined above, using acetyl-N-phenylglycine and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 485 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][C:16]=2[OH:27])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][C:16]=2[O:27][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CCOc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)c(O)c1
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(OCC=C(C)C)ccc1C(=O)C=Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 45.1 g of 4-t-butyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone in 500 ml of acetone was added 10.6 g of potassium hydroxide, and the mixture was stirred for 5 minutes. Then, 21.5 g of ethyl bromoacetate was added, and the mixture was stirred for 45 minutes. After neutralization with dilute hydrochloric acid, the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to give 47.6 g of 4-t-butyl-2'-ethoxycarbonylmethoxy-4'-(3-methyl-2-butenyloxy)chalcone as a pale yellow powder.
Reaction SMILES: [OH:1][C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:7][C:4]([CH3:5])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[O:1][S:15]([CH3:14])(=[O:17])=[O:16]
Reactant: CNC(=O)C(C(O)=NO)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CNC(=O)C(C(=NO)OS(C)(=O)=O)C(C)(C)C
Temperature: 35 °C

Procedure:
A solution of 7.5 g (0.04 mol) of 1-hydroxy-3,3-dimethyl-2-methylcarbamyloximinobutane and 5.0 g (0.044 mol) of methanesulfonyl chloride in 50 ml of benzene is treated dropwise with 4.6 g (0.044 mol) of triethylamine with cooling to keep the temperature below 35° C. After the addition, the stirred mixture is heated at 35° C. for two hours and then washed with aqueous sodium bicarbonate and with water. The organic layer is dried over magnesium sulfate, filtered, and stripped of volatiles to give 6.7 g (63%) of amber, viscous liquid residue, nD25 1.4810.