Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]2[O:24][C:2]3[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13](=[O:16])[C:14]=2[CH3:15])=[CH:21][CH:20]=1)#[N:18]
Reactant: CCOC(=O)c1cccc(C(=O)CC)c1O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cccc2c(=O)c(C)c(-c3ccc(C#N)cc3)oc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A solution of 5.2 g of ethyl 2-hydroxy-3-propionylbenzoate in 30 ml of anhydrous pyridine was added dropwise over 20 minutes at room temperature into a stirred mixture of 4 g of 4-cyanobenzoyl chloride in 30 ml of anhydrous pyridine. The solution was stirred for 1 hour at the same temperature, then 2.6 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene was added and the solution was heated at 100° C. for 2 hours. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was quenched with 100 ml of water containing 40 ml of 6N aqueous hydrochloric acid solution. The mixture was extracted twice with 100 ml aliquots of dichloromethane, the organic layer was separated, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with n-hexane-ethyl acetate gradient (95:5 to 60:40), obtaining 3 g of the title compound after crystallization from ethanol, m.p. 181°-183° C.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:52][CH3:53]>>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:52][CH3:53])[C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@H:14]2[CH3:46])[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=1
Reactant: CCI
Reactant: CCOC(=O)C[C@H]1CC[C@H](C(=O)Nc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C[C@H]1CC[C@H](C(=O)N(CC)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1

Procedure:
Ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}carbonyl)cyclohexyl]acetate (637 mg; 0-913 mmol) was treated with sodium hydride (60% in oil; 40 mg; 1.0 mmol) and iodoethane (110 mL; 1.37 mmol) as described in EXAMPLE 86 to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]carbonyl}cyclohexyl)acetate as a yellow oil. LCMS=727.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.92 (s, 1 H), 7.80 (s, 1 H), 7.74 (s, 1 U), 7.28-7.22 (m, 1 H), 7.19-7.16 (m, 1 H), 7.14-7.11 (m, 1 H), 5.66 (d, J=8.0 Hz, 1 H), 4.92 (d, J=14.9 Hz, 1 H), 4.25 (d, J=16.9 Hz, 1 H), 4.23-4.05 (m, 4 H), 3.54-3.46 (m, 1 H), 3.08-3.00 (m, 1 H), 2.66-2.58 (m, 1 H), 2.22-2.18 (m, 1 H), 2.09-2.06 (m, 1 H), 1.92-1.52 (m, 6 H), 1.26-1.12 (m, 7 H), 0.81-0.66 (m, 4 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@@H:14]3[C@@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.BrC1C=CC(F)=C([C@]2(C(F)[F:35])[C@@H]3[C@@H](C3)OC(N)=N2)C=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH:16]([F:35])[F:17])[C@H:14]3[C@H:12]([CH2:13]3)[O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@H]2C[C@H]2O1
Product: NC1=N[C@](c2cc(N)ccc2F)(C(F)F)[C@@H]2C[C@@H]2O1

