Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14](N3CCOCC3)[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].C([O-])(O)=[O:32].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[CH:17][C:18]([N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=3)[O:15][CH:14]([OH:32])[CH2:13]2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: O=C([O-])O
Reactant: COc1cc(C2CC(N3CCOCC3)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C2CC(O)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Yield: 80 %

Procedure:
The [4-(3-bromo-4,5-dimethoxy-phenyl)-2-morpholin-4-yl-chroman-7-yl]-dimethyl-amine was hydrolyzed to the lactol by heating 160 mg of crude solid in a mixture of acetic acid (2 ml) and water (2.4 ml) at 50° C. for 20 min. The reaction mixture was slowly added to saturated NaHCO3. It was extracted with dichloromethane (100 ml) and washed with brine (10 ml). The extract was dried over sodium sulphate and the solvent was evaporated. The crude product was passed through a bond-elute (hexane:ethyl acetate=9:1 and 4:1), yielding the title compound (110 mg; 80%). 1H NMR (CD3OD): 6.96 and 6.91 (two broad signals, 1H), 6.82 and 6.80 (two broad signals, 1H), 6.58 and 6.51 (d each, J=8.6 Hz, 1H), 6.28-6.34 (m, 1H), 6.23 and 6.22 (d each, J=2.1 Hz, 1H), 5.47 (broad signal) and 5.37 (d, J=8.9 Hz) (1H), 4.11-4.17 (m, 1H), 3.795, 3.793, 3.785 and 3.782 (s each, 6H), 2.871 and 2.868 (s each, 6H), 1.87-2.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24](=[O:29])[C:25]([O:27]C)=[O:26])=[C:16]2[N:15]=1.O[Li].O>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24](=[O:29])[C:25]([OH:27])=[O:26])=[C:16]2[N:15]=1
Reactant: COC(=O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
(R)-methyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylamino)-2-oxoacetate (Example 104; 100 mg, 0.249 mmol) was dissolved in a mixture solvent of THF:MeOH:water (2:2:1, 1 mL), followed by addition of LiOH—H2O (31.4 mg, 0.747 mmol). The reaction was stirred at ambient temperature for 10 minutes to reach completion. The reaction was concentrated, re-dissolved in water (20 mL) and acidified with 6 N HCl. The precipitate was vacuum-filtered, rinsed with water, heptane, and dried on high vacuum, giving the final product as a fine pale-yellowish powder (50 mg, 52% yield). MS (apci negative) m/z=386.1 (M−H).
Reaction SMILES: [F:1][C:2]1[C:3]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([O:33][C:34](=[O:37])[CH2:35]Br)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]([C@@H:8]([NH:9][C:10]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH2:35][C:34]([OH:37])=[O:33])=[CH:15][CH:16]=2)=[O:18])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F)c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)COc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)—N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-5-hydroxypicolinamide (Example 173) (0.145 g, 0.371 mmol) in DCM (2 mL) and DMF (0.2 mL) were added bromoacetic acid t-butyl ester (0.072 mL, 0.445 mmol) and cesium carbonate (0.241 g, 0.741 mmol). The resulting mixture was then stirred at rt for 2 h. Then, the mixture was filtered and the solid was washed with DCM (1×1 mL) and MeOH (1×1 mL). The combined filtrates were concentrated and dried to give the desired product, which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Br:18])=[C:12]([CH2:17][Br:35])[CH:13]=2)[N:8]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(C)cc2c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2c(F)cccc2F)c2cc(Br)c(CBr)cc2c1=O

Procedure:
A mixture of 7-bromo-1-(2,6-difluorobenzyl)-1,4-dihydro-6-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester (3.5 g, 8 mmol), prepared according to the procedure outlined in PCT application WO97/14682, Reference Example 3, NBS (1.5 g, 8.4 mmol) and 2,2′-azobisisobutyronitrile (AIBN, 100 mg) in DCM (200 mL) was stirred at reflux for 4 h. Additional NBS (750 mg) was added and the mixture was refluxed for 4 h. Column chromatography (hexanes:ethyl acetate=3:7) yielded the product as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:35])/[CH:18]=[CH:19]\[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:21]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:18]([CH2:19][C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])[C:17]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:35])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCOC(=O)/C=C\C(=O)OCCCCCCCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)OCCCCCCCCCCCC

Procedure:
The procedure of Example 1 is repeated using 7.15 grams of 2,6-di-tert-butyl-4-mercaptophenol, 13.58 grams of di-n-dodecyl maleate, and 0.3 gram of triethylamine. The product is purified by dry column chromatography to give a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].COCN[C:19]([C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:24][CH:25]=1)=[O:20]>C1COCC1>[C:26]1([C:23]2[S:24][CH:25]=[C:21]([C:19]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[O:20])[N:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COCNC(=O)c1csc(-c2ccccc2)n1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Yield: 27.3 %

