Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][NH:6][C:7](=[O:40])[C@H:8]([C:17]([S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:19])[CH3:18])[NH:9]C(OC(C)(C)C)=O)[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][NH:6][C:7](=[O:40])[C@H:8]([C:17]([S:20][C:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:19])[CH3:18])[NH2:9])[CH3:2]
Reactant: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CNC(=O)[C@@H](N)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
To the solution of N-t-butoxycarbonyl-S-trityl-L-penicillamylglycine ethyl ester (B-2) (4.5 g) and 2,6lutidine (2.8 ml) in dichloromethane (100 ml), was added dropwise at 0° C. the solution of trimethylsilyl trifluoromethanesulfonate (3.9 ml), and the mixture was stirred for 1 hour while the temperature was gradually returned to the room temperature. To the reaction mixture was added ice-water, and the organic layer was washed with 1N-hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate, water, and saturated saline, in this order, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, to give S-trityl-L-penicillamylglycine ethyl ester (3.8 g)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[CH2:33](O)[CH3:34].Cl>O1CCOCC1>[OH2:3].[CH2:1]([O:3][C:4]([C:6](=[C:22]1[S:26][C:25](=[S:27])[N:24]([CH2:28][C:29]([O:31][CH2:33][CH3:34])=[O:30])[C:23]1=[O:32])[C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2)n1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=C(C(=O)OCC)c2csc(NC(=O)Nc3ccccc3)n2)SC1=S
Product: O

Procedure:
Following a procedure similar to that described in Example 30, the desired compound was prepared from 2 g of 5-{1-ethoxycarbonyl-1-[2-(3-phenylureido)thiazol-4-yl]methylene}rhodanine-3-acetic acid, 3 g of ethanol and 30 ml of a 4N dioxane solution of hydrogen chloride. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>C(O)C>[C:18]([CH:19]=[CH:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(C=CC(=O)c2ccccc2)cc1

Procedure:
7.1 Parts of ethyl (4-formylphenoxy)-2,2-dimethylacetate described in U.S. Pat. No. 3,842,120 and 4.7 parts of acetophenone in 10 parts by volume of ethanol containing 0.01 part of sodium ethyl are reacted for 2 hours. This reaction mixture is quenched with 100 parts of cold water and extracted with ether. The ether extracts are dried over magnesium sulfate. Filtration of the magnesium sulfate, removal of the ether by evaporation at reduced pressure, and column chromatography on silica gel provides ethyl 2-[4-(2-benzoylethenyl)phenoxy]-2,2-dimethylacetate, melting at 68° to 70° C. This compound has the following structural formula ##STR5##
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:13][C:9]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cccnc1-n1cccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cccnc1-n1cccc1Br
Temperature: 25 °C
Reaction time: 6 h
Yield: 25.4 %

Procedure:
To a solution of 3.0 g of 3-chloro-2-(1H-pyrrol-1-yl)pyridine in 30 ml of N,N-dimethylformamide was added 3.1 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.1 g of 2-(2-bromo-1H-pyrrol-1-yl)-3-chloropyridine of the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C@:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C@@:5]12[C:21]([F:23])([F:22])[CH2:20][O:19][C:18]([NH2:24])=[N:17]1.[C:25]([C:27]1[CH:28]=[C:29](B(O)[OH:34])[CH:30]=[CH:31][CH:32]=1)#[N:26]>>[CH:20]([OH:19])=[O:34].[NH2:24][C:18]1[O:19][CH2:20][C:21]([F:23])([F:22])[C@:5]2([N:17]=1)[C:4]1[C:14](=[CH:15][CH:16]=[C:2]([C:31]3[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=3)[C:25]#[N:26])[CH:3]=1)[O:13][C@:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6]2
Reactant: NC1=N[C@@]2(C[C@@]3(CCCOC3)Oc3ccc(Br)cc32)C(F)(F)CO1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(C[C@@]4(CCCOC4)O3)N=C(N)OCC2(F)F)c1
Product: O=CO
Yield: 25 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2′R,4R)-6′-bromo-5,5-difluoro-5,5″,6,6″-tetrahydro-4″H-dispiro[1,3-oxazine-4,4′-chromene-2′,3″-pyran]-2-amine (intermediate B6.7) with 3-cyanophenylboronic acid and chromatography on preparative HPLC yielded the title compound (25% yield) as a pale yellow solid. MS (ISP): m/z=426.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[Cl:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([N:37]=[CH:38][N:39]=2)[N:36]=1>O1CCCC1>[ClH:30].[ClH:30].[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:31]3[CH:32]=[CH:33][C:34]4[N:35]([N:37]=[CH:38][N:39]=4)[N:36]=3)[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1ccc2ncnn2n1
Reactant: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: c1ccc(C(c2ccccc2)N2CCN(CCCOc3ccc4ncnn4n3)CC2)cc1
Temperature: 0 °C
Yield: 95 %

