Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:28][CH2:27][C@:5]2([NH:9][C@@H:8]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[CH:13]=[CH:12][N:11]=3)[CH2:7][CH2:6]2)[C:4]1=[O:29].Cl>C(Cl)Cl>[ClH:1].[CH3:2][N:3]1[CH2:28][CH2:27][C:5]2([NH:9][CH:8]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:26])[F:24])[CH:17]=4)[CH:13]=[CH:12][N:11]=3)[CH2:7][CH2:6]2)[C:4]1=[O:29]
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cccc(OC(F)(F)F)c4)ccn3)N2)C1=O
Agent: Cl
Solvent: ClCCl
Product: CN1CCC2(CCC(c3cc(-c4cccc(OC(F)(F)F)c4)ccn3)N2)C1=O
Yield: 58 %

Procedure:
This was converted to the (2R,5S)-7-methyl-2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]-nonan-6-one hydrochloride (E1) by addition of HCl (1 M in diethyl ether) to a DCM solution of the free base. Evaporation followed by further drying under reduced pressure gave an amber solid. The latter was further dried under reduced pressure at 40° C. to give the title compound in 58% yield;
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[CH3:5][CH:6]([CH3:15])[CH2:7][CH2:8][C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1>C(O)(=O)C>[CH3:5][CH:6]([CH3:15])[CH2:7][CH2:8][CH:9]1[CH:13]([CH:1]=[CH2:2])[CH2:12][CH2:11][C:10]1=[O:14]
Reactant: CC(C)CCC1=CCCC1=O
Reactant: C=C[Mg]Cl
Solvent: CC(=O)O
Product: C=CC1CCC(=O)C1CCC(C)C
Temperature: -25 °C
Reaction time: 4 h

Procedure:
Vinylmagnesium chloride (H2CHCClMg, 1 L) and cuprous chloride were charged to a dried flask under nitrogen and cooled to −25° C. with a dry ice bath. The resulting mixture was fed with 2-(3-methyl-butyl)-cyclopent-2-enone (226 g, 1.49 mol, obtained as detailed above) slowly for over 4 hours, aged for another 4 hours, and allowed to warm to 0° C. The reaction mixture was then poured into acetic acid solution and washed to neutral with saturated Na2CO3 solution. The distillation process provided the product 2-(3-methyl-butyl)-3-vinyl-cyclopentanone.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:35])[C:6]2[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][C:9]3[NH:10][C:11](=[O:28])[CH2:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([N:21]5[C:25]([CH2:26]O)=[CH:24][N:23]=[N:22]5)[CH:16]=4)=[N:14][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.O=S(Cl)Cl.[CH:40]1([NH2:43])[CH2:42][CH2:41]1>>[CH:40]1([NH:43][CH2:26][C:25]2[N:21]([C:17]3[CH:16]=[C:15]([C:13]4[CH2:12][C:11](=[O:28])[NH:10][C:9]5[CH:29]=[C:30]([C:31]([F:33])([F:34])[F:32])[C:6]([N:5]([CH2:4][CH:1]6[CH2:2][CH2:3]6)[CH3:35])=[CH:7][C:8]=5[N:14]=4)[CH:20]=[CH:19][CH:18]=3)[N:22]=[N:23][CH:24]=2)[CH2:42][CH2:41]1
Reactant: NC1CC1
Reactant: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Solvent: O=S(Cl)Cl
Product: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CNC3CC3)c1)=N2

Procedure:
The title compound was prepared from 7-(cyclopropylmethyl-methyl-amino)-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 78) (145 mg, 0.3 mmol) by treatment with SOCl2 (3 eq.) and cyclopropyl amine (10 eq.) as described in Example 45. Obtained as a yellow solid (97 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]2>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:33]([CH3:34])[CH:30]3[CH2:29][CH2:28][C:27]4[C:32](=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][CH:26]=4)[CH2:31]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNC1CCc2cccc(OC)c2C1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C1CCc3cccc(OC)c3C1)CC2

Procedure:
The title compound is prepared analogously to Example 1 by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane, triethylamine and 8-methoxy-2-methylamino-1,2,3,4-tetrahydronaphthalene. Mp: 141°-143° C. (decomp.).
Reaction SMILES: O=C1N([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H](CC=O)CC1.[NH2:17][C@H:18]([C:24]([OH:26])=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22].C(=O)C1C=CC=CC=1.[BH4-].[Na+]>>[C:8]1([CH2:7][NH:17][C@H:18]([C:24]([OH:26])=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=Cc1ccccc1
Product: O=C(O)CC[C@H](NCc1ccccc1)C(=O)O

