Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][CH2:8][CH2:9]Cl)=[O:6])([CH3:3])[CH3:2].[I-:11].[Na+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)(Cl)Cl>[CH:1]([O:4][C:5]([O:7][CH2:8][CH2:9][I:11])=[O:6])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)OC(=O)OCCCl
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)OC(=O)OCCI
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A mixture of isopropoxycarbonyloxyethyl chloride (=2-chloroethyl isopropylcarbonate) (1.67 g), carbon tetrachloride (10 ml), sodium iodide (2.10 g) and anhydrous zinc chloride (0.08 g) is stirred at room temperature for 2 hours, and thereafter, ice water is added to the mixture. The organic layer is separated, and the aqueous layer is extracted twice with carbon tetrachloride. The combined organic layers are washed, dried and evaporated under reduced pressure to give isopropoxycarbonyloxyethyl iodide (=2-iodoethyl isopropylcarbonate) (1.48 g) as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:25].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cccc(F)c34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(4-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (104) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1>>[Cl:5][CH2:6][CH2:7][C:8]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=1[F:18])=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCl)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a stirred mixture of aluminium (III) chloride (11.70 g, 88.0 mmol) in 1,3-difluorobenzene (21 mL) at RT was added 3-chloropropionyl chloride (4.0 mL, 41.9 mmol). The reaction mixture was stirred at 60° C. for 6 h. The mixture was cooled to RT and was poured into an ice/2M aqueous hydrochloric acid mixture (100 mL). After vigorous stirring, the mixture was extracted with DCM (2×75 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give 8.68 g (quantitative yield) of crude title compound as an orange oil.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:2][CH2:3][CH2:4][OH:5])=[C:9]([C:14]([F:15])([F:16])[F:17])[CH:8]=1
Reactant: OCCCI
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: OCCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
3-Iodopropanol (11.23 g) was added to a mixture of 4-bromo-2-(trifluoromethyl)-phenol (15 g) and potassium carbonate (172 g) in acetonitrile (150 ml). The above mixture was refluxed for 4 hours then diluted with ethyl acetate (500 ml) and water (300 ml). Organic layer was seperated, dried over magnesium sulphate, solvent removed under reduced pressure to give expected product clean enough for use at the next step (18.6 g). 1H NMR (CDCl3) δ: 7.67 (d, 1H), 7.58 (dd, 1H), 6.90 (dd, 1H), 4.18 (t, 2H), 3.87 (q, 2H), 2.07 (tt, 2H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C1C(=O)N([Br:30])C(=O)C1>C(Cl)Cl>[Br:30][C:19]1[S:18][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:21]([CH3:22])[CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(CC)c1cc(C)nn2c(-c3sccc3C)c(C)nc12
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 8-(1-Ethyl-propyl)-2,6-dimethyl-3-(3-methyl-thiophen-2-yl)-imidazo[1,2-b]pyridazine (8.83 g, 28.17 mmol) and CH2Cl2 (90 mL) is added NBS (5.26 g, 29.58 mmol). The solution is stirred at ambient temperature for 2 hours. The solution is washed with water (3×75 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (10.5 g, 26.76 mmol, 95%). 1H NMR (CDCl3), δ 0.87 (t, J=7.3 Hz, 6H), 1.73-1.93 (m, 4H), 2.09 (s, 3H), 2.44 (s, 3H), 2.51 (s, 3H), 3.26-3.36 (m, 1H), 6.68 (s, 1H), 6.98 (d, J=4.9 Hz, 1H) ppm. LC/MS (m/z): calcd. for C18H22BrN3S (M+H)+: 392.6; found: 392.1, 394.1.
Reaction SMILES: [N:1]1([CH:6]2[CH:11](O)[C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[O:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[NH4+].[OH-]>C(O)(=O)C>[N:1]1([C:6]2[CH2:7][O:8][C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: OC1c2cc(Cl)ccc2OCC1n1ccnc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)C=C(n1ccnc1)CO2
Temperature: 0 °C
Yield: 77.8 %

