Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.O>C(Cl)(Cl)Cl.CC(O)=O>[Br:19][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2ccsc2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Brc1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
3-Phenylthiophene (0.58 g, 3.62 mmol) was dissolved in 15 mL of a 1:1 solution of CHCl3 and AcOH followed by the portion-wise addition of 0.77 g (4.3 mmol) of NBS. The mixture was stirred at room temperature for 1 h, poured into 25 mL of H2O, and diluted with 30 mL of hexanes. The organic layer was washed successively with 2×10 mL of 10% aqueous KOH solution, 2×10 mL of H2O, and 2×10 mL of brine, and concentrated in vacuo to provide 0.68 g (78% yield) of 2-bromo-3-phenylthiophene as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].Cl[C:16](=[O:21])[C:17]([O:19][CH3:20])=[O:18].CCN(CC)CC.O>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[C:16]([NH:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1N
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Yield: 55.7 %

Procedure:
To a suspension of 2-tert-Butyl-5-nitro-phenylamine (4.04 g, 20.80 mmol) in CH2Cl2 (20 mL) at 0° C. was added 1.1 equiv of Methyl chlorooxoacetate (2.10 mL, 22.88 mmol) and followed by dropwise addition of 1.1 equiv of Et3N (3.19 mL, 22.88 mmol). After stirring at 0° C. and allowing to warm up to room temperature over 4 hrs, the reaction mixture was treated with water (20 mL), stirred for 10 min and then partitioned between EtOAc/water. The organic phase was washed with 0.5N HCl (2×25 mL), and saturated NaCl solution (50 mL), dried over Na2SO4 and evaporated to dryness. The residue was purified by flask column chromatography on silica gel eluting with EtOAc/Hexane (5–25%) to give the title compound (3.25 g, 56%) as light yellow crystals. TLC (30% EtOAc/Hexane) Rf=0.39; 1HNMR (CDCl3) δ 9.36 (br.s, 1H), 8.97 (d, J=2.4 Hz, 1H), 8.02 (dd, J=9.0, 2.4 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 4.03 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)[C:4]#[N:5].[Cl:18]N1C(=O)CCC1=O.O.CCOCC>C(Cl)(Cl)(Cl)Cl>[CH3:1][CH:2]([CH3:17])[CH:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][C:8]=1[Cl:18])[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C(C#N)Nc1ccc(C(F)(F)F)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 484 mg (2 mmol) of 3-methyl-2-(4-trifluoromethylphenylamino)butyronitrile in 5 ml of carbon tetrachloride was added 267 mg (2 mmol) of N-chlorosuccinimide. The mixture was heated at 65°. After about 48 hours, the mixture was poured into water and ether. The organic fraction was separated, washed with water and brine, dried over sodium sulfate, and solvent removed to give 3-methyl-2-(2-chloro-4-trifluoromethylphenylamino)butyronitrile in virtually quantitative yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](OC)[CH:13]=2)[NH:8][CH:7]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[C:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=1>>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]2[CH2:31][CH2:32][C:27]([C:21]3[C:20]4[C:24](=[CH:25][CH:26]=[CH:18][CH:19]=4)[NH:23][CH:22]=3)=[CH:28][CH2:29]2)=[CH:7]1
Reactant: COc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: Oc1ccc2[nH]cc(C3=CCNCC3)c2c1
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCCCc2c[nH]c3ccccc23)C1

Procedure:
of 3-(4-chlorobutyl)-5-methoxyindole with 4-(5-hydroxyindol-3-yl)-1,2,5,6-tetrahydropyridine:
Reaction SMILES: [F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.Cl.[NH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[NH2:17]>C(O)(=O)C>[F:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:17]([NH:16][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:5]2=[O:7]
Reactant: NNc1ccncc1
Reactant: COc1ccc2c(c1F)C(=O)OC2=O
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1F)C(=O)N(Nc1ccncc1)C2=O
Yield: 72.4 %

Procedure:
