Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C)C)(=O)CCCCCCCCCCCCCCCCC.C([O:43][CH:44]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH3:45])(=O)CCCCCCCCCCCCCCCCC>O>[CH3:45][C@H:44]([OH:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(C)CCCCCCCC
Agent: CCCCCCCCCCCCCCCCCC(=O)OC(C)C
Solvent: O
Product: CCCCCCCC[C@H](C)O
Temperature: 85 °C
Reaction time: 0.02 h
Yield: 73.5 %

Procedure:
In a 300 ml separable flask were put 1 g of Lipase PL, and 40 g of (R,S)-2-decanol, and the mixture was subjected to ultrasonication with the same ultrasonic wave generating equipment as used in Example 1 at room temperature and 90 kHz for 1 minute. To the mixture was added 60 g of isopropyl stearate, followed by stirring at 85° C. and 250 rpm for 30 hours to carry out interesterification. The water content of the reaction system was 0.02% by weight, and 96% of the lipase particles had a particle size of 10 to 40 μm. Gas chromatographic analysis of the reaction mixture revealed that 57 mol % of (R,S)-2-decanol had been converted to 2-decyl stearate. Lipase was removed by filtration in the same manner as in Example 8, and the filtrate was subjected to simple distillation at 70° C. and 5 mmHg to recover unreacted (S)-(+)-2-decanol (yield: 73.5%; chemical purity: 99.9%; optical purity: 93% ee).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]([C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4].[ClH:20]>CCOCC>[ClH:20].[CH3:1][N:2]([CH3:19])[C:3]([C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N(C)C
Agent: Cl
Solvent: CCOCC
Product: C[C@H]1CCNC[C@H]1C(=O)N(C)C
Reaction time: 0.5 h

Procedure:
To cis-tert-butyl 3-(dimethylcarbamoyl)-4-methylpiperidine-1-carboxylate (0.3 g, 1.12 mmol) was added a solution of hydrogen chloride in ether. The mixture was stirred for 30 min, and then was concentrated under reduced pressure to afford cis-N,N,4-trimethylpiperidine-3-carboxamide hydrochloride (0.16 g) as a white solid. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]([C:20]([F:23])([F:22])[F:21])[CH:18]([C:24]([O:26]CC)=[O:25])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:19]([C:20]([F:23])([F:21])[F:22])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]3)=[CH:13][CH:14]=2)=[O:7])=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1C=NN(c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)C1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(-n2ncc(C(=O)O)c2C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
A mixture of ethyl 1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-4H-pyrazole-4-carboxylate (150 mg), 1 N sodium hydroxide aqueous solution (1 ml) and ethanol (2 ml) was stirred at 45° C. for 4 hours. After spontaneous cooling, 1 N hydrochloric acid aqueous solution (2 ml) was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethanol to give 1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (91 mg) as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH2:11][CH:10]2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:15](=[O:17])[CH:10]3[CH2:11][CH2:12][C:13](=[O:14])[N:9]3[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CCC(=O)N1Cc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccc(Cl)cc2CN2C(=O)CCC12
Temperature: 5 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 25.37 g of (±)-1-[(3-chlorophenyl)methyl]-5-oxo-2-pyrrolidinecarboxylic acid in sieve dried dichloromethane (20 ml), 13.09 g of thionyl chloride was added, and the resultant solution was stirred and refluxed with the exclusion of moisture for 6 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5° C. and 40 g of aluminum chloride was added in portions with exclusion of moisture and vigorous stirring. The reaction was slightly exothermic and a solid began to precipitate. The flask was heated intermittently with a steam bath to increase the rate of the reaction. After each heating, the gas evolution was allowed to subside. When heating did not produce gas evolution, ice chips were added to quench the reaction. Water was then added to the mixture and the phases were separated. The aqueous phase was extracted with dichloromethane and the combined organic phase was dried (Na2SO4). The mixture was vacuum filtered and concentrated to a solid to which ethyl acetate was added and the resultant mixture was vacuum filtered to give 11.56 g of a solid. The solid was dried overnight under vacuum.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][N:23]([C:25]([O:27]C(C)(C)C)=O)[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([O:32][CH3:33])[CH:3]=1.[C:34](O)(=O)[CH:35]=C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>Cl.CO.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH:21]3[CH2:24][N:23]([C:25](=[O:27])[CH:34]=[CH2:35])[CH2:22]3)[CH2:19][CH2:20]2)=[O:14])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(Cl)c(C(C)C)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: C=CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C(C)C)c(Cl)cc3OC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A mixture of tert-butyl 3-(4-(2-(4-chloro-5-isopropyl-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate (102 mg, 0.212 mmol) in HCl/MeOH (2.86 M, 5 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the crude product, the crude was dissolved in DMF (5 mL) at RT, acrylic acid (17 mg, 0.233 mmol), BOP (113 mg, 0.254 mmol) and DIEA (82 mg, 0.636 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (77 mg, 85% yield, 2 steps). ESI-MS m/z: 435.4[M+H]+.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([NH2:26])[C:17]=3[N:27]=[C:14]2[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:26][C:18]1[C:17]2[N:27]=[C:14]3[CH2:13][O:12][CH2:11][C@H:10]([CH2:9][OH:8])[N:15]3[C:16]=2[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccccc2)COC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](CO)COC1
Reaction time: 18 h
Yield: 38.1 %

