Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.Cl.Cl.[CH3:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[N:6]=[C:5]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][C:15]3[CH:24]=[CH:25][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)[CH2:23][CH2:22]2)[S:4][N:3]=1
Reactant: Clc1nc(Br)ns1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN2CCN(c3nc(Br)ns3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (300 mg, 1.5 mmol), 1-(4-methoxyphenethyl)piperazine dihydrochloride (485 mg, 1.65 mmol) and DIPEA (641 mg, 867 μl, 4.96 mmol) in EtOH (10 mL) was stirred over night at ambient temperature. The mixture was concentrated in vacuo and the residue was purified by silica column chromatography eluting with a gradient formed from heptane and ethyl acetate to yield after evaporation of the product containing fractions 489 mg (85%) of the title compound as off-white solid. MS (m/e): 383.2 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccccc1
Yield: 51.5 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) and benzoyl chloride (0.64 mL, 5.5 mmol) in pyridine (10 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (0.75 g). Mp 178-180° C.; Anal. Calcd. for C19H17NO2: C, 78.33; H, 5.88; N, 4.81; Found: C, 78.10; H, 5.86; N, 4.81.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:35][S:36]([CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:38])=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][S:36]([CH3:35])(=[O:37])=[O:38])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[C:24]([O:30][CH2:31][CH3:32])=[N:25][C:26]([CH3:29])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1nc(C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 16) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (example 3) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C30H34N6O4SCl2 [(M+H)+] 645.1812, observed 645.1814.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20]CO)[CH3:19])[CH3:14].CO>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:12][CH:13]([CH3:14])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)CCCC(C)CCO
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCOC(=O)c1ccc(N)cc1
Yield: 28.8 %

Procedure:
Na metal (200 mg, cat.) was added to a suspension of methyl 4-aminobenzoate (45 g, 300 mmol), tetrahydrogeraniol (48 g, 300 mmol) in PhMe (250 mL). The suspension was heated under reflux for 3 hours with the azeotropic removal of MeOH. The mixture was cooled and filtered through a plug of silica (400 mL) with cyclohexane: EtOAc (9:1) as eluant to give the ester (24 g, 30%) as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10]([C:13]1[C:14]2[CH:15]=[CH:16][N:17]=[CH:18][C:19]=2[CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:22]=1)(=[O:12])=[O:11])(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[ClH:32].[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:22]=[C:13]([S:10]([CH2:9][CH2:8][NH2:7])(=[O:12])=[O:11])[C:14]3[CH:15]=[CH:16][N:17]=[CH:18][C:19]=3[CH:20]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2cc(S(=O)(=O)CCNC(=O)OC(C)(C)C)c3ccncc3c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(S(=O)(=O)CCN)c3ccncc3c2)cc1
Yield: 99 %

