Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[CH2:25][CH2:26][OH:27])=[CH:17][CH:16]=1>ClCCl>[S:8]([O:27][CH2:26][CH2:25][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:24]=2)[CH:19]=[CH:20][CH:21]=1)(=[O:10])(=[O:9])[CH3:11]
Reactant: COc1ccc2cccc(CCO)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cccc(CCOS(C)(=O)=O)c2c1
Temperature: -10 °C

Procedure:
In a 250-cm3 flask, 4 g of 2-(7-methoxy-1-naphthyl)ethanol are dissolved in 100 cm3 of dichloromethane, and 3.3 cm3 of triethylamine are added. The mixture is cooled in an ice bath at -10° C. and 2.75 g of mesyl chloride are then added dropwise and with stirring. The mixture is left stirring for 30 minutes. The aqueous phase is extracted with 3 times 50 cm3 of dichloromethane, and the organic phase is washed with 3 times 20 cm3 of 1N hydrochloric acid solution and then with water, dried over potassium carbonate and evaporated. The oily residue is recrystallized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[NH2:24][CH2:23][CH2:22][CH2:21][N:10]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][S:12][C:11]1=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2csc(=Nc3ccccc3)n2CCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2csc(=Nc3ccccc3)n2CCCN)cc1
Yield: 122.7 %

Procedure:
A mixture of t-butyl 3-[4-(4-methoxyphenyl)-2-(phenylimino)thiazol-3(2H)-yl]propylcarbamate (400 mg) and a 4N solution of hydrogen chloride in dioxane (8 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the residue was added diethyl ether. The insoluble salt was collected by filtration to give the title compound (379 mg) as hydrochloride.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:34])[C:20]([C:27]4[N:31]([CH3:32])[N:30]=[N:29][C:28]=4[CH3:33])=[CH:21][C:22]=3[Br:26])[C:17]2=[O:35])=[C:13]([CH3:36])[CH:12]=[C:11]([CH3:37])[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Br:26][C:22]1[CH:21]=[C:20]([C:27]2[N:31]([CH3:32])[N:30]=[N:29][C:28]=2[CH3:33])[C:19]([Cl:34])=[C:18]2[C:23]=1[CH2:24][CH2:25][N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:37])=[CH:12][C:13]=1[CH3:36])[C:17]2=[O:35]
Reactant: Cc1cc(C)c(CN2CCc3c(Br)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3c(Br)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293i, 76 mg, 0.13 mmol) in dichloromethane (4 mL) was cooled in an ice-water bath. Trifluoroacetic acid (6 mL) was added, and the mixture stirred and allowed to warm to room temperature overnight. After removal of the volatiles under vacuum, the residue was purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) to give 5-bromo-8-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 293, 56.9 mg, 90% yield) as a white solid). 1H NMR (400 MHZ, Methanol-d4): δ 7.79 (s, 1H), 6.10 (s, 1H), 4.75 (s, 2H), 3.84 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 3.07 (t, J=6.2 Hz, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H). MS: 492 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.C[Si]([N:29]=[N+:30]=[N-:31])(C)C.C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[C:3]([C:17]2[N:29]=[N:30][NH:31][C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1nc2cc(Cl)c(Cl)c(C#Cc3ccccc3)c2nc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(-c3nn[nH]c3-c3ccccc3)c2nc1OC
Temperature: 170 °C
Yield: 58 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-(2-phenylethynyl)quinoxaline (2.0 g, 5.57 mmol) and trimethylsilyl azide (20 mL) was heated at 170° C. in a sealed vessel for 18 hours. After cooling, water (20 mL) was added followed by saturated aqueous sodium hydrogen carbonate solution (50 mL) and the mixture extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 98:2, by volume) to afford the title compound (1.3 g, 58%) as a brown foam.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=3[CH3:27])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=3[CH3:27])[CH:13]=[N:12]2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: Cc1ccc(C)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1C
Product: Cc1ccc(C)c(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c1C
Yield: 93 %