Procedure:
A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI (6 mmol) and HOBt (5 mmol) in CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol) and HNCH3OCH3 (5 mmol) were added and stirring continued at RT for 6-8 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide. A solution of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1 equiv) in CH2Cl2 was cooled to 0° C., and distilled DBU (2 equiv) was added. Bromotrichloromethane (1.7 equiv) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to RT and stirred overnight. Upon washing with satd. aqueous NH4Cl (2×50 mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography as needed providing 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)+. To a solution of 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF was charged a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures were stirred for 30 min until amides disappeared on TLC plates. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1h. Yield: 27.3%. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s, 3H). MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C@H:3]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].CCC(C)[BH-](C(C)CC)C(C)CC.[K+].OO>C1COCC1>[OH:8][C@@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:2]([CH3:1])[CH2:7][CH2:6]1
Reactant: CCOC(=O)[C@@H]1CC(=O)CC[C@H]1C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@@H](O)CC[C@H]1C
Temperature: -50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a cold (−78° C.) solution of 11 (14.9 g, 80.8 mmol) in THF (250 mL) was added K-Selectride (potassium tri-sec-butylborohydride) (95.0 mmol, 1.0 M in THF). After addition was complete, the mixture was allowed to warm to −50° C. and stirred for an additional 4 h, whereupon the reaction was complete by TLC. The reaction was quenched by addition to 2.2 M NaH2PO4/K2HPO4 buffer (300 mL, pH =7). This was cooled (0° C.) and 30% hydrogen peroxide (42 mL, 370 mmol) was added and the mixture was allowed to stir overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate (4×200 mL). The combined organics were washed with brine (300 mL), 1.0 M sodium sulfite (300 mL), dried (MgSO4) and the volatiles were removed in vacuo to yield an oil which was further purified by flash chromatography (12.48 g, 83% yield). Rf 0.35 (ethyl acetate/hexane 3:7); 1H NMR (300 MHz, CDCl3) δ 4.45-4.54 (m, 1H), 4.10 (q, J=7.2, 2H), 2.34-2.44 (m, 1H), 2.00-2.30 (b, 1H), 1.26-1.91 (m, 7H), 1.22 (t, J=7.2, 3H), 0.89 (d, J=6.4, 3H); 13C NMR (75 MHz, CDCl3) δ 176.1, 65.4, 60.0, 45.1, 35.8, 33.9, 32.0, 27.6, 20.2, 14.2; MS (EI) m/z 186 (M+, 3), 168 ([M-H2O]+, 37), 141 ([M-OCH2CH3]+, 25), 130 (12), 95 (100), 73 (27), 55 (34); [α]D−27.4° (c=1.10, CH2Cl2). Analysis calcs'd for C10H18O3: C, 64.49; H, 9.74. Found: C, 64.19; H, 9.62.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[H-].[Na+].Cl[S:7]([CH:10]1[CH2:15][CH2:14][N:13](C(OCC2C=CC=CC=2)=O)[CH2:12][CH2:11]1)(=[O:9])=[O:8].O>CN(C)C=O>[CH3:1][N:2]([CH3:3])[S:7]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8]
Reactant: CNC
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 133.3 %