Procedure:
Treat a slurry of {2-[7-(4-methoxy-phenyl)-isoquinoline-5-sulfonyl]-ethyl}-carbamic acid tert-butyl ester (11.00 g, 24.85 mmol) in anhydrous MeOH (150 mL) with 4N HCl in dioxane (350 mL). Stir the resulting reaction mixture at room temperature overnight, then concentrate in vacuo to ½ volume and treat with excess EtOAc, causing a yellow solid to precipitate. Recover the resulting solid by vacuum filtration under an N2 atmosphere; wash with EtOAc and dry under vacuum (under an N2 atmosphere) to afford the title compound (10.23 g, 99% yield) as a yellow solid: MS (ES): m/z 343.0 (M++H).
Reaction SMILES: [Mg].[N+:2]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].C1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>CCOCC>[C:18]([O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
Magnesium turnings (1.2 g) were added to a solution of m-nitrophenol (6.95 g), benzene (40 ml) and acetyl chloride (4 g) and the solution heated for 1 hour at 90° C. The reaction mixture was diluted with ether and decanted from unreacted magnesium. The ether layer was washed successively with water, dilute NaOH and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to give m-nitrophenyl acetate. m.p. 55°-56° C. 1H n.m.r. δ2.4, s, 3H, H3C--CO--; 7.4-8.4, m, 4H, ArH. υmax 1770 cm-1.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:13]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C@@H:22]1Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([C@@H:22]3[O:23][C@H:24]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:21]3[O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A suspension of 240 mg of sodium hydride, 1.54 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, and 6 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 15 minutes, cooled, and added to 4.83 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride in 4 ml of DMF. The solution is stirred at ambient temperature for two hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate-water. Chromatography of the dried ethyl acetate layer over silica gel with 4:1 benzene-ethyl acetate provides 3.3 g of yellow, syrupy 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18]C3C=CC=CC=3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][C:31](S)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([C:31]3[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(c2ccc([N+](=O)[O-])cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-benzyl-1H-pyrazol-5(4H)-one and 4-nitrobenzenethiol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.99 (s, 3H) 6.65 (s, 1H) 7.03-7.10 (m, 2H) 7.44 (d, J=8.34 Hz, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.08 (d, J=8.08 Hz, 2H) 13.12 (bs, 1H); ESI-MS: m/z calc'd for C19H14N4O3S 378.08. found 379.2 (M+H)+.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>C(#N)C>[CH2:35]([NH:37][C:38]([NH:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:34])[N:18]([C:25]1([CH3:33])[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24])=[O:39])[CH3:36]
Reactant: CCN=C=O
Reactant: CC1(N2C(=O)c3cccc(CN)c3C2=O)CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)NCc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.2 g, 2.2 mmol) was added to a stirred suspension of 4-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.3 g, 1.0 mmol) in acetonitrile (40 mL). After stirring for 30 minutes, ethyl isocyanate (0.09 g, 1.3 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The mixture was concentrated and the residue was dissolved in methylene chloride (60 mL). The methylene chloride solution was washed with water (2×30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed and purified by chromatography (silica gel) to give 1-ethyl-3-[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.2 g, 55%) as a white solid: mp 220-222° C.; 1H NMR (DMSO-d6) δ 0.99 (t, J=7.1 Hz, 3H, CH3), 1.90 (s, 3H, CH3), 2.03-2.09 (m, 1H), 2.50-2.74 (m, 3H), 2.97-3.07 (m, 2H), 4.59 (d, J=5.8 Hz, 2H), 6.09 (t, J=5.0 Hz, 1H), 6.41 (t, J=5.6 Hz, 1H), 7.65-7.82 (e, 3H, Ar), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 15.59, 21.01, 28.58, 29.11, 34.16, 38.65, 58.69, 121.25, 126.64, 131.37, 133.26, 134.46, 140.79, 157.92, 167.78, 168.41, 172.14, 172.22; Anal. calcd. for C18H20N4O5+0.08H2O: C, 57.83; H, 5.44; N, 14.99. Found: C, 57.26; H, 5.21; N, 14.79.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: COc1ccc(N(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CNC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(p-anisidino)butyric acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(p-anisidino)butyryl]glycinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(p-anisidino)butyryl]glycine (viscous oil).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[I:10]I.[OH-].[K+]>CN(C)C=O>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Ic1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
To a stirred solution of indole 7 (1.0 eq.) in dimethylformamide (4.4 mL/mmol) under argon was added iodine (1.98 eq.) and potassium hydroxide (1.0 eq.). The reaction mixture was stiffed for 3 hours. The reaction mixture was quenched by addition of water (8.8 ml/mmol) and product precipitated, which was filtered and dried. The solid was resubmitted to reaction conditions (dimethylformamide (4.4 mL/mmol) under argon, iodine (0.4 eq.) and potassium hydroxide (0.2 eq.) and stiffed for 1 h) to convert the remaining starting material. The reaction mixture was quenched by addition of water (8.8 ml/mmol) and product precipitated, which was filtered and dried to afford 3-iodoindole 8. Beige solid. 1H NMR (d6-DMSO, 400 MHz) δ 1.39 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 7.35-7.42 (m, 2H), 12.66 (s, 1H), 19F NMR (d6-DMSO, 376 MHz) δ −126.87, MS (ESI−) m/z=366.13 (M−H)− 100%, 368.15 (M−H)− 35%.
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[S:9]1[CH2:14][CH2:13][CH:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1>C1COCC1>[O:16]=[C:15]([CH:12]1[CH2:13][CH2:14][S:9][CH2:10][CH2:11]1)[CH2:1][C:2]#[N:3]
Reactant: CC#N
Reactant: COC(=O)C1CCSCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCSCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A solution of CH3CN (48.7 mmol, 2.54 mL) in 10 mL of THF was added dropwise to a solution of nBuLi (48.7 mmol) in 15 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of methyl tetrahydro-2H-thiopyran-4-carboxylate (24.3 mmol, 3.90 g) in 10 mL of THF was added dropwise and the resulting reaction mixture was stirred at −78° C. for 1 h, and then slowly warmed to −40° C. in 2 h. The reaction was quench with 1 N HCl (pH<1). THF was removed and the residue was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes) to afford 3-oxo-3-(tetrahydro-2H-thiopyran-4-yl)propanenitrile (3.60 g, 87.5%) as a light brownish oil. LCMS tR=1.29 Min. Mass calculated for, M+ 1694.1, observed LC/MS m/z 170.1 (M+H)
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.C1N=C[N:23](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:23])=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (77 mg, 0.28 mmol, 1.0 eq.) and CDI (101.3 mg, 0.62 mmol), 2.5 eq.) in DMF (3.0 mL) was added Ammonium carbonate (123.3 mg, 1.28 mmol, 4.5 eq.). The mixture was stirred at room temperature overnight. The mixture was treated with H2O (5 mL) and the layers were separated. The aqueous was extracted with EtOAc (2×5 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as a white solid. LCMS (m/z) 270 (M+H); 1H NMR (DMSO-d6) δ: 9.14 (s, 1H), 7.87-7.92 (m, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 4H), 4.93 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:31])[CH:28]([CH3:30])[CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[C:32]([O-:35])(=O)[CH3:33].[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][C@@H:27]([NH:31][C:16]([CH:18]3[CH2:33][CH2:32][O:35][CH2:23]3)=[O:17])[CH:28]([CH3:29])[CH3:30])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(C)C(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)[C@@H](CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)NC(=O)C1CCOC1

