Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.C(OCC)(=O)C>CN(C=O)C>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc([N+](=O)[O-])cc3)CC2)n1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(N)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)-4-{(1R,2S)-2-[2-(4-nitrophenoxy)ethyl]cyclopropyl}piperidine (353 mg, 0.881 mmol) in DMF (5 ml) was added at tin(II) chloride dihydrate (994 mg, 4.41 mmol) and the resulting mixture stirred at room temperature for 2 hours, then heated to 50° C. for 13 hours. Ethyl acetate (50 mL) was added and the solution washed with saturated aqueous sodium hydrogen carbonate followed by brine. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure (328 mg). The residue was purified by flash chromatography on silica gel using a 25 g column, eluting with 1 column volume of DCM, followed by a linear gradient of ethyl acetate in DCM from 0% to 100% over 15 column volumes, to afford the title compound. LCMS: retention 0.79 min/2.0 minute run: (ESI) m/z 371 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH:18](Cl)(Cl)Cl>>[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:13][CH3:18])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:3]1[C:14]([O-:16])=[O:15]
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)C=CC1C(C(=O)O)C1(C)C
Product: CC(C)(C)OC(=O)C=CC1C(C(=O)[O-])C1(C)C
Product: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C

Procedure:
Using the procedure of Example 9, the product of Step D and (RS) cyano 2-(6-phenoxy-pyridyl)-methanol were reacted to obtain (RS) cyano 2-(6-phenoxy-pyridyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+68°±1.5° (c=1% in chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([O:21][CH3:22])=[O:20])[NH:14]1.ClCCl.N1C=CC=CC=1.[F:32][C:33]([F:37])([F:36])[S:34]Cl>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:34][C:33]([F:37])([F:36])[F:32])[C:15]([C:19]([O:21][CH3:22])=[O:20])=[N:14]1
Reactant: FC(F)(F)SCl
Reactant: COC(=O)c1cc(=O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 10 g (0.028 mole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(methoxycarbonyl)-pyrazol-5-one in 150 ml of dichloromethane containing 2.45 g (0.03 mole) of pyridine, cooled to -10° to 0° C., was added 3.75 ml (0.04 mole) of trifluoromethanesulfenyl chloride. The reaction mixture was allowed to stir overnight, then diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated to afford 13.0 g of a tan colored solid. Recrystallization from hexane:methyl-t-butyl ether afforded 5.5 g of a product, m.p. 216.5°-217.5° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[CH2:3]1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=[O:24])C.[ClH:28]>C(O)(C)C>[ClH:28].[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][CH:2]([NH:1][CH2:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:24])[CH2:3]2)=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CC(N)CC2
Reactant: C=Cc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Yield: 31 %

Procedure:
An amount of 3.01 g of 2-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene is reacted under stirring at room temperature for 4 days with 2.04 g of styrene. After addition of ethyl acetate, to the reaction mixture there is added a saturated solution of hydrogen chloride in isopropyl alcohol to obtain the 2-[(7-methoxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol hydrochloride. Yield: 31% of the theoretical value.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[O:13]1[CH2:18][CH:17]=[C:16]([C:19]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:22]=[C:21]([C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[N:20]=2)[CH2:15][CH2:14]1.[NH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.CCN(CC)CC>C(Cl)Cl>[O:13]1[CH2:14][CH:15]=[C:16]([C:19]2[N:24]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:22]=[C:21]([C:31]3[CH:36]=[CH:35][C:34]([NH:37][C:5]([NH:38][C:39]4[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=4)=[O:11])=[CH:33][CH:32]=3)[N:20]=2)[CH2:17][CH2:18]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(-c2nc(C3=CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(C3=CCOCC3)nc(N3CCOCC3)n2)cc1
Reaction time: 0.25 h
Yield: 34.7 %

Procedure:
To a stirred solution of triphosgene (140 mg, 0.47 mmol) in CH2Cl2 (6 mL) was added 4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (200 mg, 0.59 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (166 mg, 1.77 mmol) and NEt3 (814 μL, 5.89 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were distilled and the crude mixture was purified by semi-prep-HPLC (TFA-method) to give 1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (75 mg, 22% yield); MS (ESI) m/z 460
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])(=O)C.[K+].O>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:9]1[CH:13]=[C:12]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:11][C:10]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1sccc1C
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1sc(-c2ccccc2)cc1C
Temperature: 150 °C
Yield: 4.5 %

