Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]1
Reactant: OCCC1CCNCC1
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: OCCC1CCN(c2cc(Cl)nnc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a 50 mL round bottom flask, 9.18 g (0.05 mol) of 3,4,6-trichloro-pyridazine, 5.30 g (0.05 mol) of anhydrous sodium carbonate and 20 mL of N,N-dimethylacetamide (DMA) were added, stirred at room temperature, then 6.54 g (0.05 mol) of 2-(piperidin-4-yl)-ethanol (dissolved in 10 mL DMA) was added dropwise slowly, after the dropwise addition, the agitation was kept overnight, the reaction liquid was poured into 100 mL of distilled water on the next day, extracted for three times by using total 200 mL of dichloromethane, the extract solutions were combined together, dried over anhydrous Na2SO4, concentrated, and separated by using column chromatograph (eluent, petroleum ether:acetone=10:3) to obtain 6 g of 2-[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-ethanol, yield: 43.6%, 1H-NMR(400 MHz, DMSO-D6) δppm: 1.21˜1.31(m, 2H), 1.39˜1.43(m, 2H), 1.59 ˜1.67(m, 1H), 1.76 ˜1.79(dbrs, 2H), 2.82 ˜2.88(dt, 2H, J=11 Hz), 3.45˜3.49(m, 2H), 3.70˜3.73(dbrs, 2H), 4.40˜4.42(t, 1H, J=5 Hz), 7.35(s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:44]=[CH:43][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:16]3[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]4[C:17]=3[CH:18]=[CH:19][N:20]4C(OC(C)(C)C)=O)([OH:15])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.CO>Cl>[F:13][C:11]([F:12])([F:14])[C:10]([C:8]1[NH:7][C:6]2[CH:43]=[CH:44][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([OH:15])[C:16]1[C:24]([O:25][CH3:26])=[CH:23][C:22]([CH3:27])=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(O)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (2.2 g, 3.49 mmol) was dissolved in 1.25 M HCl in MeOH (55.8 mL, 69.8 mmol) and heated at 60° C. for 17 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resulting residue was diluted with MeOH and basified by adding NH4OH. The crude mixture was directly loaded onto a silica column and purified by flash chromatography (0-100% ethyl acetate in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.00 (br. s., 1H) 8.11 (s, 1H) 7.61-7.69 (m, 1H) 7.55-7.60 (m, 1H) 7.24 (t, J=2.84 Hz, 1H) 6.75 (s, 1H) 6.50 (br. s., 1H) 3.29 (s, 3H) 2.47 (d, J=0.51 Hz, 3H). HRMS calcd. for C20H16F3N4O2 (M+H)+ 401.122. found 401.1226.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N+:13]2([CH2:19][C:20](=[O:27])[NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)[CH3:18])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:35](O)(=O)C(C1C=CC=CC=1)(C1C=CC=CC=1)O>>[Br-:1].[OH:34][C:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([O:11][CH2:12][C@@H:17]1[CH2:16][CH2:15][CH2:14][N+:13]([CH2:19][C:20](=[O:27])[NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)([CH3:35])[CH2:18]1)=[O:10]
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H](COC(=O)C(O)(c2ccccc2)c2ccccc2)C1

Procedure:
This compound is prepared by an analogous method (1R/S,2R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide: (Example 2) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with benzilic acid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]12[CH2:23][CH2:22][C@H:21]3[C@@H:11]([CH2:12][CH2:13][CH:14]4[C@:19]3([CH3:20])[CH2:18][CH2:17][C@H:16](O)[CH2:15]4)[C@H:10]1[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[NH:25]=[N+:26]=[N-:27].B(F)(F)F.CCOCC>>[C:1]([O:4][CH2:5][C@:6]12[CH2:23][CH2:22][C@H:21]3[C@@H:11]([CH2:12][CH2:13][CH:14]4[C@:19]3([CH3:20])[CH2:18][CH2:17][C@H:16]([N:25]=[N+:26]=[N-:27])[CH2:15]4)[C@H:10]1[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@]12CCC[C@@H]1[C@@H]1CCC3C[C@@H](O)CC[C@]3(C)[C@H]1CC2
Reactant: [N-]=[N+]=N
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OC[C@@]12CCC[C@@H]1[C@@H]1CCC3C[C@@H](N=[N+]=[N-])CC[C@]3(C)[C@H]1CC2

Procedure:
Using the procedures of Example 1, acetoxy-3β hydroxy-14β androstane was treated with an aromatic solution of hydrazoic acid and boron trifluoride etherate.
