Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[CH2:9]1[O:11][C@H:10]1[CH2:12]Cl.C[O-].[Na+]>C(O)C>[O:11]1[CH:10]([CH2:12][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:9]1
Reactant: ClC[C@H]1CO1
Reactant: C1COCCN1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C1CN(CC2CO2)CCO1
Temperature: 250 °C
Yield: 96.4 %

Procedure:
To 1 L 3-neck round bottom flask, fitted with mechanical stirring, thermocouple and addition funnel, was charged morpholine (91.5 g, 91.5 ml, 1.05 mole, 1.0 eq.) and 200 ml of methanol. The solution was stirred rapidly while adding R-epichlorohydrin (100 g, 84.5 ml, 1.08 mole, 1.03 eq.) from the addition funnel over about 30 minutes. The temperature was monitored and when the pot temperature reached 27° C., the reaction was cooled with an ice water bath. The clear solution was stirred for 18 hours. The reaction was assayed by GC (dilute 5 drops of reaction mixture into 1 ml of ethanol and inject onto a 15 m DB-5 capillary GC column with the following run parameters, Injector 250° C., detector 250° C., initial oven temperature 28° C. warming to 250° C. at 10° C. per minute.) The reaction was complete with less than 3% morpholine remaining. The solution was cooled to 10° C. and a 25 wt. % solution of sodium methoxide in methanol (233 g, 1.08 mole, 247 ml) was added dropwise keeping the temperature less than 15° C. The resulting white slurry was stirred at 10–15° C. for 2 hours and checked by GC using the above conditions. None of the chlorohydrin could be observed. The mixture was concentrated on the rotoevaporator using 50° C. bath and full house vacuum. The resulting mixture was diluted with water (500 ml) and methylene chloride. The phases were separated and the aqueous phase washed with methylene chloride (500 ml). The combined organic layers were dried over sodium sulfate and concentrated to a clear, colorless oil. This provided 145 g, 97% yield of 1,2-epoxy-3-morpholin-4-ylpropane. 1H NMR (400 MHz, DMSO-d6) δ 3.3 (dd, 4H), 3.1 (m, 1H), 2.6 (dd, 1H), 2.5 (dd, 1H), 2.4 (m, 4H), 2.2 (dd, 2H); 13C NMR (100 MHz, DMSO-d6) δ 65.4, 60.1, 53.1, 48.9, 43.4.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].[OH-:7].[Li+].[C:9](#[N:12])[CH:10]=[CH2:11]>>[C:9]([CH:10]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])[CH3:11])#[N:12].[C:9]([CH2:10][CH2:11][O:7][CH:1]([OH:6])[CH2:2][CH2:3][CH3:4])#[N:12]
Reactant: CCC(O)CO
Reactant: [OH-]
Reactant: C=CC#N
Agent: [Li+]
Product: CCC(O)COC(C)C#N
Product: CCCC(O)OCCC#N
Temperature: 40 °C

Procedure:
Into a 2 liter 3-necked round bottomed flask equipped with pressure equalizing dropping funnel, reflux condenser, and magnetic stirring bar was added 1177 g (13.08 moles) of 1,2-butanediol and 3.5 g of anhydrous lithium hydroxide. The solution was heated to 40° C. with stirring and then 570 g (10.75 moles) of acrylonitrile was added dropwise over a period of 2 hours and 45 minutes. The mixture then was allowed to react an additional one hour at temperature.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:33]2[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 125.7 %

