Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](CC)(CC)O[C:5]1([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][C:8](=O)[CH:7]=[CH:6]1)C.Cl.[NH2:21]CC(OCC)=O.C(=O)(O)[O-].[Na+].C(O)C>O>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:10]=[CH:9][C:8]([NH2:21])=[CH:7][CH:6]=1
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)C=CC(=O)C=C1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture of 400 mg (1.4 mmol) of 4-triethylsiloxy-4-trifluoromethyl-2,5-cyclohexadien-1-one, 572 mg (4.2 mmol) of ethyl glycinate hydrochloride, 298 mg (3.6 mmol) of sodium bicarbonate, and 10 mL of 95% ethanol was heated to reflux for 6 hours, allowed to cool to room temperature, and poured into 25 mL of water. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. The organic layers were combined and extracted with six 5 mL portions of 1N HCl. Combination of the aqueous layers and treatment with solid sodium bicarbonate until neutral to pH paper gave a cloudy mixture that was extracted with three 10 mL portions of dichloromethane. The organic layers were combined, dried (MgSO4), and stripped to give a residue which was purified by PTLC (one 2 mm silica gel plate eluted with dichloromethane), affording 160 mg (73% yield) of 4-trifluoromethylaniline.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.O1CCCC1>[C:15]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1)#[N:16]
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Temperature: 200 °C

Procedure:
To a solution of 4-bromo-2,5-dimethylbenzenesulfonamide (4.6 g, 22 mmol, the product of Step A) in N-methylpyrrolidinone (30 mL) was added copper cyanide (2.5 g, 28 mmol), and the reaction mixture was heated at 200° C. for 30 min. The reaction was then allowed to cool and poured into 200 mL of crushed ice to precipitate a solid. To this mixture was added dichloromethane (500 mL), and the mixture was warmed to dissolve the white solid. The mixture was then filtered to remove any undissolved solids, the phases were separated, and the dichloromethane was washed with water (2×100 mL), dried over magnesium sulfate, and evaporated under reduced pressure to obtain an oil. The oil was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and the solution was concentrated under reduced pressure to precipitate a solid. This solid was isolated by filtration and washed with water to afford 2.5 g of the title compound. 1H NMR (CDCl3) δ 7.98 (s, 1H), 7.56 (s, 1H), 4.89 (br s, 2H), 2.66 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34]CC4C=CC=CC=4)=[C:27]([C:42]([F:45])([F:44])[F:43])[CH:26]=3)=[O:23])=[C:17]([F:46])[CH:16]=2)=[C:11]([O:47][CH2:48][CH3:49])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:48]([O:47][C:11]1[C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][OH:34])=[C:27]([C:42]([F:44])([F:45])[F:43])[CH:26]=3)=[O:23])=[C:17]([F:46])[CH:16]=2)=[CH:13][NH:14][C:9](=[O:8])[CH:10]=1)[CH3:49]
Reactant: CCOc1cc(OCc2ccccc2)ncc1-c1ccc(CC(=O)Nc2ccc(OCCOCc3ccccc3)c(C(F)(F)F)c2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2ccc(OCCO)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
A mixture of 2-(4-(6-(benzyloxy)-4-ethoxypyridin-3-yl)-2-fluorophenyl)-N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)acetamide (60 mg, 0.089 mmol), Pd/C (9.46 mg, 0.089 mmol) in MeOH (10 mL) was stirred for 16 h under a H2 atmosphere at 25° C. Then the mixture was filtered and the filtrate was concentrated to give the residue which was purified by preparative HPLC to yield 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)acetamide (17.76 mg, 0.034 mmol, 38.8% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.4 Hz., 1H), 7.73-7.70 (m, 1H), 7.35-7.29 (m, 2H), 7.42 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.23-7.21 (m, 2H), 7.17-7.14 (d, J=4.6 Hz, 1H), 6.03 (s, 1H), 4.13-4.11 (m, 4H), 3.87 (t, J=5.0 Hz, 2H), 3.76 (s, 2H), 1.37 (t, J=7.0 Hz, 3H); ES-LCMS m/z 495 (M+H).
Reaction SMILES: [CH:1](O)=O.Cl.[Cl:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][Cl:11]>C=O>[ClH:5].[Cl:5][CH2:6][CH2:7][N:8]([CH3:1])[CH2:9][CH2:10][Cl:11]
Reactant: ClCCNCCCl
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: CN(CCCl)CCCl
Temperature: 25 °C

