Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:12]=2)[CH:3]=1
Reactant: C1CCNC1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Cl)cc1Oc1cccc(CN2CCCC2)c1
Yield: 35 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), pyrrolidine (0.14 mL, 0.12 g, 1.7 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 5 days. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[3-(pyrrolidin-1-ylmethyl)phenoxy]benzonitrile fumarate (117 mg, 35%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I>C1COCC1>[F:13][C:14]1[C:19]([I:24])=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1nc(C(F)(F)F)ccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of N,N-diisopropylamine (1.4 mL, 10.0 mmol) in anhydrous THF (15 mL) is cooled under N2 to −78° C. and nBuLi (2.5 M in hexanes, 4.0 mL, 10.0 mmol) is added dropwise at a rate to maintain the temperature below −65° C. A solution of 2-fluoro-6-(trifluoromethyl)pyridine (1.65 g, 10.0 mmol) in anhydrous THF (15 mL) is added dropwise over 10 min and the resulting orange solution is stirred for 2 h at −78° C. Iodine (2.54 g, 10.0 mmol) in anhydrous THF (12.5 mL) is then added dropwise over 15 min (keeping the temperature under −65° C.), causing the colour of the solution to change to red-brown and a precipitate to form. After 30 min the mixture is allowed to warm to 10° C. and the solvent is evaporated under reduced pressure. The residue is diluted with diethyl ether (25 mL) and washed with Na2S2O3 (2 M aq., 10 mL), HCl (2 M aq., 2×12.5 mL), NaHCO3 (sat. aq., 12.5 mL) and brine (12.5 mL). The organic solvents are dried over Na2SO4 and evaporated under reduced pressure to afford a yellow oil. The product is purified by silica chromatography, eluting with cyclohexane, to afford the title compound as a white solid (1.36 g). Alternatively, this compound may be used directly in the next step without further purification.
Reaction SMILES: Cl.[O-:2][OH:3].[C:4]1([CH:10]([CH3:12])[CH3:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(C)(C)C>[C:10]([O:2][O:3][C:10]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:12])[CH3:11]
Reactant: [O-]O
Reactant: CC(C)c1ccccc1
Agent: Cl
Solvent: CC(C)(C)O
Product: CC(C)(OOC(C)(C)c1ccccc1)c1ccccc1
Yield: 36 %

Procedure:
The fourth method is the only method relevant to this invention. The other methods and their short-comings in the preparation of cumyl peroxide are thoroughly discussed in U.S. Pat. No. 4,133,835 (Bafford). This invention is essentially an improvement over Bafford's process as taught in U.S. Pat. No. 4,133,835. Prior art pertaining to the fourth method above is: Kato et. al. (Auslegeschrift No. 2,035,127) published a process for preparing t-cumyl type peroxides by reacting a tertiary hydroperoxide with an aralkyl halide, such as t-cumyl chloride, at 0°-80° C. in the presence of an acid binding agent such as a t-alcohol or an aliphatic olefin. The mole ratio of the aralkyl halide to the hydroperoxide could vary from 1:1 to 1:1.5. In this process the hydroperoxide reacts with the aralkyl halide to form the peroxide; the HCl generated is taken up by the acid binding agent. There is no regeneration of the t-cumyl chloride. Kato's process was run with an acid sensitive aralkyl hydroperoxide, cumene hydroperoxide, with t-cumyl chloride in the presence of t-butyl alcohol (see Example XX). Although the reaction ran quite fast, only a 36% yield of dicumyl peroxide was obtained. There was a considerable amount of phenol generated during the reaction indicating the t-butyl alcohol was not a good scavenger of the hydrogen chloride; consequently a large amount of the cumene hydroperoxide underwent acid catalyzed decomposition to form phenol and acetone.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and m-anisidine (22 μl, 0.193 mmol) similar to Example 13 and isolated as a yellow solid (31 mg, 46%). 1H NMR (CDCl3): 8.77-8.75 (m, 2H), 8.28-8.25 (m, 2H), 7.36 (t, J=8.3 Hz, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 6.98-6.96 (m, 2H), 6.83-6.81 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2([C:15]3[NH:32][C:18]4=[N:19][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29](O)=[O:30])[CH2:24]5)=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:14][CH2:13]2)[CH:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:6][C:7]1[CH:8]=[N:9][N:10]([C:12]2([C:15]3[NH:32][C:18]4=[N:19][C:20]([N:23]5[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:1]6[CH2:5][CH:4]=[CH:3][CH2:2]6)=[O:30])[CH2:24]5)=[CH:21][CH:22]=[C:17]4[N:16]=3)[CH2:14][CH2:13]2)[CH:11]=1