Procedure:
A solution of DIAD (11.4 mL; 55.0 mmol) in THF (15 mL) was added dropwise over 35 min to an ice-cold solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (10.06 g; 50.0 mmol), 4-chlorophenol (5.1 mL; 50.4 mmol) and triphenylphosphine (14.44 g; 55.1 mmol) in THF (40 mL). After 2.9 days at room temperature the solvent was removed on a rotary evaporator leaving a viscous liquid; hexanes was added then evaporated leaving a solid. Ether (25 mL), followed by hexanes (100 mL), was added and the solid was filtered and washed with hexanes. The filtrate was concentrated on a rotary evaporator leaving a golden, viscous liquid (19.6 g). The crude product was used as is. ESIMS 311.9/313.8 (25/10) [MH+], 296.9/298.8 (100/34) [MH+—C4H9+CH3CN], 255.9/257.8 (94/32) [MH+—C4H9], 212.0/214.0 (13/5) [MH+—C4H9—CO2].
Reaction SMILES: C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2[N:69]=[C:68]3[N:70]([CH2:73][C:74]([F:77])([F:76])[F:75])[N:71]=[CH:72][C:67]3=[C:66]([N:78]3[CH2:84][CH:83]4[O:85][CH:80]([CH2:81][CH2:82]4)[CH2:79]3)[N:65]=2)=[CH:60][CH:59]=1)=[C:56]=[O:57]>ClCCl.C(N(CC)CC)C>[N:45]1([C:48]2[N:53]=[CH:52][C:51]([NH:54][C:56]([NH:55][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[N:69]=[C:68]5[N:70]([CH2:73][C:74]([F:76])([F:77])[F:75])[N:71]=[CH:72][C:67]5=[C:66]([N:78]5[CH2:84][CH:83]6[O:85][CH:80]([CH2:81][CH2:82]6)[CH2:79]5)[N:65]=4)=[CH:60][CH:59]=3)=[O:57])=[CH:50][CH:49]=2)[CH2:46][CH2:47][O:42][CH2:43][CH2:44]1
Reactant: O=C=Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(CC(F)(F)F)c3n2)cc1)Nc1ccc(N2CCOCC2)nc1
Reaction time: 8 h

Procedure:
A solution of 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (50 mg, 0.12 mmol) in dichloromethane (4 mL) was treated with triethylamine (0.16 mL), followed by a solution of triphosgene (19 mg, 0.064 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 6-morpholinopyridin-3-amine (86 mg, 0.48 mmol)—was added to the 3-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile over 30 minutes to provide 1-(6-morpholin-4-ylpyridin-3-yl)-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea.TFA (18 mg, 21%). MS (ES+): 610.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)NCCCl
Reactant: Brc1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCN1CCN(c2ccc(Br)cc2)CC1
Temperature: 130 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
A mixture of 1-(4-bromophenyl)piperazine (0.018 mol) and ethyl (2-chloroethyl)-carbamate (0.036 mol) was stirred for 2 hours at 130° C. Triethylamine (3 ml) was added and the mixture was stirred for 15 minutes at 130° C. The reaction mixture was cooled to room temperature, CH2Cl2 was added and the resulting mixture was washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 4.3 g (67.2 %) of ethyl [2-[4-(4-bromophenyl)-1-piperazinyl]-ethyl]carbamate (interm. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[CH:6]=[C:7]2[C:11]=1[N:10](C1CCCCO1)[N:9]=[CH:8]2.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2
Reactant: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)cc2cn[nH]c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (980 mg, 4.45 mmol) in THF (10 mL), water (10 mL) and LiOH (560 mg, 13.4 mmol) was heated at 40° C. for 3 hours and then stirred at room temperature overnight. The reaction was not complete so the mixture was heated to 45° C. and heated overnight. The mixture was then concentrated to dryness, acidified to pH 6 with conc. HCl and partitioned between EtOAc and water. The resultant solids were collected by vacuum filtration, rinsed with EtOAc and dried under high vacuum to afford a white solid. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to provide an off-white solid. Both batches of white solid were combined to afford the title compound (642 mg, 75%).
Reaction SMILES: [C:1]1(CCl)[CH:6]=[CH:5][C:4]([CH2:7]Cl)=[CH:3][CH:2]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+].[OH2:17]>>[C:1]1([CH2:11][OH:14])[CH:6]=[CH:5][C:4]([CH2:7][OH:17])=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O
Reactant: ClCc1ccc(CCl)cc1
Agent: [K+]
Product: OCc1ccc(CO)cc1
Temperature: 25 °C