Procedure:
The process set forth in Scheme I comprises the preparation of the intermediate, (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidineacetaldehyde (10a). Thus, L-glutamic acid (3) can be reductively alkylated with benzaldehyde and sodium borohydride to yield the N-(1-phenylmethyl)-L-glutamic acid (4a). Acidification of the solution with hydrochloric acid to pH 3, followed by heating at reflux and then esterification of the crude product with methanol and sulfuric acid in toluene gives the (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinecarboxylic acid methyl ester (5). Reduction of (5) with sodium borohydride in methanol and t-butanol gives the hydroxymethyl compound characterized by formula (6). The optical purity of (S)-5-(hydroxymethyl)-1-(phenylmethyl)-2-pyrrolidinone (6), can be established by formation of the ester derived from (S)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetic acid ((-)-MTPA) following the procedure of Mosher, et al. [J. Org. Chem. 1969, 34, 2543]. Conversion of (6) to the tosylate (7) was accomplished by treatment with p-toluenesulfonyl chloride and 4-dimethylaminopyridine. Treatment of the tosylate (7) with sodium iodide in acetone at reflux gives the iodide (8). Coupling of (8) with vinylmagnesium chloride, catalyzed by dilithium tetrachlorocuprate, leads to the propenyl compound (9), which can be ozonized in methanol with a methyl sulfide workup to yield the aldehyde, (S)-5-oxo-1-(phenylmethyl)-2-pyrrolidineacetaldehyde (10a). All of the steps described in Scheme I can be carried out using DL-glutamic acid or D-glutamic acid as the starting material, if it is desired to prepare enantiomeric or racemic (10a). ##STR19##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:24]([O:31][C:32]1[C:33]([CH3:40])=[CH:34][C:35]([F:39])=[C:36]([OH:38])[CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[K+]>CS(C)=O.O>[CH2:24]([O:31][C:32]1[C:33]([CH3:40])=[CH:34][C:35]([F:39])=[C:36]([CH:37]=1)[O:38][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCCOc1cc2nccc(Cl)c2cc1C#N
Reactant: Cc1cc(F)c(O)cc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COCCOc1cc2nccc(Oc3cc(OCc4ccccc4)c(C)cc3F)c2cc1C#N
Temperature: 160 °C
Yield: 62.7 %

Procedure:
4-Chloro-6-cyano-7-(2-methoxyethoxy)quinoline (187 mg, 0.71 mmol), (prepared as described for the starting material in Example 1 but with an aqueous sodium hydrogen carbonate work up), was added to a solution of 5-benzyloxy-2-fluoro-4-methylphenol (248 mg, 1 mmol), (prepared as described for the starting material in Example 3), and potassium t-butoxide (120 mg, 1 mmol) in DMSO (5 ml) and the mixture then heated at 160° C. for 1.5 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/ethyl acetate (55/45) followed by preparative reverse-phase HPLC eluting with aqueous ammonium carbonate (2 g/1, adjusted to pH7 with carbon dioxide) and methanol (20/80) to give 4-(5-benzyloxy-2-fluoro-4-methylphenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (204 mg, 63%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[H-].[Na+].[CH3:17]I>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH3:17])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCNc1cccc(CC(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCNc1cccc(CC(=O)OC)c1
Reaction time: 1 h

Procedure:
A solution of 20.7 g. of 3-(allylamino)phenylacetic acid in 25 ml. of hexamethylphosphoramide is added to a stirred mixture of 0.800 g. of sodium hydride (57% in mineral oil) and 25 ml. of hexamethylphosphoramide. The solution which forms after one hour is treated with 11.0 g. of methyl iodide and is then stirred at 25° C. for 18 hours. Dilution with water followed by filtration affords a white solid which is crystallized from ethanol to yield methyl 3-(allylamino)phenylacetate
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]1[O:14][CH2:13]1)[CH:2]1[O:4][CH2:3]1.[CH2:15]([OH:18])[C:16]#[CH:17]>>[CH2:15]([O:18][CH2:13][CH:12]([OH:14])[CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:1][CH:2]([OH:4])[CH2:3][O:4][CH2:3][C:2]#[CH:1])[C:16]#[CH:17]
Reactant: C(CCOCC1CO1)COCC1CO1
Reactant: C#CCO
Product: C#CCOCC(O)COCCCCOCC(O)COCC#C

Procedure:
Analogous to Example 1, 475 g 1,4-diglycidyloxybutane was reacted with 528 g of propargyl alcohol to give 1,4-bis(3-propargyloxy-2-hydroxypropyl) oxybutane.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:5]3[CH:14]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:4]2[C:3]3[C:2]([C:33]4[C:29]([CH3:28])=[N:30][O:31][C:32]=4[CH3:37])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:26][CH:25]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1.12-a]indol-1-yl]acetate (Example 7, Step 9) and 3,5-dimethylisoxazol-4-ylboronic acid, the title compound was synthesized following the procedures described Example 108.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]2[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:14][C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:16][C:5]1=2)(=[O:30])=[O:29]
Reactant: OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21

