Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70](O)=[O:71]>CC(N(C)C)=O>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[CH2:69][C:70]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[C:9]([O:16][CH2:17][CH3:18])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)=[O:71]
Reactant: O=C(O)Cc1cc(F)ccc1Cl
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(N)ccc1Oc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOc1cc(=O)n(C)cc1-c1cc(NC(=O)Cc2cc(F)ccc2Cl)ccc1Oc1ccc(F)cc1F

Procedure:
A solution of Example 1G and DIPEA (0.182 M and 0.52 M in DMA, respectively, 221 μL, 0.40 mmol Example 1G (1.0 equivalent) and 1.21 mmol DIPEA (3.0 equivalents)), HATU (0.182 M in DMA, 221 μL, 0.40 mmol, 1 equivalent) and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in DMA, 151 μL, 0.60 mmol, 1.5 equivalents) were mixed through a perfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into an injection loop. The reaction segment was injected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., and passed through the reactor at 180 μL min−1 (10 minute residence time). Upon exiting the reactor, the solution was loaded directly into an injection loop and purified by preparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5% A) to provide the title compound. 1H NMR (400 MHz, DMSO-d6/D2O) δ 10.37 (s, 1H), 7.59-7.46 (m, 4H), 7.37-7.27 (m, 2H), 7.18 (td, J=8.5, 3.1 Hz, 1H), 7.14-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.85 (s, 2H), 3.36 (s, 3H), 1.14 (t, J=7.0 Hz, 3H). MS (APCI+) m/z 543.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[CH:4]=[N:3]1.P(Cl)(Cl)([Cl:14])=O>>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[N:9][C:10]([Cl:14])=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2c(=O)[nH]cnc21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1ncc2c(Cl)ncnc21
Reaction time: 12 h
Yield: 60.5 %

Procedure:
80 g. of 1-methyl-1,5-dihydro-4H-pyrazolo[3,4-d]- pyrimidin-4-one are added to 300 ml. of phosphorus oxychloride and the mixture is refluxed. After distilling off the excess phosphorus oxychloride, the semi-solid residue is extracted with 3 × 100 ml. of boiling benzene. The benzene extracts are combined and concentrated to half-volume, then added to petroleum ether. After standing 12 hours in the refrigerator, the precipitated 1-methyl-4-chloropyrazolo[3,4-d]- pyrimidine is filtered under suction and recrystallized from cyclohexane to obtain 54 g. of white crystals, m.p. 93°-96° (yield 60.5%).
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)=[O:3].[CH3:15][Zn]C>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:2]([CH:4]1[CH2:9][CH2:8][C:7]([CH3:14])([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:15]
Reactant: C[Zn]C
Reactant: COC(=O)C1(C)CCC(C(=O)Cl)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C1(C)CCC(C(C)=O)CC1
Temperature: 38 °C

Procedure:
To a deoxygenated solution of methyl 4-(chlorocarbonyl)-1-methylcyclohexanecarboxylate (7.282 g, 33.3 mmol) and palladium (II) acetate (374 mg, 1.665 mmol) in 1,4-dioxane (200 mL) was added dimethylzinc (2.0 M in toluene, 16.65 mL, 33.3 mmol). The black reaction mixture was heated under an inert atmosphere at 38° C. for 15 hours before being diluted with water (30 mL). The resulting suspension was filtered twice through CELITE. The filtrate was dried over magnesium sulfate and concentrated under reduced pressure. The resiude was purified by chromatography on silica gel (5-45% ethyl acetate/hexanes) to afford methyl 4-acetyl-1-methylcyclohexanecarboxylate. MS ESI calc'd. for C11H18O3 [M+H]+ 199. found 199.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=O.[F:13][C:14]1[CH:15]=[C:16]([CH2:21][NH2:22])[CH:17]=[CH:18][C:19]=1[F:20]>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([NH:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]([F:20])=[C:14]([F:13])[CH:15]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: NCc1ccc(F)c(F)c1
Solvent: C1CCOC1
Product: Nc1cc(C(=O)NCc2ccc(F)c(F)c2)ccc1F
Temperature: 25 °C

