Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2[C:40]([O:42][CH2:43][CH:44]2[C:56]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:41])=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-])=O)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl>>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[C@H:9]([NH:27][C:28]([C@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2[C:40]([O:42][CH2:43][CH:44]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:50]=3[C:51]3[C:56]2=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:41])=[O:29])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17][CH2:16]1
Reactant: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2[N+](=O)[O-])CC1)[C@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Yield: 57.8 %

Procedure:
Fluoren-9-ylmethyl (3R)-3-(N-{(1R)-2-[4-(2-aminophenyl)piperazinyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared according to the procedure for Preparation II using fluoren-9-ylmethyl (3R)-3-(N-{(1R)-1-[(4-chlorophenyl)methyl]-2-[4-(2-nitrophenyl)-piperazinyl]-2-oxoethyl}carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (1.4 g, 1.8 mmol) and SnCl2.2H2O (1.7 g, 7.3 mmol) (Aldrich). The crude product was purified by flash chromatography (SiO2, 1:1 EtOAc:hexane) and concentrated in vacuo to afford the desired compound (770 mg). MS (ESI, pos. ion) m/z: 740 (M+H), (ESI, neg. ion) m/z: 738 (M−H). Calc'd for C44H42ClN5O4: 739.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]([CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:10]1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([C:14]2[CH:15]=[N+:16]([O-:35])[CH:17]=[CH:18][CH:19]=2)=[CH:12][C:11]([CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[N:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1cccnc1
Solvent: ClCCl
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc[n+]([O-])c1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 3-[1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-pyridine (9 mg, 0.023 mmol) (Example 44) in 1 mL of DCM at Rt was added m-chloroperoxybenzoic acid (60%)(7.9 mg, 0.028 mmol) and the mixture stirred for 1 hr at Rt. The solvents were evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 30-70% CH3CN in 0.1% TFA/H2O over 10 mins to give 8 mg (71%) of the title compound as white solid containing 0.5 eq of TFA.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:34][CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 1-(bromomethyl)-4-(trifluoromethyl)benzene in a manner similar to that described in Example 25 as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.69-7.63 (m, 1 H), 7.60 (d, J=8.0 Hz, 2 H), 7.44-7.32 (m, 5 H), 7.06 (d, J=3.5 Hz, 1 H), 6.28 (d, J=3.5 Hz, 1 H), 5.71-5.51 (m, 3 H), 2.76 (s, 3 H), 2.48 (s, 3 H), 0.96 (s, 9 H); LCMS (m/z) ES+=511 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][C:30]([C:33]4[NH:34][C:35]5[CH:41]=[C:40]([C:42]([OH:44])=O)[CH:39]=[CH:38][C:36]=5[N:37]=4)([CH3:32])[CH3:31])=[O:28])=[CH:23][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:45][NH:46][CH3:47].O1CCCC1.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O.O.CO>[CH3:45][N:46]([CH3:47])[C:42]([C:40]1[CH:39]=[CH:38][C:36]2[N:37]=[C:33]([C:30]([NH:29][C:27]([C:24]3[CH:25]=[CH:26][C:8]4[C:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[C:16]5[N:10]([CH2:11][CH2:12][O:13][C:14]6[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=65)[C:9]=4[CH:23]=3)=[O:28])([CH3:32])[CH3:31])[NH:34][C:35]=2[CH:41]=1)=[O:44]
Reactant: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)c3nc4ccc(C(=O)O)cc4[nH]3)cc21
Reactant: CNC
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)NC(C)(C)c3nc4ccc(C(=O)N(C)C)cc4[nH]3)cc21
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-{1-[(12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-1-methylethyl}-3H-benzimidazole-5-carboxylic acid (0.07 g, 0.12 mmol) in N,N-dimethylformamide (1.0 ml) were successively added 2M dimethylamine-tetrahydrofuran solution (0.30 ml, 0.59 mmol), N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (0.03 g, 0.15 mmol) and 1-hydroxybenzotriazole monohydrate (0.02 g, 0.15 mmol) at room temperature, and the mixture was stirred overnight. Saturated aqueous sodium hydrogen carbonate solution, methanol and water were added to the reaction mixture. The precipitate was collected by filtration, washed with water, and dried in vacuo to give N-[1-(6-dimethylcarbamoyl-1H-benzimidazol-2-yl)-1-methylethyl]-12-cyclohexyl-3-methoxy-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxamide (0.05 g, yield 63%).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH:17]([O:19]CCCC)=[CH2:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd]Cl.CC(O)C>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[N:6]1[C:5]2[CH:15]=[CH:16][C:2]([C:17](=[O:19])[CH3:18])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Brc1ccc2c(c1)ncn2C1CCCCO1
Reactant: C=COCCCC
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.1 %

