Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[C@@H:11]([OH:18])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:15])[C:12]([CH3:16])([CH3:17])[C@@H:11]([OH:18])[CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC1(C)C(=O)N[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)C(C)(C)[C@@H](O)C[C@H]1c1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of cis-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethylpiperidin-2-one from Step B (17.1 g, 67.0 mmol) in THF (400 mL) at 0° C. was added NaH (60% dispersion in oil, 4.91 g, 73.7 mmol). After 30 min, ethyl bromoacetate (8.20 mL, 73.7 mmol) was added. After 30 min, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL), diluted with H2O (700 mL) and brine (100 mL) and extracted with EtOAc (700 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the alcohol as a mixture of four isomers. Additional purification was achieved by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—90:10:0.1. The first major peak to elute was a mixture of ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 5:1). The second major peak to elute was a mixture of ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate (ca. 3:1). Further purification of the second major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH—90:10:0.1, to give ethyl [(4R,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4R,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second. Further purification of the first major peak was achieved by SFC, using a ChiralPak AD column and eluting with CO2:MeOH:Et2NH—90:10:0.1, to give ethyl [(4S,6R)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted first, and ethyl [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetate, which eluted second, the title compound. MS: m/z=342 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[C:24]1([C:30]([NH2:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:23])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: CC(N)(c1ccccc1)c1ccccc1
Product: CC(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)(c1ccccc1)c1ccccc1
Yield: 55 %

Procedure:
The title compound was prepared in a yield of 55% in a similar manner to that described in Example 2 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1,1-diphenylethylamine.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].[N:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1[CH:61]=[CH:60][C:59](B(O)O)=[CH:58][CH:57]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[C:38]1([C:28]2[CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:31]=[C:26]([C:21]3[CH:20]=[C:19]([C:59]4[CH:58]=[CH:57][C:56]([C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][N:50]=5)=[CH:61][CH:60]=4)[CH:24]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:22]=3)[N:27]=2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(-c3ccccc3)nc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
In a stream of argon, 0.714 g (3.22 mmol) of 9-phenanthreneboronic acid, 1.50 g (3.22 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenylpyrimidine and 37.2 mg (0.0322 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 120 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 50° C. To the suspension, 9.66 mL (9.66 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 18 hours. Then the mixture was cooled to room temperature, and 0.961 g (4.83 mmol) of 4-(2-pyridyl)phenylboronic acid and 9.66 mL (9.66 mmol) of an aqueous 1M K2CO3 solution were added. Then the mixture was heated to 60° C. and maintained at that temperature for 4 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 1.28 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-4′-(2-pyridyl)biphenyl-3-yl]-pyrimidine as a white solid (yield: 62%).
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[CH3:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([OH:23])=[C:14]2[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:23][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[CH3:8])[C:14]=1[C:19]([F:20])([F:21])[F:22]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc2c(C(F)(F)F)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C)cccc2c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Dimethylsulfate (1.13 g, 8.75 mmol, 0.85 mL) was added to a stirred suspension of 5-methyl-1-(trifluoromethyl)-2-naphthalenol (1.8 g, 7.96 mmol) and potassium carbonate (2.2 g, 15.9 mmol) in dimethylformamide (20 mL). After stirring the reaction mixture for 2 hr at 25° C., the solid in the reaction mixture was removed by filtration. The filtrate was extracted with hexane (400 mL). The extract was washed with brine, dried (MgSO4) and concentrated to dryness giving 1.7 g (90% yield) of the title compound. This product was used for the reaction described in the next example. A sample of the product, recrystallized from hexane, had mp 70°-71° C.; nmr (CDCl3) δ 2.65 (s, 3H), 3.95 (s, 3H), 7.2 (m, 2H), 7.35 (q, J=8 Hz, 1H), 8.0 (m, 1H), 8.1 (d, J=9 Hz, 1H); ir (CHCl3) 1390, 1340, 1280, 1255, 1245, 1110, 1095, 1085,1045 cm-1 ; uvλmax (MeOH) 336 nm (ε2,910), 323 (2,645), 297 (4,440), 286 (4,880), 236 (30,050), 224 (46,730).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[CH2:39]([O:41][C:42](=[O:57])[C:43]1[CH:48]=[C:47]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[CH:46]=[C:45]([CH2:55]Br)[CH:44]=1)[CH3:40]>ClCCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[N:20]([CH2:55][C:45]4[CH:44]=[C:43]([CH:48]=[C:47]([CH2:49][O:50][CH2:51][CH2:52][O:53][CH3:54])[CH:46]=4)[C:42]([O:41][CH2:39][CH3:40])=[O:57])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: CCOC(=O)c1cc(CBr)cc(COCCOC)c1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1cc(COCCOC)cc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)c1

