Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([C:16]4[O:20][C:19]([C:21]5[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=5)=[N:18][N:17]=4)[C:13]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:12][CH:11]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:59]([S:61](Cl)(=[O:63])=[O:62])[CH3:60]>C(Cl)Cl>[CH2:59]([S:61]([NH:1][CH:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([C:16]4[O:20][C:19]([C:21]5[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=5)=[N:18][N:17]=4)[C:13]([N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:12][CH:11]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1)(=[O:63])=[O:62])[CH3:60]
Reactant: CCS(=O)(=O)Cl
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(N)[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CC[C@H]2CN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C[C@@H]12
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (150 mg, 0.22 mmol) and triethylamine (24 mg, 33 μL, 0.23 mmol) in DCM (1 mL) at 0° C. was added ethanesulfonyl chloride (29 mg, 21 μL, 0.22 mmol). The reaction mixture was stirred for 30 min. The solvent was evaporated and the crude material was purified via silica gel column chromatography using 10 to 70% EtOAc in DCM to obtain tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-(ethylsulfonylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (110 mg, 650%). LC/MS m/z 799.5 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[C:54]([C:55](O)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[C:54]([C:55]([N:1]3[CH2:5][CH2:4][CH:3]([C:6]4[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=4)[CH2:2]3)=[O:56])=[CH:53][O:52][N:51]=2)=[CH:48][CH:49]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
A solution of 3-pyrrolidin-3-ylpyridine (6 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents from the pure fractions, the residue was dissolved in chloroform and washed with diluted NaOH to provide the neutral compound in the organic phase that was dried (Na2SO4) and evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1479.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N:32]=[C:31]([CH3:36])[N:30]=1>>[CH3:36][C:31]1[N:30]=[C:29]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)[CH:34]=[C:33]([CH3:35])[N:32]=1
Reactant: Cc1cc(Br)nc(C)n1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)nc(C)n1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyrimidine in Step 4. LC-MS Method 2 tR=1.073, m/z=464.1; 1H NMR (CD3OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.82 (m, 2H), 2.15 (m, 1H), 2.23 (m, 2H), 2.38 (m, 1H), 2.46 (s, 3H), 2.62 (s, 3H), 3.08 (m, 1H), 3.39 (m, 2H), 5.51 (m, 1H), 6.95-7.08 (m, 4H), 7.21 (m, 2H), 7.51 (s, 1H), 7.83 (d, 2H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20]O)=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.C(OCC)C>[CH2:5]([O:12][C:13]1[C:18]([Cl:19])=[CH:17][C:16]([CH2:20][Br:2])=[CH:15][C:14]=1[Cl:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: Clc1cc(CBr)cc(Cl)c1OCc1ccccc1
Reaction time: 2 h

Procedure:
Phosphorous tribromide (2 mL) was added to a solution of (4-benzyloxy-3,5-dichlorophenyl)-methanol (CAB02117, 5.50 g, 19.4 mmol) in dichloromethane (80 mL) at 0° C. The mixture was stirred at this temperature for 2 h, diluted with diethyl ether (150 mL), transferred into a separation funnel and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/hexane. 1H-NMR (400 MHz, CDCl3) δ=4.39 (s, 2H, —CH2Br), 5.05 (s, 2H, —CH2Ph), 7.37 (s, 2H), 7.38-7.44 (m, 3H), 7.54-7.58 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=31.48, 75.39, 128.73, 129.68, 129.70, 129.72, 130.06, 135.46, 136.27, 151.23.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
5-Amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carbonitrile (15 g, 50 mmol) was taken up in conc. H2SO4 (45 mL) and stirred at room temp for 16 h. The reaction was then poured onto 3 N NaOH (850 mL) at 0° C. The resulting solid was then filtered and washed with H2O (1 L). The product was then dried under vacuum to yield the desired amide (14 g, 88%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH:14]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:21]1([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A 200 ml eggplant-shaped flask was charged with 5.38 g of methyl 4-bromomethylphenylacetate, 6.06 g of 1-benzhydrylpiperazine, 6.1 ml of triethylamine, and 100 ml of dioxane and the mixture was stirred at room temperature for 5 hours. The solvent was then distilled off and the residue was extracted with ethyl acetate. The extract was washed with water, the solvent was distilled off, and the residue was recrystallized from methanol to provide 8.33 g of methyl 4-[(4-diphenylmethyl-1-piperazinyl)methyl]phenylacetate melting at 124° C.-125° C.
