Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].[C:52]([CH2:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])#[N:53]>C1C=CC=CC=1>[C:52]([CH:54]([CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([O:15][CH:16]4[CH2:21][CH2:20][CH:19]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2)[C:55]([O:57][CH2:58][CH3:59])=[O:56])#[N:53]
Reactant: IC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Reactant: CCOC(=O)CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A mixture of (3S)-3-(iodomethyl)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (287 mg, 0.57 mmol, 1.00 equiv), 18-Crown-6 (190 mg, 0.72 mmol, 1.25 equiv), potassium carbonate (141 mg, 1.02 mmol, 1.78 equiv) and ethyl 2-cyanoacetate (678 mg, 5.99 mmol, 10.43 equiv) in benzene (20 mL) was stirred overnight at 80° C. under nitrogen. After cooling to room temperature, the solvent was removed under vacuum and the residue was purified by a silica gel column with DCM/MeOH (30:1-10:1) to provide 230 mg (83%) of ethyl 2-cyano-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanoate as a light yellow solid. MS (ES): m/z 485 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].N1C=CC=CC=1>C(Cl)Cl>[CH2:34]([O:33][C:31](=[O:32])[NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13](=[O:21])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:22])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:19][CH:18]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N)cc1)C(C)(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(NC(=O)OCc2ccccc2)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.9 %

Procedure:
A solution of [1(S)-(4-aminobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (67 mg, 0.22 mmol) and triethylamine (95 μL, 0.69 mmol) in DCM (3 mL) was cooled on an ice bath prior to addition of benzyl chloroformate (98 μL, 0.69 mmol). The reaction was warmed to room temperature and left for 15 hours. Examination by T.l.c. suggested minimal conversion to product hence pyridine (0.10 mL, 1.2 mmol) was added and the reaction left for a further 2 hours. Solvent was removed in vacuo and the residue taken up in ethyl acetate (20 mL). The organic phase was washed with 1M HCl (1×20 mL), brine (1×20 mL), 1M Na2CO3 (1×20 mL) and brine (1×20 mL, dried over MgSO4, filtered and the solvent removed in vacuo, giving a yellow solid. Purification by column chromatography (SiO2, 9:1 isohexane:ethyl acetate) afforded the title compound as a yellow solid (90 mg, 90%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]=1[CH2:12][CH2:13][C:14](=[O:26])[NH:15]2.Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1>C(OCC)(=O)C.O>[C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:31]=[CH:30][C:29]([CH2:28][N:15]2[C:16]3[C:11](=[C:10]([O:9][CH3:8])[CH:19]=[CH:18][C:17]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:13][C:14]2=[O:26])=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2ccccc2)c2c1CCC(=O)N2Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
Sodium hydride (60% in oil) (0.87 g) was added at 0° C. to a DMF solution (50 ml) of 5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one (5.0 g), followed by stirring for 30 minutes. 4-Bromomethylbiphenyl (5.37 g) was added, and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction with ethyl acetate was performed. The extract was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:10→1:5). The purified product was recrystallized from an ethyl acetate-n-hexane-diethyl ether mixed solvent to thereby obtain 6.8 g (yield: 82%) of 1-(biphenyl-4-ylmethyl)-5-methoxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one as a white powder.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][S:11]3(=[O:19])=[O:18])=[CH:4][C:3]=2[O:2]1.[H-].[Na+].[Cl:22][CH2:23][CH2:24][CH2:25][N:26](CCC1C=CC(OC)=C(OC)C=1)[CH3:27]>CN(C)C=O>[ClH:22].[CH3:27][NH:26][CH2:25][CH2:24][CH2:23][C:10]1([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[S:15](=[O:16])(=[O:17])[CH2:14][CH2:13][CH2:12][S:11]1(=[O:19])=[O:18]
Reactant: O=S1(=O)CCCS(=O)(=O)C1c1ccc2c(c1)OCO2
Reactant: COc1ccc(CCN(C)CCCCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNCCCC1(c2ccc3c(c2)OCO3)S(=O)(=O)CCCS1(=O)=O
Product: Cl
Temperature: 25 °C