Procedure:
A mixture of example 2 step (ii) (0.41 g) and bis[trimethylsilyl]trifluoroacetamide (0.73 g) in 1,2-dichloroethane (10 ml) was heated at reflux for 1 hour. The product from step (i) (0.45 g) was added and the mixture was heated at reflux for 7 hours. The mixture was evaporated and the residue purified by chromatography eluting with 30% ethyl acetate in isohexane. Yield 0.52 g.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([OH:16])=[O:15].[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>C(#N)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13](=[CH2:17])[C:14]([O:16][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CC#N
Product: C=C(ON1C(=O)c2ccccc2C1=O)C(=O)OC(c1ccccc1)c1ccccc1
Yield: 99.1 %

Procedure:
2-[(1,3-Dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid (1.54 g, 4.8 mmole) was dissolved in 25 ml of acetonitrile and a solution of diphenyldiazomethane (1.17 g, 5.94 mmole/50 ml acetonitrile) was added dropwise. After approximately 1.1 equivalents of diphenyldiazomethane had been added, tlc showed no starting material remaining. The excess diphenyldiazomethane was decomposed with the addition of a small amount of acetic acid. The reaction solution was concentrated to a residue, dissolved in ethyl acetate, washed consecutively with 1N sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to a solid. After trituration with hexane, 1.9 g of the title compound was obtained.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@@H]([C@H]([C@H](CO)O)O)O.P(OC[C@H](O)[C@H](O)C(=O)CO)(O)(O)=O.O=C[C@H]([C@@H]([C@@H](CO)O)O)O>C(O)C>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@@H](O)COP(=O)(O)O
Agent: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The results presented in FIG. 3 show that in contrast to the control strain containing the shuttle vector alone (206C [pZB186]), the recombinant strain containing the added xylose isomerase, xylulokinase, L-arabinose isomerase, L-ribulokinase, L-ribulose 5-phosphate 4-epimerase, transaldolase and transketolase genes demonstrated growth on and ethanol production from xylose and arabinose, alone or in a combination as a carbon source. The recombinant strain produces ethanol from glucose as efficiently as the control strain at 94% of theoretical yield. The recombinant strain additionally produces ethanol from xylose, or arabinose, or xylose and arabinose at process yields of 91%, 55%, and 79% yield in 96 hours (47 hours for xylose only), respectively. Furthermore, in the presence of glucose and xylose and arabinose, the recombinant strain ferments all three sugars to ethanol at a process yield of 79% yield within 48 hours, thus providing the foundation for advanced process designs with cofermentation of mixed-sugar feedstocks. The recombinant strain produces ethanol from 2% xylose, 2% arabinose, 2% xylose and 2% arabinose, or 1% glucose, 2% xylose and 2% arabinose at 92%, 88%, 94% or 90% of theoretical consumed sugar yield, respectively. The control strain neither grew on nor produced ethanol from xylose, arabinose or xylose and arabinose.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]#N)[CH:6]=[CH:7][C:8]=1[CH3:9].[OH-:15].[Na+].[OH2:17]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]([OH:17])=[O:15])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O
Reactant: [OH-]
Reactant: COc1cc(CCCC#N)ccc1C
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CCCC(=O)O)ccc1C
Yield: 75.5 %

Procedure:
A solution of 6.75 g (35.7 mmol) of 3-(3-methoxy-4-methylphenyl)propyl cyanide in 75 mL of EtOH was treated with a solution of 8.0 g (0.2 mol) of NaOH in 40 mL of H2O and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in H2O. After washing with Et2O, the aqueous solution was acidified to the Congo Red end point with dilute HCl. A white solid separated which was collected and dried. There was obtained 5.6 g (75.5% yield) of the product, mp 69-70° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 209 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)C.Cl.[F:20][C:21]1[C:22](N)=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]2[NH:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=3[N:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(CCC#N)CC1
Reactant: Nc1cccc(F)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(CCc2nc3c(F)cccc3[nH]2)CC1
Reaction time: 20 h
Yield: 54.3 %