Procedure:
9-[2-(Hydroxy)ethyl]-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (I, J. Med. Chem., 38, 4161-3 (1995) is reacted with methanesulfonyl chloride by means known to those skilled in the art to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O.CO>[CH2:19]([N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 214.8 %

Procedure:
L-Phenylalanine (16.5 g) and potassium carbonate (27.6 g) were added to a mixed solvent of methanol (100 ml) and water (100 ml). Then, benzyl bromide (68.4 g) was added to the obtained mixture, and they were stirred under heating and reflux for 3 hours. The reaction mixture was cooled to room temperature, and poured on ice/water. After the extraction with diethyl ether (300 ml), the obtained solution in diethyl ether was dried over anhydrous sodium sulfate. Sodium sulfate was filtered out. 4 N solution (25 ml) of dioxane in hydrochloric acid was added to the obtained solution in diethyl ether. After stirring under cooling on ice followed by the crystallization, the crystals were separated and washed with diethyl ether. The obtained crystals were added to a mixture of water (100 ml) and toluene (100 ml) to obtain a slurry. After the neutralization with a saturated aqueous sodium hydrogencarbonate solution followed by the division into layers, the product was extracted again with toluene. The obtained toluene layers were combined together and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered out and the solvent was evaporated under reduced pressure to obtain the intended benzyl ester of N,N-dibenzyl-L-phenylalanine (37.06 g) in a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH:13]([NH2:37])[C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]3[C@@H:34]4[C@@H:29]([NH:30][C:31]([NH:33]4)=[O:32])[CH2:28][S:27]3)[NH:8]2)=[C:4]([O:38][CH2:39][C:40]2[CH:53]=[CH:52][C:43]([CH2:44][NH:45]C(=O)C(F)(F)F)=[CH:42][CH:41]=2)[N:3]=1.CN>CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][CH2:12][CH:13]([NH2:37])[C:14](=[O:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][C@H:26]3[C@@H:34]4[C@@H:29]([NH:30][C:31]([NH:33]4)=[O:32])[CH2:28][S:27]3)[NH:8]2)=[C:4]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][C:43]([CH2:44][NH2:45])=[CH:52][CH:53]=2)[N:3]=1
Reactant: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c2nc(CCC(N)C(=O)CCCCCNC(=O)CCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)[nH]c2n1
Agent: CN
Solvent: CO
Product: NCc1ccc(COc2nc(N)nc3[nH]c(CCC(N)C(=O)CCCCCNC(=O)CCCC[C@@H]4SC[C@@H]5NC(=O)N[C@@H]54)nc23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoroacetamide 49 (Example 32, 15.1 mg, 0.019 mmol) are dissolved in 1 mL methanol, and 2 mL methylamine (33% in ethanol) are added. The reaction mixture is stirred at room temperature for 48 h and all volatiles are removed in vacuo. The product is used without further purification. MS (ESI) m/z 667.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[N+](=[CH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N-]>>[CH3:7][C:6]1([CH3:8])[CH:5]([CH:4]=[C:2]([CH3:3])[CH3:1])[CH:11]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)=CC=C(C)C
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Product: CC(C)=CC1C(C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
In a 50 mL Schlenk tube purged with nitrogen, 22 mg of 2,2-bis[2-[(4S)-1-naphthyloxazoline]]propane was added to a white suspension containing 18 mg of cuprous trifluoromethanesulfonate and 5 mL of dichloroethane and stirred at a room temperature for 10 minutes to prepare a blue color homogeneous solution of an asymmetric copper complex. After that, 7.8 g of 2,5-dimethyl-2,4-hexadiene was added thereto and the inner temperature was adjusted to 40° C. and 1.4 g of tert-butyl diazoacetate was dropwise added for 2 hours and the resulting mixture was stirred at the same time further for 30 minutes to effect reaction and tert-butyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained in a yield of 89% (based on tert-butyl diazoacetate). Trans-isomer/cis-isomer ratio=81/19. The optical purity of the trans-isomer was 86% e.e. and that of the cis-isomer was 60% e.e.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([OH:18])[CH2:6]1)=[O:4].N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(O)(C)C.[OH-].[Na+].C(Cl)(Cl)Cl>[C:11]([NH:10][C@@H:8]1[CH2:9][C@H:5]([C:3]([OH:2])=[O:4])[CH2:6][C@@H:7]1[O:18][Si:28]([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a stirring solution of N-Boc-1(R)-amino-2(S)-hydroxy-cyclopentane-4(S)-carboxylic acid methyl ester (0.622 g, 2.40 mmol) in DCM (1.9 mL) was added imidazole (0.164 g, 2.41 mmol), DMAP (0.047 g, 0.35 mmol) and TBSCl (0.363 g, 2.40 mmol) and the reaction was stirred at room temperature for 18 hours, followed by heating at 40° C. for 1 hour. The reaction mixture was cooled to room temperature, and was quenched with H2O (3 mL). The organic layer was separated and was concentrated to dryness to yield a residue, which was dissolved in isopropanol (6 mL) and 1M NaOH (2.9 mL), and the reaction was heated at 60° C. for 1 hour. The reaction was cooled to 0° C. and slowly acidified to pH 3 with 1M HCl (3 mL). After adding chloroform (18 mL), the organic layer was separated, dried over Na2SO4, and concentrated to dryness to yield the desired acid (0.75 g, 2.09 mmol, 87.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([C:31]([C:27]5[O:26][CH:30]=[CH:29][CH:28]=5)=[O:32])[CH2:22][CH2:21]4)=[N:18][CH:19]=3)[NH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Reactant: O=C(Cl)c1ccco1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccco1)N1CCN(c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)c[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
To a solution of {5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (150 mg, 0.40 mmol) in chloroform (10 ml) was added 4-dimethylaminopyridine (50 mg, 0.44 mmol, 1.1 equiv), followed by furan-2-carbonyl chloride (40 μl, 53 mg, 0.44 mmol, 1.1 equiv). The reaction was stirred for two days at room temperature. The reaction mixture was then diluted with dichloromethane (10 ml) and extracted with an aqueous solution of saturated sodium bicarbonate (2×10 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (20% ethyl acetate/hexanes grading to 100% ethyl acetate, then 10% methanol/dichloromethane) provided the desired product (110 mg, 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2]>C(Cl)(Cl)Cl.CO>[CH2:9]([C:8]1[NH:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=2[N:10]=1)[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 78 %