Procedure:
6.08 g of 2-(3,4-methylenedioxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (prepared as described in Example 2) are stirred under argon with 25 ml of absolute dimethylformamide and treated with 0.8 g of a 55% sodium hydride suspension. The mixture is left to react for 0.5 hour at room temperature and for 1 hours at 40° C. After cooling to room temperature, 4.8 g of N-(3-chloropropyl)-3,4-dimethoxy-N-methyl-phenethylamine (prepared as described in Example 3) are added and the mixture is heated at 100° C. for 16 hours. The cooled mixture is then poured on to ice and extracted three times with ethyl acetate. The organic extracts are washed with water, dried over magnesium sulphate and evaporated in vacuo. The residual oil is dissolved in acetone and treated with 5 ml of a 6-N hydrogen chloride solution in dioxane. The precipitate, which is filtered off under a vacuum, is recrystallized from acetone. There are obtained 7.5 g of N-3,4-dimethoxyphenethyl)-N-methyl-2-(3,4-methylenedioxyphenyl)-m-dithiane-2-propylamine- 1,1,3,3-tetraoxide hydrochloride of melting point 247°-248° C.
Reaction SMILES: B1(C=C)OB([CH:7]=[CH2:8])OB(C=C)O1.C1C=CN=CC=1.Br[C:20]1[C:21]([C:35]([NH:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:36])=[N:22][O:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[CH:38]1([NH:37][C:35]([C:21]2[C:20]([CH:7]=[CH2:8])=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:23][N:22]=2)=[O:36])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(NC1CCCC1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Br
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: O
Solvent: c1ccncc1
Solvent: COCCOC
Product: C=Cc1c(C(=O)NC2CCCC2)noc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 80 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (57.9 mg, 0.05 mmol) was added to a stirred suspension of 2,4,6-trivinylcyclotriboroxane pyridine complex (121 mg, 0.50 mmol), 4-bromo-N-cyclopentyl-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxamide (202 mg, 0.50 mmol) and potassium carbonate (138 mg, 1.0 mmol) in DME (4.7 mL) and water (1.6 mL) and heated to 100° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and partitioned between water and ethylacetate. The organics were dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography eluting with heptane to 20% ethylacetate in heptane to obtain N-cyclopentyl-5-(4-(trifluoromethyl)phenyl)-4-vinylisoxazole-3-carboxamide (140 mg, 0.40 mmol).
Reaction SMILES: COC(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)N.C=O.FC(F)(F)C(O)=O.C[N:27]1[CH:39]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]=2[CH2:28]1>[Pd].C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH:28]1[C:29]2[NH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]=2[CH:38]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[N:27]=1
Reactant: COC(=O)C1Cc2c([nH]c3ccccc23)CN1C
Agent: [Pd]
Agent: C=O
Agent: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 1 h
Yield: 46 %

Procedure:
This compound was prepared by a modification of a known procedure (Couts et al., Heterocycles 1984, 22:131). To a mixture of the free base of L-tryptophan methyl ester (161 g, 0.738 mol) and paraformaldehyde (22 g, 0.733 mol) was added toluene (1 L). The mixture was refluxed with efficient mechanical stirring, and the water removed using a Barrett trap. After 1 hour, nearly the theoretical amount of water was collected (13 mL). Trifluoroacetic acid (5 mL, 0.065 mol, 8.8 mol %) was added through the top of the condenser (exothermic), and the mixture refluxed for another 1.5 hours. The solvent was evaporated and 10% palladium-on-carbon was added to the pot (44 g of moist material recovered from a previous run; dry wt=38 g based on water removed in subsequent step; ˜0.036 mol Pd, or 4.8 mol %). Xylene (800 mL) was added, and the mixture vigorously stirred (mechanical stirrer) and refluxed overnight with a Barrett trap to remove the water from the Pd/C. The reaction mixture was then cooled in an ice bath, then in a freezer at −20° C. overnight. The resulting sludge was filtered, affording mother liquors containing impurities, including a compound consistent with methyl 2-methyl-1,2,3,4-tetrahydro-9H-β-carboline-3-carboxylate, and a gray filter cake containing a mixture of the product and Pd/C. The filter cake was transferred to a paper thimble and extracted in a Soxhlet apparatus with methanol (800 mL in a 2-L recovery flask) in several batches. As the product crystallized in the pot, the slurry was filtered, the light yellow solid was washed with methanol and dried, and the filtrate was returned to the pot. Three batches of product were collected, affording a total of 76 g of product (46% yield from tryptophan methyl ester).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:31]([C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[O:21][CH3:20])(=[O:32])=[O:33])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2n1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.13 g of sodium hydride as an 80% dispersion in oil was added in portions, with stirring, to a solution of 1 g of 5-chloro-3-cyclohexyl-1,3-dihydro-2H-benzimidazol-2-one in 10 ml of DMF at room temperature; 1.1 g of 2-methoxy-4-nitrobenzenesulfonyl chloride were then introduced and the reaction medium was stirred at room temperature for 4 hours. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected product in the form of a slightly yellow solid, which crystallized from absolute EtOH. m=1.52 g. M.p.=185° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O1CCCC1.C(NC(C)C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7])#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#CCCCCC
Reactant: Brc1ccsc1Br
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCC#Cc1sccc1Br
Temperature: 70 °C
Yield: 99.4 %