Reaction SMILES: [C:1]1([S:7]([C@H:10]2[C@H:16]3[C@H:14]([O:15]3)[CH2:13][C@H:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C@@H:11]2[CH:25](C)C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl>[C:1]1([S:7]([C@H:10]2[C@H:16]3[C@H:14]([O:15]3)[CH2:13][C@H:12]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[C@@H:11]2[CH3:25])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)[C@@H]1[C@@H](S(=O)(=O)c2ccccc2)[C@@H]2O[C@@H]2C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: ClC(Cl)Cl
Product: C[C@@H]1[C@@H](S(=O)(=O)c2ccccc2)[C@@H]2O[C@@H]2C[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
1H NMR (CDCl3): δ 7.91 (m, 2H), 7.62 (m, 3H), 4.15 (ddd, J=10.4 Hz, 6.3 Hz, 4.4 Hz, 1H), 3.59 (d, J=2.4 Hz, 1H), 3.35 (d, J=3.5 Hz, 1H), 3.25 (dd, J=5.0 Hz, 4.3 Hz, 1H), 2.32 (m, 1H), 1.98 (m, 2H), 1.01 (d, J=7.2 Hz, 3H), 0.86 (s, 9H), 0.05 (s, 6H). 13C NMR (CDCl3): □138.3 134.0, 129.4, 128.4, 65.7, 65.3, 52.1, 49.4, 31.8, 28.5, 14.1, −4.8, −4.9. LRMS: (CI) highest mass 383 (M+H), base peak 383. HRMS: (CI) calculated for C19H30O4SSi 383.1712, found 383.1700. [α]D (c 5.0, CHCl3)=+16°. (1R, 3S, 4S, 5R, 6R)-(5-Benzenesulfonyl-4-isopropyl-7-oxa-bicyclo[4.1.0]hept-3-yloxy)-tert-butyldimethylsilane 23b Pr Quantitative yield. 1H NMR (CDCl3): δ7.93 (m, 2H), 7.64 (m, 3H), 4.41 (ddd, J=11.1 Hz, 6.9 Hz, 4.3 Hz, 1H), 3.84 (m, 1H), 3.42 (m, 1H), 3.31 (m, 1H), 1.98 (m, 4H), 0.91 (d, J=6.6 Hz, 3H), 0.88 (s, 9H), 0.66 (d, J=6.4 Hz, 3H), 0.11 (s, 3H), 0.10 (s, 3H). 13C NMR (CDCl3): δ138.3, 134.0, 129.4, 128.5, 67.0, 62.6, 52.5, 48.8, 42.6, 29.0, 26.9, 25.8, 23.5, 22.0, 17.9, −4.7, −5.0. LRMS: (CI) highest mass 411 (M+H), base peak 137 HRMS: (CI) calculated for C21H34O4SSi 411.2025, found 411.2005. [α]D (c 38.0, CHCl3)=−1°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])[CH:16]=1)[C:10](=[O:30])[NH:9]2)=[O:4].O.C(=O)([O-])[OH:33].[Na+].OOS([O-])=O.[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:23])=[O:33])[CH:16]=1)[C:10](=[O:30])[NH:9]2)=[O:4]
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cccc(SC(C)c4ccccc4)c3)c(=O)c12
Reactant: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1scc2[nH]c(=O)n(-c3cccc(S(=O)C(C)c4ccccc4)c3)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-methoxycarbonyl-3-[3-(1-phenyl -ethylthio)phenyl]thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione (50 mg) in acetone (3 mL)-water (0.6 mL) were added sodium hydrogen carbonate (24 mg) and OXONE (registered trademark) (84 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:10]=[CH:11][C:12]([C:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=2)=[N:13][C:14]=1[C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:20]1([C:17]2[O:16][C:15]([C:14]3[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([C:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=4)[N:13]=3)=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccccc4)o3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Reaction time: 8 h
Yield: 152.6 %

Procedure:
Tert-butyl 4-(5-(bis(tert-butoxycarbonyl)amino)-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.4 g, 3.867 mmol) was dissolved in DCM (40 mL) and treated with TFA (8 mL, 103.8 mmol). The reaction was allowed to stir overnight and then the solvent was removed in vacuo. The mixture was azeotroped with DCM (×3) and dried under vacuum to give the desired product as an orange solid (1.89 g, 100% Yield).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:17])([CH3:6])([CH3:5])[CH3:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CCOCC.C1(C)C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:12][C:7]=2[C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