Procedure:
A mixture of 80 (2.81 g, 0.01 mol), butyl vinyl ether (1.5 g, 0.015 mol), PdCl2 (26 mg, 0.14 mmol), (o-tolyl)3P (88 mg, 0.29 mmol), K3PO4 (1.5 g, 0.02 mol), and IPA (20 ml) was heated at reflux under nitrogen overnight. The mixture was cooled to RT and the solvent was removed in vacuo. To the residue was added 6M HCl (60 mL) and the resulting solution stirred for 15 min. The mixture was adjusted to pH 8 with aqueous NH4OH (35%) and was extracted with EtOAc (300 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (5 to 10% MeOH) to afford 1.2 g (86%) of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethanone (82) as yellow oil: MS (ESI) m/z=245.3 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([O:25][C:26]2[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[C:28]([Cl:34])[CH:27]=2)[C:18]=1[F:35])C(=O)[O-])(C)C>C(Cl)Cl>[NH2:12][CH2:16][C:17]1[C:18]([F:35])=[C:19]([O:25][C:26]2[CH:31]=[C:30]([CH:29]=[C:28]([Cl:34])[CH:27]=2)[C:32]#[N:33])[C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=1
Reactant: CCc1ccc(CN(C(=O)[O-])C(C)(C)C)c(F)c1Oc1cc(Cl)cc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 16 h
Yield: 101 %

Procedure:
TFA (1.903 ml, 24.70 mmol) was added to a solution of 1,1-dimethylethyl({3-[(3-chloro-5-cyanophenyl)oxy]-4-ethyl-2-fluorophenyl}methyl)carbamate (0.5 g, 1.235 mmol) in DCM (30 mL) at RT under an atmosphere of nitrogen. After 16 h, the solution was concentrated under vacuum. Saturated NaHCO3 solution (100 mL) and ethyl acetate (100 mL) were added and the mixture was stirred for 1 h. The organic layer was separated, washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (0.38 g, >99%) as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29-7.33 (m, 1H), 7.21-7.27 (m, 1H), 7.13 (t, 1H), 7.09 (d, 1H), 6.98 (s, 1H), 3.92 (s, 2H), 2.54 (d, 2H), 1.54 (d, 2H), 1.13-1.19 (m, 3H).
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.S(=O)(=O)(O)O>>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: Oc1ccccn1
Agent: O=S(=O)(O)O
Product: O=c1ccccn1C(c1ccccc1)c1ccccc1

Procedure:
Combine 92.1 g (0.5 mole) of benzhydrol with 142.7 g. (1.5 mole) of 2-hydroxypyridine and heat to 190° C. with stirring. Add 1.5 ml. of concentrated sulfuric acid and follow the procedure of Example III, step A to obtain thereby the product of this step yield 68 g., m.p. 142°-145° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[C:19]([C:23]1[O:24][C:25]([CH3:31])=[C:26]([CH2:28][CH2:29]O)[N:27]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:29][CH2:28][C:26]2[N:27]=[C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])[O:24][C:25]=2[CH3:31])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1oc(C(C)(C)C)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(C(C)(C)C)oc2C)cc1C)OCC