Procedure:
2 ml (18.0 mmol) of 2,3-dibromothiophene, commercially available from Aldrich under the Product No. D4,390-5, and 3.5 ml (27.0 mmol) of 1-heptyne, commercially available from Aldrich under the Product No. 24, 441-4, were mixed with a solvent of tetrahydrofuran/diisopropylamine (1:1), and 0.23 g (0.36 mmol) of palladium dichlorodiphosphine, 70 mg (0.36 mmol) of copper iodide and 0.1 g (0.36 mmol) of triphenylphosphine were sequentially added thereto. The reaction solution was heated at 70° C. for 8 hours, and washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over magnesium sulfate, dried under reduced pressure, and purified using silica gel column chromatography, thus obtaining 4.6 g of 2-heptynyl 3-bromothiophene. The compound thus obtained was added with 3.3 ml (23.2 mmol) of trimethylsilylacetylene, commercially available from Aldrich under the Product No. 21, 817-0 and then subjected to the above synthesis process, to prepare 2.7 g (9.84 mmol) of 2-heptynyl-3-trimethylsilylethynylthiophene, which was then mixed with 12.8 ml (12.8 mmol) of lithium diisopropylamide (1 M) at about −78° C. The reaction mixture was stirred at the same temperature for 30 minutes, then combined with 2.4 ml (11.8 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, commercially available from Aldrich under the Product No. 41,714-9, and allowed to react in a bath while the temperature was increased to room temperature. The resultant reaction solution was poured into an aqueous solution of 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate and distilled under reduced pressure, thus obtaining 4.1 g of a compound 1a in an oil phase. Analysis of the compound 1a produced the following NMR data: 1H NMR (300 MHz, CDCl3), δ(ppm) 0.24 (s, 9H), 0.92 (t, 3H, J=7.2 Hz), 1.24-1.64 (m, 18H), 2.49 (t, 2H, J=7.0 Hz), 7.47 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[C:10]([OH:11])=[C:9]([CH3:12])[C:8]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:7]([CH3:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]1([C:44]2[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=2)[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[OH-:54].[Na+]>CC(C)=O.O>[C:1]([C:5]1[CH:10]=[C:9]([CH3:12])[C:8]([CH2:13][N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:40]([C:37]2[CH:38]=[CH:39][C:34]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([N:14]([CH2:13][C:8]4[C:7]([CH3:33])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[C:10]([OH:11])[C:9]=4[CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:52])=[O:51])=[CH:46][CH:45]=3)=[CH:35][CH:36]=2)(=[O:42])=[O:41])=[C:7]([CH3:33])[C:6]=1[OH:54])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: CCCCCCCCCCCCCCCCCCNCc1c(C)cc(C(C)(C)C)c(O)c1C
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCN(Cc1c(C)cc(C(C)(C)C)c(O)c1C)S(=O)(=O)c1ccc(-c2ccc(S(=O)(=O)N(CCCCCCCCCCCCCCCCCC)Cc3c(C)cc(C(C)(C)C)c(O)c3C)cc2)cc1
Temperature: 35 °C
Yield: 76.8 %

Procedure:
To a stirred solution of 6-t-butyl-3-(octadecylaminomethyl)-2,4-dimethylphenol (9.18 grams; 0.02 mole) in acetone (80 mls) at 35° C. there is added 4,4'-biphenyldisulfonyl chloride (3.5 grams; 0.01 mole) over a period of 20 minutes while maintaining the temperature at 35° C. The mixture is stirred for an additional hour at 35° C. and a solution of 50% caustic soda (1.6 grams; 0.02 mole) in water (8 mls) is added to the reaction mixture which is then allowed to stir at room temperature for 20 hours. The reaction mixture is then treated with water (50 mls) and the resulting precipitate is recovered by filtration, washed with methanol, and dried to obtain the crude product (9.2 grams; 77% of theoretical). Recrystallization of the crude product from n-propanol affords the pure product (4.2 grams; m.p. 208°-210° C.).
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].F[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:25]3[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=3[C:27]#[N:28])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccccc3C#N)cc2)CC[C@@]1(C)C(N)=O
Yield: 99 %