1.02 g (0.026 mol) of 60% oil-dispersed sodium hydride were dissolved in 20 mL of ether and cooled to 5° C. 20 mL of an ether solution containing 5.00 g (0.024 mol) of 2,4-di-tert-butylphenol were dropped in over the course of 15 minutes at 5° C. and stirred for 30 minutes followed by dropping in 20 mL of a toluene solution containing 4.16 g (0.022 mol) of p-toluenesulfonyl chloride over the course of 20 minutes, stirring for 30 minutes at 25° C. and confirming the 2,4-di-tert-butylphenol to no longer be present. Following completion of the reaction, water was added and the organic layer was extracted with ethyl acetate followed by washing twice with saturated aqueous NaHCO3 solution and once with saturated brine, drying with MgSO4 and concentrating. The resulting crystals were purified by crystallizing with n-hexane to obtain 3.0 g (yield: 38%) of 2,4-di-tert-butylphenyl p-toluenesulfonate (white crystals, melting point: 81° C.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[Br:20]N1C(=O)CCC1=O>CN(C=O)C>[Br:20][C:15]1[CH:16]=[N:17][N:18]([CH3:19])[C:14]=1[C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][Br:1]
Reactant: Cn1nccc1-c1cc([N+](=O)[O-])ccc1OCCBr
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cn1ncc(Br)c1-c1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A mixture of 5-[2-(2-bromo-ethoxy)-5-nitro-phenyl]-1-methyl-1H-pyrazole (200 mg, 0.61 mmole), and N-bromosuccinimide (0.61 mmole, 1.0 eq) in 2 mL of DMF was stirred at 100° C. for 10 minutes in the Microwave. The mixture was quenched with water, extract with ethyl acetate, and dried in vacuo give the title compound as a yellow solid (200 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 3.53-3.64 (m, 2H), 3.78 (s, 3H), 4.38-4.49 (m, 2H), 7.11 (d, 1H), 7.57 (s, 1H), 8.23 (s, 1H), 8.39 (d, 1H). Exact mass calculated for C12H11Br2N3O3 402.9, found 406.1 (MH+).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])=[N:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[CH3:1][S:2]([CH:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])=[CH:7][CH:6]=1)[CH3:4])=[N:17][C:16]#[N:15]
Reactant: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Reactant: N#CN
Agent: CC(c1ccc(C(Cl)(Cl)Cl)nc1)/S(C)=N/C#N
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(c1ccc(C(Cl)(Cl)Cl)nc1)S(C)=NC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-[1-(methylthio)ethyl]-2-(trichloromethyl)-pyridine (B) (0.55 g, 2.3 mmol) and cyanamide (0.097 g, 2.3 mmol) in THF (7 mL) cooled to 0° C. was added iodobenzene diacetate (0.75 g, 2.3 mmol) in one portion. The resulting mixture was stirred at 0° C. for 1 hr and then at room temperature for 2 hr. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 50% acetone in hexane to give 0.254 g of (1E)-methyl{1-[6-(trichloromethyl)pyridin-3-yl]ethyl}-λ4-sulfanylidenecyanamide (C) as an off-white solid in 40% yield. 1H NMR for the diastereomeric mixture (300 MHz, d6-acetone) δ 8.87 (s, 1H), 8.21-8.25 (m, 2H), 4.65-4.76 (m, 1H), 2.86-2.66 (m, 3H), 1.88-1.92 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cccc(C)c1-c1cccc2c1CC(CN)O2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1cccc2c1CC(CNC(=O)OCc1ccccc1)O2
Yield: 94.8 %

Procedure:
Treatment of (±)-1-[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.2 g, 4.14 mmol) with diisopropylethylamine (0.803 g, 6.21 mmol) followed by benzyl chloroformate (0.848 g, 4.97 mmol) generally according to the procedure described for Intermediate 12 provided 1.52 g (95%) of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C25H25NO3: C, 77.49; H, 6.5; N, 3.61. Found: C, 76.66; H, 6.31; N, 3.44. Chiral HPLC separation of (±)-benzyl {[4-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OD, ethanol) provided two fractions. Fraction 1 (Rt=4.818 min, Chiralcel OD, ethanol); Fraction 2 (Rt=6.985 min, Chiralcel OD, ethanol).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[C:4]=1I)[CH3:2].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[C:4]=1[C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH3:2]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1I
Reactant: C#C[Si](C)(C)C
Product: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1C#C[Si](C)(C)C

Procedure:
Prepared as in Example 7 from 6-ethyl-5-iodo-4-(cis-4-phenylcyclohexylamino)pyrimidine (Example 8) and trimethylsilylacetylene (colorless solid).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N1C=CC=CC=1>CC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To a stirred solution of methyl 4-amino-2-fluorobenzoate (800 mg, 4.6 mmol, 1.0 eq) in acetone (10 mL) was added phenyl chloroformate (0.6 mL, 4.6 mmol, 1.0 eq) and followed by pyridine (1.1 mL, 13.8 mmol, 3.0 eq) at 0° C. and stirred at RT for 1 h. The acetone in the RM was evaporated and diluted with water (50 mL) extracted with EtOAC (2×100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude product was washed with n-pentane to yield methyl 2-fluoro-4-(phenoxycarbonylamino)benzoate (1.2 g, 89.6%) as white solid (TLC: EtOAc/PE (2:3); Rf: 0.3).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][N:24](C)C=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.[C-]#N.[Zn+2].[C-]#N>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:23]#[N:24])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)N1c2ccc(C#N)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
A solution of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Example 4) (355 mg, 0.962 mmol) in N,N-dimethylformamide (DMF) (5 mL) at room temperature was degassed over 30 min under house vacuum and quenched several times with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol) and zinc(II) cyanide (153 mg, 1.3 mmol) were then added and the resulting yellow mixture was stirred under nitrogen at 100° C. for 5 h then cooled to room temperature. The insoluble were filtered off, rinsed with AcOEt then destroyed with bleach. The organic phase was washed with water. The aqueous phase was extracted with AcOEt. The combined organic phases were washed twice with water then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 10 G silica cartridge (gradient: 13 to 63% AcOEt in Hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-cyano-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (238 mg, 0.755 mmol, 78% yield) as a white solid.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][S:4][S:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:42][O:43][C:44](=[O:47])[CH2:45][NH2:46]>ClCCl.CCOC(C)=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:46][CH2:45][C:44]([O:43][CH3:42])=[O:47])=[O:12])[CH2:3][S:4][S:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