Procedure:
A suspension of an amine such as dimethylamine (4.72 mmol) and sodium hydride (4.72 mmol) in N,N-dimethylformamide (10 ml) was stirred for five minutes at room temperature. Then phenylmethyl 4-(chlorosulfonyl)-1-piperidinecarboxylate (1.60 mmol) was added to the reaction mixture and stirred at 100° C. for 3 hours. The reaction mixture was poured into water (25 ml) and extracted with ethyl acetate (3×25 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (410 mg, 80% yield) as an off-white solid. MS(ES)+ m/e 327.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39].[Na]>ClCCl.CN(C)C1C=CN=CC=1>[C:38]([O:1][N:2]([CH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:18]([CH2:19][C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=2)=[C:17]([CH:28]([CH3:30])[CH3:29])[C:15](=[O:16])[NH:14][C:12]1=[O:13])[C:3]([NH2:5])=[O:4])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)cc(Cc2c(C(C)C)c(=O)[nH]c(=O)n2COCCCN(O)C(N)=O)c1
Agent: CN(C)c1ccncc1
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON(CCCOCn1c(Cc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O)C(N)=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 1-(3-N1-hydroxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil obtained in the above Example 1-C (85 mg, 0.2 mmol) in dichloromethane (3.5 ml), was added DMAP (4-dimethylaminopyridine) (5 mg, 0.04 mmol), triethylamine (45 μl, 0.3 mmol) and acetic anhydride (25 μl, 0.24 mmol) and the mixture was stirred for 3 hours at 20° C. Then, it was added thereto dichloromethane (5 ml) and an aqueous saturated sodium hydrogenocarbonate solution (5 ml). The reaction medium was then extracted with dichloromethane (50 ml) and the organic phase was washed with water (10 ml) and then with a saturated sodium chloride solution (10 ml) and dried (sodium sulfate). The organic phase was then concentrated and subjected to a flash column chromatography on silica gel (dichloromethane/methanol 9:1) to give 70 mg (75%) of the desired 1-(3-N1-acetoxyureidopropyloxymethyl)-6-(3,5-dimethylbenzyl)-5-isopropyluracil in the form of a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([OH:22])([CH3:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].C[Si]([N-][Si](C)(C)C)(C)C.[CH:35]1[CH:40]=[CH:39][C:38]([O:41][C:42](Cl)=[S:43])=[CH:37][CH:36]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]([CH3:21])([O:22][C:42]([O:41][C:38]2[CH:39]=[CH:40][CH:35]=[CH:36][CH:37]=2)=[S:43])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:24])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(C)(O)Cc2ccccc2)COC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(C)(Cc2ccccc2)OC(=S)Oc2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of (R)-4-(1-hydroxy-1-methyl-2-phenyl-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.50 g) in THF (25 ml) was cooled under an argon atmosphere to −78° C. and treated dropwise with 1 M lithium-bis-(trimethylsilyl)amide in THF (1.79 ml). The solution was allowed to warm to r.t. Then, phenyl chlorothionoformate (0.3 ml) was added. After stirring at r.t. for 2 hrs, the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated to give crude (R)-2,2-dimethyl-4-(1-methyl-1-phenoxythiocarbonyloxy-2-phenyl-ethyl)-oxazoli-dine-3-carboxylic acid tert-butyl ester as pale yellow oil which was used in the next reaction step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C.[O:30]=[C:31]1[CH2:36][O:35][CH2:34][CH2:33][N:32]1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([C@H:46]2[CH2:50][C@@H:49]([OH:51])[CH2:48][NH:47]2)=[O:45])=[CH:39][CH:38]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:30]=[C:31]1[CH2:36][O:35][CH2:34][CH2:33][N:32]1[C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:44]([C@H:46]2[CH2:50][C@@H:49]([OH:51])[CH2:48][N:47]2[C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:45])=[CH:41][CH:42]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.4 %

Procedure:
0.25 g (1.46 mmol) of 4-chlorophenylacetic acid and 0.36 g (1.46 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added successively at room temperature to a solution of 0.5 g (1.46 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide (Example 7.2) and 0.2 ml of triethylamine in 20 ml of toluene. The resultant reaction mixture is subsequently left to stir at room temperature for 12 hours, then washed successively with 10 ml of 1N hydrochloric acid and 10 ml of saturated sodium hydrogencarbonate solution, and the organic phase is dried over sodium sulfate. After the solvent has been stripped off, the crude product is purified by preparative HPLC, giving 0.31 g (46.4%) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[2-(4-chlorophenyl)acetyl]-4-hydroxypyrrolidine-2-carboxamide as a white powder, ESI 458, m.p. 141°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=2[N+:19]([O-])=O)[CH2:8][C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].[CH:31](O)(C)C>[Ni]>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:11]3[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=3[N:19]=[CH:31]2)[CH2:8][C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(C)O
Reactant: CC(=O)OC[C@@H]1C[C@H](Nc2cc(Cl)c(Cl)cc2[N+](=O)[O-])[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ni]
Product: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
(±)-(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(4,5-dichloro-2-nitroanilino)-1,2-cyclopentanediyl diacetate (2.75 g, 5.93 mmol) and Raney nickel (aqueous slurry, Aldrich, 300 mg wet) in isopropanol (250 mL) was shaken under hydrogen (40 psi) in a Parr shaker for 2.25 hours. Catalyst was filtered off with Celite and the filtrate acidified with 98% formic acid (5 mL) and concentrated to an orange oil. The oil was diluted with additional 98% formic acid (45 mL) and the resulting orange solution refluxed for 40 minutes. Volatiles were removed and the remaining dark oil dissolved in chloroform (100 mL). The chloroform solution was washed with saturated aqueous sodium bicarbonate (3×10 mL), dried (sodium sulfate), and evaporated to a foam which was chromatographed on silica gel. Title compound eluted with methanol:chloroform/3:97 as a white foam from ethyl acetate (2.26 g, 86%); 1H-NMR (DMSO-d6) δ: 8.57, 8.17, 7.97 (all s, 1 each, 3 benzimidazole CH), 5.6 (m, 1, CHO), 5.3-5.1 (m, 2, CHO and CHN), 4.35-4.15 (m, 2, CH2O), 2.6-2.4 (m overlapping solvent, 2 CH), 2.10, 2.06, 1.92 (all s) overlapped by 2.0 (m, total 10,3CH3CO and CH).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][CH2:4][C@@H:5]([C:16](=[O:38])[NH:17][CH:18]1[C:24](=[O:25])[NH:23][C:22]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:21]=2[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:19]1)[C@H:6]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([OH:9])=O.[Cl-].[NH4+].CC[N:45](C(C)C)C(C)C>CS(C)=O>[CH3:31][O:30][C:28]1[CH:27]=[CH:26][C:22]2[NH:23][C:24](=[O:25])[C@@H:18]([NH:17][C:16](=[O:38])[C@H:5]([CH2:4][CH2:3][C:2]([F:39])([F:1])[F:40])[C@H:6]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]([NH2:45])=[O:9])[N:19]=[C:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:21]=2[CH:29]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NC(NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(=O)O)C(=O)N2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(c1ccccc1)=N[C@H](NC(=O)[C@H](CCC(F)(F)F)[C@H](CCC(F)(F)F)C(N)=O)C(=O)N2
Temperature: 25 °C