Procedure:
The title compound was prepared following a procedure similar to that described in step 8 for the synthesis of 6h-B, but using (1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (16f-B) MS m/z=272.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[NH:22][C:21](=[O:23])[CH2:20][CH2:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:29]([O:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][C:37]([NH:22][C@@H:18]([C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:19][CH2:20][CH2:21][OH:23])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC[C@H](c2nc(-c3ccccc3)c(-c3ccccc3)o2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of (5R)-5-(4,5-diphenyloxazol-2-yl)pyrrolidin-2-one (12 g) in tetrahydrofuran (THF) (200 ml) were added butyllithium (26 ml, 1.6N solution in hexane) and benzyloxycarbonyl chloride (6.8 ml) at -78° C. under N2. The mixture was stirred for 1 hour at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo, the residue was dissolved in THF (200 ml), and 1N-NaOH (87 ml) was added at 0° C. After being stirred for 12 hours at room temperature, the solvent was evaporated in vacuo. After the residue was partitioned between hexane and water, aqueous layer was adjusted to pH=2 and extracted with ethyl acetate. The organic layer was washed with water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was dissolved in THF (200 ml). To the solution were added triethylamine (9.0 ml) and ethyl chloroformate (5.0 ml) at ±5° C. under N2 and the mixture was stirred for 1 hour at the same temperature. After the filtration, the solution was dropwise added to the solution of NaBH4 (3.2 g) in a mixture of THF (100 ml) and water (100 ml) at 0° C. and stirred for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (13 g). MS (m/z): 443 (M+ +1) IR (Neat): 3300, 1700 cm-1NMR (CDCl3, δ): 1.6-2.2 (4H, m), 3.68 (2H, m), 5.10-5.2 (1H, m), 5.14 (2H, s), 5.73 (1H, d, J=10.0 Hz), 7.2-7.7 (10H, m)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[CH:4][N:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:21]=1)[NH2:18].CS(O)(=O)=O>O1CCOCC1>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:18][C:17]2[CH:19]=[C:20]([B:22]3[O:26][C:25]([CH3:27])([CH3:28])[C:24]([CH3:30])([CH3:29])[O:23]3)[CH:21]=[C:15]([CH3:14])[CH:16]=2)[N:7]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COCCCOc1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: COCCCOc1ccnc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
The product of Step 1 (107 mg, 0.528 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (123 mg, 0.528 mmol) were dissolved in Dioxane (4 ml), and methanesulfonic acid (0.036 ml, 0.554 mmol) was added. The mixture was heated to 100° C. for 18 h. The mixture was allowed to cool to room temperature, quenched with saturated aqueous sodium bicarbonate and extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 4-(3-methoxypropoxy)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (165 mg, 78%) as a brown solid. MS ESI: [M+H]+ m/z 400. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=5.8, 1H), 7.82 (s, 1H), 7.59 (s, 1H), 7.32 (s, 1H), 6.17 (d, J=4.4, 1H), 4.48 (t, J=5.8, 2H), 3.53 (t, J=5.5, 2H), 3.34 (s, 3H), 2.37 (s, 3H), 2.05 (dd, J=3.3, 9.4, 2H), 1.34 (s, 12H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 130 °C

Procedure:
Into a 5 mL microwave tube was charged 4-fluoro-2-methoxy-1-nitrobenzene (1 g, 0.584 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.321 g, 1.753 mmol), triethylamine (0.244 mL, 1.753 mmol), and acetonitrile (1.948 mL). The reaction was heated in Biotage microwave reactor at 130° C. for 40 minutes. The solvent was removed under reduced pressure, and the reaction purified by flash chromatography using a gradient 100% CH2Cl2 to 1:1 CH2Cl2/methanol to provide the title compound. MS (ESI) m/e 335 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:7]([CH3:14])[O:6][C:4]1=[O:5].C(=O)(O)[O-:16].[Na+]>C(Cl)Cl>[NH2:2][C@@H:3]([C@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:7]([OH:6])[CH3:14])[C:4]([OH:16])=[O:5]
Reactant: O=C([O-])O
Reactant: CCOC(=O)[C@H]1[C@H](N)C(=O)O[C@@H]1C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]([C@H](N)C(=O)O)[C@@H](C)O

Procedure:
56.0 g of 2(S)-amino-3(S)-ethoxycarbonyl-4(R)-pentanolide hydrochloride are dissolved in methylene chloride and the pH is adjusted to 7.5 with sodium bicarbonate solution. The methylene chloride phase is separated off, the aqueous phase is saturated with sodium chloride and extracted repeatedly with methylene chloride, and the organic phases are concentrated by evaporation. 106 ml of 2N sodium hydroxide solution are added dropwise to the residue in 120 ml of ethanol at 0° C. within a period of 6 hours. The solution is then concentrated to half its volume, adjusted to pH 3.9 with 103 ml of 2N hydrochloric acid, and completely concentrated by evaporation. The residue is crystallised from isopropanol/diisopropyl ether, stirred up with methanol and filtered over silica gel. [α]36520 =+14.5° (1% in H2O), m.p. 150°-151° C.
Reaction SMILES: [Si]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(C(C)(C)C)(C)C.C([Li])CCC.[CH2:18]([N:21]([CH2:35][CH2:36][CH3:37])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32](I)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:19][CH3:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:35]([N:21]([CH2:18][CH2:19][CH3:20])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:36][CH3:37]
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: CC(C)(C)[Si](C)(C)n1ccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-tert-butyldimethylsilylimidazole (602 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.63 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 9.9 mL, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate prepared by the method in Example SP-281, step 2 (1.17 g, 3 mmol) followed by palladium(0)tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 15 h. The reaction mixture is diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1-5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.19 (s, 2H), 3.96 (s, 3H), 3.51 (m, 2H), 3.32 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.01 (m, 3H), 0.73 (m, 3H).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:21]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Temperature: 12.5 °C
Yield: 84.3 %

