Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH3:9]O.Cl>>[OH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([O:6][CH3:9])=[O:5]
Reactant: CO
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: COC(=O)CC(C)(C)O
Reaction time: 8 h

Procedure:
In 50 ml of 7 wt. % hydrochloric acid methanol solution was dissolved 1.18 g of β-hydroxyisovaleric acid, and an reaction was allowed to proceed at room temperature overnight. The solvent was removed from the solution as reacted by distillation under a reduced pressure to obtain 1.30 g of crude methyl β-hydroxyisovalerate. The crude methyl β-hydroxyisovalerate was dissolved in diethyl ether, and 0.91 g of 3,4-dihydro-2H-pyran and a catalytic amount of p-toluenesulfonic acid were added thereto. Stirring was continued at room temperature overnight for reaction. The resultant reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water and dried over magnesium sulfate. The solvent was removed from the dried reaction mixture by distillation under a reduced pressure to obtain 1.98 g of crude methyl β-dihydropyranyloxyisovalerate.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[Cl:12][S:13]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:8][C:9]([NH2:11])=[O:10])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: NC(=O)COc1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of phenoxyacetamide (50 g, 0.333 mol) in dichloromethane (500 mL) was added dropwise chlorosulfonic acid (174.7 g, 1.5 mol) at 0° C. at such a rate to maintain internal temperature between 0 to +5° C. (about 45 min). Some solid formed during this addition. The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The lower layer in the reaction mixture was added into a vigorously stirring mixture of water (500 mL) and crushed-ice (1500 g). The solid was collected, washed with water (750 mL), and pressed well with a rubber dam. The solid was suspended in acetone (100 mL), stirred for 30 min and collected. After drying, the title compound was isolated as a white solid, weighed 67.3 g (81%).
Reaction SMILES: C1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.CI.[Mg].[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1.[Co+3:23].C/C(/[O-])=C/C(C)=O>C1COCC1>[CH:7]1[CH2:12][CH:13]=[CH:14][CH:5]=1.[CH:19]1([Co:23])[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: c1ccc2cc3ccccc3cc2c1
Reactant: [Co+3]
Agent: C1=CCC=C1
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: [Co]C1C=CC=C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.1 g (6.2 mMoles) of anthracene, 300 ml of THF and 0.1 ml of methyliodide are added with stirring in an inert gas atmosphere at 20° C. to 7.2 g (300 mMoles) of magnesium powder (particle size <0.15 mm). After about 2 hours, the reaction mixture is activated for about 3 hours in an ultrasonic bath (cf. Example 1). The mixture is then heated with stirring to 60° C. After the addition of 52.8 g (800 mMoles) of monomeric cyclopentadiene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III)-acetylacetonate are added over a period of 30 minutes, the reaction mixture changing color to deep red-brown with a vigorous heat effect (65° C.). After cooling to 23° C., the reaction mixture is filtered off from any insoluble fractions through a G-3-glass frit and the deep red-brown filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr). The residue is taken up in 500 ml of pentane and any insoluble fractions eliminated by filtration. The clear deep red filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr) and the residue sublimated at 10-3Torr (bath temperature up to 60° C., sublimation beginning at a bath temperature of 30° C.). The sublimate is dissolved in approximately 100 ml of pentane and the complex crystallized out at -80° C. 11.9 g (62.6 mMoles=62.6% of the theoretical) of η5 -cyclopentadienyl cobalt cyclopentadiene are obtained in the form of wine-red crystals melting at 98° to 99° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:11]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH2:12])=[CH2:10])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2:30].[Na+].[Na+]>C(O)C>[CH2:16]([O:15][P:13]([CH:11]1[CH:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][S:30][CH2:12]1)([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: C=C(C(=C)P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(OCC)C1CSCC1P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.3 %

Procedure:
In ethanol, 2.02 g (6.19 mmols) of 2,3-bis(diethoxyphosphoryl)-1,3-butadiene was dissolved, to which 1.63 g (6.81 mmols) of commercially available sodium sulfide nonahydrate was added, followed by stirring at room temperature for 3 days. After completion of the reaction, the reaction mixture was dried over anhydrous sodium sulfate for 1 hour. Ethyl acetate was added to and the resulting mixture was charged into a silica gel column to dissolve out the specified substance with ethyl acetate. Thereafter, the solvent was removed, and the resulting crude product was purified with a silica gel column (ethyl acetate:chloroform=1:2) to obtain the specified substance in the form of a yellow oil at a yield of 1.88 g (yield: 84.3%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([O:41][C:42]([NH:44][C@@H:45]([CH2:50][C:51]#[CH:52])[C:46]([O:48][CH3:49])=[O:47])=[O:43])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[CH3:31])=[CH:22][C:21]([C:52]#[C:51][CH2:50][C@H:45]([NH:44][C:42]([O:41][C:38]([CH3:40])([CH3:39])[CH3:37])=[O:43])[C:46]([O:48][CH3:49])=[O:47])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)NC(C)C
Product: COC(=O)[C@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Yield: 55.2 %

Procedure:
A solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO2005/002577 intermediate 4D, 1 g, 1.877 mmol), methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 1, 1.279 g, 5.63 mmol), Pd(PPh3)2Cl2 (0.066 g, 0.094 mmol), copper(I) iodide (0.018 g, 0.094 mmol), triphenylphosphine (0.049 g, 0.188 mmol) in triethylamine (2 ml)/diisopropylamine (8 ml) was heated at 100° C. under microwave irradiation for 30 mins. The solvents were evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a column 40+M and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluent to afford the title compound (750 mg, 1.036 mmol, 55.2% yield) as a white solid. UPLC: Rt 1.02 min, m/z 724 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10]O)[C:6]=2[CH:12]=1.S(Cl)([Cl:15])=O>C(Cl)Cl.CN(C)C=O>[Cl:15][CH2:10][C:7]1[C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: OCc1coc2ccc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc2occ(CCl)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 mL) was treated successively with 5 drops of dimethylformamide and thionyl chloride (28 mL). After stirring for 16 h at room temperature the reaction was concentrated in vacuo giving 3-chloromethyl-5-fluorobenzofuran as an oil (19.4 g).
Reaction SMILES: [CH3:1][C@@H:2]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:4]([O:6]N1C(=O)CCC1=O)=O.[NH2:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:3]([C:4]([NH:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:6])[C@@H:2]([CH3:1])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
20.2 g of Z-Thr(tBu)-OSU, 13.3 g of H-Phe-Pro-OH (monohydrate) and 6.54 ml of triethylamine are dissolved in 80 ml of dimethylformamide, allowed to stand overnight at about 20°C and then concentrated in a high vacuum until a sticky mass forms. The latter is dissolved in 500 ml of ethyl acetate and washed five times with 100 ml at a time of 5 % strength tartaric acid solution and subsequently with water until neutral. The organic phase is concentrated to dryness and the remaining solid foam is powdered and dried in a high vacuum at 40°C. On twice reprecipitating from ethyl acetate-peptroleum ether 13.3 g of amorphous chromatographically pure tripeptide derivative having an unsharp melting range at about 75°-85°C are obtained. In a thin layer chromatogram on silica gel RF115 = 0.68; Rf121A = 0.57.
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1C=CC=C[CH:21]=1.[Cl-].[Mg+2].[Cl-].C([Mg]Br)C>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH2:20][CH3:21]
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Yield: 28 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]-octane prepared from 1.76 g of (S)-2-(anilinomethyl)pyrrolidine, as described in Example 8, was dissolved in 50 ml of THF, then admixed with 1.05 g of anhydrous magnesium chloride and refluxed by heating for 10 minutes. To the mixture cooled to -70° C., was added dropwise an ether solution containing 1.46 equivalents of ethylmagnesium bromide. The resulting mixture was treated as described in Example 12 to obtain 694 mg (28%) of 2-propionyl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ (ppm)=1.0 (3H, triplet), 1.4-2.1 (4H, multiplet), 2.1-2.6 (2H, multiplet), 2.6-3.3 (3H, multiplet), 3.5-3.9 (2H, multiplet), 4.2 (1H, singlet), 6.1-7.1 (5H, multiplet).