Procedure:
(11S)-11-[(Benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (297 mg, 0.825 mmol) was dissolved in 20 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 230 mg) and 0.5 mL of 3 M HCl in ethanol were then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 18 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The residue was dissolved in H2O and the solution was made basic by the addition of concentrated aqueous NH4OH solution. The aqueous solution was extracted with 10% MeOH/CH2Cl2 several times and the combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 25-75% CMA/CHCl3) gave a white powder. Crystallization from ethyl acetate gave 85 mg of the title compound as white, fluffy crystals, mp 238.6-239.8° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([CH3:13])=[O:12])[CH:5]=1)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C1(C)C=CC=CC=1>CCOC(C)=O>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:1][C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[CH3:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Yield: 95 %

Procedure:
A mixture of 3-acetamidoacetophenone (3 kg; Lancaster), dimethylformamide dimethylacetal (7 L; Lancaster) and toluene (12 L; Mallinckrodt) is heated at reflux and methanol collected as it is formed. The mixture is heated overnight and a precipitate forms during this time. The reaction may be monitored by TLC analysis (EtOAc: starting material Rf=0.46; product Rf=0.10) to ensure it goes to completion. The reaction mixture is cooled and the solid is collected by filtration. The cake is washed with hexanes (4 L) then dried to give 3.77 kg (95% yield) of a light yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Cl)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:12][NH2:13].CC([O-])(C)C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[NH:13][CH3:12]
Reactant: COc1cc(Cl)cc(OC)c1
Reactant: CN
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Product: CNc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
Following general procedure A, a mixture of 3,5-dimethoxychlorobenzene (173 mg, 1.0 mmol), 2M methylamine (1 mL, 2.0 mmol), NaOt-Bu (120 mg, 1.2 mmol), BrettPhos precatalyst 10 (8 mg, 0.01 mmol), and t-BuOH (1 mL) was stirred at room temperature for 2 h. The crude product was purified via column chromatography (80:20 to 50:50 Hexanes/EtOAc gradient) to provide the title compound as a pale yellow liquid (150 mg, 90%). 1H NMR (400 MHz, CDCl3) δ: 5.89 (t, J=2.2 Hz, 1H), 5.80 (t, J=2.2 Hz, 2H), 3.76 (s, 7H), 2.81 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 161.9, 151.5, 91.4, 89.7, 55.3, 30.9 ppm. Brown, F. J.; Bernstein, P. R.; Cronk, L. A.; Dosset, D. L.; Hebbel, K. C.; Maduskuie, T. P.; Shapiro, H. S.; Vacek, E. P.; Yee, Y. K.; Willard, A. K.; Krell, R. D.; Snyder, D. W. J. Med. Chem. 1989, 32, 807.
Reaction SMILES: NC1N=C2C(C3C=CC(C(N4CCOCC4)=O)=CC=3)=NC=CN2N=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.[CH3:63][C:64]1[N:68](COCC[Si](C)(C)C)[C:67]2[CH:77]=[CH:78][C:79]([NH:81][C:82]3[N:104]=[C:85]4[C:86]([C:90]5[CH:95]=[CH:94][C:93]([C:96]([N:98]6[CH2:103][CH2:102][O:101][CH2:100][CH2:99]6)=[O:97])=[CH:92][CH:91]=5)=[N:87][CH:88]=[CH:89][N:84]4[N:83]=3)=[CH:80][C:66]=2[N:65]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.C(C1C=CC=CC=1)C.C(O)C>[CH3:63][C:64]1[NH:68][C:67]2[CH:77]=[CH:78][C:79]([NH:81][C:82]3[N:104]=[C:85]4[C:86]([C:90]5[CH:91]=[CH:92][C:93]([C:96]([N:98]6[CH2:99][CH2:100][O:101][CH2:102][CH2:103]6)=[O:97])=[CH:94][CH:95]=5)=[N:87][CH:88]=[CH:89][N:84]4[N:83]=3)=[CH:80][C:66]=2[N:65]=1
Reactant: Cc1nc2cc(Nc3nc4c(-c5ccc(C(=O)N6CCOCC6)cc5)nccn4n3)ccc2n1COCC[Si](C)(C)C
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCc1ccccc1
Solvent: CCO
Product: Cc1nc2cc(Nc3nc4c(-c5ccc(C(=O)N6CCOCC6)cc5)nccn4n3)ccc2[nH]1
Temperature: 110 °C