Procedure:
Stearyl alcohol (2.7 g, 0.01 mol), and triphosgene (0.99 g, 0.0067 mol) were dissolved in 20 ml methylene chloride, stirred and cooled to 10-15° C. Anhydrous pyridine (0.8 g of, 0.02 mol) was added dropwise into the pre-cooled solution over a 1 hr period. The reaction mixture was stirred for an additional 1 h, then heated in a water bath at 65° C. for 15 min until all the methylene chloride evaporated. The residue was washed 3 times with cold water, dried over Na2SO4 and evaporated to give stearyl chloroformate (1.88 g, 83% yield), also known as octadecyl chloroformate.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:27]([O:29][C:30]([C:32]1[NH:33][CH:34]=[CH:35][C:36]=1[NH2:37])=[O:31])[CH3:28]>O1CCOCC1>[N:37]1([C:36]2[CH:35]=[CH:34][NH:33][C:32]=2[C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH:3]=[CH:7][CH:6]=[CH:5]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)c1[nH]ccc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]ccc1-n1cccc1
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a stirred solution of 2,5-dimethoxytetrahydrofuran (b) (1.6 mL, 12.4 mmol, 1.3 equiv) and PPTS (3.2 g, 12.4 mmol, 1.3 equiv) in 1,4-dioxane (20 mL) at 50° C., a solution of aminopyrrole (a) (1.47 g, 9.55 mmol, 1.0 eq.) in 1,4-dioxane (6 mL) was added slowly. The resulting mixture was brought to reflux and stirred for 1 h. The reaction mixture was then concentrated, dissolved in EtOAc (50 mL) and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography (10% EtOAc in Hexane) to give (c) as a yellow solid (1.036 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1H), 7.04-7.01 (m, 2H), 6.89 (t, J=3.1 Hz, 1H), 6.29 (t, J=2.9 Hz, 1H), 6.27-6.24 (m, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[CH2:11][C@H:10]([O:12][CH3:13])[CH2:9][CH2:8][C@@H:7]1[N:14]1[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OCC2C=CC=CC=2)[C:15]1=[O:30])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:19][C@H:16]1[CH2:17][CH2:18][N:14]([C@H:7]2[CH2:8][CH2:9][C@@H:10]([O:12][CH3:13])[CH2:11][C@H:6]2[CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:15]1=[O:30]
Reactant: CO[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CNC(C)=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CO[C@@H]1CC[C@H](N2CC[C@H](N)C2=O)[C@H](CNC(C)=O)C1
Yield: 98.4 %

