Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O:3]([N:5]=[C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([O:9]C)=[O:8])[CH3:4].O>CO>[CH3:4][O:3][N:5]=[C:6]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8]
Reactant: CON=C(C(=O)OC)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CON=C(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
2N-Sodium hydroxide (8.27 ml.) was added to a solution of methyl 2-methoxylimino-2-(thien-2-yl)-acetate (syn-isomer) (3.28 g.) in methanol (50 ml.) and the solution was stirred at room temperature for 18 hours. Water (20 ml.) was added and the solution was evaporated to remove methanol, and then washed with ethyl acetate. The pH of the solution under ethyl acetate (50 ml.) was altered to 2 with 2N-hydrochloric acid. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried, and evaporated to a white solid (2.58 g.). This was crystallised from cyclohexane, producing the title compound (2.23 g., 73%), m.p. 105.5°, λmax.EtOH 289 nm (λ 10,100), λinf. 262 and 271 nm. (ε 7,750 and 8.150), τ (CDCl3) values include 0.32 (OH) and 5.92 (OCH3).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:49]1[CH2:54][CH2:53][CH:52]([O:55][C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)[CH2:51][CH2:50]1>CN(C)C=O.C(#N)C.O>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:59]1[CH2:60][CH2:61][CH:56]([O:55][C:52]2[CH:53]=[CH:54][N:49]=[CH:50][CH:51]=2)[CH2:57][CH2:58]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1cc(OC2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of 0.19 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) in 1 ml N,N-dimethylformamide were added successively 0.29 mmol TBTU, 0.97 mmol N-ethyldiisopropylamine and 0.19 mmol 4-(piperidin-4-yloxy)-pyridine. The reaction mixture was stirred at RT for 16 h and then concentrated in vacuo. Reversed phase HPLC (acetonitrile/water) afforded the title compound as amorphous white solid (yield 75%). MS (m/e): 419.2 (M+H+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=1)=[O:4].[CH3:21][NH:22][CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[O:20]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:22]([CH3:23])[CH3:21])[CH:19]=[CH:18][C:17]=2[NH:16]1
Reactant: CNC
Reactant: O=C(CCl)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc2[nH]c(=O)c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared from the compound of Example 2 and dimethylamine. To a solution of 2-chloro-N-(5,6-dihydro-6-oxo-2-phenanthridinyl)-acetamide (635 mg) in N,N-dimethylformamide (100 mL) was added potassium phosphate (918 mg) and dimethylamine (1.3 ml, 2 molar soln.). The solution stirred at room temperature for 5 hours followed by evaporation of the solvent. The light brown product was washed with water and filtered. Concentrated HCl (0.3 mL) was added to a solution of the product in dioxane (150 mL) to precipitate the hydrogen chloride salt (400 mg), mp>300° C. 1H-NMR (300 MHz, DMSO-d6), 11.63 (br s, 1H), 10.92 (br s, 1H), 8.63 (s, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.91 (t, J=9.0 Hz, 1H), 7.69 (m, 2H), 7.38 (d, J=9.0 Hz, 1H), 4.19 (br s, 2H), 2.91 (br s, 6H). Anal. (C17H17N3O2.HCl 0.9 H2O), Calc for: C, 58.67; H, 5.73; N, 12.07; Cl, 10.19. Found: C, 58.91; H, 5.59; N, 11.80; Cl, 9.95.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].CS(O)(=O)=O.[CH3:20][OH:21]>>[CH3:20][O:21][C:6]1[C:5]2[C:10](=[CH:11][CH:2]=[C:3]([O:13][CH3:14])[CH:4]=2)[C:9](=[O:12])[NH:8][CH:7]=1
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Reactant: CO
Agent: CS(=O)(=O)O
Product: COc1ccc2c(=O)[nH]cc(OC)c2c1
Yield: 48.8 %