Procedure:
4-(Diphenylmethyl)-1-piperazinepropanol (466 mg) was dissolved in dried tetrahydrofuran (10 ml), followed by addition of sodium t-butoxide (173 mg). The mixture was refluxed under, heating for 30 minutes. After the mixture was cooled, 6-chloro[1,2,4]triazolo[1,5-b ]pyridazine (268 mg) was added to the mixture. The resulting mixture was refluxed under heating for 3 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of ethyl acetate and methanol (10:1). Fractions containing the objective compound were collected and dissolved in ethyl acetate (10 ml), followed by addition of 4N HCl in ethyl acetate solution (0.7 ml). The resulting crystals were recrystallized from 95% aqueous ethanol to yield the title compound (413 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[C:37]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:38]=1>O.ClCCl>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[C:37]([CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:12]([O:8][CH:3]([C:4]([F:7])([F:6])[F:5])[C:2]([F:10])([F:9])[F:1])=[O:14])[CH2:44][CH2:45]2)[CH:38]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Clc1ccc(N2CCCC2)c(CN2CCNCC2)c1
Reactant: OC(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2cc(Cl)ccc2N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-ol (126 mg, 0.750 mmol, 1.00 equiv), triphosgene (74.0 mg, 0.250 mmol, 0.33 equiv), dichloromethane (10 mL). N,N-Diisopropylethylamine (290 mg, 2.24 mmol, 2.99 equiv) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 h. 1-[[5-Chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine (210 mg, 0.750 mmol, 1.00 equiv) was added. The resulting solution was stirred for 2 hours at room temperature and diluted with H2O (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with H2O (3×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3). The crude product (150 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 51.5 mg (14% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[5-chloro-2-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. 1H NMR 300 MHz (CDCl3) δ 7.42 (d, J=2.4 Hz, 1H), 7.09-7.13 (m, 1H), 6.85 (d, J=8.9 Hz, 1H), 5.69-5.82 (m, 1H), 3.52-3.58 (m, 6H), 3.10-3.14 (m, 4H), 2.46-2.49 (m, 4H), 1.86-1.96 (m, 4H). LCMS (ESI, m/z): 474 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[N:12]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:15])[NH:14][C:10]=2[CH:9]=1.IC.C([O-])(O)=O.[Na+]>CS(C)=O>[Br:7][C:8]1[CH:24]=[CH:23][C:11]2[N:12]([CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:15])[N:14]([CH3:1])[C:10]=2[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]c2cc(Br)ccc2n1CCN1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: Cn1c(=O)n(CCN2CCCC2)c2ccc(Br)cc21
Reaction time: 0.5 h

Procedure:
73 mg (0.65 mmol) potassium-tert-butoxide are added to a solution of 200 mg (0.65 mmol) 5-bromo-1-(2-pyrrolidin-1-yl-ethyl)-1,3-dihydro-benzimidazol-2-one in 4 mL DMSO at RT. The reaction solution is stirred for 30 min and then 40 μL (0.65 mmol) iodomethane are added and stirred for a further 30 min. The mixture is combined with semisaturated NaHCO3 solution and the aqueous phase is extracted twice with 30 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[C@H:16]([CH3:17])[C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:10]([N:12]2[C@H:16]([CH3:17])[C@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:14][C:13]2=[O:24])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)=CCBr
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)CCc1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC[C@@H](Cc1ccc(Cl)cc1)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Temperature: -78 °C
Yield: 36 %

