Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:10]>O1CCOCC1>[Br:1][C:2]1[C:3]([CH:8]=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ncccc1Br
Solvent: C1COCCO1
Product: O=Cc1ncccc1Br
Yield: 28.9 %

Procedure:
To a solution of 3-bromo-2-picoline (prepared as described by Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem. 1987, 30, 871–880) (249 mg, 1.45 mmol) in dioxane (2 mL) was added selenium(IV) oxide (212 mg, 1.91 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1) to afford the title compound (78 mg, 29%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.38 (dd, 1H, J=9, 6 Hz), 8.05 (d, 1H, J=9 Hz), 8.76 (d, 1H, J=3 Hz), 10.25 (s, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1.Cl[CH2:14][C:15]1[S:19][C:18]([CH3:20])=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH:16]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:20][C:18]1[S:19][C:15]([CH2:14][N:3]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]2)=[CH:16][C:17]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1sc(CCl)cc1-c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2cc(-c3cccc(C(F)(F)F)c3)c(C)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (55% in mineral oil, 0.11 g) in tetrahydrofuran (4 mL) was cooled in an ice bath, and a solution of ethyl 1H-pyrazole-4-carboxylate (0.29 g) in tetrahydrofuran (2 mL) was added dropwise. The mixture was stirred at room temperature for 30 min, and a solution of the compound obtained in Example 126d in tetrahydrofuran (2 mL) was added dropwise. After stirring at room temperature for 6 hr, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.20 g) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([O:20]C)[N:14]=[C:13]([O:22]C)[N:12]=2)=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1>Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[C:9]([C:11]1[NH:12][C:13](=[O:22])[NH:14][C:15](=[O:20])[C:16]=1[CH:17]([CH3:18])[CH3:19])=[O:10]
Reactant: COc1nc(OC)c(C(C)C)c(C(=O)c2cc(C)cc(Br)c2)n1
Agent: Cl
Product: Cc1cc(Br)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Compound (27) (34.6 g, 91 mmol) was refluxed with conc. HCl (200 ml) for 3 hr. After cooling to room temperature, the white precipitate was collected by filtration, washed with cold water and hexane, and dried in high vacuo to afford 30 g (94%) of a white solid; m.p. 266-267° C.; 1H NMR (200 MHz, DMSO-d6) δ 1.05 (6H, d, J=6.8 Hz), 2.26 (1H, m), 2.40 (3H, s), 7.82 (2H, s), 7.93 (1H, s), 11.02 (1H, s), 11.17 (1H, s).
Reaction SMILES: OC(C1C=CC=CC=1)C([NH:5][CH:6]([CH3:16])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O>Cl>[CH3:16][C@H:6]([NH2:5])[CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1
Agent: Cl
Product: C[C@H](N)CCCc1cccnc1

Procedure:
A solution of 160 g of crude [S-(R*,R*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide in 800 mL of 6N HCl was treated with 85 mL conc. HCl and then was heated at reflux overnight as described in Example 16. The crude amine (~85 g), isolated in the normal manner, was distilled to furnish 76.4 g of (S)-alpha-methyl-3-pyridinebutanamine, (60% ee; bp 89°-91°/0.15 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:4]2[CH:3]=[C:2]([NH:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:13][CH2:12]1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cccc(N2CCN(C(=O)c3ccccc3)CC2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCN(c2cccc(Nc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A suspension of (4-(3-aminophenyl)piperazin-1-yl)(phenyl)methanone (0.5 g, 1.8 mmol), copper acetate (0.65 g, 3.6 mmol), triethylamine (1.7 ml, 12.4 mmol), 4 Å molecular sieves (0.5 g) and phenylboronic acid and pyridine complex (0.70 g, 1.8 mmol) in 30 ml dry dichloromethane was stirred at room temperature overnight. The reaction was quenched with 20 ml water extracted with dichloromethane (3×40 ml), followed by drying over anhydrous sodium sulfate. 3-(4-Benzoylpiperazin-1-yl)-N-phenylbenzenamine (0.42 g, 66%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.20 (d, br, 4H), 3.65 (d, br, 4H), 5.73 (s, 1H), 6.54 (dd, J=8.0, 1.6 Hz, 1H), 6.67 (m, 2H), 6.97 (t, J=7.4 Hz, 1H), 7.11 (dd, J=8.6, 1.0 Hz, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.44 (m, 2H), 7.48 (m, 5H). 13C NMR (125 MHz, CDCl3): δ (ppm) 50.0, 50.1, 50.3, 106.5, 110.0, 110.7, 118.6, 121.6, 127.6, 129.0, 129.8, 130.3, 130.5, 136.1, 143.5, 144.7, 152.6, 170.9.
Reaction SMILES: O[C:2]1[C:3]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S1C=CC=C1P.C(Cl)(Cl)(Cl)Cl.ClC(Cl)C.[NH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][CH:37]=[CH:36]2>>[NH:38]1[C:39]2[C:35](=[CH:34][C:33]([NH:32][C:2]3[C:3]4[S:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)=[CH:8][C:4]=4[N:5]=[CH:6][N:7]=3)=[CH:41][CH:40]=2)[CH:36]=[CH:37]1
Reactant: Oc1ncnc2cc(-c3ccccc3)sc12
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Pc1cccs1
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: c1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Temperature: 25 °C