Procedure:
[4-(2-Amino-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-phenyl]-morpholin-4-yl-methanone (see “C41”, 5-bromo-2-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (1.1 eq.), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl]2-(2-aminoethyl)phenyl)Pd(II) (0.03 eq), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl (0.03 eq) are dissolved in dry t-butanol under nitrogene, before lithium bis(trimethylsilyl)amide, (3 eq., 20% (ca 1.06M) solution in THF/ethylbenzene) is added. The resulting mixture is heated to 110° C. for 1 h. Work-up as described in general procedure 3 gives the SEM-protected intermediate. (4-{2-[2-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-ylamino]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-phenyl)-morpholin-4-yl-methanone is dissolved in ethanol. Concentrated HCl is added and the reaction mixture is heated to 65° C. for 4 h and monitored by LCMS. Upon completion, the mixture is neutralized with saturated NaHCO3-solution and the layers are separated, the aqueous phase is 3 times extracted with DCM. The combined organic phases are dried with Na2SO4 and concentrated. Purification gives the title compound as a solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:13]1)=O)C1C=CC=CC=1.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:13]1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NC(=O)OCc2ccccc2)CN1Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](N)CN1Cc1ccccc1

Procedure:
A solution of (2S,4R)-4-benzyloxycarbonylamino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidine (700 mg) and 30% hydrogen bromide in acetic acid (2 ml) was stirred at room temperature for 2 hours and the solvent was evaporated in vacuo to give (2S,4R)-4-amino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidine hydrobromide (800 mg) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](=[O:11])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccccn1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccc(Cl)cc1C
Product: Cc1cc(Cl)ccc1[C@H](CC(=O)Cc1ccccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 261, step 1, from (R)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-N-methoxy-N-methyl-propionamide and 2-methyl-pyridine was prepared the title compound as a yellow oil, MS (ESI+): m/z=430.0 ([M+H]+, 1Br).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:39][CH:38]=2)=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:71]>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:39][CH:38]=2)=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:21][Cl:71])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
1-[4-(2-benzyloxyethoxy)phenyl]-1,2-bis-(4-benzyloxyphenyl)-4-chloro-but-1-ene was prepared from 4-[4-(2-benzyloxyethoxy)phenyl]-3,4-bis-(4-benzyloxyphenyl)-but-3-en-1-ol (0.65 g, 0.98 mmol),triphenyl phosphine (0.5 g, 1.96 mmol) and carbon tetrachloride (0.74 g, 4.9 mmol) by the method described in example 2. The product was purified by flash chromatography (toluene). Yield 0.42 g.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7]([OH:9])=O)[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3]1.C(OC(=O)C)(=O)C>>[CH2:1]=[C:2]1[CH2:3][C@@H:4]2[C:10](=[O:11])[O:12][C:7](=[O:9])[C@@H:5]2[CH2:6]1
Reactant: C=C1C[C@@H](C(=O)O)[C@H](C(=O)O)C1
Solvent: CC(=O)OC(C)=O
Product: C=C1C[C@@H]2C(=O)OC(=O)[C@@H]2C1
Temperature: 100 °C
Yield: 28.4 %

Procedure:
A suspension of the diacid 2 (689 mg, 4.05 mmol) from Example 1 in freshly distilled acetic anhydride (7 ml) was heated for 4 hours at 100° C. The majority of acetic anhydride was removed by distillation and the remainder was removed under a stream of nitrogen leaving a residue which was distilled (170°-175° C. at 1 mm Hg) giving the desired anhydride 3 (175 mg, 28%) as an oil which crystallized on standing: mp 50°-51° C.; Anal. calcd for C8H8O3 : C, 63.15; H, 5.30. Found: C, 62.91; H, 5.43.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:41]O>>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:41])=[O:34])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 62 %

Procedure:
The title compound (1.03 g, 62%) was prepared from 3,4,5-triphenyl-1H-pyrazole-1-decanoic acid (1.60 g) by esterification in methanol using a catalytic amount of conc. sulfuric acid. MS(CI): m/e=481 (MH+).
Reaction SMILES: C([O:3][C:4]([N:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:7][C:8]([NH2:10])=[S:9])=O)C.[OH-].[Na+].Cl>O>[OH:3][C:4]1[N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:8]([SH:9])[N:10]=1
Reactant: CCOC(=O)N(NC(N)=S)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(S)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.6 %