Procedure:
A mixture comprising methyl 3-amino-4-fluorobenzoate (2 g, 11.82 mmol), (3,4-difluorophenyl)methanamine (2.54 g, 17.74 mmol) and TBD (1.646 g, 11.82 mmol) in THF (39.4 ml) was heated at 80° C. overnight. After cooling to RT, the mixture was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM to afford the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:21])[C:9]([NH:31][C:28]2[CH:29]=[CH:30][N:26]([CH2:25][CH2:24][O:23][CH3:22])[N:27]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: COCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (60 mg, 0.21 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.031 g, 0.22 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.11 g, 0.25 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 70-100% ethyl acetate/hexanes) to give (S)-3-cyclohexyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (31 mg, 36%) as an off white solid: [α]28D=−69.7°, (c=0.31, chloroform); HR-ES(+) m/e calcd for C23H30N4O3 [M+H]+ 411.2391, observed 411.2389; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.84-1.24 (m, 7H) 1.47-1.99 (m, 2H) 3.18 (s, 4H) 3.49-5.29 (m, 8H) 6.36 (s, 1H) 7.31-7.89 (m, 7H) 10.83 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22](O)=[O:23])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:61]1[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][OH:69])[CH2:63][CH2:62]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:36])[N:5]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)[C:6](=[O:25])[N:7]2[CH2:21][C:22]([N:61]2[CH2:66][CH2:65][CH:64]([CH2:67][CH2:68][OH:69])[CH2:63][CH2:62]2)=[O:23])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: OCCC1CCNCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)N2CCC(CCO)CC2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (45 mg, 87 μmol; Example 21) was initially charged in DMF (1.5 ml), HATU (165 mg, 434 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. 4-Piperidinethanol (33.6 mg, 260 μmol, 3 eq.) and N,N-diisopropylethylamine (56 mg, 434 μmol, 5 eq.) were then added, and the mixture was stirred at RT for 16 h until complete conversion had been achieved (HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (26 mg, 48% of theory, purity about 80%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:10]([OH:19])[C:11]([NH:13][O:14][CH2:15][C:16]([OH:18])=O)=[O:12])=O)(C)(C)C.Cl.[CH2:28]([O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33])[CH3:29].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[NH2:8][C@H:9]([CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH:10]([OH:19])[C:11]([NH:13][O:14][CH2:15][C:16]([NH:33][C@@H:32]([CH3:34])[C:31]([O:30][CH2:28][CH3:29])=[O:35])=[O:18])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NOCC(=O)O
Reactant: CCOC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](C)NC(=O)CONC(=O)C(O)[C@H](N)CC1CCCCC1
Reaction time: 1 h

Procedure:
A solution of Example 118A (0.17 g, 0.45 mmol), L-alanine ethyl ester hydrochloride (0.098 g, 0.64 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.098 g, 0.51 mmol), 1-hydroxybenzotriazole (0.091 g, 0.67 mmol), and N-methylmorpholine (0.11 mL, 1.0 mmol) in dichloromethane (5 mL) at room temperature was stirred for 16 hours, diluted with dichloromethane, washed sequentially with 1 M HCl, aqueous NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in saturated HCl/dioxane (4 mL), stirred for 1 hour, concentrated, then purified by HPLC to provide the desired product.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>O1CCCC1>[CH3:23][S:20]([O:1][N:2]=[C:3]([C:11]#[N:12])[C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[CH:8][CH:9]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=NO)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)c1ccc(Br)cc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
α-(Methylsulfonyloxyimino)-4-bromobenzyl cyanide was prepared in the following manner. Thus, 81.0 g (0.36 mole) of α-hydroxyimino-4-bromobenzyl cyanide and a solution prepared by dissolving 44.0 g (0.43 mole) of triethylamine in 400 ml of tetrahydrofuran were introduced into a reaction vessel to form a uniform solution which was chilled to and kept at -5° C. Into the solution in the reaction vessel were added dropwise 49.0 g (0.43 mole) of mesyl chloride over a period of 2 hours under agitation. The reaction mixture in the vessel was agitated at -5° C. for 3 hours and then at about 10° C. for additional 2 hours. The reaction mixture was freed from tetrahydrofuran as the solvent by distillation under reduced pressure at 30° C. to give 103.0 g of a solid residue which was purified by repeating recrystallization from acetonitrile to give 81.8 g of a white crystalline product having a melting point of 128° C. which could be identified to be the target compound from the results of the analysis described below. The above mentioned yield of the product corresponds to 75.0% of the theoretical value.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15]C)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:28].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:17](=[O:19])[NH:24][C:25]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][C:26]=1[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])[CH2:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
19.7 g of N-carbobenzoxy-DL-norleucine are dissolved in 200 ml of absolute tetrahydrofuran, the solution is treated dropwise while cooling with ice with 10 g of thionyl chloride and then stirred for 1 hour. To this solution there is rapidly added dropwise a solution of 17 g (0.065 L M) of 2-amino-5-nitro-2'-fluorobenzophenone in 130 ml of absolute tetrahydrofuran and the mixture is then stirred at room temperature for 60 hours. The solution is concentrtated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried with sodium sulphate, filtered and concentrated. The residue is purified on a 450 g silica gel column using methylene chloride as the eluting agent and crystallised from ethanol. There is obtained benzyl-rac-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]butyl}carbamate which melts at 148°-150° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br>C(#N)C>[CH3:12][CH:11]([CH3:13])[CH2:10][C@H:2]([N:1]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4]
Reactant: BrCCOCCBr
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1CCOCC1
Temperature: 80 °C