Reactant: C1=CCNC1
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CC=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
3-Pyrroline (98.5 mg, 1.41 mmol) was added to a solution of (R)-1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (500 mg, 1.29 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (541 mg, 1.41 mmol) and diisopropylethylamine (334.7 mg, 2.58 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude material was triturated with pentane to afford the title compound (510 mg). MS (ES+) (M+H) 438.0; LCMS retention time 4.935 min (Method R1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>O1CCCC1>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(Oc2ccnc(NC(=O)Oc3ccccc3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (707 mg) as disclosed in WO 02/32872 was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere, and then triethylamine (0.523 ml) and phenyl chloroformate (0.470 ml) were added dropwise thereto while cooling in an ice bath, followed by raising the temperature gradually to room temperature while stirring. After 6 hrs, the reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:2) to provide a crude product of 4-(4-amino-3-chlorophenoxy)-2-phenoxycarbonylaminopyridine (920 mg). The crude product was dissolved in N,N-dimethylformamide (9 ml), and then 2 M solution of ethylamine in tetrahydrofuran (4.5 ml) was added thereto, followed by stirring at room temperature for 23 hrs. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2). Fractions containing the target compound were concentrated to give a residue, to which hexane-ethyl acetate (5:1) was added to precipitate crystals. The crystals were filtered, and dried under aeration to provide the titled compound (298 mg, 32%) as white crystals.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH3:10].[B:11](OC)([O:14]C)[O:12]C.S(=O)(=O)(O)O>C1COCC1>[CH3:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[B:11]([OH:14])[OH:12]
Reactant: COB(OC)OC
Reactant: Cc1ccc(C)c(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C)c(B(O)O)c1
Temperature: 25 °C

Procedure:
Magnesium turnings (30.3 g; 0.55 mol) are placed ina baked-out apparatus flushed with argon, covered with about 30 ml of THF and treated with a few crystals of iodine. A few drops of bromo-p-xylene (cf. Example A1 a)) were subsequently added to the static solution. The Grignard reaction commenced very quickly and the remaining bromo-p-xylene (total amount: 92.5 g; about 70 ml; 0.5 mol) was subsequently added dropwise while stirring. The mixture was refluxed for 4 hours, then cooled. The Grignard solution was then transferred in a countercurrent of protective gas into a 500 ml dropping funnel and added dropwise at −70° C. to a solution of trimethyl borate (62.4 g; 67 ml; 0.6 mol) in 350 ml of THF while stirring (time: about 1 hour). During this addition, a precipitate was formed. The reaction mixture was allowed to warm to RT overnight and was then poured while stirring into a mixture of 700 g of ice and 20 ml of concentrated sulfuric acid. The organic phase was separated off, the aqueous phase was extracted three times with chloroform and the combined organic phases were evaporated. The crude product was recrystallized from chloroform/hexane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([OH:30])[CH:29]=1>C(OCCO)C>[OH:30][C:28]1[CH:29]=[C:24]([NH:23][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:25]=[CH:26][C:27]=1[O:31][CH3:32]
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(Nc2c(C#N)cnc3c(OC)cccc23)cc1O
