Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC(N(C)C)=O.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]>[F:19][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])=[N:7][C:2]([N:28]2[CH2:29][CH:26]([O:25][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:31][CH:30]=3)[CH2:27]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(OC2CNC2)cc1
Reactant: CNC(=O)c1cccc(Nc2nc(Cl)ncc2F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cccc(Nc2nc(N3CC(Oc4ccc(F)cc4)C3)ncc2F)c1
Temperature: 100 °C
Yield: 13.2 %

Procedure:
To a solution of 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-N-methylbenzamide (500 mg, 1.78 mmoL) and 3-(4-fluorophenoxy)azetidine (298 mg, 1.78 mmol) in DMA (6 mL, 3 mL/mmoL) was added cesium carbonate (580 mg, 2.67 mmol) and the reaction was degassed for 15 min. Pd2(dba)3 (80 mg, 0.089 mmol) and BINAP (55 mg, 0.089 mmol) and the reaction was allowed to heat at 100° C. in the microwave. The reaction was quenched with water and extracted with EtOAc (2×25 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure then purified by silica gel column chromatography to give 3-((5-fluoro-2-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-yl)amino)-N-methylbenzamide (97 mg, 15%) as solid. Observed mass (M+1): 412.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2.OO.[Br:19]Br>CO>[Br:19][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: BrBr
Reactant: COC(=O)c1cccc2cc(OC)ccc12
Agent: OO
Solvent: CO
Product: COC(=O)c1cccc2c(Br)c(OC)ccc12
Temperature: 70 °C
Yield: 166.8 %