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate (1.0042 g, 5.36 mmol), potassium carbonate (2.446 g, 17.69 mmol), and 1-bromo-2-(2-bromoethoxy)ethane (1.368 g, 5.90 mmol) were combined in acetonitrile (30 mL). The reaction was heated at 80° C. overnight. The reaction was cooled and filtered and the solvent removed in vacuo. The crude material was purified by silica gel chromatography using 5-50% ethyl acetate/hexanes to give (S)-tert-butyl 4-methyl-2-morpholinopentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.76-3.58 (m, 4H), 3.11 (dd, J=6.9, 8.1, 1H), 2.74-2.53 (m, 4H), 1.71-1.55 (m, 2H), 1.51-1.34 (m, 10H), 0.92 (dd, J=6.6, 7.3, 6H). (S)-tert-Butyl 4-methyl-2-morpholinopentanoate (0.637 g, 2.475 mmol) and 4 N hydrochloric acid in dioxane (5 mL) were combined. The reaction mixture was stirred at ambient temperature for 24 hours, then the solvent removed in vacuo to give (S)-4-methyl-2-morpholinopentanoic acid hydrochloride: MS (DCI+) m/z 202 (M+H)+.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16]>CCOCC>[Br:2][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 137.6 %

Procedure:
Under an argon atmosphere and cooling with ice, phosphorus tribromide (2.36 mL, 24.7 mmol) was added dropwise to a solution of (4-methoxy-3-nitrophenyl)methanol (12.2 g, 66.6 mmol) in anhydrous ether (350 mL) under stirring, and the mixture was stirred for 3.5 hours. Ice water (300 mL) was added to the reaction mixture. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by means of silica gel column chromatography (eluent: n-hexane:ethyl acetate=2:1→1:1 v/v) to afford 8.36 g (51%) of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]1([C@H:9]([NH2:31])[C:10]([N:12]2[CH2:16][C:15]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])=[CH:14][C@H:13]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:11])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:1][CH2:2][C:3]([NH:31][C@@H:9]([CH:6]1[CH2:8][CH2:7]1)[C:10]([N:12]1[CH2:16][C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:14][C@H:13]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:11])=[O:4]
Reactant: O=C(Br)CBr
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reaction time: 0.5 h