N-Boc-Cys(StBu)-OH 9 (1.00 g, 3.23 mmol) was dissolved in dry dichloromethane (25 mL) followed by the addition of EDC (0.75 g, 3.87 mmol), HOBt (0.53 g, 3.87 mmol), NMM (1.77 mL, 16.15 mmol) and glycine methyl ester hydrochloride (0.61 g, 4.84 mmol) at 0° C. under argon. The reaction mixture was then allowed to warm to room temperature and stirred overnight. After evaporation of solvent, the residue obtained was taken in EtOAc (35 mL), washed with 20% citric acid solution (2 30 mL), sat. NaHCO3 (20 mL), brine and dried over MgSO4. The EtOAc layer was evaporated in vacuo and resulting crude product was purified by flash silica gel column chromatography to get the dipeptide product 12 as white foam (1.09 g, 89% yield). 1H NMR (300 MHz, CDCl3) δ7.35, 5.81 (2H), 4.44 (1H), 3.82 (2H), 3.61 (3H), 3.02-2.83 (2H), 1.43, 1.28 (18H); 13C NMR (75 MHz, CDCl3) δ171.2, 169.9, 155.5, 80.0, 53.5, 52.3, 48.0, 41.4, 37.9, 30.0, 28.5; ESI-LRMS m/z 380.5 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([Li])[CH2:9][CH2:10]C.C(=O)=O.BrCCC>O1CCCC1.CCCCCC.O>[CH2:8]([CH:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7])[CH2:9][CH3:10]
Reactant: [Li]CCCC
Reactant: O=C1CCCCN1
Agent: O=C=O
Solvent: O
Solvent: CCCBr
Solvent: CCCCCC
Product: CCCC1CCCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To delta-valerolactam (10 g) dissolved in 80 ml of dry tetrahydrofuran, under a dry nitrogen atmosphere was deopwise added n-butyllithium (1.6M, 125 ml) in hexane while the reaction mixture was chilled in a dry ice--acetone bath. After all the n-butyllithium was added, the reaction mixture was stirred at room temperature for one hour, refluxed for thirty minutes, and cooled to room temperature. 1-Bromopropane (12.3 g) was slowly added to the reaction mixture while the mixture was chilled in an ice bath. The reaction mixture was then stirred for sixteen hours at room temperature. 100 ml of water was added slowly to the reaction mixture and the resulting mixture was stirred at room temperature for thirty minutes. The layers separated and the aqueous layers were combined, dried over sodium sulfate, and then evaporated to yield 12.4 g (88% yield) of a dark, heavy oil, which crystallized on standing. The crystals were recrystallized from petroleum ether to yield 5.4 g of α-propylvalerolactam (m.p. 75°-76° C.). A portion of the α-propylvalerolactam (2.8 g) was refluxed in 25 ml of 6N hydrochloric acid under a nitrogen atmosphere for six hours. The water was evaporated to yield 2-propyl-5-amino-pentanoic acid (2.0 g; 51% yield) and recrystallized from ethanol-petroleum ether to yield a solid (m.p. 71°-73° C.). Equimolar amounts of 2-propyl-5-aminopentanoic acid and 5-[(4,6-dichlorotriazin-2-yl)-amino]fluorescein were dissolved in methanol. The reaction was completed in about ten minutes to yield a crude product which was purified by silica gel thin-layer chromatography with chloroform/methanol (3:1) as the developing solvent to yield a 2-propyl-5-amino-pentanoic acid-DTAF conjugate of the formula: ##STR11##
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH3:18])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[N:28]1.CC(C)=O>ClCCl>[Cl:2][C:3]1[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]([CH3:18])[S:32]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 107 %

Procedure:
Dissolve [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine hydrochloride salt (1.0 g, 2.57 mmol) in dichloromethane (20 ml) and cool in an ice-bath. Add triethylamine (1.79 ml, 12.87 mmol) and then 1-methylpyrazole-4-sulfonyl chloride (465 mg, 2.57 mmol). Remove the ice-bath and allow to warm to ambient temperature and allow to stir for 20 hr. Wash the combined organic layers with aqueous sodium bicarbonate, brine and water. Dry over sodium sulfate and concentrate. Purify by chromatography, eluting with 1:2 hexanes:acetone to afford the title compound (1.1 g, 97% yield) as a white foam. MS ES: m/z=400 [M+H]+.