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:9][C:8]=2[CH3:20])[CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](OC)=O)=[CH:31][CH:30]=1)[CH3:27]>C1COCC1>[CH:1]1([CH2:5][N:6]2[C:7]3=[N:12][CH:11]=[C:10]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:9]=[C:8]3[CH:20]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOc1ccc(CC(=O)OC)cc1
Reactant: Cc1cc(NC(=O)C(C)(C)C)cnc1NCC1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc3cc(NC(=O)C(C)(C)C)cnc3n2CC2CCC2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
To a solution of N-[6-[(cyclobutylmethyl)amino]-5-methyl-3-pyridinyl]-2,2-dimethyl-propanamide (2.0 g, 7.26 mmol) in THF (70 ml) at −78° C. was added n-butyl lithium (12.7 mL of 2.0 M solution in cyclohexane, 25.4 mmol). The mixture was stirred for one hour at −20° C. and then cooled to −78° C. To this reaction mixture was cannulated to a solution of methyl 4-ethoxy-benzeneacetate (2.3 g, 11.6 mmol) in THF (50 mL) at −78° C. After stirring for 3 hours at room temperature, the mixture was quenched with NaHCO3 saturated aqueous solution (200 ml) and diluted with EtOAc (100 mL). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (100 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel flash chromatography ([3% MeOH+0.5% NH4OHaq] in CH2Cl2) to provide 650 mg of the title compound N-[1-(cyclobutylmethyl)-2-[(4-ethoxyphenyl)methyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]-2,2-dimethyl-propanamide. 1H NMR (400 MHz, DMSO-D6) δ 1.21 (s, 9 H) 1.29 (t, J=7.03 Hz, 3 H) 1.77 (m, 6 H) 2.69 (m, 1 H) 3.97 (q, J=7.03 Hz, 2 H) 4.06 (s, 2 H) 4.15 (d, J=7.23 Hz, 2 H) 5.99 (s, 1 H) 6.86 (d, J=8.59 Hz, 2 H) 7.14 (d, J=8.59 Hz, 2 H) 7.98 (d, J=2.34 Hz, 1 H) 8.21 (d, J=2.34 Hz, 1 H) 9.21 (s, 1 H). MS (ESI) (M+H)+: 421.
Reaction SMILES: [CH:1]1[C:6]2[C:7](=O)[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[NH:19]1.[OH-].[NH4+]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[CH3:17][CH:18]1[NH:19][CH:20]([CH3:24])[CH2:21][N:22]([C:7]2[C:6]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:23]1
Reactant: O=C1Nc2ccccc2Oc2ccccc21
Reactant: CC1CNCC(C)N1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC1CN(C2=Nc3ccccc3Oc3ccccc32)CC(C)N1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a stirred solution of 10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.4 g; 1.9 mmol; Aldrich) in dry toluene (20 mL) at room temperature was added 2,6-dimethyl piperazine (0.99 g; 8.7 mmol; Aldrich) followed by the dropwise addition of TiCl4 (1M in toluene, 2.27 mL; 2.27 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×75 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using CHCl3 :MeOH (94:6) eluant to give 0.353 g (60%) of 11-(3,5-dimethyl-l-piperazinyl)-dibenz [b,f][1,4]oxazepine as a pale yellow solid; m.p. 112°-114° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>CCCCCC>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.62 ml of N,N-diisopropylethylamine were added to 1 ml of hexane, then the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.55 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [P:1](Cl)([Cl:6])([O:3][CH2:4][CH3:5])=[S:2].[O-:8][CH2:9][CH2:10][CH3:11].[Na+].C(O)CC>O1CCCC1>[P:1]([Cl:6])([O:8][CH2:9][CH2:10][CH3:11])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCOP(=S)(Cl)Cl
Reactant: CCC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCO
Product: CCCOP(=S)(Cl)OCC
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To 30 g (167 mmole) of O-ethyl dichlorothiophosphate in 100 ml of tetrahydrofuran (THF) cooled to -70° C. was added a solution of sodium propoxide (from 7.4 g of 60% NaH (184 mmole) and 11 g (176 mmole) of 1-propanol) in 50 ml of THF. After warming to room temperature over 2 hours, the THF was removed in vacuo and the residue was partitioned between 50 ml diethyl ether, 50 ml hexanes, and 25 ml cold water. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and distilled (bp 45-50° C. 1 torr) yielding 20 g of the title compound, an oil. nmr 1.0 t 3H, 1.4 t 3H, 1.8 sextet 2H, 4.4 m 4H.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)[CH3:3].C([Li])CCC.[C:14](=[O:16])=[O:15]>C1COCC1.CCCCCC>[CH3:1][CH:2]([N:4]1[C:8]([C:14]([OH:16])=[O:15])=[N:7][CH:6]=[N:5]1)[CH3:3]