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 200.0 mg (0.92 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 105.7 mg (0.92 mmol) of pyridine hydrochloride and 140.6 mg (1.0 mmol) of 5-amino-2-methoxyphenol in 10 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 261.6 mg (89.0%) of the product as a deep yellow solid, m.p. 138-140° C. (dec.), mass spectrum (electrospray, m/e): M+H 321.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Br[CH2:14][CH2:15][CH2:16][Cl:17].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([C:10](=[O:12])[CH3:11])=[CH:5][C:6]=1[F:9]
Reactant: CC(=O)c1cc(F)c(O)c(F)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cc(F)c(OCCCCl)c(F)c1
Temperature: 25 °C
Yield: 110.4 %

Procedure:
A mixture of 1-(3,5-difluoro-4-hydroxyphenyl)ethanone (8.1 g, 47 mmol), 3-bromo-1-chloropropane (14.7 g, 93 mmol) and K2CO3 (21.3 g, 154 mmol) in acetone (120 mL) was stirred at reflux for 20 h. The reaction was cooled to rt and concentrated at reduced pressure, then partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride to obtain 1-[4-(3-chloropropoxy)-3,5-difluoro-phenyl]ethanone (12.9 g, quantitative yield); MS m/z 249 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]2[CH2:17][CH2:16]2)[CH:5]=[CH:4][C:3]=1[C:26]1([OH:40])[CH2:29][CH:28]([C:30]2[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=2)[CH2:27]1.[NH4+:41].[OH-]>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]2[CH2:17][CH2:16]2)[CH:5]=[CH:4][C:3]=1[C:26]1([OH:40])[CH2:29][CH:28]([C:30]2[CH:31]=[C:32]([S:36]([NH2:41])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=2)[CH2:27]1
Reactant: O=S(=O)(Cl)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(C2CC(O)(c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3Cl)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To the solution of compound 5b (30 mg) in CH3CN (2 mL) was added NH4OH (0.3 mL). The mixture was stirred at rt for 1 h. Concentration to dryness and purification by prep. RP-HPLC gave the title compound 5 (3.5 mg, 10% for two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.85 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.54-7.41 (m, 5H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (s, 1H), 6.75 (d, J=8.4 Hz, 1H), 4.83 (s, 2H), 4.77 (s, broad, 2H), 3.20 (t, J=10.4 Hz, 2H), 3.04 (m, 1H), 2.58 (t, J=10.6 Hz, 2H), 2.17 (m, 1H), 1.31-1.30 (m, 2H), 1.20-1.16 (m, 2H). MS (ESI−) m/z: 617 [M−1]−.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:16]O>>[OH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([CH:6]([CH3:11])[CH2:7][C:8]([O:10][CH3:16])=[O:9])=[O:5]
Reactant: CC(CC(=O)O)C(=O)c1ccccc1O
Reactant: CO
Product: COC(=O)CC(C)C(=O)c1ccccc1O
Yield: 94 %

Procedure:
3-(2-Hydroxybenzoyl)butyric acid (4.0 g, 0.02 mole) was esterified in methanol in a similar manner to that described in Example 4(i) to give methyl 3-(2-hydroxybenzoyl)butyrate (4.0 g, 94%) as an oil.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[NH2:2].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[C:14]=[S:15]>C(#N)C.CCOCC>[OH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([NH:1][NH:2][C:14](=[S:15])[NH:13][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:8][CH:7]=1)([CH3:10])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: CC(C)(O)c1ccc(NN)nc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(O)c1ccc(NNC(=S)Nc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
A mixture of 2-(6-hydrazinylpyridin-3-yl)propan-2-ol (250 mg, 1.495 mmol) and 1-isothiocyanato-4-nitrobenzene (269 mg, 1.495 mmol) in ACN (Volume: 2.0 mL) was stirred at room temperature for 1 hr. The reaction was diluted with Et2O (Volume: 5.0 mL), and the resulting solid was filtered. Minimal product was present in the solid. On standing for 1 hr, the filtrate had formed a precipitate. This was filtered to provide 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (175 mg, 0.504 mmol, 33.7% yield) as an orange solid. A solution of 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-N-(4-nitrophenyl)hydrazinecarbothioamide (275 mg, 0.792 mmol) in DME (Volume: 2.0 mL) was heated in a microwave on high absorbance for 3 hr at 110° C. The reaction was stripped to dryness onto silica gel via rotary evaporation and purified compound by MPLC with DCM:MeOH (98:2) to provide 2-(3-mercapto-[1,2,4]triazolo[4,3-a]pyridin-6-yl)propan-2-ol.