Procedure:
At room temperature, a solution of 4-iodobenzene (9.6 mmol) and methyl 3-methylthiophene-2-carboxylate (19.2 mmol) in dimethylacetamide (20 ml) were degassed with nitrogen for 15 minutes. Potassium acetate (0.87 mmol) and palladium acetate (0.02 mmol) were added, the reaction vessel was sealed and heated at 150° C. for 1 hour. Then, the reaction mixture was cooled down to room temperature and poured into water, extracted with dichloromethane, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: gradient of 3% diethyl ether in petroleum ether) to give 100 mg of Intermediate V.1 (22%) as a yellow solid, which was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 2.57 (s, 3H), 3.88 (s, 3H), 7.13 (s, 1H), 7.32-7.34 (m, 3H), 7.59-7.64 (m, 2H); and MS (ESI, EI+) m/z=233 (MH+).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([OH:7])=[O:6])#[N:3].[SH:8][CH2:9][CH:10]=O.C(O[C:16](=[O:18])[CH3:17])(=O)C>>[C:16]([NH:3][C:2]1[S:8][CH:9]=[CH:10][C:4]=1[C:5]([OH:7])=[O:6])(=[O:18])[CH3:17]
Reactant: N#CCC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: O=CCS
Agent: [Na]
Product: CC(=O)Nc1sccc1C(=O)O
Temperature: 20 °C

Procedure:
The 2-amino-3:5-dinitrothiophene was itself obtained by reacting the sodium salt of cyanoacetic acid with the dimer of mercaptoacetaldehyde in aqueous medium at 80° C, cooling to 20° C, adding acetic anhydride while maintaining the pH at 6-7, acidifying and isolating the 2-acetylaminothiophene-3-carboxylic acid. This was then dinitrated in sulphuric acid medium at 0° C, the resulting 2-acetylamino-3:5-dinitrothiophene being isolated and then deacetylated by heating in an aqueous solution of sulphuric acid. Table I gives further Examples of the dyestuffs of the invention of the formula ##STR16## the symbols of which have the values given in the respective columns of the Table, while the last column of the Table gives the shades obtained when the dyestuffs are applied to an aromatic polyester textile material.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][O:16][C:15]([CH3:23])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:14][CH2:13][C:12](=[O:11])[CH2:17][O:16]1
Reactant: CCOC(=O)C1(C)OCC(O)CO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1(C)OCC(=O)CO1
Reaction time: 0.33 h

Procedure:
To a chilled (−78° C.) DCM solvent (10 mL) under nitrogen was added a 2 M stock solution of oxalyl chloride (6.03 mL, 12.05 mmol), followed by the slow addition of dimethyl sulfoxide (0.927 mL, 13.06 mmol). Once evolution of gases stopped, stirring continued for another 20 minutes forming a snow white suspension. A solution of the crude ethyl 5-hydroxy-2-methyl-1,3-dioxane-2-carboxylate (Step 2, 1.91 g, 10.04 mmol) in 5 mL of DCM was transferred into the cold Swern solution over a period of 2 minutes via a cannula. The reaction was allowed to proceed at −78° C. for 30 minutes, followed by the slow addition of triethylamine (3.36 mL, 24.10 mmol). The resulting pale suspension was stirred at −78° C. for a further 30 minutes, then at 4° C. (ice bath) for 15 minutes. The Rx was quenched with saturated sodium bicarbonate solution (20 mL), followed by extraction with DCM (5×25 mL). The organic layers were combined, evaporated to an oily material (1.81 gm, 96%). 1H NMR (400 MHz, CHLOROFORM-d) δ 4.45-4.37 (m, 2H), 4.31 (q, J=7.3 Hz, 2H), 4.33-4.26 (m, 2H), 1.58 (s, 3H), 1.36 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2].[Cl:15]([OH:19])(=[O:18])(=[O:17])=[O:16]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(OCC)C>[Cl:15]([O-:19])(=[O:18])(=[O:17])=[O:16].[C:1]([NH:12][C:11]1[O:13][CH2+:5]([CH3:4])[C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=2[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(CC#N)cc1OC
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOCC
Product: CCOc1cc2c(cc1OC)C=C(NC(C)=O)O[CH2+]2C
Product: [O-][Cl+3]([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 42 h
Yield: 192626.3 %