Procedure:
In a 125 mL single neck round bottom flask with reflux condenser, 4-hydroxy-(6-phenyl)-thieno[3,2-d]pyrimidine was combined with thiphenylphosphine polymers (900 mg, 2.7 mmole), carbon tetrachloride (1.1 mL, 11 mmole) and dichloroethane (15 mL). Boiling chips were added and the mixture was refluxed for 18 hours. The mixture was cooled to ambient temperature and filtered into a second single neck round bottom flask. The polymer was washed with 25 mL 10% dichloroethane/tert-butanol. The organic layers were combined and 5-amino-indole (212 mg, 1.6 mmole) was added and the resulting solution was refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated to a green-brownish residue. The residue was partitioned between 1 N NaOH and 15% 2-propanol/chloroform. The aqueous layer is extracted 2 times with 15 mL 15% isopropanol/CHCl3. The organic layers were combined and dried over sodium sulfate and concentrated to a black residue. The residue was triturated with methanol to give 57 mg of product: MP: 255-258° C. (dec); anal. RP18-HPLC RT: 4.38 minutes; TS-MS: 343 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([OH:19])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:20][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-BOC-1,3-dihydro-2H-isoindole-1-carboxylic acid (SNPE, 10 g, 38 mmol) in CH2Cl2 (100 mL) and MeOH (100 mL) at 0° C. was added trimethylsilyldiazomethane dropwise until the yellow color persisted. After stirring at rt for 15 min, the reaction mixture was concentrated in vacuo to dryness, and the residue was azeotroped with toluene to yield N-BOC-1,3-dihydro-2H-isoindole-1-carboxylic acid, methyl ester which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.O>CN(C)C=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:11](=[O:20])[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:23][N:24]([CH3:26])[CH3:25])=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(C(=O)O)cc1)C(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)C(=O)c1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
To a solution of 3-(4-carboxyphenyl)-1-phenyl-1,2-propanedione in 100 ml of dry dimethylformamide cooled in an ice-bath was added, with stirring, 56 ml of dimethylformamide dimethyl acetal. The reaction mixture was stirred at 0°-5° C for 10 min. and then it was poured onto 1.2 l of ice-water and acidified with 130 ml of 1N hydrochloric acid. After stirring for 5 min., 1.8 l of water was added and the precipitate was collected, washed with water and air-dried. The filter cake was dissolved in 1.7 l of methylene chloride, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to about 200 ml. Ether (200 ml) was added and the solution was concentrated to about 300 ml and allowed to stand at room temperature for 2 days. The solid was collected, washed with methylene chloride-ether (1:9) and dried at 80° C for 3 hrs. to give 17.4 g (44%) of 2-(4-carboxyphenyl)-1-dimethylamino-4-phenyl-1-butene-3,4-dione as yellow crystals, m.p. 208°-209° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:19](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@@H:9]1[C:14]([O:16][CH3:19])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)[C@H]1C[C@H](C)CN1C(=O)OC(C)(C)C