Procedure:
To a solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (7 g, 40.0 mmol) in methanol (70 ml) was added iodozobenzenediacetate (14.16 g, 40.0 mmol) followed by methane sulphonic acid (11.52 g, 120 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (4 g, 48.8%) as a light red colored solid. 1H NMR (400 MHz, DMSO): δ ppm 8.11-8.09 (d, J=8 Hz, 1H), 7.19 (s, 1H), 7.13-7.11 (d, J=8 Hz, 1H), 6.72-6.71 (d, J=12 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H); MS: MS m/z 206.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[C:33]([F:34])=[C:32]([F:35])[CH:31]=[CH:30][C:29]=1B(O)O>>[F:34][C:33]1[C:28]([O:27][CH3:26])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[CH:31][C:32]=1[F:35]
Reactant: COc1c(B(O)O)ccc(F)c1F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: COc1c(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc(F)c1F

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-methoxy-3,4-difluorophenylboronic acid (CAS RN 905583-06-4) and using preparative HPLC for the chromatographic purification. Off-white solid (49%). MS (ESI): m/z=491.1 [M+H]+.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(N(CC)CC)C.O>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Triethyl orthoformate (1.7 l, 10.2 mol) and p-Toluenesulfonic acid (16.8 g, 88.3 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (1.7 Kg, 4.94 mol) in EtOH (11 l). The mixture was stirred at room temperature for 1 h. Triethylamine (1.7 l, 12.2 mol) was added. The mixture was heated under reflux for 2 h, cooled to 5° C. and water (5 l) was then added. The precipitate was filtered, washed with a 1/1 EtOH/water solution and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (1.36 Kg, yield: 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: O=C1CNCCN1
Product: O=C1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CCN1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazin-2-one according to conditions described in general procedure C. Mp: 108-110° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.35 (m, 8 H), 3.73-3.78 (m, 6 H), 6.37 (d, J=5.5 Hz, 1 H), 7.03-7.06 (m, 2 H), 7.26 (d, J=8.5 Hz, 1 H), 7.44-7.63 (m, 4 H), 7.84-7.86 (m, 1 H), 8.00-8.04 (m, 2H), 8.35 (d, J=5.1Hz, 1 H), 10.51 (s, 1 H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)C(=O)O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Boc-Ile-AMP (0.32 g, 1.0 mmole) is stirred in 10 ml of TFA-CH2Cl2 (1:1, v/v) for 30 minutes. TFA and CH2Cl2 are removed in vacuo and the residue is held under vacuum overnight. The residue is extracted with EtOAc and 5 ml of saturated aqueous NaHCO3. The organic layers are filtered through Na2SO4 and concentrated. The crude product is chromatographed on silica gel using 4% MeOH-CH2Cl2 (NH4OH sat'd) to give 0.194 g (88%) of Ile-AMP.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([N:30]([C:34]([O:36][CH2:37]I)=[O:35])[CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:37][O:36][C:34]([N:30]([CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33])=[O:35])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCN(CCC)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CCCN(CCC)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 84.4 %

Procedure:
In the same manner as in Example 81, 179 mg of the title compound was prepared from 159 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 135 mg of N,N-di(propan-1-yl)aminocarbonyloxymethyl iodide.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:15][C:16]([F:25])([F:26])[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Yield: 90.9 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (56.5 g, 0.28 mol), 4-trifluoromethoxyphenol (50 g, 0.28 mol) and triphenylphosphine (108 g, 0.42 mol) were dissolved in THF (500 ml). Diethyl azodicarboxylate (65 ml, 0.42 mol) was added dropwise to this solution under reflux, and the mixture was refluxed for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1) to afford tert-butyl 4-(4-trifluoromethoxyphenoxy)-piperidine-1-carboxylate (92 g, yield 91%) as a colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][CH:27]([N:30]([CH2:38][CH3:39])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:38]([N:30]([CH:27]1[CH2:26][CH2:25][CH:24]([O:23][C:14]2[C:13]3[C:12]4[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:22][CH2:21][C:20]=4[S:19][C:18]=3[N:17]=[CH:16][N:15]=2)[CH2:29][CH2:28]1)[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH3:39]
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Into a 50-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-ethylcarbamate (570 mg, 0.99 mmol, 1.00 equiv) in THF (6 mL) was added TBAF (522 mg, 2.00 mmol, 2.02 equiv) and the resulting solution was stirred for 2 hrs at 25° C. The reaction mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to provide the desired tert-butyl N-ethyl-N-(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate (450 mg, 98%) as a colorless oil. MS (ES): m/z 462 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu](I)I.CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:13]2[CH:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=2)=[N:6][CH:7]=1
Reactant: Sc1ccc(Br)cn1
Reactant: Clc1ccc(I)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Clc1ccc(Sc2ccc(Br)cn2)cn1
Temperature: 80 °C
Yield: 31.7 %