Procedure:
A solution of (a) (6.4 g, 30 mmol) and ethanol (2.1 ml, 40 mmol) in chloroform (60 ml) was saturated with gaseous hydrochloric acid at 0° C. for 0.5 hours. The mixture was left 20 hours at 4° C. then concentrated in vacuo to afford a white foam. This was suspended in chloroform (60 ml), treated with 3-fluorophenylenediamine (3.8 g, 30 mmol) and heated under reflux for 1 hour. The mixture was poured onto water. The aqueous phase was then basified with sodium bicarbonate and extracted three times with dichloromethane. The organic extract was washed with water, brine, dried over magnesium sulfate and evaporated. The resulting residue was triturated with ethyl acetate, then diethyl ether to give a white solid (5.2 g, 55%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.C(NCC)C.Br[CH2:52][CH2:53][CH2:54][CH2:55]Br.C(Cl)(Cl)[Cl:58]>>[Cl-:58].[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N+:42]3([CH2:55][CH2:54][CH2:53][CH2:52]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: ClC(Cl)Cl
Reactant: O=C(NC[C@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCCCCBr
Solvent: CCNCC
Product: O=C(NC[C@H]1CCC[N+]2(CCCC2)C1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]
Reaction time: 144 h

Procedure:
The method of Japan Kokai (laid-open) No. Sho 62(1987)-215588 A1 was followed. In 0.6 ml of chloroform, 41 mg of (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3S)-3-piperidylmethyl)pyrrolidine-2-carboxamide, 0.014 ml of diethylamine and 0.032 ml of 1,4-dibromobutane were dissolved, and the solution was allowed to stand in a hermetically sealed vessel for 6 days. The reaction liquid was diluted with chloroform and the solvent was distilled off under reduced pressure. The resultant residue was dissolved in a mixture of ultrapure water 0.6 ml/methanol 0.1 ml, and developed on a reversed phase medium pressure liquid chromatography [ODS-AQ 120-S50 (YMC). The product was purified and anion-exchanged by pouring 20 ml of saturated brine, washing with 150 ml of ultrapure water, and eluting from methanol/water=1/1, to provide 45 mg of the title compound as a white solid.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].[CH3:37][O:38][C:39]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50](=[O:52])[CH3:51])=[CH:44][C:40]=1[C:41](O)=[O:42].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:41]([C:40]3[CH:44]=[C:45]([CH:46]=[CH:47][C:39]=3[O:38][CH3:37])[O:48][CH2:49][C:50](=[O:52])[CH3:51])=[O:42])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(OCC(C)=O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(OCC(C)=O)ccc4OC)C3)CC2)nc2ccccc21
Yield: 85.9 %

Procedure:
Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.33 g, 0.61 mmol, Preparation 12.1), 2-methoxy-5-(2-oxo-propoxy)-benzoic acid (0.14 g, 0.61 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.73 mmol), 1-hydroxybenzotriazole hydrate (0.099 g, 0.73 mmol), diisopropylethylamine (0.25 mL, 1.2 mmol) and dichloromethane (10 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol in dichloromethane and 5% methanol in dichloromethane. Concentrate the appropriate fractions to afford 0.35 g of the title compound, Rf=0.48 (silica gel, 10% methanol in dichloromethane). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:32])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]([NH2:31])=[O:30])[O:24][CH2:23]2)[CH:17]([CH:33]([OH:35])[CH3:34])[C:16]3=[O:36])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:41].O.[H][H]>[Pd].O1CCOCC1>[Na+:41].[NH2:31][C:29]([O:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:32])[CH:18]3[N:15]([C:16](=[O:36])[CH:17]3[CH:33]([OH:35])[CH3:34])[C:14]=2[C:12]([O-:13])=[O:11])[CH2:26]1)=[O:30]
Reactant: [H][H]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COC(N)=O)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COC(N)=O)C3)C(C)C12
Yield: 67 %

Procedure:
A mixture of 0.181 g of product from Example 17, 0.032 g of sodium bicarbonate, 2 ml of water, 11 ml of dioxane and 0.100 g of 10% palladium/carbon is reduced in a Parr apparatus at 42 psi of hydrogen for 3 hours. The reaction mixture is filtered through a pad of diatomaceous earth, washed with water and concentrated to 1/2 volume. The solution is extracted with ethyl acetate and the aqueous layer is freeze-dried. The product is purified using C18 reverse phase chromatography (95/5 water/ethyl alcohol) to give 0.095 g of the desired product as a yellow solid.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][C@H:28]2[NH2:34])=[O:24]>C(Cl)Cl.C(OCC)(=O)C>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:34][C@H:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([C:23]([O:22][CH3:21])=[O:24])[CH:26]=2)[CH2:30][CH2:29]1)=[O:14]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: Cc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1C)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
N-Ethyl-diisopropylamine (2.5 eq.) and 2-methylbenzoyl chloride (1.2 equiv.) were added to an ice-cold solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-03 HCl) (0.88 mmol, 1 equiv.) in methylene chloride at 0° C. under an inert atmosphere and the mixture was then stirred at room temperature for 2 d. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over Na2SO4 and concentrated to obtain the crude product, which was purified by column chromatography (silica, cyclohexane/ethyl acetate 4:1). Yield: 70%