Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[CH3:43][O:42][C:40]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:5][CH2:4]1)=[O:41]
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCNCC3)cnc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)CC1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Piperidin-4-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride (0.07 g, 0.151 mmol) was suspended in DCM (1.5 mL) and N,N-diisopropylethylamine (0.1 mL, 0.6 mmol) was added. Methyl chloroformate (0.018 mL, 0.227 mmol) was added and the resulting solution stirred at RT. After 4 hours the solvent was evaporated. The remaining oil was purified by SiO2 chromatography (11 g SiO2, DCM/MeOH 0-4% MeOH). Obtained 0.052 g of 4-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-ureido}-piperidine-1-carboxylic acid methyl ester as light brown foam (76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(N(CC)CC)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1)=[O:27])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-amino-2-(trifluoromethyl)benzonitrile (commercially available, for example from Maybridge, Cornwall, United Kingdom, 85.0 g) in DCM (1 liter) at 0° C. was added triethylamine (92.2 g, 0.913 mol) and the reaction stirred for 15 minutes. Then acetoxyacetylchloride (74.5 g, 0.547 mol) was added at 0° C. and the reaction stirred for 4 hours at room temperature. The reaction mixture was diluted with DCM and washed with ice water followed by aqueous NaHCO3. The organic layer was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by triturating with diethyl ether (500 mL) to yield 2-{[4-cyano-3-(trifluoromethyl)phenyl]amino}-2-oxoethyl acetate (85.0 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1O[CH2:8]1)[CH:2]1[O:4][CH2:3]1.OC1[CH:16]=[CH:15][C:14]([C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])=CC=1>>[CH3:19][C:17]([C:14]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:1][CH:2]2[O:4][CH2:3]2)=[CH:24][CH:25]=1)[CH3:18]
Reactant: C(OCC1CO1)C1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1

Procedure:
By use of The Dienoxy A copolymer described above, a 1,2-polybutadiene epoxy copolymer composition of approximately 33/67 composition was prepared and both the epoxy constituent and the polybutadiene constituent were cured. It should be noted that the blend of Dienoxy A copolymer with the additional diglycidylether of bisphenol A (DGEBA) and the anhydride curative system formed a stable dispersion while a blend of 1,2-polybutadiene with DGEBA and the anhydride curative system rapidly separated into two phases.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[C:8]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]c2ccc(Cl)cc2n(C2CCCCC2)c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(Cl)cc2n(C2CCCCC2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A solution of 3.1 g (11 mmol) 1-cyclohexyl-7-chlorquinoxaline-2,3(1H,4H)-dione in 100 ml concentrated sulfuric acid (95-97%) was ice-cooled and then added 1.1 g (11 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and then at 25° C. for 17 h. The reaction mixture was poured into 500 ml ice-water. The precipitate was filtered off and washed with water to give 3.0 g (82%) 1-cyclohexyl-6-nitro-7-chlorquinoxaline-2,3(1H,4H)-dione. M.p. (DSC): decomp. 1H-NMR (DMSO-d6): 12.2 (1H, broad s), 7.9 (2H, s), 4.0-1.0 (11H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[CH2:6][OH:7]
Reactant: Nc1ccc(CO)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(CO)cc1N
Yield: 82 %

Procedure:
Six grams (0.035 mole) of 4-amino-3-nitrobenzyl alcohol, 95 ml. of tetrahydrofuran and 0.5 g. of Raney Nickel were hydrogenated at 40 psi at room temperature until 3 moles of hydrogen were absorbed. The catalyst was filtered and the filtrate was evaporated in vacuo to yield 4.83 g. (82 percent yield) of 3,4-diaminobenzyl alcohol, mp. 74°-75° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH2:8][O:9][C:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[O:11].C1C2C(=CC=CC=2)C=CC=1S([N:34]=[N+:35]=[N-])(=O)=O>C1(C)C=CC=CC=1>[N+:34](=[C:12]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:9][CH2:8][CH3:7])=[O:11])=[N-:35]
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=[N+]=[N-])P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.5 %