Procedure:
5-Bromo-2-pyridinethiol (633 mg, 3.33 mmol, Combi-Blocks, Inc., San Diego, Calif.), 2-chloro-5-iodopyridine (798 mg, 3.33 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (32 mg, 0.17 mmol, Strem Chemical Inc, Newburyport, Mass.), potassium carbonate (921 mg, 6.67 mmol), ethylene glycol (0.37 mL, 6.67 mmol), and 2-propanol (8 mL) were added to a reaction vial. The vial was sealed, purged with nitrogen for several minutes, and heated at 80° C. for 16 h. After cooling to room temperature, the solvents were removed under vacuum. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexanes, to provide 5-bromo-2-((6-chloro-3-pyridinyl)sulfanyl)pyridine (318 mg) as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:24][CH2:25][CH2:26][NH:27][C:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]1([CH2:7][CH2:8][NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)NCCCN(CCCCCCCCN(CCCNC(=O)Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CCNCCCN(CCCCCCCCN(CCCNCCc2ccccc2)Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
Add a solution of 1,18-bis[[(phenyl)methyl]carbonyl]-5,14-bis-[(phenyl)methyl]-1,5,14,18-tetraazaoctadecane (3 g) in tetrahydrofuran (150 mL) dropwise to a suspension of lithium aluminum hydride (0.5 g) in tetrahydrofuran (500 mL). Stir the reaction for 48 hours at room temperature. Decompose the excess reducing agent by dropwise addition of water (1 mL), 15% sodium hydroxide (1 mL) and water (3 mL). Filter the mixture and concentrate the filtrate under vacuum. Dissolve the residue in ethanol (100 mL) and add anhydrous hydrogen chloride gas to provide the tetrahydrochloride salt of 1,18-bis[(2-phenyl)ethyl]-5,14-bis-[(phenyl)methyl]-1,5,14,18-tetraazaoctadecane. Scheme D, step C: Hydrogenate this product in ethanol (150 mL) in the presence of Pearlman's catalyst (0.3 g) at 43 psig on a Parr hydrogenation apparatus for 24 hours. Filter the reaction and concentrate the filtrate under vacuum. Crystallize the residue from 2-propanol to provide the title compound as a hemihydrate, mp 322-324° C. (dec.).
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:5])C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH2:34])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(OCC)(=O)C>CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][NH:34][C:4]([C:6]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=3)[O:8][N:7]=2)=[O:5])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: CCOC(=O)c1noc(-c2ccc(C#N)cc2)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCNC(=O)c2noc(-c3ccc(C#N)cc3)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 3-ethoxycarbonyl-5-(4-cyanophenyl)-1,2,4-oxadiazole (2.0 g) and 2-(1-tert-butoxycarbonylpiperidin-4-yl)ethylamine in N,N-dimethylformamide (1 ml) was heated at 120° C. for 5 hours. The mixture was dissolved with ethyl acetate, washed with water, brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to afford 3-[{2-(1-tert-butoxycarbonylpiperidin-4-yl)ethyl}carbamoyl]-5-(4-cyanophenyl)-1,2,4-oxadiazole (2.6 g).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13]([OH:15])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].[NH2:26][C@H:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:2]([C:13]([NH:26][C@H:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10]
Reactant: N=C(NCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)OCc1ccccc1