Procedure:
In analogy to the Mitsunobu-procedure described in example 1, step f, [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 46 b]) was reacted with 2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethanol (example 1, step e]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield [rac]-3-{4-[2-(2-tert-butyl-5-methyl-oxazol-4-yl)-ethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH2:38][CH2:39][CH2:40][CH3:41])[C:3]([NH:5][CH2:6][C@H:7]([OH:37])[C@@H:8]([NH:29]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([CH2:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:17][CH:16]=1)[CH:11]([CH3:13])[CH3:12])=[O:4]>Cl.CO>[NH2:29][C@@H:8]([CH2:9][C@H:10]([CH2:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][N:21]2[CH2:24][CH2:25][CH2:26][O:27][CH3:28])=[CH:17][CH:16]=1)[CH:11]([CH3:13])[CH3:12])[C@@H:7]([OH:37])[CH2:6][NH:5][C:3](=[O:4])[C:2]([CH3:42])([CH3:1])[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@@H](N)C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
tert-Butyl (2S,3S,5S)-1-(2,2-dimethylhexanamido)-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (335 mg, 75%) (83 mg, 0.15 mmol) was dissolved in a solution of 2N HCl in methanol (6 mL) and the reaction mixture was stirred at 40° C. for 2 h. The solvent was removed in vacuo to produce N-((2S,3S,5S)-3-amino-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptyl)-2,2-dimethylhexanamide (58 mg, 80%). 1H NMR (400 MHz, CDCl3): 0.86 (m, 3H), 0.92 (m, 3H), 0.99 (m, 3H), 1.13 (s, 6H), 1.16 (m, 2H), 1.27 (m, 3H), 1.49 (m, 2H), 1.70 (m, 3H), 1.88 (m, 1H), 2.11 (m, 2H), 2.62 (m, 1H), 2.85 (m, 1H), 2.97 (m, 1H), 3.10 (m, 1H), 3.28 (s, 3H), 3.36 (m, 1H), 3.64 (m, 1H), 4.49 (m, 2H), 7.06 (d, 1H), 7.39 (s, 1H), 7.67 (d, 1H), 7.97 (s, 1H); MS: 488 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][C:21](OC)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][OH:22])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)CC1CCCCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCCCC1CCO
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a slurry of lithium aluminum hydride (580 mg in 65 mL dry diethyl ether) at 0° C. was added dropwise a solution of 2-(methoxycarbonylmethyl)piperidine-1-carboxylic acid tert-butyl ester (5.47 g in 40 mL dry diethyl ether) over a period of 30 minutes. The reaction was allowed to continue at 0° C. for an additional hour, at which time it was quenched by the careful addition of 0.58 mL water followed by 0.58 mL 2N sodium hydroxide and 1.8 mL water. The resulting suspension was stirred vigourously for 30 minutes then filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound (4.61 g).
Reaction SMILES: C([N:8]1[CH2:12][C@@:11]2([C:24]([O:26][CH3:27])=[O:25])[CH2:13][C@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:20]([O:19][C:17]([NH:16][C@@H:14]1[CH2:15][C@H:10]2[CH2:9][NH:8][CH2:12][C@@:11]2([C:24]([O:26][CH3:27])=[O:25])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@]12C[C@H](NC(=O)OC(C)(C)C)C[C@H]1CN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@]12CNC[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)C2
Reaction time: 8 h

Procedure:
To a solution of the product from Step C (28.6 g, 76.4 mmol) in methanol (200 mL) was added 5% palladium hydroxide on carbon (0.26 g). Hydrogenation proceeded overnight in Parr shaker at rt at 50 psi. Filtration and evaporation to dryness gave the product as a yellow gel. 1H-NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 1.72-1.90 (m, 2H), 1.93-2.05 (m, 1H), 2.05-2.17 (m, 1H), 2.67 (dd, J=11.6, 5.8 Hz, 1H), 2.77 (d, J=12.1 Hz, 1H), 2.82-2.94 (m, 1H), 3.30 (dd, J=11.6, 8.1 Hz, 1H), 3.44-3.57 (m, 2H), 3.68-3.79 (m, 3H), 4.14 (d, J=6.3 Hz, 1H), 4.85 (d, J=5.8 Hz, 1H). LC/MS: C14H24N2O4: m/z 285.2 (M+H).
Reaction SMILES: C([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH2:17][N:18]2[C:24](=[O:25])[CH:23]([NH:26][C:27](=[O:37])[C:28]3[CH:33]=[C:32]([Cl:34])[C:31]([OH:35])=[C:30]([Cl:36])[CH:29]=3)[CH2:22][CH2:21][CH2:20][N:19]2[S:38]([CH3:41])(=[O:40])=[O:39])=[O:16])[CH2:12][C:11](=[O:42])[O:10]1)C1C=CC=CC=1.Cl>CC#N>[Cl:36][C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([Cl:34])[C:31]=1[OH:35])[C:27]([NH:26][CH:23]1[C:24](=[O:25])[N:18]([CH2:17][C:15]([NH:14][CH:13]([CH:9]=[O:8])[CH2:12][C:11]([OH:42])=[O:10])=[O:16])[N:19]([S:38]([CH3:41])(=[O:39])=[O:40])[CH2:20][CH2:21][CH2:22]1)=[O:37]
Reactant: CS(=O)(=O)N1CCCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)N1CCCC(NC(=O)c2cc(Cl)c(O)c(Cl)c2)C(=O)N1CC(=O)NC(C=O)CC(=O)O
Yield: 47 %