Procedure:
A suspension of potassium t-butoxide (4.42 g, 39.4 mmol) in toluene (200 ml) was stirred at 0° under Ar for 10 minutes. A solution of ethyl diethoxyphosphoryl acetate (6.53 ml, 32.9 mmol) in toluene (20 ml) was added in 20 minutes keeping the temperature below 5°. Another solution of 2-naphthalenesulfonyl azide (7.67 g, 32.9 mmol) was added dropwise below 5°, and the reaction mixture was warmed to RT and stirred overnight. The resulting suspension was filtered and the filtrate washed with toluene. The pooled organic phase was concentrated and the brown oily residue distilled producing pure title compound (6.12 g, 24.5 mmol, yield 74.3%) as a yellow oil, b.p.=70-73°/0.02 mmHg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C.[CH2:28]([O:30][CH:31]=[CH:32][C:33](Cl)=[O:34])[CH3:29]>C(N(CC)CC)C>[CH2:28]([O:30][CH:31]=[CH:32][C:33]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:34])[CH3:29]
Reactant: CCOC=CC(=O)Cl
Reactant: c1ccc(CN2CCC(Nc3ccccc3)CC2)cc1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CCOC=CC(=O)N(c1ccccc1)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 89.3 %

Procedure:
To a mixture of N-(1-benzyl-4-piperidinyl)aniline (0.9 g), diisopropyl ether (30 ml) and triethylamine (0.5 g) is added β-ethoxyacrylic acid chloride (0.7 g) in portions at 60° C. After refluxing for 1 hour, the reaction mixture is poured into ice-water and extracted with ethyl acetate. The extract is dried and concentrated and to the resulting residue is added n-hexane and the formed crystals are separated by filtration and recrystallized from n-hexane to give N-(β-ethoxyacryloyl)-N-(1-benzyl-4-piperidinyl)aniline (1.1 g) as white powders, m.p. 106°-108° C.
Reaction SMILES: C[NH2:2].[CH2:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([CH:14]=O)=[C:10]2[CH3:16])[CH3:4].[BH4-].[Na+].O>CO>[CH3:4][CH2:3][C:5]1[C:13]2[NH:12][C:11]([CH2:14][NH2:2])=[C:10]([CH3:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: CCc1cccc2c(C)c(C=O)[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCc1cccc2c(C)c(CN)[nH]c12
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
Methylamine (0.7 mL, 17.6 mmol) was added to a solution of 7-ethyl-3-methyl-1H-indole-2-carbaldehyde (1.1 mg, 5.8 mmol) in methanol (5 mL) and stirred for 5 h. The mixture was cooled to 0° C. and sodium borohydride (218 mg, 5.8 mmol) added slowly. The mixture was warmed to rt and stirred overnight. Water (3 mL) was added slowly at 0° C. and evaporated to a paste. Water was added and the mixture extracted with dichloromethane. The organic phase was washed with water, dried and evaporated to afford the title compound (826 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.96 (d, J=6.8 Hz, 1H), 3.87 (s, 2H), 2.79 (q, J=7.5 Hz, 2H), 2.45 (s, 3H), 2.24 (s, 3H), 1.31 (t, J=7.6 Hz, 3H)
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[C:10]=2[N:14]=1
Reactant: CCC(CC)c1ccc(C(=O)OC)c2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(CC)c1ccc(C(=O)OC)c2nc(Cl)n(C)c12
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of methyl 7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (1.30 g, 4.70 mmol) and phosphoryl chloride (10 ml) was heated at 100° C. for 3 h. The mixture was diluted with toluene and concentrated in vacuo to remove excess reagent. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on column silica gel with a 10% ethyl acetate/n-hexane to give 1.18 g (4.00 mmol, 85%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: C#CCN1CCOCC1
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC(C)C)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC(C)C)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and 4-prop-2-ynyl-morpholine (221 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (44%). HPLC-MS: m/z: 511.9 (M)+; Rt: 2.00 min.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O>O>[Br:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:28]([F:36])[F:27])[C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Br)c(C)c(CCCO)c1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Br)c(C)c(CCCOC(F)F)c1
Temperature: 50 °C