Procedure:
A solution of 3-(1-imidazolyl)-2,3-dihydro-6-chloro-4H-1-benzopyran-4-ol (5.4 g), acetic acid (81 ml) and sulphuric acid (27 ml) was heated at 80° C. for 8 hours. The solution, poured into ice water (200 ml), neutralized with NH4OH, extracted with CH2Cl2, dried and evaporated to dryness gave 3.9 g of 3-(1-imidazolyl)-6-chloro-2H-1-benzopyran, m.p. 118°-120° C. (isopropyl alcohol).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH:20]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[CH3:23]>>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]([CH3:19])[C:16](=[O:18])[NH:17][C:12]=2[CH:11]=[C:10]([CH2:20][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:25]([NH:24][CH2:22][CH3:23])=[O:38])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(Cc3ccccc3)cc(C=O)cc2NC1=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc(Cc4ccccc4)c4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Using 353A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as a light grey solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.32 (d, J=6.82 Hz, 3H) 2.41-2.49 (m, 4H) 3.16-3.29 (m, 6H) 3.38 (s, 2H) 3.89 (s, 2H) 4.53-4.60 (m, 1H) 6.75-6.82 (m, 2H) 6.93 (m, 2H) 7.14-7.19 (m, 1H) 7.19-7.23 (m, 2 H) 7.24-7.29 (m, 2H) 7.71 (m, 2H) 8.17 (t, J=5.68 Hz, 1H) 10.59 (s, 1H). ESI-MS: m/z 499.4 (M+H)+. mp=198.1-205.7° C.
Reaction SMILES: [CH:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[CH2:16]([O:15][C:13]([C:12]1[N:8]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:9][CH:11]=1)=[O:14])[CH3:17]
Reactant: NC(=S)C1CCCCC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1csc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of cyclohexanecarbothioic acid amide (115, 5.5 g, 38.3 mmol) and ethyl 3-bromopyruvate (90%, 8.3 g, 38.3 mmol) in THF (200 mL) was heated to reflux. After 2 h, the reaction mixture was cooled to room temperature for 12 h. Then, the solvent was evaporated and the residue was purified by column chromatography (gradient of heptane/AcOEt, 90:10 to 75:25) to afford 6.8 g (74%) of the title compound 116 as a clear liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:10]([C:7]2[CH:8]=[CH:9][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH:6]=2)=[O:12])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1ccc2sccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc3sccc3c2)Cc2ccccc2C1
Yield: 88.6 %

Procedure:
To a 40 mL vial containing a stirring bar, benzo[b]thiophene-5-carboxylic acid (434 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and DIPEA (0.95 mL, 8 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 64 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.4 g of an off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 4 through 16 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.79 g.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CO.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: CO
Product: COc1cccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)c1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 3-methoxyaniline (61.6 mg, 0.50 mmol) as described in General Procedure X to afford Iag (26 mg, 37.7%) as an ivory colored solid, tlc Rf=0.6 (5% MeOH/CH2Cl2−0.2% Et3N), m/z obs=404 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:19][NH2:20].C(O)(=O)C>O>[NH:19]([C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[NH2:20]
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cn1cnc2c(NN)nc3ccccc3c21

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (10.0 g, 0.0385 moles, U.S. Pat. No. 4,689,338 Example 77) was added to hydrazine (30 mL). The mixture heated rapidly to reflux. The solid dissolved with a vigorous heat of reaction then a precipitate formed as the reaction mixture refluxed. The reaction mixture was diluted with water. The precipitate was isolated by filtration then suspended in water (100 mL). The solid was brought into solution by the addition of acetic acid. The solution was filtered to remove traces of undissolved solid. The filtrate was made basic by the addition of ammonium hydroxide. The resulting precipitate was isolated by filtration, washed with water then dried to provide 8.0 g of crude product as a white solid. A sample of this material was recrystallized from methanol to provide 4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 202°-205° C. Analysis: Calculated for C14H17 N5 : % C, 65.86; % H, 6.71; % N, 27.43; Found: % C, 65.20; % H, 6.6; % N, 27.5.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([C:27]1[S:31][C:30]([S:32][CH3:33])=[N:29][CH:28]=1)=[C:7]2[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][C:40](Cl)=[O:41].C(N(CC)CC)C>O1CCCC1>[CH:14]([O:13][C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[C:27]1[S:31][C:30]([S:32][CH3:33])=[N:29][CH:28]=1)[CH:2]([NH:1][C:40](=[O:41])[CH2:39][C:35]1[S:34][CH:38]=[CH:37][CH:36]=1)[C:9]2=[O:10])=[O:12])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4cccs4)C3SC2)s1