Procedure:
N-{2-[(2-Benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-1-methanesulfonyl-3-oxo-[1,2]diazepan-4-yl}-3,5-dichloro-4-hydroxy-benzamide (26b) was stirred in CH3CN (0.5 mL) and 2N HCl (1 mL) for 7 hours. The solution was concentrated in vacuo to half of the volume and extracted with ether (2 mL×4). The combined ether layers was diluted with ethyl acetate/hexane (1/9, 3 mL), washed with 1M Na2CO3 (2 mL). The aqueous solution was washed with ethyl acetate/hexane (1/9, 2 mL×2), acidified with 6N HCl to pH˜3, extracted with ethyl acetate (1.5 mL×3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo to afford 20 mg (47% yield) of the title compound. 1H-NMR (500 MHz, CDCl3 +CD3OD) δ 0.75-0.90 (m, 1H), 1.18-1.30 (m, 3H), 1.67-1.88 (m, 1H), 1.93-2.30 (m, 2H), 2.40-2.61 (m, 1H), 3.10-3.16 (m, 3H), 3.95-4.30 (m, 2H), 4.30-4.50 (m, 1H), 5.00-5.08 (d, 1H), 7.81 (s, 2H). Analytical HPLC: 8.10 min. LC-MS (ES+): m/e=553, 555 (M+H+).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[C:7]([C:17]([O:19][CH2:34][O:33][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:18])=[C:8]4[S:16][CH2:15][CH2:14][N:9]43)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)C(=O)OCOC(=O)c1c2n(c3cc4c(cc3c1=O)OCO4)CCS2
Temperature: 100 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
7,8-Methylenedioxy-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylic acid (200 mg, 0.687 mmol) was dissolved in 5 ml of dimethyl formaide, then 152 mg of anhydrous potassium carbonate (1.1 mmol) and 328 mg (2.18 mmol) of pivaloyloxymethyl chloride were added thereto, the mixture was heated with stirring at 100° C. for six hours, the content was concentrated under reduced pressure, water was added to the residue, then insoluble matter was collected by filtration, washed with water, air dried and recrystallized from a mixture of chloroform and ether to give 200 mg of the title compound (71.9 percent yield). Melting point 229.0° to 229.5° C. Elementary analysis calculated as C19H19NO7S.1/4 H2O: C 55.67, H 4.79, N 3.42; Found: C 55.65, H 4.59, N 3.49.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH2:4][OH:5]>CC(C)=O.[O-2].[Mn+4].[O-2]>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1cc(I)ccc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=Cc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
To a stirred solution of 2-hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0 mmol) in acetone (700 mL) was added 85% activated manganese(IV) oxide (5 micron, 50 g, 494.0 mmol) and the solution stirred at room temperature for 16 hours. The manganese oxide was removed by filtration through diatomaceous earth and the filtrate concentrated in vacuo. The product was purified by flash silica chromatography (0–20% ethyl acetate in hexanes) The 2-hydroxy-5-iodobenzaldehyde was obtained as a greenish-yellow solid (24.3 g, 58%). A small amount of the 2-hydroxy-5-iodobenzaldehyde was recrystallized from methanol/water to afford an analytical sample and the remainder of the compound was used without further purification: mp 99–101° C. 1H NMR (CDCl3/300 MHz) 9.83 (s, 1H), 7.79 (d, 1H, J=2.2 Hz), 7.77 (dd, 1H, J=8.7 Hz, J=2.2 Hz), 6.81 (d, 1H, J=8.7 Hz). ESHRMS 246.9229 (M−H Calc'd 246.9256).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2nnco2)cc1
Product: O=C/C=C/c1ccc(-c2nnco2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1,3,4-oxadiazol-2-yl)benzaldehyde (prepared as described in Reference Example 77) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[NH2:13][NH2:14].[ClH:15]>CN1CCCC1=O>[ClH:15].[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:13][NH2:14])[CH:3]=1
Reactant: NN
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Product: NNc1cc(Br)c(F)cc1C(=O)O
Temperature: 95 °C
Yield: 44 %

Procedure:
A mixture of 4-bromo-2,5-difluorobenzoic acid (2.50 g, 10.6 mmol) and hydrazine (3.81 mL, 121 mmol) in N-methyl-2-pyrrolidinone (2 mL) was heated at 95° C. for 4 h. The cooled mixture was poured into vigorously stirred 6 M aqueous HCl (400 mL) which was cooled in an NaCl-ice bath. The resulting precipitate was collected by filtration, washed with 6 M aqueous HCl (200 mL) and dried under vacuum to give 4-bromo-5-fluoro-2-hydrazinylbenzoic acid hydrochloride as a yellow solid (1.88 g, 71% purity, 44% yield), used without further purification.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[S:38])([CH3:29])[CH3:28].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:38])([CH3:29])[CH3:28]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1NC(=S)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
In a 25 mL flask, to a solution of 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (0.160 g, 0.442 mmol) in dichloromethane (2 mL) was added 1-isopropyl-2-isothiocyanatobenzene (0.156 g, 0.530 mmol) in dichloromethane (5 mL) followed by triethylamine (0.062 mL, 0.442 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and adsorbed onto Celite®. Purification by flash column chromatography provided the title compound as a white solid (110 mg, 49%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a mixture of 2-nitroaniline (1.38 g) and triethylamine (1.67 ml) in dichloromethane (30 ml) were added 4-nitrobenzoyl chloride (1.85 g) and the solution was stirred at ambient temperature for 4 hours. The solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and brine, and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with n-hexane to give 2-nitro-N-(4nitrobenzoyl)aniline (1.82 g).