Reactant: CC(C)n1cncn1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)n1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
1-(1-Methylethyl)-1H-1,2,4-triazole (1 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6 M solution of butyllithium in hexane (5.9 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml), concentrated in vacuo and dried in a vacuum oven for 1 day at 50° C. to give the title compound (1.29 g) as a white solid.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1)(OC(C)(C)C)=O.[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH2:35][CH2:36][CH3:37])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42]N(C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH2:35][CH2:36][CH3:37])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42][N:14]([C:15](=[O:23])[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Reactant: CCCc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2cc(CC)sc2n1
Product: CCCc1nc(N2CCN(C(=O)Cc3ccccc3)CC2)c2cc(CC)sc2n1
Yield: 36 %

Procedure:
Phenylacetamidopiperazine hydrochloride (Example 141) was reacted 2-propyl-4-chloro-6-ethylthienopyrimidine (Example 159) according to Example 87. Yield 36%, ES-MS: (M+H)+ 409.
Reaction SMILES: C1(C[O:8][P:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:44]2C(=O)C3=CC=CC=C3C2=O)([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)C=CC=CC=1.[OH2:55].NN>O1CCOCC1.C1(C)C=CC=CC=1>[C:14]1([CH2:13][O:55][N:11]([PH:9]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44])=[O:8])[C@H:12]([C:20]([NH:22][C@H:23]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCCCCCN1C(=O)c2ccccc2C1=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O
Agent: NN
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)N(OCc1ccccc1)[PH](=O)CCCCCCN)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-[N-[(phenylmethoxy)(6-phthalimidohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester in dioxane is treated with hydrazine hydrate and stirred at room temperature under argon. After 24 hours, the mixture is diluted with toluene and the solvents decanted and evaporated to dryness. The residue is purified by extraction and flash chromatography to give N-[(phenylmethoxy)[(6-aminohexyl)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:29])[C@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl.[CH2:31]([O:38][C:39](=[O:47])[C@H:40]([CH3:46])[NH:41][C:42](=[O:45])[CH2:43][NH2:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN1CCOCC1>C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:47])[C@H:40]([CH3:46])[NH:41][C:42](=[O:45])[CH2:43][NH:44][C:11](=[O:29])[C@H:12]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Reactant: C[C@H](NC(=O)CN)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A solution of 17.6 parts N-t-butoxycarbonyl-L-tyrosine 2,4,5-trichlorophenyl ester, 9.0 parts glycyl-L-alanine benzyl ester hydrochloride and 1.2 parts N-methylmorpholine in 200 parts methylene chloride is stirred for 16 hours at room temperature. Removal of the solvent under reduced pressure affords a crude product which is purified by low pressure column chromatography to give N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine benzyl ester. The purified material is dissolved in 400 parts methanol. Then, 0.4 part palladium black metal catalyst is added and the mixture shaken with hydrogen at atmospheric pressure and room temperature for about 5 hours. The catalyst is removed by filtration, and the solvent is removed by evaporation under reduced pressure. The resulting material is purified by low-pressure chromatography to give N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine. This compound is represented by the following formula