Procedure:
Crude 7-amino-2-benzhydryloxycarbonyl-3-(2-methylthiothiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.3 g) is dissolved in tetrahydrofuran (30 cc) and is then acylated with (thien-2-yl)-acetyl chloride (0.83 cc) in the presence of triethylamine (0.94 cc) in accordance with the working method described in Example 1. The crude product obtained is chromatographed on a column (height: 30 cm; diameter: 4 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 1 bar (100 kPa), with a 70:30 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 16 to 27, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C., and the residue is triturated with isopropyl ether (30 cc). 2-Benzhydryloxycarbonyl-3-(2-methylthio-thiazol-5-yl)-8-oxo-7-(thien-2-yl-acetamido)-5-thia- 1-azabicyclo[4.2.0]oct-2-ene (1.6 g) is obtained in the form of a yellow solid.
Reaction SMILES: C1COCC1.[C:6]1([Mg]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[O:25][CH2:24][CH2:23][O:22]1.C(OCC)C>CCCCCC>[C:19]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:15][CH:20]=1
Reactant: Clc1ccccc1C1OCCO1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2ccc(C3OCCO3)cc2)cc1
Reaction time: 48 h
Yield: 88 %

Procedure:
Using a THF solution of phenylmagnesium bromide (1.34 mL, 1.01 M, 1.35 mmol) and 2-chlorophenyl-[1,3]-dioxolan (184.6 mg, 1.0 mmol) as starting material, the reaction was performed at a scale of 1.0 mmol at 70° C. for 48 hours in the same manner as in Example 2. After performing silica gel column chromatography (diethylether=5, 10 and 20% in hexane), the above compound was obtained as a white solid (0.199 g, yield=88%, purity=>99% (GC analysis)).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1.O.NN>C(O)C>[NH2:3][CH2:12][C@H:13]([NH:26][C:27](=[O:36])[C@H:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:18][CH:19]=1
Reactant: CC[C@H](C)COc1ccc([C@H](CN2C(=O)c3ccccc3C2=O)NC(=O)[C@@H](C)c2ccccc2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC[C@H](C)COc1ccc([C@H](CN)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 60 °C
Yield: 51.3 %

Procedure:
A mixture of (S)-N-((R)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-(4-((S)-2-methyl-butoxy)-phenyl)-ethyl)-2-phenyl-propionamide (320 mg, 0.66 mmol) and ethanol (20 mL) was treated dropwise with hydrazine monohydrate (0.32 mL, 6.6 mmol), and the resulting reaction was maintained at 60° C. overnight. The mixture was allowed to cool to room temperature and the solids were removed by filtration. The filtrate was concentrated to dryness, and triturated with ethyl acetate (15 mL), and the mixture was filtered. The collected solids were air dried, then dissolved in diethyl ether (5 mL). The resulting solution was treated with concentrated HCl (0.05 mL), and the precipitate was collected by filtration to afford (2S)-N-((1R)-2-amino-1-[4-((S)-2-methylbutoxy)phenyl]-ethyl)-2-phenylpropionamide (120 mg, 52% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 7.21-7.31 (m, 5H), 7.09 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 5.12 (dd, J=8.8, 5.8 Hz, 1H), 3.81 (dd, J=9.3, 6.1 Hz, 1H), 3.70-3.77 (m, 2H), 3.23-3.30 (m, 2H), 1.81 (s, 1H), 1.57 (ddd, J=13.4, 7.6, 5.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.24-1.33 (m, 1H), 1.02 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LRMS (ESI) m/e 355.1 [(M+H)+, calcd for C22H31N2O2 355.5].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:38])=[C:17]([NH:19][C:20](=[O:37])[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH:18]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:27]([NH:26][C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([NH:19][C:17]2[CH:18]=[C:13]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:14]=[CH:15][C:16]=2[CH3:38])=[O:37])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc(C)c(NC(=O)COCC(=O)Nc2ccc(Cl)cc2C(=O)O)c1

Procedure:
Using the same method as in Example 19-(ii), 2-methoxybenzene boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester to give 5-chloro-2-[((2-[(2′-methoxy-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[N:20]=[C:21]([CH2:24]Br)[S:22][CH:23]=1)=[O:18])C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:24][C:21]2[S:22][CH:23]=[C:19]([C:17]([OH:18])=[O:16])[N:20]=2)[CH:8]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)c1csc(CBr)n1
Product: O=C(O)c1csc(COc2cccc(-c3ccccc3)c2)n1