Reaction SMILES: [OH-].[Na+].O.NN.[CH2:6]([O:13][C:14]1[C:19]([Br:20])=[CH:18][C:17]([C:21](=O)[CH3:22])=[C:16]([O:24][CH3:25])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)COCCOCCO>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([O:24][CH3:25])[C:17]([CH2:21][CH3:22])=[CH:18][C:19]=1[Br:20])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(OCc2ccccc2)c(Br)cc1C(C)=O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CCc1cc(Br)c(OCc2ccccc2)cc1OC
Temperature: 170 °C
Yield: 41.5 %

Procedure:
Sodium hydroxide (0.39 g, 9.7 mmol) and hydrazine monohydrate (0.57 mL, 11.7 mmol) were added to a solution of 1-(4-benzyloxy-5-bromo-2-methoxy-phenyl)-ethanone (1.3 g, 3.9 mmol) dissolved in triethylene glycol (5 mL). The reaction mixture was heated to 170° C. for 24 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% EtOAc in hexanes) to give the title compound (0.52 g, 40%). 1H NMR (400 MHz, CDCl3): δ 1.14 (t, J=7.3 Hz, 3 H), 2.53 (q, J=7.3 Hz, 2 H), 3.75 (s, 3 H), 5.14 (s, 2 H), 6.48 (s, 1 H), 7.26 (s, 1 H), 7.32 (m, 1 H), 7.39 (m, 2 H), 7.49 (d, J=8.3 Hz, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([C@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCC[C@@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 65 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[6-(4-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1-(2-{5-[6-(4-{2-[1-(2R)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 65%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+). Found: 823.8 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of rotomers) 7.62-8.02 (m, 9H), 7.36-7.43 (m, 6H), 7.22 (s, 2H), 6.01 (s, 1H), 5.29-5.53 (m, 4H), 4.35 (t, 1H), 3.73-3.87 (m, 2H), 3.68 (s, 3H), 3.63 (s, 3H), 3.22 (q, 2H), 2.82-2.96 (m, 2H), 2.37 (m, 1H), 2.23 (m, 2H), 1.90-2.11 (m, 4H), 0.87-0.93 (m, 6H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])=[CH:15][CH:14]=1.O>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH2:20][C:21](=[O:23])[CH3:22])[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)/C=C/c1ccc(F)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of benzaldehyde (1.650 ml, 16.32 mmol) in DMF (5 ml) was added dropwise over the course of ½ hour to a mixture of sodium cyanide (0.401 g, 8.17 mmol) in DMF (20 ml) at 35° C. Stirring was then continued for 1.5 hours at 35° C. A solution of (E)-4-(4-fluorophenyl)but-3-en-2-one (2.0 g, 12.18 mmol) and DMF (10 ml) was then slowly added dropwise over the course of 3.5 hours at 35° C. Stirring was then continued for 3.5 hours at the same temperature. The reaction mixture was treated with twice its volume of water and extracted with DCM. The combined extracts were washed with water and brine, dried with Na2SO4, filtered and concentrated to give a liquid, which was further purified by chromatography on silica gel using an automated Biotage system and EtOAc/Hex (0-50%) to give 2-(4-fluorophenyl)-1-phenylpentane-1,4-dione (1.5 g, 5.55 mmol, 45.6% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.95-7.93 (m, 2H), 7.50-7.46 (m, 1H), 7.40-7.32 (m, 3H), 7.26-7.21 (m, 3H), 5.11 (dd, 1H), 3.59 (dd, 1H), 2.76 (dd, 1H), 2.19 (s, 3H).
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].[C:18]([C:20]1[CH:38]=[CH:37][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:36])[C@H:30]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH2:31])[CH3:27])=[CH:22][CH:21]=1)#[N:19].O>C(Cl)Cl>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH:26]([NH:28][C:29](=[O:36])[C@H:30]([CH2:32][CH:33]([CH3:34])[CH3:35])[NH:31][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH3:27])=[CH:37][CH:38]=1)#[N:19]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)NC(C)COc1ccc(C#N)cc1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)Oc1ccccc1)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
0.5 g of N-methylmorpholine, and subsequently 0.8 g of phenyl chloroformate were added to a suspension containing 1.5 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-leucinamide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed tinder reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.5 g of the desired product in the form of colorless powder (yield: 73%)
Reaction SMILES: C([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:20])[CH2:13][CH:14]([S:16][C:17](=[O:19])[CH3:18])[CH3:15])(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:17]([S:16][CH:14]([CH3:15])[CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:21])=[O:5])=[O:20])(=[O:19])[CH3:18]
Reactant: CC(=O)SC(C)CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SC(C)CC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
The 1-(3-acetylthiobutanoyl)-L-proline tert-butyl ester of Example 55 (5.2 g.) is dissolved in a mixture of trifluoroacetic acid (60 ml.) and anisole (30 ml.) and the solution is kept at room temperature for one hour. The solvents are removed in vacuo and the residual 1-(3-acetylthiobutanoyl)-L-proline is reprecipitated from ether-hexane several times, yield 4 g.. The dicyclohexylamine salt is made by the procedure of Example 44, m.p. 175°-176°.