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[6-oxo-4-(2,3,6-trimethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 66) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2,3,6-trimethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (1.27 g, 93%); ES+-HRMS m/e calcd for C28H37N5O4 [M+H+] 508.2919 found 508.2921. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.18 (m, 1H), 1.04 (s, 3H), 1.05 (s, 3H), 1.23-1.79 (m, 8H), 1.83-1.98 (m, 1H), 2.01 (s, 3H), 2.06 (s, 3H), 2.17-2.32 (m, 1H), 2.25 (s, 3H), 3.89 (s, 2H), 4.68 (s, 1H), 5.37-5.50 (m, 2H), 6.39 (d, J=2.1 Hz, 1H), 7.01-7.19 (m, 2H), 7.52 (d, J=2.1 Hz, 1H), 8.19 (d, J=2.7 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20]CC)=[O:19]>CC(C)=O>[I:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1ccc(O)c(I)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(OCC(=O)O)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
The mixture of 6-iodo-2-picolin-5-ol (235 mg, 1.0 mmol), potassium carbonate (455 mg, 3.3 mmol), ethyl bromoacetate (250 mg, 1.49 mmol) and acetone (15 ml) was refluxed for 15 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 3, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 165 mg 6-iodo-2-methylpyridine-5-oxyacetic acid as white crystals, mp 170-172° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][O:6][C:7]2=[O:12].CN1CCOCC1.[C:20]12([CH2:30][C:31](Cl)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>O1CCOCC1>[C:20]12([CH2:30][C:31]([NH:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][O:6][C:7]4=[O:12])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Nc1cccc2c(=O)occc12
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)occc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a solution of 5-amino-1H-isochromen-1-one (2.95 g, 18.3 mmol) and NMM (2.02 mL, 18.3 mmol) in 1,4 dioxane (55 mL) was added dropwise at room temperature a solution of 1-adamantaneacetic acid chloride (3.9 g, 18.3 mmol) in 1,4-dioxane (40 mL). The reaction mixture was stirred at room temperature for 3 h and then partitioned between DCM (400 mL) and water (200 mL). The layers were separated. The aqueous phase was washed with DCM (100 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was suspended in hexane (100 mL) and filtered off. The solid was collected on the filter and dried in vacuo to yield 2-adamantan-1-yl-N-(1-oxo-1H-isochromen-5-yl)-acetamide as a yellow solid (5.6 g, 16.7 mmol, 91%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH:11]([OH:13])[CH3:12])=[N:8][C:7]=2[CH:14]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[S:18]([O:13][CH:11]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:14][C:7]=2[N:8]=1)[CH3:12])(=[O:20])(=[O:19])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1nc2cc(C(F)(F)F)ccc2s1
Solvent: c1ccncc1
Product: CC(OS(C)(=O)=O)c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 1-(5-trifluoromethyl-2-benzothiazolyl)ethanol (m.p. 93°-94° C., 4.94 g) in dry pyridine was added methanesulfonyl chloride (4.58 g) and the resulting solution stirred at 0° C. for 1 hour. It was poured onto water, extracted with ether and the ether layer washed with 10% hydrochloric acid (2×20 ml). The organic extract was dried, evaporated and the residue triturated with hexane to obtain the desired compound as solid, m.p. 89° C. (5.89 g).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cn1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cn1
Temperature: 50 °C
Yield: 54.7 %

Procedure:
A mixture containing 2-[2-cyclopentyl-1-(6-ethoxy-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.18 mmol) and 10% palladium on activated carbon (60 mg) in methanol (20 mL) was heated at 50° C. under hydrogen (5 atm) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(6-ethoxy-pyridin-3-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (33 mg, 54%): LC/MS m/e calcd for C21H25N3O [M+H]+ 336.45, observed 336; 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 1.47 (m, 2H), 1.62 (m, 2H), 1.68-1.87 (m, 3H), 2.09 (m, 1H), 2.23 (m, 1H), 4.15 (t, J=7.8 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 6.32 (s, 1H), 6.65 (d, J=8.6 Hz, 1H), 7.06 (dd, J=5.0, 7.8 Hz, 1H), 7.49 (dd, J=2.1 Hz, J=8.6 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 8.13 (m, 2H), 11.47 (s, 1H).
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])(=O)=O.[CH3:20][CH:21]([CH3:24])[CH2:22][SH:23]>O1CCCC1>[CH2:22]([S:23][CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH3:12])[CH:21]([CH3:24])[CH3:20]
Reactant: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reactant: CC(C)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CSCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a stirred suspension of sodium hydride (336 mg: 60% dispersion in oil) in anhydrous tetrahydrofuran (12 ml) was added a solution of 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (2.139 g) in tetrahydrofuran (10 ml) dropwise over 5 minutes. After being stirred for 30 minutes, the mixture was cooled to 0° C., and 2-methyl-1-propanethiol (758 mg) was added dropwise at 0°-5° C. The mixture was then allowed to warm to ambient temperature and stirred for 24 hours. Additional 168 mg of sodium hydride and 379 mg of 2-methyl-1-propanethiol was added above the same condition. After being stirred for another 16 hours, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (100 ml). The solution was washed with 0.5N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml), and brine (100 ml) successively, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give 3-(N-t-butoxycarbonyl-N-methylamino)propyl isobutyl sulfide (595 mg) as an oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](Cl)=[O:26]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:26]
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: CCOC(=NC(=O)c1ccc(Cl)c(Cl)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 3,4-dichlorobenzoyl chloride, there is obtained ethyl N-(3,4-dichlorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 138° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[Br:14]Br.C(Cl)Cl>C(OCC)C>[Br:14][CH:7]1[C:6](=[O:13])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:9][CH2:8]1
Reactant: BrBr
Reactant: COc1ccc2c(c1)C(=O)CCO2
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(Br)CO2
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 6-methoxy-4-chromanone (35 g) in ethyl ether (1.6 liters) at 5-101 C. was added dropwise over 30 minutes 10.6 ml of bromine. The mixture was stirred at 5-10° C. for 30 minutes and then allowed to warm to room temperature. After 2 hours tlc (CH2Cl2) indicated formation of less polar products and only a trace of starting material remaining. The reaction mixture was washed with water (1 liter), saturated NaHCO3 (500 ml), and brine (500 ml). dried over MgSO4, and concentrated in vacuo to a yellow solid. The crude product was purified by silica gel flash column chromatography on 2.4 Kg fine silica gel, eluting with a gradient system consisting of 3:1 hexanes/dichloromethane followed by 2:1 hexanes/dichloromethane and finally 30% hexanes/dichloromethane. This afforded title product as a yellow solid in 80% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH:15]C(=O)OCC3C=CC=CC=3)[CH2:6][C:5]2=1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][C@@H:7]([NH2:15])[CH2:6][C:5]2=1
Reactant: O=C(N[C@@H]1CCc2[nH]c3ccc(F)cc3c2C1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H]1CCc2[nH]c3ccc(F)cc3c2C1
Yield: 110.3 %