Procedure:
Prepared from 4-nitrophenylenediamine in a manner similar to that of Example 4c. Yield: 78%; Rf (9/1 chloroform/methanol): 0.70; 1H-NMR (CDCl3) 10.2 (bs, 1H); 8.4 (d, J=1.5 Hz, 1H); 8.1 (dd, J=8.6 Hz, 1.53 Hz, 1H); 7.5 (d, J=8.6 Hz, 1H); 3.0 (t, 2H); 1.90 (m, 2H); 1.6-1.1 (m, 4H); 0.87 (t, 3H).
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([F:19])=[CH:16][C:17]=2[F:18])=[CH:10][C:9]([C:20]([OH:22])=[O:21])=[C:8]([OH:23])[CH:7]=1.[CH3:24][CH2:25]O>C(Cl)Cl>[F:18][C:17]1[CH:16]=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[C:11]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([C:20]([O:22][CH2:24][CH3:25])=[O:21])[CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Yield: 78 %

Procedure:
H2SO4 (1 mL, 18.76 mmol) was added to a solution of diflunisal (1.50 g, 5.995 mmol) in EtOH (50 mL). The reaction mixture was refluxed for 2 days, allowed to reach r.t., and diluted with CH2Cl2 (200 mL). The organic layer was washed with Na2CO3 (1 M aqueous solution, 200 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated to furnish 1.30 g of ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 78%).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:22][CH2:21][CH2:20]C[N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@@H]1N(C(C2C=CC=CC=2)C2C=CC=CC=2)C[C@@H](O)C1)[OH:61].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:22][C@H:21]([OH:61])[CH2:20][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](O)CN2)C1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
Step 15 (A): (3S,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation K, 60 mg, 0.129 mmol) in EtOH (5 mL) was added a solution of LiOH (62 mg, 2.58 mmol) in H2O (1.25 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl (8 mL) solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo to give the title compound (47.3 mg, 84% yield) as an opaque oil: 1H NMR (CDCl3, 300 MHz) δ 2.32-2.39 (1H, m), 2.49-2.62 (3H, m), 2.79-2.80 (1H, m), 3.18 (1H, d, J=12 Hz), 3.49-3.58 (2H, m), 4.28 (1H, t, J=6 Hz), 4.63 (1H, s), 5.55 (1H, s), 5.96 (4H, brd s), 6.62-6.68 (3H, m), 7.20-7.36 (6H, m), 7.77 (4H, d, J=6 Hz). HPLC retention time: 1.20 min (method A). MS (ESI) (M+H)+ 439.16.