To a solution of 2-(3-fluoro-4-methoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (34.0 g) in dry tetrahydrofuran (300 ml) sec-butyllithium (140 ml of a 1.3 M solution in cyclohexane) was added dropwise at -78° C. with stirring, under nitrogen. The reaction mixture was stirred 15 mins, and carbon dioxide was bubbled below the surface. The reaction was stirred for 1 hr and water added dropwise. The mixture was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The aqueous extract was cooled to 0° C. and an equal volume of concentrated hydrochloric acid was added dropwise. The solution was stirred, under reflux overnight, cooled and the solid collected. The solid was washed with cold water and dried in vacuo to give 26.6 g of 3-fluoro-4-methoxyphthalic acid. A mixture of 3-fluoro-4-methoxyphthalic acid (26.6 g ) in acetic anhydride (100 ml) was stirred, under reflux, under nitrogen, for 4 hrs. The reaction mixture was cooled to -60° C. and filtered. The solid was collected, washed with ether and dried in vacuo to give 19.9 g (67%) of 3-fluoro-4-methoxyphthalic anhydride, mp 128-130° C. A mixture of 3-fluoro-4-methoxyphthalic anhydride (10.0 g) and 4-hydrazinopyridine hydrochloride (7.42 g) in glacial acetic acid (50 ml) was stirred, under reflux, under nitrogen, for 4 hrs and stirred at ambient temperature overnight. The solid was collected, washed with ether and dried in vacuo at 80° C. overnight to give 10.6 g (64%) of 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindol-1,3-dione. To a mixture of lithium aluminum hydride (3.72 g) and dry tetrahydrofuran (100 ml), 4-fluoro-5-methoxy-2-(4-pyridinylamino)isoindole-1,3-dione hydrochloride (10.60 g) was added in portions with rapid stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred at ambient temperature, under nitrogen, for 3 hrs, and sodium sulfate decahydrate was added in portions. The mixture was filtered through a bed of celite, the filter pad was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane:methanol:ammonium hydroxide. The residue was crystallized from absolute ethanol to give 3.2 g (8%) of product, (dried under vacuum at 80° C. overnight) mp 206-210° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N([OH:25])N=NC=2C=1.[NH:26]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:27]([C:29]([OH:31])=O)[CH3:28].[NH2:39][CH:40]([CH2:43][OH:44])[CH2:41][OH:42]>>[NH:26]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@@H:27]([C:29]([NH:39][C@H:40]([C:43]([OH:25])=[O:44])[CH2:41][OH:42])=[O:31])[CH3:28]
Reactant: NC(CO)CO
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)O

Procedure:
BOC-D-Ala-SerOH was prepared on a 1.0 mMol-scale by the DCC-HOBT mediated condensation of BOC-D-Ala and serinol following the procedure described in Example 21. The crude reaction product was purified by chromatography on a 1.7×24 cm column of BioSil A by successive elution with (A) 100 ml CHCl3, (B) 100 ml of 1% (v/v) MeOH/CHCl3, (C) 100 ml of 2% MeOH/CHCl3, (D) 100 ml of 4% MeOH/CHCl3, (E) 100 ml of 8% MeOH/CHCl3, and (F) 100 ml of 12% MeOH/CHCl3. The appropriate column fractions were combined and concentrated to dryness on the rotary evaporator. The oily residue was then taken up in 10 ml of CH2Cl2, filtered from the small amount of insoluble material, and again concentrated to dryness. The residue was further dried under high vacuum to yield 168 mg (68%) of product as a colorless viscous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:31][NH2:32].[CH2:33](O)[CH3:34]>>[CH3:4][C:16]1[CH:15]=[C:17]([CH:18]=[CH:33][CH:34]=1)[CH:22]=[N:31][NH:32][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH:16]=[C:4]2[N:3]=1
Reactant: CCO
Reactant: NN
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ccc(-c2cc3nc(NN=Cc4cccc(C)c4)cc(N4CCOCC4)n3n2)cc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