Procedure:
A sample of the benzyl (S)-1-((1S,2S,4R)-2-(acetamidomethyl)-4-methoxycyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (614 mg, 1.471 mmol) and Pd/C (62.6 mg, 0.294 mmol) were stirred in MeOH (30 mL) at room temperature under 50 psi hydrogen atmosphere for 2 h. The suspension was filtered through Celite with EtOAc, concentrated and dried in vacuo to yield N-(((1S,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-methoxycyclohexyl)methyl)acetamide (410 mg, 1.447 mmol, 98% yield) as a white solid. LC/MS found [M+H]+=284.24.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([OH:14])=O)=[O:6])[CH:2]=[CH2:3].[CH:15]1(N=C=NC2CCCCC2)CCCCC1.CC1(C)OC(=O)CC(=O)O1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:12]([C@@H:8]1[CH2:9][CH2:10][CH2:11][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:14])[CH3:15]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C=CCOC(=O)N1CCC[C@H]1C(=O)O
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1CCC[C@H]1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-carboxypyrrolidine (10 g) in dichloromethane (100 ml) were added dicyclohexylcarbodiimide (9.8 g), Meldrum's acid (6.8 g) and 4-dimethylaminopyridine (5.8 g) at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid solution, evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (80 ml) and water (60 ml), and refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (2S)-2-acetyl-1-allyloxycarbonylpyrrolidine (4.1 g).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:11]=[CH:10]2>>[CH3:21][CH:17]([C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]=2)[CH:13]=1)[C:18]([OH:20])=[O:19]
Reactant: CCCCI
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CCCCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-iodobutane and racemic 6-hydroxy-α-methyl-2-naphthaleneacetic acid. White crystals are obtained having a melting point of 125°-127° c.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[S:37][C:16]2[NH:17][C:18]([C:20]([NH:22][C@@H:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:24]3[NH:32][C:33](=[O:36])[CH2:34]Cl)=[O:21])=[CH:19][C:15]=2[CH:14]=1.CCN(CC)CC>C1COCC1>[Cl:12][C:13]1[S:37][C:16]2[NH:17][C:18]([C:20]([NH:22][C@@H:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@H:24]3[NH:32][C:33](=[O:36])[CH2:34][N:8]([CH2:9][CH2:10][OH:11])[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:21])=[CH:19][C:15]=2[CH:14]=1
Reactant: OCCNCc1ccccc1
Reactant: O=C(CCl)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CN(CCO)Cc1ccccc1)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
2-(Benzylamino)ethanol (160 mg, 1.06 mmol) was added to a solution of 2-chloro-N-{(1R,2R)-1-[(chloroacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 23; 216 mg, 0.53 mmol) and Et3N (500 μL, 3.60 mmol) in anhydrous THF (5 mL) and the reaction stirred for approximately 16 hours at room temperature then for a further 16 h at 50° C. The volatiles were removed under reduced pressure, the residue dissolved in EtOAc (10 mL), washed with H2O (2×10 mL) and dried (MgSO4). The solvent was removed under reduced pressure, the residue triturated (EtOAc:isohexane, 1:5), collected by filtration, washed with isohexane (10 mL) and dried to give the title compound (100 mg, 36%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: O=C1CNC(=O)N1
Solvent: O
Solvent: NCCO
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1
Reaction time: 4 h
Yield: 76.9 %

Procedure:
A mixture of 3,5-dimethoxybenzaldehyde (2.550 g.) and hydantoin (1.505 g., 1 molar ratio) in water (15 ml) was heated to 70°. Monoethanolamine (1.38 g., 1.5 molar ratio) was added and the 2 layer liquid mixture was magnetically stirred at 90°-92° (bath temperature) for 4 hours. Isolation in the usual manner gave the title compound as a beige solid (2.870 g.), m.p. 285°-287°.
Reaction SMILES: [N:1]#[C:2]Br.[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9])[CH2:5][CH3:6].O>CCOCC>[CH2:4]([C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][C:2]#[N:1])[CH2:5][CH3:6]
Reactant: N#CBr
Reactant: CCCc1ccccc1N
Solvent: O
Solvent: CCOCC
Product: CCCc1ccccc1NC#N
Reaction time: 2.5 h
Yield: 41.8 %

Procedure:
A mixture of cyanogen bromide (1.89 g, 17.9 mmol), and 2-n-propylaniline (3.87 g, 28.65 mmol) in ether (50 mL) was stirred for 2.5 hours under nitrogen atmosphere. The mixture was poured into water and extracted with diethylether. The solvent was dried over magnesium sulfate and concentrated in vacuo at room temperature to give 2-propylphenylcyanamide (1.2 g, 26%) as an off white solid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]1([Mg]Cl)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>C1COCC1>[CH:5]1([C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cl[Mg]C1CCCCC1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C2CCCCC2)CC1

Procedure:
Anhydrous cerium(III) chloride (10.0 g) was added to THF (100 ml) with stirring under ice-cooling and a mixture was stirred at ambient temperature overnight and then cooled in an ice bath. A solution of cyclohexyl magnesium chloride (2M solution in diethyl ether) (20.3 ml) was dropwise added to the mixture with stirring on ice bath (keeping the temperature below 6° C.). To the mixture was added dropwise a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.38 g) in THF (25 ml) and the mixture was stirred at 0-6° C. for 1 hour. 10% aqueous acetic acid (100 ml) was added to the reaction mixture and extracted twice with ethyl acetate (100 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-cyclohexyl-4-hydroxy-1-piperidinecarboxylate (7.27 g).