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-(2-(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl)-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>O.CCO>[C:13]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])(=[O:25])=[O:24])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C(C)(C)C)cc3)c(C)o2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
A solution of Na2SO3 (126 mg, 1.0 mmol) and Na2CO3 (106 mg, 1.0 mmol) in water (2 mL) was added to a suspension of 4-tert-butylbenzenesulfonyl chloride (233 mg, 1.0 mmol) in water (5 mL) and the mixture was stirred at 100° C. for 2 h. A solution of chloride 2 (268 mg, 1.0 mmol) in EtOH (5 mL) was added and the mixture stirred at 100° C. for 16 h. The mixture was cooled and diluted with water (40 mL) and stirred for 15 min. The precipitate was filtered, washed with water (5 mL). The residue purified by column chromatography, eluting with a gradient (20-50%) of EtOAc/pet. ether, to give benzoate 22 (112 mg, 26%) as a white powder: mp (EtOAc) 190-192° C.; 1H NMR (CDCl3) δ 8.05 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-2, H-6), 7.89 (ddd, J=8.6, 1.8, 1.5 Hz, 2H, H-3, H-5), 7.71 (ddd, J=8.6, 2.2, 1.8 Hz, 2H, H-2′, H-6′), 7.51 (ddd, J=8.6, 2.2, 1.8 Hz, 2H, H-3′, H-5′), 4.30 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.32 (s, 3H, CH3), 1.33 [s, 9H, C(CH3)3]; MS m/z 428.5 (MH+, 100%). Anal. calcd for C23H25NO5S: C, 64.62; H, 5.89; N, 3.28. Found: C, 64.70; H, 5.94; N, 3.25%.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[Na+]>C(O)C>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:3][C:4]2[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=2)=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1cc(CCl)cc(C)n1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(COc2ccc(S(C)(=O)=O)cc2)cc(C)n1
Yield: 46.6 %

Procedure:
To a solution of 1.0 g (5.21 mmol) of 4-chloromethyl-2,6-dimethylpyridine hydrochloride and 1.1 g (6.25 mmol) of 4-methylsulfonylphenol in ethanol (3.5 mL) was added 3.5 mL (14.0 mmol) of 4 N aqueous sodium hydroxide solution, followed by heating under reflux for 90 minutes. After standing to cool, ethanol was evaporated under a reduced pressure. To the obtained residue, water was added and the precipitates were collected by filtration and then dried under a reduced pressure to obtain 707 mg (yield 46.6%) of 4-(4-methanesulfonylphenoxymethyl)-2,6-dimethylpyridine (VI-4) as a colorless crystal. Its physical property is shown below.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:26]([CH3:27])=[N:25][N:24]([CH3:28])[C:12]2=[N:13][C:14]=1[N:15]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:16][CH:17]1[CH2:19][CH2:18]1.Cl[C:39]1[N:44]=[CH:43][C:42]([C:45](=[O:47])[CH3:46])=[CH:41][N:40]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:17]1([CH2:16][N:15]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[C:14]2[N:13]=[C:12]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:11]3=[CH:10][C:9]=2[CH2:8][N:7]([CH2:6][C:5]2[CH:29]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:31]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:4]=2)[C:39]2[N:44]=[CH:43][C:42]([C:45](=[O:47])[CH3:46])=[CH:41][N:40]=2)[CH2:18][CH2:19]1
Reactant: Cc1nn(C)c2nc(N(CC3CC3)CC3CC3)c(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Reactant: CC(=O)c1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3c(C)nn(C)c3nc2N(CC2CC2)CC2CC2)nc1
Temperature: 65 °C
Reaction time: 14 h