Procedure:
To a cooled (−78° C.) solution of 3-[3-(4-chloro-phenyl)-propionyl]-4-(R)-methyl-5-(S)-phenyl-oxazolidin-2-one, 32, (500 mg, 1.46 mmol) in THF (15 mL) is added sodium bis(trimethylsilyl)-amide (1.75 mL, 1.0M solution in THF, 1.75 mmol). The resulting solution is stirred at −78° C. then 4-bromo-2-methyl-2-butene (0.20 mL, 1.75 mmol) is slowly added. The resulting solution is stirred at room temperature overnight, and the solvent removed under reduced pressure. The crude product is purified by preparative HPLC to afford 213 mg (36% yield) of the desired compound as a colorless oil. 1H NMR (CDCl3 300 MHz) δ 0.83 (d, J=6.6 Hz, 3H), 1.62 (s, 3H), 1.70 (s, 3H), 2.20–2.55 (m, 2H), 2.77–3.10 (m, 2H), 4.20–4.35 (m, 1H), 4.55–4.68 (m, 1H), 5.15–5.25 (m, 1H), 5.38 (d, J=7.2 Hz, 1H), 7.15–7.45 (m, 9H). MS (ESI) m/z 412 (M+H+)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:18]2[C@@H:14]([O:15][C:16]([CH3:20])([CH3:19])[O:17]2)[C@@H:13]([CH2:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[O:12]1.[CH:30]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31]1>C(O)C.C(N(CC)CC)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:22][CH2:21][C@@H:13]1[C@H:14]2[C@@H:18]([O:17][C:16]([CH3:20])([CH3:19])[O:15]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[NH:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:12]1
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21

Procedure:
To a solution of 1-{[(2S,1R,4R,5R)-4-(6-chloropurin-9-yl)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl]methylthio}-2-fluorobenzene, a compound of formula (3), (0.125 g, 2.86 mmoles) in 10 mL of ethanol and 1 mL of triethylamine was added cyclopentylamine in excess, and the mixture refluxed under nitrogen for 24 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC using 1:1 EtOAc:Hexanes to give (9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine, a compound of formula (4), as a yellow oil (80 mg, 56%)
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[N+:12]([CH3:15])([O-:14])=[O:13].N(CN[C:20]1[CH2:21][C:22](=[O:37])[N:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)=O>O.C(O)(=O)C>[C:31]1([N:23]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[NH:26][C:20](=[CH:15][N+:12]([O-:14])=[O:13])[CH2:21][C:22]2=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[N+](=O)[O-]
Reactant: O=NCNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(=C[N+](=O)[O-])Nc2ccccc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium t-butoxide, 3.15 g (0.0281 moles) was added to a mixture of 70 ml of dimethylformamide and 14 ml of nitromethane. After stirring for 30 min at room temperature under nitrogen, 6.9 g (0.0234 moles) of 3,5-dihydro-2-(N-nitrosomethylamino)-5-phenyl-4H-1,5-benzodiazepin-4-one, was added and stirring was continued for 48 hours. The mixture was acidified with acetic acid and diluted with water. The precipitate was collected, washed with water and recrystallized from methylene chloride/ethanol to yield end product with mp 231°-234°. Recrystallization for analysis from the some solvents raised the melting point to 233°-235°.
Reaction SMILES: C([O:3][C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:29])[NH:15][C:16]2[C:17](=[O:28])[O:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[C:21]([O:26][CH3:27])[CH:20]=3)[C:6](=[O:30])[CH:5]=1)C>C1COCC1.C(Cl)Cl.Cl.O>[CH3:27][O:26][C:21]1[CH:20]=[C:19]2[C:24]([CH:25]=[C:16]([NH:15][C:14](=[O:29])[O:13][CH2:12][CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][C:6]3=[O:30])[C:17](=[O:28])[O:18]2)=[CH:23][CH:22]=1
Reactant: CCOC1=CC(=O)C(CCCOC(=O)Nc2cc3ccc(OC)cc3oc2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2cc(NC(=O)OCCCC3CCC(=O)CC3=O)c(=O)oc2c1
Yield: 59.2 %

Procedure:
Compound 5 (240 mg, 0.58 mmol) was stirred in a mixture of THF/DCM (3/1 v/v, 4 mL) and 3N HCl (4 mL) for 1 hr. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×30 mL). The combined organic phases were dried over anhydrous MgSO4 and reduced to dryness to yield the crude product, which was purified by flash column chromatography (EtOAc/acetone 4/1) to yield 7 as an off-white solid (133 mg, 59.4%). Rf 0.62 (hexanes/EtOAc/MeOH 6/3/1); Mp. 154-156° C.; 1H NMR (300 MHz, CDCl3) δ 8.25 (1H, s), 7.42 (1H, s), 7.39 (1H, d, J=8.7 Hz), 6.88 (1H, dd, J=8.6 Hz, 2.1 Hz), 6.83 (1H, d, J=2.1 Hz), 4.23 (2H, t, J=6.5 Hz), 3.86 (3H, s), 3.44 (2H, d, J =5.1 Hz), 2.78-2.69 (1H, dt, J=16.4 Hz, 4.4 Hz), 2.67-2.51 (2H, m), 2.24-2.15 (1H, dq, J=14.1 Hz, 4.8 Hz), 2.03-1.95 (1H, m), 1.88-1.47 (6H, m); 13C NMR (75 MHz, CDCl3) δ 204.2, 203.8, 161.2, 158.9, 153.5, 151.3, 128.4, 122.0, 121.8, 113.3, 113.2, 100.9, 65.6, 58.5, 55.9, 49.1, 39.9, 26.6, 25.7, 24.8; ESI MS m/z 410 (M++Na+), 388 (M++H+); CHN calc. for C20H21NO7.0.5H2O, C: 60.59, H: 5.61, N: 3.53, found C: 61.31, H: 5.56, N: 3.48.
Reaction SMILES: ClC1C=C(C=CC=1I)N.[C:10]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[C:20]([Cl:25])[CH:19]=1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].[Na+].Br[CH:29]([CH3:37])[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>CN(C=O)C.ClCCl>[CH2:33]([O:32][C:30](=[O:31])[C@H:29]([CH3:37])[N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:18]1[CH:23]=[CH:22][C:21]([I:24])=[C:20]([Cl:25])[CH:19]=1)[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)c(Cl)c1
Reactant: CC(C)COC(=O)C(C)Br
Agent: Nc1ccc(I)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)c1ccc(I)c(Cl)c1
Temperature: 100 °C