Procedure:
To an ice-cooled and stirred soluton of 25 grams 4-ethoxy-3-methoxyphenylacetonitrile (0.13 mmol) in 74 ml acetic ahnydride (0.785 mol) was slowly added perchloric acid (70%, 11.7N, 15.5 ml, 0.182 mol) over a 15 minute period. The dark reaction mixture slowly became a yellow slurry and was stirred at room temperature for 42 hours. The mixture was diluted with 200 ml diethyl ether and a crystalline yellow solid was isolated by filtration, washed with diethyl ether and dried in vacuo to provide 47.3 grams of product (100% yield) having a melting point of 188°-189° C. (with decomposition).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[N:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([NH2:20])[CH:16]=2)=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.[NH:30]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[Na+].[I-]>CC(N(C)C)=O>[N:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:19][N:18]=[C:17]([NH:20][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCCCBr
Reactant: C1CCCNCC1
Reactant: Nc1cc(-c2ccncc2)[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCN1CCCCCC1)Nc1cc(-c2ccncc2)[nH]n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product was prepared according to the general synthetic method for the one-pot synthesis of ω-amino-alkanoic acid (1H-pyrazol-3-yl-5-aryl)-amides. A solution of 5-bromovaleryl chloride (0.125 mL, 0.94 mmol) in dry DMA (1 mL) was cooled to −10° C. (ice/water bath) under N2; 5-Pyridin-4-yl-1H-pyrazol-3-ylamine (151 mg, 0.94 mmol) and diisopropylethylamine (0.324 mL, 1.88 mmol) in dry DMA (1 ml) were added. The reaction was left stirring for 1 h at 0° C. and then azepane (0.265 mL, 2.35 mmol) and NaI (0.94 mmol, 1 eq) were added.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:25]([OH:26])=[CH:24][C:23]3[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[C:9]([F:31])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:35])(=O)=O.C(OCC)C>ClCCl>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:25]([OH:26])=[C:24]([Cl:35])[C:23]3[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[C:9]([F:31])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(F)cc(NC(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1c(F)cc(NC(=O)c2cc3c(c(Cl)c2O)C(C)(C)CCC3(C)C)cc1F

Procedure:
To a solution ethyl 2,6-difluoro-4-[(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-benzoate (Compound C, 227 mg, 0.52 mmol) in 10 ml of anhydrous dichloromethane under nitrogen at 25° C. was added sulfuryl chloride (0.0413 ml, 0.57 mmol) and anhydrous ethyl ether (0.054 ml, 0.52 mmol). Reaction was instantaneous at 25° C. as monitored by 1H NMR. The reaction mixture was quenched with saturated NaHCO3 then extracted with ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. The title compound was obtained as a white solid after column chromatography with ethyl acetate:hexane (1:9).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=3)[CH:19]=2)[CH:3]=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=3)[CH:19]=2)[CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc([N+](=O)[O-])c3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(-c3cccc(N)c3)c2)c1
Yield: 75.1 %

Procedure:
A mixture of the above prepared 4-methyl-2′-(3-nitro-phenyl)-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (1.12 g, 3.0 mmol) in THF-MeOH 1:1 (100 mL) and 10% palladium on carbon (1 mol %) was hydrogenated (1 bar hydrogen) at 23° C. for 2 h. The catalyst was filtered off, washed with MeOH and the filtrate was completely evaporated totally to leave a crude product, which was purified by trituration with diethyl ether to give the title compound as a light brown solid (0.914 g, 88%). MS (ISP) 406.5 [(M+H)+]; mp 87° C. (dec.).
Reaction SMILES: [Cl: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=[N:12]O.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28]N[CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][CH:7]2[N:12]1[CH2:28][CH2:29][C:24]2([N:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:21][NH:22][C:23]2=[O:30])[CH2:25][CH2:26]1
Reactant: ON=C1CCCc2c(Cl)cccc21
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCc3c(Cl)cccc31)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=396.2 (M+H+) was prepared in accordance with the general method of example 11 from 5-chloro-3,4dihydro-1(2H)-naphthalenone oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].CN[C:21](Cl)=[O:22].[O:24]1CCC[CH2:25]1>N1C=CC=CC=1.O>[CH3:25][O:24][C:21](=[O:22])[NH:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:16]#[N:17])[CH:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNC(=O)Cl
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Nc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.4 g, 1.7 mmol) in anhydrous pyridine. Add a solution of methylcarbamyl chloride (0.17 g, 1.8 mmol) in anhydrous tetrahydrofuran carefully to the reaction and stir overnight at room temperature. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:dichloromethane, and then further purify on C-18 silica, eluting with 10:90 to 50:50 using an aqueous 0.1% solution of trifluoroacetic acid and a 0.1% solution of trifluoroacetic acid in acetonitrile). Concentrate, partition the residue between ethyl acetate and an aqueous saturated solution of sodium bicarbonate and separate the layers. Wash the organic layer with an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter and concentrate to give the title compound as a white solid (25 mg, 5%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:16][C@H:15]1[CH2:17]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:17][C@@H:15]2[CH2:16][O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CO2)CC1
Yield: 68 %