There was suspended, in ethanol (2 mL), 5-chloro-2-(4-methylphenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine (50.0 mg, 0.152 mM) and then potassium carbonate (23.1 mg, 0.152 mM) and hydrazine monohydrate (36.9 μL, 0.760 mM) were added to the resulting suspension. This suspension was stirred at 150° C. for 20 minutes under the irradiation with microwaves, diluted with a saturated common salt aqueous solution and then extracted with ethyl acetate. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and then the solvent was distilled off. The resulting residue was suspended in ethanol (2 mL), then acetic acid (5.0 μL, 0.087 mM) and 3-methyl-benzaldehyde (17.9 μL, 0.152 mM) were added to the suspension and then the resulting mixture was stirred at room temperature for one hour. This reaction mixture was filtered and then the resulting solid was purified by the NH-silica gel column chromatography (methylene chloride) to thus give the title compound (31.4 mg, overall yield of these two steps: 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10]C1CCCCO1.[Li]CCCC.[B:22](OC(C)C)(OC(C)C)[O:23]C(C)C.Cl>C1COCC1.O.CCOC(C)=O>[B:22]1([OH:23])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][O:10]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccccc1CCOC1CCCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OB1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2-[2-(2-bromo-phenyl)-ethoxy]-tetrahydro-pyran (1.0 g, 3.5 mmol, 1.0 eq.) in THF (20 mL) at −78° C. was slowly added BuLi (2.4 mL, 2.5 M solution in THF, 3.8 mmol, 1.1 eq.) under nitrogen atmosphere. Triisopropyl borate (1.2 mL, 5.25 mmol, 1.5 eq.) was then added and the mixture was allowed to warm to room temperature gradually and stirred overnight. After carefully adding HCl (10 mL, 6N), the yellowish solution was stirred at room temperature for another 1 h and then poured into a mixture of EtOAc (30 mL) and H2O (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×30 mL). Combined organic extracts was washed with H2O (50 mL), brine (50 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The oily residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 100:0) to give 3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol as a light yellow solid. 1H NMR (acetone) δ: 7.73 (d, J=7.2 Hz, 1H), 7.33-7.39 (m, 1H), 7.15-7.26 (m, 3H), 4.10 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H). Amount obtained 497 mg, 95.9% yield.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:44]([O:46]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:17][C@@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43])=O)(C)(C)C.C(OC(N[C@H](C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)CSCCN1C2C=CC=CC=2C(C2C=CC=CC=2)=N[C@H](NC(C2NC3C(C=2)=CC=CC=3)=O)C1=O)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:44]([OH:46])=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:17][C@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CSCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of a mixture (0.66 g) of (3R)-1-[2-((2R)-2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one and (3S)-1-[2-((2R)-2-tert-butoxycarbonylamino-2benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one, anisole (0.6 ml), trifluoroacetic acid (1.5 ml) and dichloromethane (15 ml) was stirred for 3.0 hours at room temperature. After removal of the solvent, the residue was mixed with ethyl acetate (50 ml) and water (50 ml). The mixture was adjusted to pH 6-7 with 5% aqueous solution of sodium bicarbonate under stirring. The organic layer was separated and concentrated. The resultant precipitate was collected by filtration, washed with water and dried to give a mixture (0.20 g) of (3R)-1-[2-((2R)-2-amino-2-carboxyethylthio)ethyl]-1,3-dihydro -3-(2-indolylcarbonylamino -5-phenyl-2H-1,4-benzodiazepine- 2-one and (3S)-1-[2-((2R)-2-amino-2-carboxyethylthio) ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])[CH:19]=1)[CH2:10][CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[O:16][CH:11]([C:12]([F:13])([F:14])[F:15])[CH2:10][N:9]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:29])([F:30])[CH:26]([F:27])[F:28])[CH:19]=3)[C:3]=2[CH:4]=1