Procedure:
5-(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-N,N-bis(cyclopropylmethyl)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-amine (0.761 mmol, 0.400 g) in DMF was treated with 1-(2-chloropyrimidin-5-yl)ethanone (0.761 mmol, 0.119 g) and K2CO3 (2.283 mmol, 0.315 g). The reaction mixture was stirred at 60-70° C. for 12-16 h. The reaction mixture was then extracted with EtOAc. The combined organic layer was washed with water and brine solution, dried over sodium sulphate, concentrated under reduced pressure and purified by column chromatography using silica gel and 50% EtOAc in petroleum ether as eluent to get the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][O:28][C:29]1[O:33][C:32]([C:34](O)=[O:35])=[N:31][CH:30]=1>>[CH3:27][O:28][C:29]1[O:33][C:32]([C:34]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][N:12]([C:8]4[CH:7]=[CH:6][CH:5]=[C:4]5[C:9]=4[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]5)[CH2:17][CH2:16]3)[CH:21]=2)=[O:35])=[N:31][CH:30]=1
Reactant: COc1cnc(C(=O)O)o1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: COc1cnc(C(=O)Nc2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)o1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 5-(methyloxy)-1,3-oxazole-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccsc1N
Product: CC(=O)Nc1sccc1C#N
Reaction time: 3 h

Procedure:
2-Amino-3-cyanothiophene (12 g) was heated at reflux in acetic anhydride (34 ml) for 15 minutes, cooled and refrigerated for 3 h. The crystalline product was filtered off (13.6 g).
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H][H]>[Pt](=O)=O.CO>[C:16]1([CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:6]2[CH2:7][CH2:8][CH:3]([NH2:2])[CH2:4][CH2:5]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc[n+](C(c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Br-]
Solvent: CO
Product: NC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a solution of 15.5 parts of 4-amino-1-(diphenylmethyl)-pyridinium bromide in 600 parts by volume of methanol is added 1.6 part of platinum dioxide catalyst and the resulting mixture is shaken with hydrogen at 60 psi pressure and room temperature for forty-two hours. The catalyst is then removed by filtration and the filtrate evaporated to dryness in vacuo. The residue is suspended in 200 parts by volume of 10% sodium carbonate solution and extracted with three 200 parts by volume portions of methylene chloride. The methylene chloride extracts are combined, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid residue obtained is triturated with 250 parts by volume of anhydrous ethyl ether, filtered and the filtrate evaporated to yield 1-(diphenylmethyl)-4-piperidinamine, as a colorless solid melting at about 84°-95° C. This compound is represented by the following structural formula. ##STR20##
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([S:18][CH2:19][C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][N:12]=1.[OH-].[Na+].C(OC(C)C)(C)C>>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][S:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16]=1[CH3:17]
Reactant: Cc1c(SCc2ccco2)ccnc1CCl
Reactant: Sc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: Cc1c(SCc2ccco2)ccnc1CSc1ccncc1
Yield: 89 %

Procedure:
According to the procedure indicated in Example 1, reaction of 4-mercaptopyridine with 2-chloromethyl-4-(2-furylmethylthio)-3-methylpyridine hydrochloride and sodium hydroxide solution, subsequent chromatography on silica gel (ethyl acetate/ethanol) and crystallization from diisopropyl ether gives the title compound as a colorless powder; m.p. 126-128° C.; yield 89% of theory.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH2:17]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2)[CH3:18]
Reactant: CCOc1ccccc1N
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: CCOc1ccccc1Nc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 86.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-ethoxyaniline (119 mg, 0.87 mmol) to provide 198 (123 mg, 86% yield) as a white solid. LC-MS (M+H=332, obsd.=332).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:42](C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH2:42])=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(N)=O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.02 g (0.32 mmole) of ammonium chloride was then added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give 0.029 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzamide (I-170).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12].[N+:17]([C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)([O-:19])=[O:18].C(=O)(O)[O-].[Na+]>CC(C)=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([S:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C(O)c1cccc(S)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1

Procedure:
A suspension of potassium carbonate (18 g) in acetone (140 mL) at ambient temperature was treated with 3-mercaptobenzoic acid (10 g, 64.4 mmol, 1 eq) followed by 4-nitrofluorobenzene (18 g, 127.7 mmol, 2 eq). The resultant mixture was stirred for 18 h and then poured onto saturated sodium bicarbonate and washed with ethyl acetate. The basic aqueous layer was acidified with SN HCl and extracted into ethyl acetate (3×100 mL). The combined organics were dried with anhydrous sodium sulphate and concentrated in vacuo to give the product as a solid.