Procedure:
Formic acid (10.0 g; 0.2 mol) and 37% formaldehyde (20 ml) were mixed in a 250 ml round-bottom flask equipped with reflux condenser. 1,5-Dichloro-3-azapentane, hydrochloride (17.0 g; 0.1 mol) was added and the solution was heated with magnetic stirring at 100 C. After 3 h the temperature was increased to 120 C for 20 min and finally allowed to cool to room temperature before the solvent was evaporated in vacuo to afford 3 as white solid in quantitative yield. 1HNMR (CD3OD, 400 MHz) δ 3.0 (s, 3H); 3.45 (br s, 2H); 3.62 (br s, 2H); 4.07 (br s, 4H).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:20].[CH2:23]([N:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)[C:32]([CH3:49])=[C:31]1[CH3:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C.O>[CH2:23]([N:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)[C:32]([CH2:49][OH:20])=[C:31]1[CH3:50])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)ccnc12
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(CO)c2nccc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The compound prepared in Example 6 (501.1 mg, 1.23 mmol) was treated with a saturated sodium bicarbonate solution to obtain 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (433.6 mg, 1.18 mmol). Ammonium cerium (IV) nitrate (1.94 g, 3.54 mmol) was added at room temperature to a solution of 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (433.6 mg, 1.18 mmol) in acetic acid (10 ml). The reaction mixture was stirred for 4 hours at 55° C., cooled to room temperature, poured in water, and then extracted with ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (20 ml). 2N Lithium hydroxide (5.0 ml) was added to the solution, which was then stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure to discard methanol, and then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[3,2-b]pyridine, which was then dissolved in ethyl acetate. The solution was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid (69 mg, 13.9%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:47])[NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:37]=4[F:46])=[C:29]([F:48])[CH:28]=3)[C:9]([CH2:24][O:25][CH3:26])=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]2=[C:8]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:35][C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:39]=[CH:38][C:37]=4[F:46])=[O:47])=[C:29]([F:48])[CH:28]=3)[C:9]([CH2:24][O:25][CH3:26])=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1C1CCNCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 70.4 %

Procedure:
To a flask charged with tert-butyl 4-{4-amino-5-[3-fluoro-4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate was added methylene chloride (12.5 mL). To this suspension was added 12.5 mL of trifluoroacetic acid. The homogeneous solution was allowed to stir at rt under nitrogen for 17 hours. The reaction mixture was concentrated and the residue dissolved in EtOAc. The organic phase was washed with saturated sodium bicarbonate solution (2×), brine (1×), separated and the organic layer dried (Na2SO4). The organic layer was filtered, concentrated and left under vacuum overnight to yield the title compound (150 mg, 70.4% yield). 1H-NMR (DMSO-d6) MS [M+H]+=576; LCMS RT=2.51 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14](P(OCC)(OCC)=O)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:27]([C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:32]=[CH:31][C:30]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=O>C1COCC1>[CH2:3]([O:10][C:11]([NH:13]/[C:14](=[CH:27]\[C:29]1[C:30]([NH:41][C:42]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:48])=[CH:31][N:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:34]=1)/[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(OCC)C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.7 %

Procedure:
To a slurry of 60% of sodium hydride (228 mg, 5.7 mmol) in THF (17 mL) at 0° C. was added 1A (1.88 g, 5.24 mmol) in several portions over 10 min. The reaction mixture was then brought to RT for 20 min, then cooled again at 0° C. A suspension of 3C (1.42 g, 4.76 mmol) in THF (17 mL) was added over 10 min at 0C, then the reaction was warmed up to RT. After stirring for 20 min, the reaction was quenched with water (40 mL). The aqueous layer was extracted with EtOAc (50 mL×2). The combined EtOAc extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (110 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as an off-white solid (1 g, 42%). LC/MS (method A): retention time=3.33 min, (M+H)+=504.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([CH3:15])[CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)CCC(=O)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Br)ccc1CCCC(=O)O
Temperature: 90 °C
Yield: 42 %