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cc(F)ccc1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)N(Cc1cccc(OC(F)(F)C(F)F)c1)CC(C(F)(F)F)O2
Temperature: 145 °C
Yield: 45.2 %

Procedure:
The 3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.45 mmol) product from EX-661B was dissolved in anhydrous dimethylformamide (20 mL), and powdered K2CO3 (180 mg) was added. The mixture was stirred and heated to 145° C. for 15 h. The mixture was diluted with water (60 mL) and extracted into ether (2×40 mL), which was washed with brine and water. The ether solution was dried over anhydrous MgSO4, and the ether was removed in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:15) to give 86.9 mg (48%) of the desired 6-fluoro-3,4-dihydro-4-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-2-(tri-fluoromethyl)-2H-1,4-benzoxazine product as a yellow oil, 98% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.39 (t, 1H), 7.17 (m, 3H), 6.88 (m, 1H), 6.41 (m, 2H), 5.92 (tt, 1H), 4.54 (m, 1H), 4.45 (s, 2H), 3.44 (m, 2H). 19F NMR (CDCl3) δ −77.7 (d, 3F), −88.6 (m, 2F), −120.28 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C18H13F8NO2: 428.0899 [M+H]+, found: 428.0910.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[S:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Solvent: Cc1ccccc1C
Product: COC(=S)c1cccc(OCc2ccccc2)c1
Yield: 101.7 %

Procedure:
In an analogous manner to that described in Example 1(B), 40 g (0.165 mol) of methyl 3-(benzyloxy)benzoate were heated at reflux for 8 hours with 33.4 g (0.0826 mol) of Lawesson reagent in xylene and thereafter chromatographed on silica gel, whereby there were obtained 21.7 g (51%) of O-methyl 3-(benzyloxy)thiobenzoate as a red-brown oil which gradually crystallized upon standing.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=[O:25].Cl>O1CCCC1>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:24](=[O:25])[CH2:23][C:11]([CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:27][CH:28]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCc1ccccc1)(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a 500 mL 3-neck round-bottom flask equipped with an argon inlet and an addition funnel, was added sodium hydride (95%, 1.40 g, 58.3 mmol) followed by tetrahydrofuran (30 mL). The resulting suspension was then cooled to 0° C. and diethyl 2-(2-phenylethyl)malonate (14.0 g, 53.0 mmol) in tetrahydrofuran (20 mL) was added dropwise over 20 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to rt over 45 minutes. A solution of 2-bromo-1-(4-bromophenyl)ethanone (14.72 g, 58.26 mmol) in tetrahydrofuran (40 mL) was rapidly added and the resulting orange-red mixture was stirred at rt for 16 h. The mixture was carefully poured into 300 mL of 1N hydrochloric acid, and the resulting mixture was stirred for 10 minutes and extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane) to afford diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (14.8 g, 61%). LC-MS ret. time 3.89 min, m/z 461.2 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.26 (t, 6H), 2.41-2.45 (m, 2H), 2.56-2.59 (m, 2H), 3.67 (s, 2H), 4.23 (q, 4H), 7.14-7.22 (m, 3H), 7.22 (d, 2H), 7.61 (d, 2H), 7.79 (d, 2H).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:40])[C@@H:24]([NH:30][C:31]1[O:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.Cl.[H][H]>CO.O1CCOCC1.[Pd]>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH2:11][C@@H:10]([NH:22][C:23](=[O:40])[C@@H:24]([NH:30][C:31]1[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=1)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][OH:8])[CH2:13][CH2:14]2
Reactant: [H][H]