Procedure:
To an acetonitrile (0.6 M) suspension of methyl 3-bromo-5-(3-hydroxypropyl)-4-methylbenzoate (1 eq.) from the previous step and sodium sulfate (0.2 eq.) was added dropwise at 50° C. difluoro(fluorosulfonyl)acetic acid (1 eq.) over a period of 10 min. After the completion of addition, the reaction suspension was heated at 50° C. for another 16 h. The reaction mixture was then cooled to RT, poured into water and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:23][C:24]1[C:25]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[C:34](=O)[CH3:35]>C(Cl)Cl>[Si:8]([O:15][C:34]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[N:26]=[C:25]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:24]([CH3:23])=[CH:33]2)=[CH2:35])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(=O)c1cccc2cc(C)c(Oc3ccccc3)nc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cc(C)c(Oc3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Et3N (0.105 mL, 0.751 mmol) and TBSOTf (0.146 mL, 0.635 mmol) were sequentially added (TBSOTf: dropwise, over 2 min) to a solution of 1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (160.1 mg, 0.577 mmol) in DCM (3.0 mL) at 0° C., and the resulting was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to provide 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-phenoxy quinoline (214.0 mg, 0.547 mmol, 95% yield) as a colorless oil. This material was taken up in THF (3.0 mL), water (0.166 mL, 9.24 mmol) and NBS (103 mg, 0.577 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 15 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo to provide 2-bromo-1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (240 mg) as a light-yellow oil: m/z (ESI, +ve) 356.0 (M+H)+. NH4OAc (178 mg, 2.309 mmol) and piperidine-2,4-dione (78 mg, 0.693 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (3.0 mL) and stirred at 25° C. for 5 min. The reaction vial was sealed under argon and heated at 50° C. for 14.5 h. The mixture was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(3-methyl-2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.4 mg, 0.145 mmol, 25% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 11.28 (1H, br. s.), 7.92-8.00 (2H, m), 7.50-7.58 (3H, m), 7.34-7.43 (2H, m), 7.29 (2H, d, J=7.8 Hz), 7.08 (1H, d, J=1.8 Hz), 5.36 (1H, br. s.), 3.50 (2H, t, J=6.7 Hz), 2.56 (3H, s), 2.42 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 370.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH:6]([C:5]([OH:12])=[O:14])[C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCOc2ccc(F)cc21
Agent: [Tl+3]
Product: O=C(O)C1COc2ccc(F)cc21

Procedure:
The title compound was prepared from 6-fluoro-4-chromanone (D12) (9.96 g, 0.06 mole) and thallium trinitrate (0.083 mole) on K10 clay (84 g) by the method of Description 1, as a yellow solid, (1.66 g, 15%).
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:57]\[H])/[C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[CH3:56][C:53]1[CH:54]=[CH:55][C:50]([C:49]2[N:57]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]3=[O:1])[O:22][N:48]=2)=[CH:51][CH:52]=1
Reactant: [H]/N=C(\NO)c1ccc(C)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: Cc1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-4-methylbenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.93-7.87 (m, 2H), 7.43-7.22 (m, 10H), 7.08 (s, 1H), 6.90-6.81 (m, 1H), 4.88 (s, 2H), 3.56 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H), 2.42 (s, 3H)); MS (DCI) m/z 410.1 (M+H)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Si:9]([O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:18]=1[C:19]([O:21][CH3:22])=[O:20])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl.[W].N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11])[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 32.7 %