Procedure:
108 g (0.50 mol) of methyl 6-methoxy-1-naphthoate are dissolved in 2500 ml of methanol, and 30 g of 35% hydrogen peroxide solution are added. 42 g (0.26 mol) of bromine are then added dropwise at 35° C. in the course of 60 minutes. The mixture is subsequently heated at 70° C. When the reaction has ended, the mixture is concentrated in vacuo to a total volume of approximately 500 ml, allowed to cool to 20° C. and subjected to filtration with suction, and the filter cake is washed with methanol and water. Drying in vacuo at 60° C. gives 128.0 g of methyl 5-bromo-6-methoxy-1-naphthoate in the form of fine white needles.
Reaction SMILES: [CH3:1][Si](N([Li])[Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:15]([F:26])=[CH:14][N:13]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][C:21](=[CH2:1])[CH2:20]2)[C:15]([F:26])=[CH:14][N:13]=1
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (0.86 g, 2.40 mmol) in THF (100 mL) in a flamed dry flask was added (bis(trimethylsilyl)amino)lithium (2.40 mL of 1 M solution, 2.40 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 1 hr. A solution of (S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanone, 29b, (0.48 g, 2.00 mmol) in 20 mL of THF was added. The reaction was allowed to stir at room temperature for 2 hrs. The mixture was quenched by pouring into brine and the aqueous phase was extracted with EtOAc. The layers were separated and the organic was dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 270 mg of the desired product: LCMS RT: 3.83 min, (M+1): 242.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18](I)=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[C:32]#[CH:33].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]#[C:32][C:26]3[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=3[Cl:24])=[C:17]([O:22][CH3:23])[CH:16]=2)[N:10]=1
Reactant: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1I
Reactant: C#Cc1cc(Cl)ccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C#Cc1cc(Cl)ccc1Cl
Yield: 18.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 3-(2-chloro-6-fluorophenyl)-1-(4-iodo-3-methoxyphenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-32, 0.050 g, 0.11 mmol), 1,4-dichloro-2-ethynylbenzene (Intermediate-23, 0.029 g, 0.16 mmol), TBAF (0.101 g, 0.33 mmol), bis(triphenylphosphine)palladium(IT) chloride (0.005 g, 0.04 mmol) and DMSO (3.0 mL) at 80° C. to afford 0.010 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.89 (s, 3H), 7.49-7.56 (m, 3H), 7.59-7.73 (m, 6H), 12.90 (br s, 1H); MS (m/z): 487.95 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C@@:4]12[C@@H:19](O)[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3].C(N(S(F)(F)[F:33])CC)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][CH:2]([C@@:4]12[C@H:19]([F:33])[C@:18]34[O:21][C@H:17]3[CH2:16][C@@H:15]3[C@:10]([CH3:26])([CH2:11][CH2:12][C:13]5[C:24](=[O:25])[O:23][CH2:22][C:14]=53)[C@:8]34[O:9][C@H:7]3[C@@H:5]1[O:6]2)[CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@@H]2O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@]12O[C@H]1[C@@H]1O[C@]13[C@]1(O[C@H]1C[C@H]1C4=C(CC[C@@]13C)C(=O)OC4)[C@H]2F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of PG490 (triptolide, 17.3 mg, 0.048 mmol) in dichloromethane (1.0 ml) at 0° C. was added (diethylamino)sulfur trifluoride (DAST, 100 μl, 0.763 mmol) under N2. The reaction mixture was stirred at 0° C. for 2 hrs, and saturated NaHCO3 solution (0.8 ml) was then added. The reaction mixture was extracted with 3×2 ml of dichloromethane. The combined organic layer was dried over anhydrous NaSO4 and concentrated under vacuum. The desired product (PG763) was obtained in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12].O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Commercially available 4-hydroxybenzaldehyde (17.8 g, 0.15 mol) was dissolved in dry pyridine (100 ml) and to the solution was dropwise added under cooling, octyl chloroformate (25 g, 0.13 mol), followed by agitating the mixture at 50°-60° C. for about 2 hours, adding water and toluene thereto, sufficiently agitating the mixture, washing the separated toluene layer with 6N-HCl, then 2N-NaOH aqueous solution and further with water until the washing water became neutral, drying the layer with anhydrous sodium sulfate and distilling off toluene to obtain 4-octyloxycarbonyloxybenzaldehyde (33 g, 0.12 mol), dissolving this compound (33 g, 0.12 mol) in acetic acid (90 ml), dropwise adding to the solution, a solution of chromium oxide (25.2 g, 0.25 mol) dissolved in acetic acid (30 ml) and water (20 ml), at about 20° C., heating the mixture up to 40° C., keeping it for 8 hours, placing water therein, filtering off deposited crystals, washing with water and recrystallizing from ethanol to obtain 4-octyloxycarbonyloxybenzoic acid (31 g), adding thereto thionyl chloride (20 g), refluxing the mixture for about 2 hours, and removing excess thionyl chloride under reduced pressure to obtain 4-octyloxycarbonyloxybenzoic chloride (30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: O=[N+]([O-])c1cccnc1N1CCC(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Yield: 99.9 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 2-chloro-3-nitropyridine (97 mg, 0.61 mmol) to afford the title compound (212 mg), a yellow solid, in 74% yield.
Reaction SMILES: [Br:1]Cl.C(=O)=O.[CH2:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].C1(C=CC=C(O)C=1)O>S(=O)=O>[CH2:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([CH3:9])[CH3:8].[Br:1][C:13]1[CH:14]=[CH:15][C:10]([CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=1
Reactant: ClBr
Agent: O=C=O
Agent: O=S=O
Agent: Oc1cccc(O)c1
Solvent: CC(C)Cc1ccccc1
Product: CC(C)Cc1ccc(Br)cc1
Yield: 83 %

Procedure:
Bromine chloride (Dow, 1.12 g, 9.7 milliMoles) is condensed in a tube using Dry Ice cooling, then it is diluted with 20 ml of liquid sulfur dioxide and the resultant solution is cooled to -72° C. Isobutylbenzene (1.57 ml, 10.0 milliMoles) is added, and the resultant mixture is stirred at -70° for 65 minutes before quenched with 1.2 grams (10.9 milliMoles) of resorcinol. Workup and analysis as above gives 8% isobutylbenzene, 6% ortho-, and 83% para-bromoiso-butylbenzene. This result indicates that the bromination with bromine chloride is faster than that with molecular bromine, and the extent of ortho-bromination is somewhat higher.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([OH:14])=O)=[CH:3]1.[CH2:16]([NH2:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:15])[C:12]([NH:24][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:14])=[CH:3]1
Reactant: Cn1cc(C(=O)C(=O)O)c2ccccc21
Reactant: NCCc1ccccc1
Solvent: CC#N
Product: Cn1cc(C(=O)C(=O)NCCc2ccccc2)c2ccccc21