Procedure:
To a solution of 55A (542 mg, 2 mmol) in TFA (5 mL) was added triethylsilane (0.8 mL, 5 mmol) and the mixture heated at 90° C. for 7 h. The reaction was quenched with 1N NaOH (20 mL) and washed with EtOAc (20 mL). Aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc (2×20 mL). The combined organics were washed with brine (10 mL) and dried (MgSO4). The organic layer was concentrated in vacuo and the residue purified by flash chromatography (0-100% EtOAc/Hexane) to afford 55B (216 mg, 42%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (t, 3 H) 2.42 (q, 2 H) 2.73 (t, 2 H) 4.10 (t, 2 H) 6.82 (d, 1 H) 7.02 (d, H) 7.09 (t, 2 H) 7.15 (t, 1 H) 7.36 (d, 1 H) 7.58-7.63 (m, 1 H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[N:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2].CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH:20]=[CH:24][CH:23]=[CH:22]3)[N:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(N)nc21
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(-n3cccc3)nc21
Reaction time: 8 h

Procedure:
4.6 Grams of 1-ethyl-1,4-dihydro-4-oxo-7-amino-1,8-naphthyridine-3-carboxylic acid (U.S. Pat. No. 3,149,104) and 2.7 grams of 2,5-dimethoxytetrahydrofuran are placed under reflux for 30 minutes in 70 ml of glacial acetic acid. The mixture is allowed to cool then left for 8 hours at 5° C., and a precipitate is obtained which, when filtered off and recrystallized in acetonitrile, gives 4.3 grams of needles, of melting point 230°-232° C.
Reaction SMILES: [CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>C(O)C.CC(OC)(C)C>[CH:1]1([CH:6]([CH3:12])[CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CCCC=O)C1CCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Product: CC(CCCCO)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
5-Cyclopentylhexanal (4.2 g; 25 mmol) in ethanol (40 ml) was added to sodium borohydride (1.2 g; 32 mmol) suspended in the same solvent (50 ml) at 10° C. The reaction mixture was stirred at room temperature for 2 hours and then 1 N HCl (50 ml) was added dropwise at 0° C. The mixture was diluted with MTBE (150 ml), the organic layer separated, washed with brine (3×250 ml), dried (MgSO4), concentrated in vacuo, and bulb-to-bulb distilled (125° C./0.2 torr) to give 3.4 g (80% yield) of 5-cyclopentylhexan-1-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)[N:13]=[CH:12]1.[NH2:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1>>[O:32]1[CH:33]=[CH:34][C:30]([NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[CH:18]=4)[N:13]=[CH:12]3)[CH:4]=2)=[N:31]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(CN3CCOCC3)cc2c1=O
Reactant: Nc1ccon1
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1cnc2ccc(CN3CCOCC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 4, 4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzoic acid was reacted with 3-aminoisoxazole to give N-isoxazol-3-yl-4-methyl-3-[6-(morpholin-4-ylmethyl)-4-oxoquinazolin-3(4H)-yl]benzamide; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.41 (t, 4H), 3.60 (t, 4H), 3.65 (s, 2H), 7.06 (d, 1H), 7.62 (d, 1H), 7.77 (d, 1H), 7.87 (m, 1H), 8.10 (m, 2H), 8.15 (d, 1H), 8.32 (s, 1H), 8.86 (s, 1H), 11.47 (s, 1H); Mass Spectrum: M+H+ 446.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([F:21])=[CH:19][C:18]([C:22]3[CH2:27][CH2:26][C:25](=[O:28])[NH:24][N:23]=3)=[CH:17][C:16]=2[F:29])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:20]1[CH:19]=[C:18]([C:22]2[CH2:27][CH2:26][C:25](=[O:28])[NH:24][N:23]=2)[CH:17]=[C:16]([F:29])[C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc(C3=NNC(=O)CC3)cc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(c2cc(F)c(OC3CCNCC3)c(F)c2)=NN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 113.2 %

Procedure:
A solution of 4-[2,6-difluoro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.42 g, 1 mmol) in methylene chloride (5 mL) was treated with trifluoro acetic acid (10 mL). The mixture was stirred at RT for 3 h and TFA was concentrated at reduced pressure to give 6-[3,5-difluoro-4-(piperidin-4-yloxy)-phenyl]-4,5-dihydro-2H-pyridazin-3-one (0.35 g, quantitative yield), MS m/z 310 (M+H).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.CCCCCC.C([Li])CCC.[CH3:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=O.[Cl-].[Na+]>O1CCCC1>[O:31]([C:28]1[CH:27]=[CH:26][C:25]([C:23](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH3:22])=[CH:30][CH:29]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
2-Trimethylsilyl-1,3-dithiane, 1.92 g, was dissolved in 20 ml of tetrahydrofuran and 6.3 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow under ice cooling. The mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2.33 g of 4-phenoxyacetophenone in 10 ml of tetrahydrofuran was dropwise added under ice cooling followed by stirring at the same temperature for 30 minutes and at room temperature for an hour. After saturated sodium chloride aqueous solution was added, the mixture was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate : hexane =1 : 10) to give 2.7 g of the oily product.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(-c2c(NC(=O)C(F)(F)F)nc3ccc(C(=O)c4ccccc4)cn23)cc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2c(N)nc3ccc(C(=O)c4ccccc4)cn23)cc1