Procedure:
Bromoacetyl bromide (49 μL, 0.56 mmol, 1.1 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 181 mg, 0.511 mmol, 1 equiv) and N,N-diisopropylethylamine (107 μL, 0.613 mmol, 1.20 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was allowed to stir for 30 minutes. The reaction mixture was partitioned between water (70 mL) and dichloromethane (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-bromo-N-{(1S)-1-cyclopropyl-2-[(2S) (2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}acetamide (25-1) as a pink foam. LRMS m/z (M+H) 477.3 found, 477.1 required.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]1[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14](=[O:21])[C:13]=1[CH:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][C:26]#[C:27][CH2:28][OH:29]>C(OCC)(=O)C>[CH3:11][C:12]1[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14](=[O:21])[C:13]=1[CH:22]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][OH:29]
Reactant: CC1=C(C)C(=O)C(C(CCCC#CCO)c2ccccc2)=C(C)C1=O
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC1=C(C)C(=O)C(C(CCC/C=C\CO)c2ccccc2)=C(C)C1=O
Yield: 93.6 %

Procedure:
Rindler catalyst (90 mg) and quinoline (15 μl) were added to a solution of 7-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)-7-phenyl-2-heptyn-1-ol (1.01 g, 3.0 mmole) in ethyl acetate (20 ml), and catalytic reduction was carried out at room temperature. 3 Hours later, when absorption (73 ml) of hydrogen was almost stopped, the reaction was suspended and the catalyst was filtered out. The ethyl acetate was distilled off under reduced pressure, and the residue was chromatographed on a silica gel column to elute with isopropayl ether to give (Z)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenyl-2-hepten-1-ol (0.95 g, 94%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([NH:20][NH2:21])=[O:19].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:21][NH:20][C:18](=[O:19])[C:17]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=3)=[O:13])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNC(=O)c1cc2nc(Cl)ccc2[nH]1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 5, 20.0 mg, 0.10 mmol) in DMF (5 mL) was added 3,4-dichlorobenzoic acid hydrazide (23 mg, 0.11 mmol), DIPEA (19.5 μL, 0.11 mmol) and HOBt (14.0 mg, 0.10 mmol). The resulting solution was stirred for 5 min prior to the addition of EDCI (23 mg, 1.20 mmol). The reaction mixture was stirred for 16 hr at rt then partitioned between water (10 mL) and dichloromethane (20 mL) on a hydrophobic frit. The aqueous phase was extracted with a further portion of dichloromethane (30 mL) and the combined organics were concentrated in vacuo. Trituration of the resulting residue with ethyl acetate/dichloromethane gave the title compound. δH (d6 DMSO): 12.25 (1H, s), 10.83 (2H, d), 8.17 (1H, s), 7.55-7.97 (3H, m), 7.38 (1H, s), 7.26 (1H, d); m/z (ES+)=383 [M+H]+; RT=3.37 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:12][C:5]2[S:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[C:3]1=[O:13].[F:15][C:16]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][C:17]=1[NH2:18].N1C=CC=CC=1>C(Cl)Cl>[F:15][C:16]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:28])([CH3:29])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][C:17]=1[NH:18][C:9]([C:7]1[S:6][C:5]2[CH2:12][C:2]([CH3:1])([CH3:14])[C:3](=[O:13])[C:4]=2[CH:8]=1)=[O:11]
Reactant: CC1(C)Cc2sc(C(=O)O)cc2C1=O
Reactant: CC1(C)OB(c2ccc(F)c(N)c2)OC1(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)Cc2sc(C(=O)Nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)cc2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 9 (270 mg, 1.29 mmol) and methylene chloride (3 mL). The solution Was cooled to 0° C., and 15 (172 mg, 1.29 mmol) was added dropwise. After this addition was complete, the reaction was warmed to room temperature and stirred for 2 h. 14 (305 mg, 1.29 mmol) was then added. After this addition, the reaction was cooled to 0° C., and anhydrous pyridine (306 mg, 3.87 mmol) was added. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 16 h. After this time, the solvents were removed under reduced pressure, and the resulting residue was partitioned between water (10 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×10 mL). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 27 in 45% yield (235 mg) as a white solid: mp 88-89° C.; 1H NMR (500 MHz, CDCl3) δ 8.73 (d, J=8.5 Hz), 7.87 (s, 1H), 7.62 (s, 1H), 7.56 (t, 1H, J=6.5 Hz), 7.14 (dd, 1H, J=11.0, 8.5 Hz), 3.11 (s, 2H) 1.38 (s, 12H), 1.33 (s, 6H); MS (APCI+) m/z 430.3 (M+H).