Procedure:
2-(1-Methyl-1H-indol-3-yl)-2-oxo-N-phenethyl-acetamide was synthesized following scheme II above starting from (1-methyl-1H-indol-3-yl)-oxo-acetic acid and phenethylamine. Yield (61%). HPLC ret. time 3.38 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 8.80 (t, J=5.9 Hz, 1H), 8.73 (s, 1H), 8.25 (m, 1H), 7.60 (m, 1H), 7.36-7.20 (m, 7H), 3.91 (s, 3H), 3.47 (m, 2H), 2.86 (t, J=7.4 Hz, 2H); ESI-MS 307.3 m/z (MH+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH4+].[OH-]>C(O)C.[Ni].O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH2:29])[CH2:20][CH2:21]2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Yield: 105.7 %

Procedure:
4-(2-Cyanophenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (˜5.3 mmol) was dissolved in 50 mL of ethanol. 5 mL of aqueous NH4OH was added along with 500 mg of 50% Raney nickel in water. The reaction mixture was hydrogenated in a Parr shaker at 45 psi overnight. The reaction mixture was filtered through a plug of Celite and concentrated under vacuum. 2.5 g of crude product was obtained, and used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:39]1[CH2:40][CH2:41][N:42]([C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])[CH2:43][CH:44]=1)(=O)=O>COCCOC.C(=O)(O)[O-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:46])[CH2:41][CH:40]=2)=[CH:19][CH:18]=1)=[O:32])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2=CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (8.0 g, 6.92 mmol) was added to a stirred suspension of N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)benzamide (288 g, 657 mmol; prepared as described in International Patent Publication number WO 03/087057, Method 13, page 60) and benzyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (240 g, 657 mmol; prepared as described in Method 3 below) in 1,2-dimethoxyethane (3000 ml) and saturated aqueous sodium bicarbonate solution (3000 ml). The reaction mixture was heated to 80° C. for 7 h, before being allowed to cool to ambient temperature, with stirring. The reaction mixture was then poured onto water (2000 ml) and extracted with ethyl acetate. The organic extracts were then dried over magnesium sulfate, filtered and evaporated to dryness to give the crude product as a grey solid. This was purified by flash column chromatography on silica, eluting with ethyl acetate/hexane (30:70 v/v) to afford the title compound (279 g, 82%); NMR Spectrum: (DMSO-d6) δ 1.44 (s, 9H), 2.56 (m, 2H), 3.66 (m, 2H), 4.14 (m, 2H), 5.13 (s, 2H), 6.34 (m, 1H), 7.18 (m, 2H), 7.33 (m, 1H), 7.40 (m, 4H), 7.54 (m, 2H), 7.62 (d, 2H), 7.94 (d, 2H), 8.64 (br s, 1H), 9.81 (br s, 1H); Mass Spectrum: MNa+ 550.
Reaction SMILES: C(OC([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27]CC=C)=[O:26])[CH2:9][C@H:8]1[CH2:31][O:32][CH2:33][C:34]([NH:36][C:37]([NH2:39])=[O:38])=[O:35])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCOCC1.C(O)=O>O1CCCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].C(OCC)(=O)C>[OH:23][C@@H:21]([C@H:17]1[C:16](=[O:24])[N:15]2[C@@H:18]1[C@@H:19]([CH3:20])[C:13]([S:12][C@@H:10]1[CH2:11][NH:7][C@H:8]([CH2:31][O:32][CH2:33][C:34]([NH:36][C:37]([NH2:39])=[O:38])=[O:35])[CH2:9]1)=[C:14]2[C:25]([OH:27])=[O:26])[CH3:22]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCC(=O)NC(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: O=CO
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](COCC(=O)NC(N)=O)C3)[C@H](C)[C@H]12
Yield: 50.1 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-{(ureidocarbonylmethyl)oxymethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.23 g) in a mixture of tetrahydrofuran (11.5 ml) and water (2.3 ml) were added triphenylphosphine (23 mg), morpholine (0.12 ml), formic acid (0.05 ml), and tetrakis(triphenylphosphine)palladium(O) (26 mg) successively with stirring under ice-cooling. The mixture was stirred at the same temperature for 1 hour and at ambient temperature for 2 hours, and poured into a mixture of ethyl acetate (50 ml) and water (50 ml). The aqueous layef was separated and washed 2 times with ethyl acetate (50 ml). This aqueous layer was concentrated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin, "Diaion HP-20" (made by Mitsubishi Chemical Industries) (10 ml), eluting in turn with water, and a mixture of acetone and water (5:95 V/V). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo 3-[(2S,4S)-2-{(ureidocarbonylmethyl)oxymethyl}pyrrolidin-4-yl]thio-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.09 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11]CC)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].ClC1C=C(C(O)=O)NC=1C>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cc(Br)c(CC)[nH]1
Agent: Cc1[nH]c(C(=O)O)cc1Cl
Product: CCc1[nH]c(C(=O)O)cc1Br