Procedure:
The 2-trifluoroacetamido-3-(4-carbomethoxyphenyl)-6-benzoyl-imidazo[1,2-a]pyridine (2.13 g, 16.8 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.44 g. (85%). EA, MS(FD).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]3[N:18]=[CH:19][CH:20]=[CH:21][C:9]=3[N:8]=2)[CH:2]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: CN(C)CCCCl
Reactant: c1cncc(C2=Nc3cccnc3Nc3ccccc32)c1
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2cccnc2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(3-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:16]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:16]1([C:23]([O:1][C:2]2[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Reactant: O=C(Cl)C1CCCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)C1CCCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture, of 7.3 g of methyl 2-hydroxy-3-propionylbenzoate, 4.7 g of 4-dimethylaminopyridine and 50 ml of dichloromethane was stirred at room temperature. Cycloheptanecarbonyl chloride, 56 g, in 10 ml of dichloromethane, (prepared as described in P. W. Collins et al., J. Med. Chem. 32, 1001-1006 (1989)) was added to the solution using dropwise addition. The mixture was stirred at room temperature for 5 hours and allowed to stand overnight. The reaction mixture was washed, in succession, with 3% hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. This was followed by drying over anhydrous sodium sulfate and evaporation to dryness to provide 9.8 g of crude methyl 2-cycloheptanecarbonyloxy-3-propionylbenzoate. This product was utilized without further purification.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([Br:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[C:14](Cl)(Cl)=[S:15]>O>[Br:13][C:4]1[C:3]([N:2]=[C:14]=[S:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[N:6]=[CH:7][CH:8]=[N:9]2
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2nccnc2c1Br
Agent: Br
Solvent: O
Product: S=C=Nc1ccc2nccnc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-amino-5-bromoquinoxaline hydrobromide (10 g) in distilled water (150 ml) is added thiophosgene (3 ml). The solution is stirred for two hours at room temperature and the resultant precipitate is collected by filtration, washed with water, and dried to afford 5-bromo-6-isothiocyanato-quinoxaline.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([Cl:13])[N:7]=2)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47](O)=[O:48]>C(Cl)Cl>[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]([N:2]1[CH2:5][CH:4]([C:6]2[C:11]([Br:12])=[CH:10][N:9]=[C:8]([Cl:13])[N:7]=2)[CH2:3]1)=[O:48]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: Clc1ncc(Br)c(C2CNC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2nc(Cl)ncc2Br)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.5 %

Procedure:
To a solution of 4-azetidin-3-yl-5-bromo-2-chloro-pyrimidine hydrochloride (0.57 mg, 2.0 mmol) in DCM (20 mL) were added HATU (1.5 g, 4.0 mmol), TEA (404 mg, 4 mmol) and 1H-benzoimidazole-2-carboxylic acid (398 mg, 2.4 mmol). The reaction mixture was stirred at RT for 12 h. TLC showed that most of starting materials were consumed completely. Then the solution was washed with aqueous HCl (1 mol/L) (50 mL×3), saturated aqueous NaHCO3 (50 mL×3) and brine, dried over MgSO4. The solution was evaporated, the residue was purified by column chromatography to give the product (206 mg, 0.53 mmol, yield: 27%). ESI-MS (M+1): 392 calc. for C15H11BrClN5O 391
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]>CCOCC>[CH3:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8][C:9]([O:11][CH3:3])=[O:10]
Reactant: CC(C)=CCCC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCC=C(C)C
Temperature: 0 °C

Procedure:
Freshly prepared diazomethane in ether was added to an ice-cooled solution of 5-methyl-4-hexenoic acid (4.5 g, 35.16 mmol) in ether (10 mL) until the solution became slightly yellow in color. The solvent was then evaporated under vacuum to afford the title product as a colorless liquid in near quantitative yield (4.90 g). This product was used in the next reaction step without further purification. 1H NMR (CDCl3) δ 1.62 & 1.68 [2s, 6H, C(CH3)2], 2.30 [m, 4H, (CH2)2], 3.69 (s, 3H, COOCH3) and 5.07 (t, 1H, CH).