Reaction SMILES: C(N(CC)CC)C.ClS(NC(=O)OC)(=O)=O.[NH2:17][C:18](=O)[C@@H:19]([NH:28][C:29]([C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[CH2:20][C:21]1[CH:22]=[N:23][C:24]([Br:27])=[CH:25][CH:26]=1>C(Cl)Cl>[Br:27][C:24]1[N:23]=[CH:22][C:21]([CH2:20][C@H:19]([NH:28][C:29]([C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[C:18]#[N:17])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Agent: COC(=O)NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
Triethylamine (3.46 mL) in DCM (5 mL) was stirred under nitrogen and to the solution was added a solution of methyl chlorosulfonylcarbamate (1.658 g) in DCM (5 mL). The mixture was stirred at room temperature for 15 min then a solution of (S)-tert-butyl 2-((S)-1-amino-3-(6-bromopyridin-3-yl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (1.74 g) in DCM (5 mL) was added. Stirring was continued overnight. The reaction mixture was washed with water then brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude product was purified by flash silica chromatography eluting with 40% ethyl acetate in isohexane to give the title compound (1.2 g) as a white solid.
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl>ClCCl.C(O)CCC>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([NH:23][S:14]([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][CH2:13][NH:4][CH2:5]3)=[CH:10][CH:9]=2)(=[O:15])=[O:16])[CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCO
Product: O=S(=O)(Nc1cccc(C(F)(F)F)c1)c1ccc2c(c1)CNCC2

Procedure:
2-Acetyl-7-chlorosulphonyl-1,2,3,4-tetrahydroisoquinoline was reacted with 3-trifluoromethylaniline in dichloromethane according to the method generally described in EP No. 0038177-A. The resulting product was deacetylated by heating with aqueous hydrochloric acid in butanol to give 7-(3-trifluoromethylphenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([CH3:23])[CH:3]=1.Cl[S:25]([OH:28])(=[O:27])=[O:26]>C(Cl)Cl>[CH2:21]([O:20][C:18]([C:10]1[CH:11]=[N:12][C:13]2[N:14]([N:15]=[CH:16][C:17]=2[S:25]([OH:28])(=[O:27])=[O:26])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:23])=[O:19])[CH3:22]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(F)cc1C
Solvent: ClCCl
Product: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
Ethyl 7-(4-fluoro-2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (0.500 g, 1.59 mmol) obtained in step 1 was dissolved in methylene chloride (6 mL), chlorosulfonic acid (0.21 mL, 3.19 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, a 1/1 mixed solvent of diisopropyl ether and 2-propanol was added, and the mixture was stirred at room temperature for 1 hr. The resulting crystals were suction filtered and washed with 2-propanol to give the title compound (0.580 g, 92%). ESI-MS m/z: 395 (M+H)+; 1H-NMR (CDCl3, δ): 1.13 (t, J=7.2 Hz, 3H), 2.29 (s, 3H), 3.94 (q, J=7.2 Hz, 2H), 6.96-7.46 (m, 4H), 8.28 (s, 1H), 8.50 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]C(=O)N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOC(C)=O.C(#[N:25])C.CC(OI(OC(C)=O)C1C=CC=CC=1)=O>O>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][NH2:25]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Temperature: 16 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A slurry of N-Boc-L-asparagine (5.00 g, 21.5 mmol), EtOAc (24 mL), acetonitrile (24 mL), water (12 mL), and PIDA (8.32 g, 25.8 mmol) was cooled and stirred at 16° C. for 30 min. The temperature was then allowed to reach 20° C., and the reaction was stirred until completion (ca. 4 h). The mixture was cooled to 0° C. and filtered. The filter cake was washed with EtOAc (10 mL) and dried in vacuo to give 1 (2.73 g, 62% yield). 1H NMR (CD3OD and a drop of TFA) δ4.05 (1H), 3.20-3.08 (2H), 1.45 (9H).