Procedure:
440 g (2.52 moles) of p-xylylene dichloride, 637 g (4.57 moles) of anhydrous potassium carbonate and 6 liters of water were charged to a flask. The temperature was raised until refluxing began at 103° C. and this temperature was maintained for 5 hours with the contents of the flask being stirred. Approximately 3 liters of water were then removed by distillation. Upon cooling to room temperature white crystals of p-xylylene glycol appeared. The p-xylylene glycol was obtained by filtration and was recrystallised from hot water.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:25]3=[N:26][NH:27][C:28](=[O:33])[C:29]4[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=43)[NH:22][CH:21]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:16][CH:15]=1)[C:3](=O)OCC1C=CC=CC=1>[Pd].CO>[CH3:1][NH:2][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:25]3=[N:26][NH:27][C:28](=[O:33])[C:29]4[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=43)[NH:22][CH:21]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:18][CH:19]=1.[CH3:3][N:2]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:25]3=[N:26][NH:27][C:28](=[O:33])[C:29]4[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=43)[NH:22][CH:21]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:18][CH:19]=1)[CH3:1]
Reactant: CN(Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Product: CNCc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of benzyl methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate (80 mg, 0.26 mmol), 10% Pd/C (20 mg) of methanol (50 ml) was stirring at room temperature for 4 h. The mixture solution was then filtered and evaporated under reduced pressure. The residue was purified by prep-HPLC. 3 mg of 9-(4-((methylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one and 6 mg of 9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one were obtained, yield 9%. For 9-(4-((methylamino)methyl)-phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one: 1H-NMR (400 MHz, CD3OD) δ: 2.50 (s, 3H), 3.87 (s, 2H), 4.38 (d, 1H), 4.75 (d, 1H), 7.15-7.17 (m, 2H), 7.19-7.25 (m, 5H), 7.27-7.28 (m, 3H), 7.57 (d, 1H), 7.65 (t, 1H). LC-MS (ESI) m/z: 383 (M+1)+. For 9-(4-((dimethylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one: 1H-NMR (400 MHz, CD3OD) δ: 2.31 (s, 6H), 3.57 (s, 2H), 4.33 (d, 1H), 4.73 (d, 1H), 7.10-7.12 (m, 2H), 7.19-7.21 (m, 6H), 7.26-7.27 (m, 2H), 7.58 (d, 1H), 7.64 (t, 1H). LC-MS (ESI) m/z: 397 (M+1)+.
Reaction SMILES: [C:1]([C:9]1[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:10]=1[C:11]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[Br:35][C:33]1[CH:34]=[C:9]2[C:10](=[CH:31][CH:32]=1)[C:11](=[O:12])[N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:14]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Yield: 72.3 %

Procedure:
[Step 3] To a solution (40 ml) of 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxopentyl)benzamide (2.0 g) in toluene was added 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.1 g), and the mixture was heated under reflux for 48 hrs. The reaction mixture was concentrated under reduced pressure. To the residue were added water and 10% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization (THF-diisopropyl ether) to give the title compound (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:46]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=1)[CH2:47][CH2:48][NH2:49])[CH3:45]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:49][CH2:48][CH2:47][N:46]([CH2:44][CH3:45])[C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[CH:51]=2)=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: CCN(CCN)c1cccc(C)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1OC)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (84 mg) was added. thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (130 mg, yield 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=2)=[CH:12]1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: c1ccc2c(CCOc3cncc(N4CCNCC4)n3)c[nH]c2c1
Temperature: 110 °C
Yield: 23 %