Reactant: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](COCc1ccccc1)CN1CCc2cc(F)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)C[C@H](Nc1nc2ccccc2o1)C(=O)N[C@@H](CO)CN1CCc2cc(F)ccc21
Reaction time: 2 h
Yield: 58.5 %

Procedure:
The title compound of example 6 (34 mg, 70 μmol) was dissolved in MeOH (3 mL) and treated with 4 M HCl in dioxane (0.5 mL). The reaction was then treated with 10% Pd/C (7 mg) and the atmosphere was exchanged for hydrogen by sparging the solution with a needle and a balloon. After 2 h under a hydrogen balloon, the atmosphere was exchanged back to nitrogen and the catalyst was removed by filtration through celite. The solvent was removed and the residue was purified by preperative reverse phase HPLC to afford the title compound as a gum (18.6 mg, 47%); 1H NMR (CDCl3, 400 MHz) δ 0.97 (s, 9H), 1.69 (dd, 1H, J1=9.0, J2=14.5), 1.81 (dd, 1H, J1=3.4, J2=14.5), 2.71-2.90 (m, 2H), 3.04-3.16 (m, 1H), 3.19-3.31 (m, 2H), 3.40-3.50 (m, 1H), 3.66 (d, 1H, J=5.2), 4.13-4.21 (m, 1H), 4.38 (dd, 1H, J1=3.4, J2=9.0), 6.44-6.52 (m, 1H), 6.59-6.66 (m, 1H), 6.70-6.74 (m, 1H), 7.14 (dd, 1H, J1=J2=7.7), 7.23 (dd, 1H, J1J2=7.6), 7.30 (d, 1H, J=7.8), 7.33 (d, 1H, J=8.0); HPLC-MS calcd. for C25H31FN4O3 (M+H+) 455.2, found 455.5.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:10]([O:27][C@H:28]1[CH2:32][CH2:31][C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH2:42])[C@@H:29]1[CH2:43][O:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N.CO.ClCCl>N1C=CC=CC=1>[Si:10]([O:27][C@H:28]1[CH2:32][CH2:31][C@H:30]([N:33]2[CH:41]=[N:40][C:39]3[C:34]2=[N:35][CH:36]=[N:37][C:38]=3[NH:42][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:29]1[CH2:43][O:44][C:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:23]([CH3:26])([CH3:24])[CH3:25])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@H](n2cnc3c(N)ncnc32)[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)[Si](O[C@H]1CC[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Benzoyl chloride (0.28 g, 0.231 ml, 2.0 mmol) was added dropwise to a cooled (ice-water bath) solution of compound 61 (0.97 g, 1.33 mmol) in anhydrous pyridine (10 ml). The bath was removed and reaction was stirred overnight, then cooled (ice-water bath) and treated with 2.5 ml of 7 N NH3/MeOH (added over 5 min). The reaction was removed from the bath, stirred under argon for 3 h to decompose the bis-benzoylated by-product and then concentrated in vacuo. The resultant residue was diluted with EtOAc and washed with 10% citric acid, saturated NaHCO3, saturated NaCl, dried over MgSO4 and concentrated in vacuo. The obtained material was chromatographed on silica eluting with 1:1 ethyl acetate: dichloromethane to give N-benzamide 62 (0.98 g, 88% yield) as a white sold foam.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1Cl.O>C(OCC)C>[C:23]1([CH3:32])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: Cc1cc(C)c(Cl)c(C)c1
Reactant: COC(=O)c1ccc(CCCCO)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCCc2c(C)cc(C)cc2C)cc1
Temperature: 0 °C

Procedure:
To a mixture of 65.07 g (1.0 eq) of methyl 4-(4-hydroxybutyl)benzoate and 33.20 (1.05 eq) of triethylamine in 350 mL of anhydrous ethyl ether, stirred under nitrogen and cooled to 0° C., are added in a dropwise fashion, 37.58 g (1.05 eq) of mesityl chloride. A solid forms and the reaction mixture is gradually brought to room temperature and stirred under nitrogen for 4 hours. Four hundred milliliters of water are then added and the organic layer is separated, washed with water, dried over magnesium sulfate, and concentrated to yield methyl 4-(4-mesitylbutyl)benzoate, m.p. 52°-53° C.; IR (KBr) vmax 3010, 2930, 2850, 1700, 1603, 1432, 1334, 1323, 1165, 1104, 937, 822, and 700 cm-1 ; 1H NMR (CDCl3) delta 7.92 (d, J=8.2 Hz, 2H, Ar), 7.22 (d, J=8.2 Hz, 2H, Ar), 4.18-4.22 (m, 2H, CH2OMs), 3.86 (s, 3H OCH3), 2.96 (s, 3H, SO2CH3), 2.65-2.68 (m, 2H, benzyl), 1.72-1.74 (m, 4H, 2° aliphatic).