Procedure:
The product of stage (a) (28.9 g) was treated with a solution of sodium hydroxide (7.5 g) in water (150 ml). The suspension was heated under reflux with stirring for 45 minutes and then cooled to 25° C. The pH of the solution was adjusted to 1.0 with concentrated hydrochloric acid and the resulting solid was filtered and washed with water to give 20.2 g of the desired product.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][N:8]([CH2:10][C:11]([F:14])([F:13])[F:12])[CH2:7][N:6]1[C:15](=[O:25])[CH:16]([NH:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]([CH3:19])[CH3:18])=[O:4].[Li+].[OH-].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:63][CH2:64][C:65]([C:67]1[CH:72]=[CH:71][C:70]([Br:73])=[CH:69][CH:68]=1)=[O:66]>C1COCC1.CO>[CH3:24][O:23][C:21](=[O:22])[NH:20][CH:16]([C:15]([N:6]1[CH:5]([C:3](=[O:4])[NH:63][CH2:64][C:65]([C:67]2[CH:72]=[CH:71][C:70]([Br:73])=[CH:69][CH:68]=2)=[O:66])[CH2:9][N:8]([CH2:10][C:11]([F:14])([F:12])[F:13])[CH2:7]1)=[O:25])[CH:17]([CH3:18])[CH3:19]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1C(=O)OC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)NC(C(=O)N1CN(CC(F)(F)F)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1-(2,2,2-trifluoro-ethyl)-imidazolidine-4-carboxylic acid methyl ester (95 mg, 0.257 mmol) was dissolved in THF (1.8 mL) and MeOH (0.9 mL). An aqueous solution of LiOH (10.8 mg, 0.208 mmol) was added and stirring at room temperature was continued. After the hydrolysis was complete, the reaction was neutralized with aqueous HCl (1M). The organic solvents were removed in vacuo and the aqueous suspension was frozen and lyophilized. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.5 mL) and HATU (97.6 mg, 0.257 mmol) and DIEA (66.3 mg, 0.514 mmol) were added. The reaction was stirred at room temperature for five minutes, after which the amino-(4′bromo) acetophenone hydrochloride salt (64.2 mg, 0.257 mmol) was added. Stirring at room temperature was continued. After 60 minutes, all volatiles were removed in vacuo and the crude material was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the slightly impure product {1-[5-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2,2,2-trifluoro-ethyl)-imidazolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (148 mg): LCMS-ESI+: calc'd for C21H26BrF3N4O5: 551.3 (M+). Found: 551.2/553.2 (M+).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C@@H:17]2[CH2:21][O:20][C@@H:19]3[C@H](O)[CH2:23][O:24][C@H:18]23)(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1C=CC=CC=1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C@@H:17]2[CH2:21][O:20][C@@H:19]3[C@@H:1]([Br:5])[CH2:23][O:24][C@H:18]23)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 65 °C
Yield: 42.7 %

Procedure:
A solution of carbon tetrabromide (18.12 g, 54.63 mmol) in pyridine (100 mL) was added to a solution of monotosylate (50) (14.9 g, 49.66 mmol) and triphenylphosphine (26.1 g, 99.32 mmol) in pyridine (150 mL) over 30 minutes, then the mixture heated at 65° C. for 1.5 hours under an atmosphere of argon. Water (200 mL) was added then the aqueous phase extracted with dichloromethane (5×100 mL). The organic phase was washed with brine (50 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue which was azeotroped with toluene (5×50 mL). Flash chromatography over silica, eluting with diethyl ether:heptane mixtures 0:100 to 100:0 gave bromotosylate (46) (7.70 g, 43%) as a white solid. [α]D17+68.6° (c=0.51, CHCl3).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[N:9]2.C(OCC)(=O)C>O1CCOCC1>[NH:1]([C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[N:9]2)[NH2:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CCC1
Reactant: NN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Temperature: 95 °C

Procedure:
Anhydrous hydrazine (25 mL, 797 mmol) was added to a stirred solution of chloronaphthyridine (1-5) (25.12 g, 51.7 mmol) in 1,4-dioxane (200 mL) under an atmosphere of nitrogen and the reaction mixture was heated to 95° C. After 30 min the solution was cooled to room temperature, ethyl acetate (400 mL) was added and the solution was washed with a saturated solution of sodium bicarbonate, followed by water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give (1-6) as an orange solid.