Procedure:
N-Bromosuccinimide (7.6 g) was added to a solution of methyl 2-(tert-butyldimethylsilyloxy)-6-methylbenzoate (Intermediate 13, 11.9 g) in carbon tetrachloride (150 mL) and the mixture was stirred and heated to reflux. Azo-bis-isobutyronitrile (0.1 g) was added and the mixture was illuminated with a 500 W tungsten filament lamp for 2 hours. The mixture was cooled and left to stand overnight then filtered through a 25 g silica cartridge eluting with a mixture of ethyl acetate and pentane (20%). The eluent was evaporated to dryness and the residue was redissolved in carbon tetrachloride (150 mL) and N-bromosuccinimide (6.96 g) was added. The mixture was heated to reflux and azo-bis-isobutyronitrile (0.1 g) was added. The resultant mixture was illuminated with a 500 W tungsten filament lamp overnight. After cooling, the mixture was filtered and the solid was washed with pentane. The combined organic solutions were evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of TBME and pentane with a gradient of 0-10% to give methyl 2-bromomethyl-6-(tert-butyldimethylsilyloxy)benzoate (4.99 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:39])[C:21]([C:23]1[N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28](Cl)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]>>[CH3:19][N:20]([CH3:39])[C:21]([C:23]1[N:32]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:26]2[N:27]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]5[CH2:14][CH2:15][CH2:16][CH2:17][CH:10]5[C:9]4=[O:18])=[CH:6][N:7]=3)[N:29]=[CH:30][C:25]=2[CH:24]=1)=[O:22]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCC1
Reactant: Nc1ccc(N2CCN3CCCCC3C2=O)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN5CCCCC5C4=O)cn3)nc2n1C1CCCCC1
Yield: 16 %

Procedure:
Following general N—C coupling procedure 1, 2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g, 0.244 mmol) was combined with 2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.075 g, 0.244 mmol, 1.0 eq) which gave 7-Cyclohexyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.020 g, 0.039 mmol) in 16% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.19-1.41 (m, 6H) 1.41-1.52 (m, 5H) 1.61-1.75 (m, 4H) 1.93 (br. s., 9H) 2.21 (td, J=11.37, 3.54 Hz, 2H) 2.40 (br. s., 2H) 2.52-2.81 (m, 7H) 2.93-3.05 (m, 4H) 3.16 (s, 11H) 3.47 (dd, J=11.37, 2.78 Hz, 2H) 3.93-4.09 (m, 2H) 4.26-4.42 (m, 2H) 6.44 (s, 2H) 7.68 (dd, J=8.84, 2.78 Hz, 2H) 8.00 (s, 2H) 8.23 (d, J=2.02 Hz, 2H) 8.63 (d, J=9.09 Hz, 2H) 8.71 (s, 2H) HRMS calc for m/z=517.3039 and found m/z=517.3046 (M+H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[N:16][C:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:22]([C:17]1[N:16]=[N:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[C:19]([CH3:20])[C:18]=1[CH3:21])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1c(Cc2ccccc2)nnc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Cc2ccccc2)nnc(C2=CCNCC2)c1C
Reaction time: 0.17 h
Yield: 125 %

Procedure:
To 4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (170 mg, 0.358 mmol) is added 50% TFA in DCM. The reaction mixture is stirred for 10 min and concentrated to afford 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine as a yellow sticky solid (125 mg, 100%). To a solution of 3-benzyl-4,5-dimethyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridazine (180 mg, 0.644 mmol) in dioxane is added methyl-5-chloropyrazine-2-carboxylate (222 mg, 1.29 mmol) and TEA (0.45 mL, 3.22 mmol) in a microwave tube. The reaction mixture is heated at 160° C. for 40 min in a microwave reactor. The mixture is concentrated to afford a brown oil and purified by prep HPLC, eluting with 10%-100% acetonitrile:water (both mobile phases modified by 3% n-PrOH). Fractions containing the desired product are combined and freeze-dried to afford a white solid (80 mg, 30%).
Reaction SMILES: OO.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1.[Se](=O)=O.O>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N:11]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12]1
Reactant: O=C1CCN(c2cc(Cl)ccc2Cl)N1
Agent: O=[Se]=O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccn(-c2cc(Cl)ccc2Cl)[nH]1

Procedure:
Hydrogen peroxide (30% solution in water, 120 ml) is slowly added to a well stirred suspension of 1-(2,5-dichlorophenyl)-3-pyrazolidone (200 g, 0.86 mol) and selenium dioxide (3.0 g) in acetic acid (1000 ml). The temperature is controlled by cooling, not to exceed +50° C. After stirring at this temperature for 1 hour crushed ice and water is added. The product is filtered and dried yielding 1-(2,5-dichlorophenyl)-3-pyrazolone, m.p. 201°-202° C.