Reaction SMILES: C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([N:26]1[CH2:31][CH:30]2[CH:28]([C:29]2([C:33]2[CH:38]=[CH:37][CH:36]=[C:35](I)[CH:34]=2)[CH3:32])[C:27]1=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([Sn](CCCC)(CCCC)[C:46]1[N:47]=[CH:48][N:49]([C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=1)CCC>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([N:26]1[CH2:31][CH:30]2[CH:28]([C:29]2([CH3:32])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:50]3[N:49]([C:51]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:58]4[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=4)[CH:48]=[N:47][CH:46]=3)[CH:34]=2)[C:27]1=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.2 %

Procedure:
To tris(dibenzylideneacetone)dipalladiunm (0) (8.7 mg, 9.5 mmol) in tetrahydrofuran (2.5 ml) at room temperature was added triphenylarsine (12 mg, 39.2 [mol). After 10 min, a solution of 3-hexyl-6-(3-iodophenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 67, 0.15 g, 3.8 mmol) in tetrahydrofuran (2.5 ml) was added. A minute later, 4-(tributylstannyl)-1-triphenylmethyl-1H-imidazole (Preparation 73, 0.332 g, 0.55 mmol) in tetrahydrofuran (3 ml) was added. The reaction mixture was stirred at room temperature for 30 min and then refluxed for 3.5 h. The cooled reaction mixture was concentrated in vacuo and chromatographed on silica gel eluting with hexane:ethyl acetate (1:1 then 0:1) to give the title compound (55 mg, 25%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:14]([F:17])([F:16])[F:15])[CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]=1[N+:35]([O-])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:35][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:26]=1[CH3:25])[C:30]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:9]=1)=[O:31]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: Cc1nccn1-c1ccc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenylamine (1.0 g, 4.15 mmol), triethylamine (1.74 mL, 12.5 mmol) in anhydrous CH2Cl2 (60 mL) at 0° C. is added 4-methyl-3-nitro-benzoyl chloride (660 μL, 4.57 mmol) dropwise. After stirring for 2 hours at room temperature, the reaction mixture is poured into 100 mL CH2Cl2 and 50 mL saturated NaHCO3 solution with rapid stirring. After 10 minutes, the mixture is partitioned in a separator funnel and extracted three times with 100 mL CH2Cl2. The organic extracts are washed with brine, and dried over MgSO4. Filtration and concentration under reduced pressure, afforded the desired compound, which is used in the next step without any further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:2]1.[C:31](Cl)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[C:31]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[C:13]4[CH:14]=[CH:15][C:16]5[N:17]([C:18]([CH3:21])=[N:19][N:20]=5)[C:12]=4[CH:11]=3)=[N:6]2)[CH2:4]1)(=[O:33])[CH3:32]
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3cccc(Cl)c3)n2)C1
Reaction time: 0.03 h
Yield: 71.4 %

Procedure:
To 7-(1-azetidin-3-yl-1H-pyrazol-3-yl)-6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (6.0 mg, 0.014 mmol, from Step 1) was added acetyl chloride (1.2 μL, 0.017 mmol, Aldrich) in DCM (0.38 mL). Triethylamine (4.0 μL, 0.029 mmol) was then added and the reaction was complete in 2 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (4.6 mg, 70%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
In chloroform (200 ml) is dissolved 2-phenylacetophenone (25.5 g) and thereto is added a solution of bromine (22 g) in chloroform (100 ml) and the mixture is stirred at room temperature for 5 hours and then allowed to stand overnight. After distilling off chloroform, to the resulting residue is added methanol. The precipitates are filtered off and the filtrate is subjected to a silica gel chromatography and eluted with chloroform. The eluates are collected and distilled to remove chloroform to give 2-bromo-2-phenylacetophenone (26 g) as an oily substance.