Procedure:
A solution of 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (D10, 60 mg, 0.187 mmol), 2-fluorobenzonitrile (45 mg, 0.374 mmol) and potassium carbonate (39 mg, 0.280 mmol) in DMF (2 ml) was heated under microwave irradiation for 30 min to 120° C. Water and ethyl acetate were added to the mixture, and the organic layer was washed with ice cold water. The solution was dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford the title compound (78 mg); Rt (HPLC): 5.44 min; Rf (cyclohexane:ethyl acetate=1:1): 0.21; MS: (ES/+) m/z: 444 [M+Na+]; C24H27N3O4 requires 421.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C(N(CC)CC)C.[CH2:17]([S:20](Cl)(=[O:22])=[O:21])[CH2:18][CH3:19].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:20]([CH2:17][CH2:18][CH3:19])(=[O:22])=[O:21]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2,4-difluoro-phenylamine (42, 3.0 mL, 29.8 mmol) in tetrahydrofuran (50 mL) were added triethylamine (9.13 mL, 65.5 mmol) and propane-1-sulfonyl chloride (2.90 mL, 25.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into 1 M HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the compound (72, 2.0 g, 28%) that was used in the next step.
Reaction SMILES: CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[NH2:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22].Cl.[NH:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:54](O)=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.CN(C=O)C>[NH:37]([C:57]([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])[C@H:38]([C:54]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:55])[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Reactant: O=C(NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 19 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
4-Methylmorpholine (1.26 g, 12.5 mmol) and HOBt (1.69 g, 12.5 mmol) were added to a solution of H-Leu-Leu-OMe.HCl (4.04 g, 13.75 mmol) in ethyl acetate (160.0 g) and DMF (36.0 g) over 15 min. Z-Lys(Z)—OH (5.18 g, 12.5 mmol) was added to this stirred mixture over 15 min. A solution of DCC (3.10 g, 12.5 mmol) in ethyl acetate (10.0 g) was added dropwise at 18-20° C. over 30 min. The reaction mixture was stirred at 18-20° C. for 16 h and filtered. The filter cake was washed with ethyl acetate (100.0 g) and the combined filtrate was washed with aqueous NaHCO3. The resulting organic layer was washed with aqueous NaCl and concentrated under reduced pressure. The residue was dissolved in MeOH (80.0 g) at about 50° C. Water (160 g) was slowly added and the mixture was stirred for about 1 h at 20° C. The resulting solid was filtered, washed with H2O (80.0 g) and dried at 40° C. in a vacuum oven to give 8.16 g, 99.6% of the product Z-Lys(Z)-Leu-Leu-OMe.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][C:16](=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]([OH:47])=[O:42].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][NH:17][C:16](=[O:19])[NH:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CNC(=O)NC3)cc2C2=CCCCC2)n1
Reaction time: 8 h
Yield: 8 %

Procedure:
4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-amide (as prepared in the previous step, 14 mg, 0.026 mmol) was dissolved in DCM (1 mL), EtOH (30 μL) and TFA (0.3 mL). The resulting mixture was stirred overnight and concentrated. The residue obtained was subjected to RP-HPLC eluting with 20% to 100% CH3CN in 0.1% TFA/H2O over 20 min on a C18 column to obtain the title compound (1.1 mg, 8%): 1H-NMR (CD3OD/CDCl3; 400 MHz): δ 8.23 (d, 1H, J=8.0 Hz), 7.90 (s, 1H), 7.20 (dd, 1H, J=8.0, 2.2 Hz), 7.09 (d, 1H, J=2.2 Hz), 5.75 (br s, 1H), 3.47 (4H, m), 3.17 (m, 1H), 2.22-2.33 (m, 4H), 1.72-1.83 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H22N6O2, 391.3 (M+H). found 391.2.
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=1.CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([CH2:14][N+:15]([O-:17])=[O:16])[C@H:2]([CH3:3])[CH:1]=[O:4])=[CH:11][CH:12]=1
Reactant: CCC=O
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: COc1ccc([C@H](C[N+](=O)[O-])[C@H](C)C=O)cc1

Procedure:
The title compound was prepared from propionaldehyde and (E)-1-methoxy-4-(2-nitrovinyl)benzene according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AS-H column at 230 nm (2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer tmajor=42.10 min, minor enantiomer tminor=60.77 min. [α]D20=−4.6 (c=1.3, CHCl3).