Procedure:
To a stirred solution of Intermediate 7E (500 mg, 1.047 mmol), pyBOP (0.65 mg, 1.25 mmol), and ammonium chloride (0.28 mg, 5.23 mmol) in DMSO (6 mL), at 0° C. under a nitrogen atmosphere, was added dropwise a solution of N,N′-diisopropylethylamine (0.36 mL, 2.09 mmol) over two minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for sixteen hours. The mixture was then poured into ice cooled water (20 grams) and stirred for one hour and then filtered. The crude residue was subjected to preparative HPLC purification/separation (Column-CHIRALCEL® ODH (250×4.6) mm 5 micron, Mobile Phase A: 0.2% diethylamine-hexane (80%), Mobile Phase B: ethanol (20%), @ 220 and 250 nm Flow-1 ml/Min, Run-20 min) to provide Intermediate 7F as a white solid: yield 180 mg (10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), 9.444-9.463 (d, J=7.6 Hz, 1H), 7.60-7.7 (brs, 1H), 7.51-7.54 (m, 3H), 7.44-7.47 (m, 2H), 7.24-7.28 (m, 2H), 7.14-7.19 (brs, 1H), 6.77-6.78 (d, J=4 Hz, 1H), 5.3-5.31 (d, J=4 Hz, 1H), 3.71 (s, 3H), 2.78-2.84 (m, 1H), 2.2.11-2.31 (m, 4H), 1.60-1.74 (m, 4H), MS (M−1)=571. HPLC RT=9.31 min (Xbridge Phenyl (4.6×150 mm), 3.5 micron; 1 mL/min flow rate; gradient 10% B-100% B over 12 min (A: 0.05% TFA in water/CH3CN (95:5), B: 0.05% TFA in water/CH3CN (5:95) @ 220 and 250 nm, 15 min run).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu](C#N)[C:15]#[N:16].N>CN1CCCC1=O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:2]=1[C:15]#[N:16]
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OC(F)(F)F)ccc1N
Temperature: 163 °C
Reaction time: 6.5 h
Yield: 75 %

Procedure:
To a solution of 2-bromo-4-(trifluoromethoxy)aniline (15.1 g, 60.0 mmol) in N-methylpyrrolidone (100 mL) was added copper cyanide (10.6 g, 118 mmol) and the reaction mixture was stirred for 6.5 h at 163° C. After cooling to ambient temperature it was poured onto ice-water (300 mL) and aqueous ammonia (350 mL). The resulting brown precipitate was collected by filtration, washed with water (150 mL) and dissolved in dichloromethane (350 mL). The insoluble material was removed by filtration and the filtrate was washed with brine (100 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 25:75:) afforded the title compound (9.09 g, 76%) as a brown solid. MS: m/e=405.1 [2M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:25]#[N:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1.Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:25]#[N:26])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(C#N)c1
Temperature: 10 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
Methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (11.60 g, 31.57 mmol) was dissolved in dioxane (160 mL) and the solution was cooled to 10° C. in an ice bath. LiOH—H2O, 1M (37.89 ml, 37.89 mmol) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with 2N HCl (100 mL) and CH2Cl2 (200 mL). Layers were separated and aqueous layer was extracted with CH2Cl2. The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered through a Celite pad and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to provide 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (7.29 g) as a white solid.