Procedure:
A mixture of the product from Step 1 above (1.07 g, 3.90 mmol), piperazine (0.98 g, 11.3 mmol) and K2CO3 (0.54 g, 3.9 mmol) in acetonitrile (11 mL) was heated at 85° C. for 5 h and at 110° C. for 8 h in a sealed pyrex flask. The reaction mixture was diluted with CHCl3, filtered, and concentrated in vacuo. The semi-solid residue was purified by chromatography on silica gel (11×4 cm) using CHCl3/MeOH (9:1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short plug of alumina, covered by K2CO3, using CHCl3 as eluent. Solvent removal in vacuo furnished 0.50 g (23%) of the title compound as an oil that solidified upon standing: mp 133-135° C. HRMS m/z calcd for C18H21N5O (M)30 323.1746, found 323.1763. Anal. (C18H21N5O) C, H, N.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H][H].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>CN(C)C=O>[CH3:3][N:4]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[N:5]([CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: [H][H]
Reactant: CN(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C#N)cc1)C(=O)OCc1ccccc1

Procedure:
A suspension of 21.5 g. of sodium hydride in 80 ml. of dimethylformamide was added slowly, while stirring to a solution of 281 g. of 1-methyl-1,2-dicarbobenzoxy-hydrazine in 300 ml. of dimethylformamide. After the evolution of hydrogen had subsided, there was added to the reaction mixture a solution of 167 g. of 4-(bromomethyl)-benzonitrile in 200 ml. of dimethylformamide and the mixture was then heated for 1 hour at 80°. The solvent was then almost completely distilled off in vacuo, the residue triturated with water and extracted with ether. The ether extract was washed with water, dried and concentrated. By recrystallization from dibutylether, there was obtained the 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzonitrile melting at 68°.
Reaction SMILES: [F-].[K+].[NH2:3][C:4]1[C:9]([F:10])=[C:8](Cl)[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH:16]=[CH2:17].CC1(C)C(C)(C)OB([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)O1.C(#N)C>C(Cl)Cl.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=2)[N:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH:16]=[CH2:17]
Reactant: C=Cc1c(C(=O)OC)nc(Cl)c(F)c1N
Reactant: CC1(C)OB(c2ccc(C=O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(C=O)cc2)c(F)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
To a 5-mL microwave safe vial was added potassium fluoride (0.378 g, 6.50 mmol), methyl 4-amino-6-chloro-5-fluoro-3-vinylpicolinate (0.5 g, 2.168 mmol), bis(triphenylphosphine)palladium(II) chloride (0.152 g, 0.217 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.528 g, 2.276 mmol). A mixture of water (1 mL) and acetonitrile (2 mL) was added and the reaction was capped and placed in a Biotage Initiator™ microwave reactor for 20 min at 115° C., with external IR-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and water (25 mL) and the organic layer was filtered through a cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a white solid (635 mg): 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.13 (dd, J=8.3, 1.6 Hz, 2H), 8.03-7.93 (m, 2H), 6.91 (ddd, J=18.1, 11.6, 0.5 Hz, 1H), 5.73 (dd, J=11.5, 1.4 Hz, 1H), 5.60 (dd, J=18.1, 1.4 Hz, 1H), 4.77 (s, 2H), 3.94 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −143.49; ESIMS m/z 301 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([C:11]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][CH:19]=3)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:37][C@@H:38]([CH2:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1)[C:39](O)=[O:40])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:7][NH:8][C:9]([C:11]2([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][CH:23]=3)[CH2:16][CH2:15][N:14]([C:39](=[O:40])[C@@H:38]([NH2:37])[CH2:42][C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)[CH2:13][CH2:12]2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: O=C(NCC1CCCCC1)C1(Cc2ccc(-c3ccccc3)cc2)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide (3.98 mmol; 1.7 g) in DMF (20 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (4.63 mmol; 1.26 g), N,N-diisopropyl-N-ethylamine (13.9 mmol; 2.46 mL) and HBTU (6.02 mmol; 2.28 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting solution was stirred for 7 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:19](=[O:20])[CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[CH:7][CH:6]=1
Reactant: ClCCOc1ccccc1
Reactant: O=C(O)Cc1ccccc1Cl
Product: O=C(Cc1ccccc1Cl)c1ccc(OCCCl)cc1

Procedure:
1-[4-(2-Chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone is prepared according to the method described in the example 4a using 2-chloroethoxybenzene and 2-chlorophenylacetic acid as starting materials.