Procedure:
Following General Procedure AR above and using 3-chloro-4-iodoaniline (Aldrich), N-BOC-3-chloro-4-iodoaniline was prepared. To a stirred slurry of 5.0 equivalents of sodium hydride in DMF was added 1.0 equivalent of N-BOC-3-chloro-4-iodoaniline and then 1.1 equivalents of iso-butyl 2-bromopropionate (from Example AD above) were slowly added. The reaction was heated to 100° C. for 10 hours, cooled, diluted with dichloromethane and washed with cold 1N HCl, water and brine. The solvents were removed at reduced pressure and the residue was chromatographed to provide N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester as a clear oil. Following General Procedure AN above, the BOC group was removed from N-BOC-N-(3-chloro-4-iodophenyl)alanine iso-butyl ester to provide the title compound. The BOC-removal reaction was monitored by tlc on silica gel (Rf=0.58 in 30% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 30% EtOAc/hexanes as the eluant). The compound was further purified by chromatography on an HPLC chiral column (Chiralcel OD).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine (Aldrich) to give the title compound. LC-MS: 593.2 [(M+H)+]
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:38]=[CH:37][C:31]4[O:32][C:33]([F:36])([F:35])[O:34][C:30]=4[CH:29]=3)[CH:25]=[C:24]([C:39](=[O:41])[CH3:40])[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C.[OH-].[Na+].Cl>C(O)C.O>[C:39]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]2[CH:38]=[CH:37][C:31]3[O:32][C:33]([F:35])([F:36])[O:34][C:30]=3[CH:29]=2)[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])(=[O:41])[CH3:40]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OC(F)(F)O4)c2)c1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OC(F)(F)O3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.8 %

Procedure:
To a solution of 4-[3-{6-[3-acetyl-5-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (300 mg) in ethanol (5 mL) was added a solution of NaOH (176 mg) in water (2 mL) and the resulting mixture was stirred at room temperature for 5 h. Then the reaction mixture was diluted with water, acidified with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a reverse-phase HPLC to yield 137 mg of the title compound (50% yield). HRMS calcd for C34H36O9F2 [M+Na]+ 649.2219, observed 649.2222.
Reaction SMILES: [C:1]([S:9][CH:10]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([O:25]C(C)(C)C)=[O:24])[CH2:18][C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH2:15]1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([S:9][CH:10]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:11]([NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([OH:25])=[O:24])[CH2:18][C:17]2[CH:34]=[CH:35][CH:36]=[CH:37][C:16]=2[CH2:15]1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(C(=O)OC(C)(C)C)N1Cc2ccccc2CC(NC(=O)C(Cc2ccccc2)SC(=O)c2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC(C)CC(C(=O)O)N1Cc2ccccc2CC(NC(=O)C(Cc2ccccc2)SC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 122.7 %

Procedure:
Dissolve 2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valeric acid, tert-butyl ester (141 mg, 0.229 mmol) in methylene chloride (5 mL) and treat with anisole (0.12 mL, 1.15 mmol) then with trifluoroacetic acid (1.5M). Stir at room temperature for 15 hours, partition between ethyl acetate (25 mL) and brine (15 mL). Wash the organic layer with brine (15 mL), dry (Na2SO4) and purify by silica gel chromatography (1:1 hexane/ethyl acetate followed by 1:1:0.01 hexane/ethyl acetate/acetic acid) to give the title compound as a white solid (157 mg).