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11](=[O:43])[C@@H:12]([C@@H:39]([CH2:41][CH3:42])[CH3:40])[NH:13][C:14](=[O:38])[C@H:15]([CH:27](CC1C=CC=CC=1)[C:28](=[O:30])[OH:29])[NH:16]C(OCC1C=CC=CC=1)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]>CO.O.[Pd].[C]>[CH2:1]([C@H:3]([NH:10][C:11](=[O:43])[C@@H:12]([C@@H:39]([CH2:41][CH3:42])[CH3:40])[NH:13][C:14](=[O:38])[C@H:15]([CH2:27][C:28](=[O:29])[OH:30])[NH2:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)[C@H](C)CC)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC[C@H](NC(=O)[C@H](NC(=O)[C@@H](N)CC(=O)O)[C@H](C)CC)c1ccccc1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of 2.81 g (4.7 mmols) of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide in 150 ml of methanol and 50 ml of water was added 2.0 g of 10% Pd-carbon (water content 50%). The mixture was reduced under hydrogen at room temperature for 5 hours. The catalyst was removed by filtration, and the resulting filtrate was concentrated under reduced pressure to be 20 ml. The crystals thus precipitated were taken out by filtration and dried to obtain 1.22 g (3.4 mmols) of α-L-aspartyl-D-isoleucine (S)-α-ethylbenzylamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:18])[CH3:17])[CH:10]([C:25](=O)[NH:26][CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:42]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH:15]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:16]([CH3:17])[CH3:18])[CH:10]([C:25]2[NH:26][CH:27]=[C:28]([C:30]3[CH:31]=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=3)[N:42]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (2.0 g, 3.43 mmol) was dissolved in m-xylenes (18 mL) and heated at 135° C. Solid ammonium acetate (1.70 g, 22.0 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w MeOH 10%/hexanes) to yield the product 3-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxycarbonylamino-3-methyl-butyryl)-piperazine-1-carboxylic acid tert-butyl ester (674 mg, 1.19 mmol): LCMS-ESI+: calc'd for C25H34BrN5O5: 564.5 (M+). Found: 564.2/566.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].B([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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:7]([C:6]1[CH:9]=[C:2]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=2)[CH:3]=[N:4][CH:5]=1)#[N:8]
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)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: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
5-bromonicotinonitrile (8.8 g, 48.08 mmol), 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b) (11.50 g, 52.89 mmol) and K2CO3 (13.3 g, 96.16 mmol were dissolved in a mixture of DME (120 mL) and water (30 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (2.7 g, 2.40 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aq. 0.5 N NaOH (100 mL) and stirred for about 30 min., and then the mixture was extracted with ether (30 mL×3) The aqueous layer was cooled to 0° C., acidified with 2 N HCl, and then extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 9.4 g of 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid as a white solid in 73% yield.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C1C=CC=CN=1)C>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[CH2:10][C@@H:9]([OH:18])[C@@H:8]([NH:19][C:20](=[O:30])[O:21][C@@H:22]3[C@H:29]4[C@H:25]([O:26][CH2:27][CH2:28]4)[O:24][CH2:23]3)[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
A mixture of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (0.100 g, 0.237 mmol), 1,3-benzodioxole-5-sulfonyl chloride (52 mg, 0.237 mmol), diisoproylethylamine (0.042 mL, 0.237 mmol) and dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature over 16 hours under an Argon atmosphere. The reaction was evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous hydrochloric acid (1N). The organic phase was separated and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 uM) eluting with 97:3 dichloromethane:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (114 mg, 80%) as a white solid. H1-NMR (chloroform-D3): 0.89 (m, 6H), 1.57 (m, 7H), 2.95 (m, 5H), 3.69 (m, 2H), 3.89 (m, 4H), 4.15 (m, 1H), 4.82 (d, 1H), 5.01 (m, 1H), 5.64 (d, 1H), 6.10 (s, 2H), 6.90 (d, 1H), 7.23 (m, 6H), 7.39 (m, 1H). MS(ESI): 629(M+Na).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].Cl[CH2:15]Cl>>[CH2:15]1[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3]1.[CH3:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:1]
Reactant: ClCCl
Agent: C=C(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: c1ccc2c(c1)CCC2

Procedure:
Alpha-methylstyrene (AMS) (2.0 L, 15.4 mole) is added slowly with stirring over 2 to 3 hours to a mixture of AlCl3 (0.7 g, 5.2 mmole) and dichloromethane (1.0 L, dried over 3 Å molecular sieves) in 4 L beaker, in a drybox at room temperature. After the addition of 1 L AMS, about 0.2 L dichloromethane is added to make up for the solvent evaporated due to the reaction exotherm. After the addition of all AMS, the reaction mixture is deactivated with 0.3 L methanol, washed three times with water, dried over calcium chloride, filtered and volatiles stripped first using a rotary evaporator and then high vacuum.