Procedure:
The same method as employed in the preparation of Intermediate 1 but starting from piperazine-1-carboxylic acid tert-butyl ester and (S)-(+)-3-nitro-benzenesulfonic acid oxiranylmethyl ester gives after flash chromatography the title compound as a yellow oil in a 68% yield.
Reaction SMILES: [C:1]1(B(O)O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.O.[C:18]([OH:22])(=[O:21])[CH:19]=O.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]1([CH:19]([N:14]2[CH2:15][CH2:16][CH:11]([O:10][CH3:9])[CH2:12][CH2:13]2)[C:18]([OH:22])=[O:21])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OB(O)C1=CCCC1
Reactant: COC1CCNCC1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1CCN(C(C(=O)O)C2=CCCC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
50 mg (0.45 mmol) of cyclopent-1-en-1-ylboronic acid, 51 mg (0.45 mmol) of 4-methoxypiperidine and 41 mg (0.45 mmol) of glyoxalic acid monohydrate were initially charged in 2 ml of dichloromethane, and 78 μl (57 mg, 0.45 mmol) of N,N-diisopropylethylamine were added. The mixture was stirred at RT for 2 d and then concentrated under reduced pressure. The residue was purified by preparative HPLC (RP18 column; acetonitrile/water gradient with addition of 0.1% TFA, 10:90→95:5; run time 38 min). This gave 31 mg (29% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=O)[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][C:42]2[CH:43]=[C:44]([C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][NH2:55])[CH:49]=3)[CH:45]=[CH:46][CH:47]=2)[CH2:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CS(C)=O.C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([C:29]([NH:55][CH2:54][C:50]4[CH:49]=[C:48]([C:44]5[CH:45]=[CH:46][CH:47]=[C:42]([CH2:41][CH:38]6[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]6)[CH:43]=5)[CH:53]=[CH:52][CH:51]=4)=[O:31])[N:28]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Process (B) In an alternate preparation of the titled compound, to a solution of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (45 mg, 0.1 mmol) in DMSO (1 mL) was added 1-{3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methanamine (28 mg, 0.095 mmol), HBTU (42 mg, 0.11 mmol) and Et3N (0.021 mL, 0.15 mmol) in DCM (3 mL). The resulting mixture was stirred at room temperature for 18 h. The reaction was quenched with H2O (2 drops), purified with a Gilson HPLC (with 0.1% TFA), concentrated, re-dissolved in EtOAc, washed with NaOH (1N), dried over Na2SO4, filtered, concentrated and dried with a high vacuum oil pump to afford the title compound as a white solid 38.5 mg (53%). LC-MS m/z 729 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[O:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:33][CH2:32][CH:31]2[C:34]([O-:36])=[O:35])[CH2:26][CH2:25]1.[Li+]>>[CH:34]([OH:36])=[O:35].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([CH:31]2[CH2:32][CH2:33][N:30]2[CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: O=C([O-])C1CCN1C1CCOCC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCOCC2)CC1
Product: O=CO

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(tetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate 20E carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(tetrahydro-2H-pyran-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide formate 1:1 epimers as a white solid (87%). MS ISP (m/e): 521.3 (100) [(M+H)]]+.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][O:20]C(=O)C)=[N+:17]([O-:24])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27]O>>[CH3:27][O:8][C:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2=[N+:10]([O-:25])[C:11]3[C:16]([N+:17]([O-:24])=[C:18]2[CH2:19][O:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: CC(=O)OCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: CO
Agent: Cl
Product: COC1(c2ccccc2)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
A stirred suspension of 0.50 g. (1.47 mmol.) of 2-benzoyl-3-acetoxymethylquinoxaline 1,4-dioxide in 10 ml. of methanol was saturated with dry hydrogen chloride. The reaction mixture was stirred at room temperature for three days and then the suspended solid was removed by filtration. The solid was washed with methanol, and dried, to give 0.28 g. (61% yield ) of 1-methoxy-1-phenyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 153°-155° C.