Procedure:
Equimolar quantities of Z-D-Arg(NO2)-OH and H-Phe-OtBu were dissolved in DMF and coupled by adding DCC and HOBt under the conditions described in Example 1(2), DCU was filtered off, and the organic EtOAc layer of the filtrate was then extracted successively with acid, base and water, dried and crystallized from EtOAc-hexane mixture. The peptide subsequently purified with the aid of an SiO2 column has an Rf of 0.52 in To/EtOH (4:1).
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH2:11]Cl)[CH:10]=1>CN(C=O)C>[Br:4][C:5]1[CH:10]=[C:9]([CH2:11][C:1]#[N:2])[CH:8]=[N:7][CH:6]=1
Reactant: [C-]#N
Reactant: ClCc1cncc(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
Potassium cyanide (0.21 g, 3.27 mmol) was added to a solution of 3-bromo-5-chloromethyl-pyridine (0.45 g; 2.18 mmol) in DMF (10 mL). Upon completion of addition, the reaction mixture was stirred at room temperature for 16 h. After this time, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over Na2SO4, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to provide 2-(5-bromopyridin-3-yl)acetonitrile (200 mg, 46.5%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, 1H, J=2 Hz), 8.51 (d, 1H, J=2 Hz), 7.88 (t, 1H, J=2 Hz), 3.77 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12](=O)C(Cl)=C(Cl)[C:15](=O)[C:16]=1Cl.Cl.CC(C=C)=O>CCO.O1CCCC1>[ClH:10].[C:6]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[CH:12][CH:11]=[C:16]2[CH3:15])#[N:7]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: C=CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccnc2ccc(C#N)cc12
Temperature: 75 °C
Reaction time: 0.06 h
Yield: 82.55 %

Procedure:
Add 95% ethanol (EtOH) (270 L, 9 vol.), 4-aminobenzonitrile (30.0 kg, 1 equiv) and 2,3,5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione, (66.81 kg 1.07 equiv) to a 200 gallon reaction vessel equipped with nitrogen purge, condenser, thermocouple, and overhead agitation. Stir for 2-5 min, then add concentrated hydrochloric acid (HCl) (62.56 L, 3.0 equiv), then heat to 75° C. Dilute methyl vinylketone (33.06 L, 1.5 equiv) in 95% EtOH (30 L, 1 vol.) then add slowly to reaction mixture over 30 min. Monitor for reaction completion by high performance liquid chromatography (HPLC). Add tetrahydrofuran (THF) (11 vol., 330 L), at 75° C., then stir for 1 hour at 60° C. Cool to room temperature and stir for 1 additional hour. Filter on agitated filter/dryer, then rinse with THF (240 L, 8 volumes). Dry overnight under vacuum at 70° C. to give the title compound (42.9 kg, 82.55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[C:21]1[C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:29])[O:23][N:22]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:26]([C:25]1[C:21]([C:15]2[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[N:22][O:23][C:24]=1[CH3:29])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCNC(=O)OC(C)(C)C
Yield: 100.4 %

Procedure:
N-t-butyloxycarbonyl-1,3-diaminopropane (574 mg, 3.29 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (903 mg, 3.29 mmol) were converted to 1.36 g of the title compound by the procedure of Preparation 1. (100%). EA calculated for: C19H23N3O4ClF: C, 55.41; H, 5.63; N, 10.20. Found: C, 55.17; H, 5.71; N, 9.99. MS(IS) m/z 412 (M+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O[CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.S(Cl)(Cl)=O>>[N:8]1[CH:9]=[CH:10][CH:11]=[N:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: NCCN
Reactant: OCc1ncccn1
Solvent: O=S(Cl)Cl
Product: NCCNCc1ncccn1

Procedure:
By the procedure of Example 34, ethylenediamine is reacted with 2-chloroemethylpyrimidine, prepared by treating 2-hydroxymethylpyrimidine with thionyl chloride, to give N-(2-pyrimidylmethyl)ethylenediamine.