Procedure:
This intermediate was synthesized from ethyl 4-bromo-5-ethyl-1H-pyrrole-2-carboxylate (Intermediate 11) by an analogous method to Intermediate 8.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:18]=[CH:17][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[C:8]([O:19][CH3:20])[CH:7]=2)[CH2:2]1.[C:21]1([C:27]2[O:31][C:30]([C:32](OCC)=[O:33])=[N:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCO>[CH3:20][O:19][C:8]1[CH:7]=[C:6]([O:5][CH:3]2[CH2:4][N:1]([C:32]([C:30]3[O:31][C:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:28][N:29]=3)=[O:33])[CH2:2]2)[CH:18]=[CH:17][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Reactant: COc1cc(OC2CNC2)ccc1CN1CCOCC1
Solvent: CCO
Product: COc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CCOCC1
Temperature: 120 °C
Yield: 44.4 %

Procedure:
A mixture of 7C (0.25 g, 0.90 mmol), ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.22 g, 1.00 mmol) and EtOH (2 mL) was heated in a microwave oven at 120° C. for 60 min. The mixture was left over-night at RT. The formed precipitate was isolated by filtration and then washed with EtOH. There was obtained 0.18 g (45%) of 7 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.33-2.66 (m, 4H), 3.50 (s, 2H), 3.65-3.78 (m, 4H), 3.81 (s, 3H), 4.29-4.39 (m, 1H), 4.59-4.70 (m, 1H), 4.72-4.80 (m, 1H), 5.02-5.19 (m, 2H), 6.25 (d, 1H), 6.42 (s, 1H), 7.26 (s, 1H), 7.50-7.63 (m, 3H), 8.13-8.20 (m, 2H), MS (APCI+) m/z 451 [M+H]+, LC purity: 99%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>>[CH:19]([C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=1)=[O:20]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: O=Cc1cccc(Br)c1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C=O)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.54 mmol) and 3-bromobenzaldehyde (0.09 mL, 0.62 mmol) according to the general procedure IC to give 93 mg (59%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.16 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 10.01 (s, 1H), 8.02 (s, 1H), 7.84-7.74 (m, 2H), 7.54-7.46 (m, 3H), 7.26-7.19 (m, 2H), 3.67 (s, 3H), 3.00-2.95 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 191.6, 173.0, 141.4, 137.0, 136.5, 132.9, 131.8, 129.1, 128.8, 128.4, 124.6, 120.6, 90.9, 87.6, 51.6, 35.3, 30.8; EI-MS m/z 292 (M+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:43])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[CH2:35][O:36]C2CCCCO2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[O:33][N:32]=[C:31]([CH3:34])[C:30]=4[CH2:35][OH:36])[CH:24]=3)[CH2:20][C:19](=[O:43])[NH:18][C:9]=2[CH:10]=1
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)c1CO

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M32) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](O)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].Cl.C(N=C=NCCCN(C)C)C.N1C2C(=NC=CC=2)N(O)N=1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 40 mg (93 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic acid (Example 35) and ethyl 2-aminoacetate hydrochloride (14 mg, 102 μmol) in DMF (0.31 mL) was treated at 0° C. with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (27 mg, 139 μmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (19 mg, 139 μmol), and sodium hydrogencarbonate (23 mg, 278 μmol), successively. After being stirred at 25° C. for 12 h, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were successively washed with 10% aq. citric acid solution, sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 40% to 60% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless film.