Procedure:
The desired compound was prepared following Method E from Intermediate 61 and the appropriate acid. 1H-NMR (300 MHz, methyl-d3 alcohol-d): δ 0.87 (m, 6H), 1.25 (d, 3H), 1.37 (d, 3H), 1.81 (m, 1H), 2.10-2.47 (m, 4H), 2.93 (m, 2H), 3.10 (m, 1H), 3.26 (m, 1H), 3.80 (m, 1H), 3.86-4.07 (m, 6H), 7.86 (d, 1H), 8.10 (m, 2H), 8.32 (d, 1H), 8.89 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.73 min. MS (M+H+): 542.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20]1([S:26]([OH:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.C1C=CC=CC=1>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH2:9][CH:8]([S:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])=[O:27])[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: O=S(O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1CC(S(=O)(=O)c2ccccc2)C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Yield: 88 %

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were dissolved in 250 ml. of benzene, 15 g. of freshly generated benzene sulfinic acid were added and then a few drops of water were added. This reaction mixture was heated at 40°-45° C. for 12 hours and then the benzene was evaporated. The white solid residue obtained was recrystallized from benzene twice and yielded white crystals, m.p. 157°-158° C. The yield was about 88%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=O)[CH2:30][C:31](OCC)=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:38][NH2:39]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:39][N:38]=[C:31]([OH:32])[CH:30]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Solvent: CCO
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2cc(O)n[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To a solution of 42 mg (0.08 mmol) of ethyl 4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in ethanol (4 mL) was added 36 μL (0.48 mmol) hydrazine monohydrate (64-65% weight percent hydrazine). The resulting colorless solution was heated at 65° C. for 3.5 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 45% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[NH:3]1.C1C=CC2N(O)N=[N:26][C:24]=2C=1.C(Cl)CCl.CN>CN(C=O)C>[CH3:24][NH:26][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH2:10][C:2](=[O:1])[NH:3]3)[CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: O=C1Cc2c(cccc2-c2cccc(C(=O)O)c2)N1
Agent: CN
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A mixture of 3-(2-oxo-2,3-dihydro-1H-indol-4-yl)benzoic acid (1.27 g, 5.0 mmol), HOBt (0.68 g, 5.0 mmol) and EDC (1.44 g, 7.5 mmol) in DMF (10 mL) was stirred at room temperature for 30 minutes. To the mixture was added methylamine (2M in THF, 3.75 mL, 7.5 mmol), it was then stirred at room temperature for overnight. Most of the solvent was removed under reduced pressure and the residue was diluted with sat. NaHCO3 (20 mL). The precipitate was collected by filtration, washed with water and dried. The crude product was recrystallized from DCM-hexane to give 1.14 g (86%) of N-methyl-3-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzamide as a light yellow solid.
Reaction SMILES: [NH2-].[Na+].C([O:10][C:11](=O)[C@H:12]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[N:13]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[CH3:55][S:56]([CH3:58])=[O:57]>O1CCCC1>[CH2:14]([N:13]([C@@H:12]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:11](=[O:10])[CH2:55][S:56]([CH3:58])=[O:57])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CS(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 74.5 °C
Yield: 85.6 %

Procedure:
3.76 g (96.39 mmol) of sodium amide was suspended in 40 ml of dimethylsulfoxide and heated at from 74 to 75° C. for 30 minutes. 40 ml of tetrahydrofuran was added to the resulting solution and cooled to 0° C. To this was dropwise added a solution of 15.47 g (90.5 wt. %, 32.14 mmol) of N,N-dibenzyl-(L)-phenylalanine benzyl ester as dissolved in 20 ml of tetrahydrofuran, while keeping it at 0° C. After these were reacted at 0° C. for 30 minutes, 120 ml of an aqueous solution of 10% citric acid and 100 ml of ethyl acetate were added to the reaction mixture, which was thus subjected to phase separation. The aqueous layer thus separated was extracted once with 50 ml of ethyl acetate, and the resulting extract was combined with the previously-separated organic layer and then washed with 60 ml of a saturated saline solution. This was dried with anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=from 2/1 to 1/3) and then crystallized in toluene/hexane to obtain 11.16 g of the above-entitled compound. The yield was 85.6%. The integral ratio in 1H-NMR of the compound verified that the ratio of the diastereomers constituting it is about 1:1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:18])=[C:9]([NH:11]C(=O)C(F)(F)F)[CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[NH2:11][C:9]1[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[CH3:18]
Reactant: CC(=O)Nc1ccc(C)c(NC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1ccc(C)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(5-Acetylamino-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.93 g, 11.24 mmol) was taken up in methanol (50 mL) and sodium carbonate (5.96 g, 56.20 mmol) was added. The reaction was stirred at room temp for 12 h. The reaction mixture was into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was utilized without further purification. Yield 1.60 g. 1H NMR (CDCl3, 300 MHz): 82.16 (s, 3H). 2.31 (s, 3H), 7.18 (d, J=9 Hz, 1H), 7.32 (d, J=9 Hz, 1H), 7.64 (s, 1H).