Procedure:
2-(Biphenyl-3-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 3-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 65 mg. Mass spectrum (ES) MH+=312.
Reaction SMILES: [CH3:1][C:2]1([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C@H:18]4[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]4[NH:16][C:15]3=[O:23])[CH2:10][CH2:9]2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:2]3([CH3:1])[CH2:7][CH2:6][N:5]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:4][CH2:3]3)[CH2:9][CH2:10]2)[C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CCOC(=O)Cl
Reactant: CC1(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(C)(N2CCC(N3C(=O)N[C@@H]4CCCC[C@@H]43)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of crude (cis)-1-[1-(4-methyl-4-piperidyl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (HCl salt, 0.3 g) in dichloromethane (10 mL) was added diisopropylethyl amine (0.337 g, 2.61 mmol) followed by a solution of ethyl chloroformate (0.119 g, 1.09 mmol) in dichloromethane (1 mL) dropwise over 30 minutes at 0° C. and the mixture stirred at this temperature for 2 h. The mixture was then quenched by ice and diluted with dichloromethane and aqueous phase was extracted with dichloromethane. The combined organic phases were dried and concentrated in vacuo. The residue was then purified by preparative LC/MS (high pH) to provide the title compound as an off white solid (60 mg, 18%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88 (s, 3H), 1.07-1.21 (m, 1H), 1.23 (t, J=7.03 Hz, 3H), 1.29-1.43 (m, 3H), 1.45-1.92 (m, 13H), 2.02-2.24 (m, 2H), 2.81-3.01 (m, 2H), 3.23-3.40 (m, 2H), 3.41-3.69 (m, 5H), 4.10 (q, J=7.29 Hz, 2H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C@:20]2([CH3:26])[CH2:24][O:23]C(=O)[NH:21]2)[CH:14]=[CH:13]3)[CH2:5][CH2:4]1)[CH3:2].C(O)C.O.[OH-].[Li+]>O>[NH2:21][C@@:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C@H:6]3[CH2:5][CH2:4][C@@H:3]([CH2:1][CH3:2])[CH2:8][CH2:7]3)[CH:11]=2)[CH:16]=1)([CH3:26])[CH2:24][OH:23]
Reactant: CC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H]1CC[C@@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Temperature: 80 °C
Yield: 8.9 %

Procedure:
(R)-4-[6-(cis-4-Ethyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.4603 g, 0.001302 mol) was dissolved in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL) was added and the mixture was heated overnight at 80° C. TLC analysis showed the reaction was complete. The mixture was concentrated to dryness under vacuum. Methylene chloride (5 mL) and water (5 mL) were added and the layers were separated by phase separator cartridge. The organic layer was dried with MgSO4, filtered, concentrated and purified by HPLC to give 0.038 g of the title compound (9% yield). MS: m/z=311.26 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.95 (t, J=7.15 Hz, 3 H), 1.28-1.38 (m, 3 H), 1.39-1.50 (m, 2 H), 1.58-1.74 (m, 4 H), 1.80 (s, 3 H), 2.04-2.14 (m, 2 H), 3.83 (d, J=11.55 Hz, 1 H), 3.94 (d, J=11.55 Hz, 1 H), 4.76 (br. s., 1 H), 7.21-7.30 (m, 2 H), 7.53 (dd, J=8.91, 1.88 Hz, 1 H), 7.82-7.88 (m, 3 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].CO.[Br:14]N1C(=O)CCC1=O>[H-].[Na+].C(Cl)Cl>[Br:14][C:7]1[CH:6]=[C:5]([O:9][CH3:10])[C:4]([OH:11])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cccc(OC)c1O
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)cc(OC)c1O
Temperature: -45 °C
Yield: 63.5 %

Procedure:
To a 2 liter flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet, was added 77 g (0.5 mol) of pyrogallol 1,3-dimethyl ether. 5.8 ml of MeOH, and 750 ml of CH2Cl2. To this solution was added 126 mg (5 mmol) of NaH (95%). The solution was stirred while cooling to −45° C. with a dry-ice acetone bath. 94 g (0.53 mol) of powdered N-bromosuccinimide was added rapidly. The reaction mixture was then stirred for 1 hour at −35° C., heated to room temperature over next 30 min, and finally refluxed for 30 min. The CH2Cl2 was removed under reduced pressure and the residue solidified. The tan solid was broken up and stirred well with 1 liter of ether. This was filtered and the residue was washed well with ether. The ether was evaporated under reduced pressure to yield a tan solid. The solid was placed in a 5 liter flask with 3 liters of ligroin (bp: 90-110° C.) and heated with stirring to 80° C. The hot solution was decanted from the brown oil and the hot yellow solution was allowed to cool at room temperature for 3 hr. The white needles was filtered off and dried to yield 74 g (63%) of 17.