Procedure:
To a solution of benzyl [(3R)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbamate (240 mg, 0.71 mmol) in ethanol was added 20 mg of 10% palladium on carbon. Hydrogenation at 50 psi overnight, followed by filtration and concentration of the filtrate, afforded 160 mg of the title compound as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[N:5]2.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=[N:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1[nH]c2ccc(O)cc2nc1-c1cccs1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccc(OCc3ccccc3)cc2nc1-c1cccs1

Procedure:
The quinoxalin-2-one of the present example is prepared treating 6-hydroxy-3-thiophen-2-yl-1H-quinoxalin-2-one from Example 43 in DMF with bromomethyl benzene in the presence of K2CO3 at a temperature between 25° C. to 80° C. The resulting reaction mixture, after workup and purification, affords 6-benzyloxy-3-thiophen-2-yl-1H-quinoxalin-2-one.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[F:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)cc1F
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (430 mg, 1.03 mmol) (from example 73, step 1) was dissolved in MeOH (3 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.302 mL, 1.03 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.063 mL, 1.03 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5.28 mL, 31.68 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow oil. Crude trans-methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (398 mg, quant.) was isolated. MS m/z 387 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([N:34]=[C:35]=[O:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:16]([NH:34][C:35](=[O:36])[NH:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 5-aminoisophthalate (Aldrich, 0.441 g, 2.12 mmol) is dissolved in dry N,N-dimethylformamide (8 mL) in a 50 mL round bottom flask under an inert atmosphere. A 2.12 M solution of octadecylisocyanate (2.12 mmol) in dry N,N-dimethylformamide (1 mL) is then added dropwise. The residual octadecylisocyanate solution is quantitatively transferred with 2 portions of N,N′-dimethylformamide (1 mL each) and the reaction is stirred overnight at room temperature. The reaction is then heated to 100° C. for 22 h, and then cooled to room temperature to give a white slurry. The solid is then vacuum filtered, washed with fresh N,N-dimethylformamide followed by deionized water. The filtrate is then concentrated by rotary evaporation to give a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22]O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cc(-c2cccnc2)on1
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2cccnc2)on1
Yield: 66 %

Procedure:
3-Hydroxy-5-(3-pyridyl)isoxazole (0.41 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.40 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 1(a) to obtain the title compound (0.50 g, 65%) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([OH:21])=[O:20])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Yield: 93.4 %

Procedure:
Twelve grams (0.04 mol) of ethyl 4,5-diphenyl-1-H-pyrazole-1-acetate of example 1 was refluxed in 40 mL of water, 40 mL of ethanol and 5 mL of 35% aqueous sodium hydroxide for 1.5 hours. The ethanol was stripped off, water was added, and the slurry was acidified with excess 6N HCl. The resulting precipitate was filtered off and rinsed with water to yield 10.4 g of free acid, mp 169°-170° C.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]=[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[Cl:3][CH:6]=[C:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)C(=O)C(=CO)Oc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)C(=CCl)Oc1ccc(F)cc1
Reaction time: 12 h
Yield: 81 %

Procedure:
297.5 g (2.5 mol) of thionyl chloride were stirred slowly into a solution, warmed to 60° C., of 404.6 g (1.7 mol) of 1-hydroxy-2-(4-fluorophenoxy)-4,4-dimethyl-penten-3-one in 3,000 ml of anhydrous toluene. The mixture was kept at the above temperature for 12 hours and then the solvent and excess thionyl chloride were distilled off. The oil which remained was distilled in vacuo. 353.3 g (81% of theory) of 1-chloro-2-(4-fluorophenoxy)-4,4-dimethyl-penten-3-one of boiling point 95°-103° C./0.3 mm Hg were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[O:28][CH3:27])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: COc1ccccc1C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccccc3OC)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 2-methoxybenzaldehyde to provide 21 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.