Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH:4][CH3:5].[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12]CC#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:1][C:2]#[C:3][CH2:4][CH3:5])[CH3:11]
Reactant: C=CC=CC
Reactant: C#CCOC(C)(C)OC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 101.9 %

Procedure:
0.89 g (127 mmol) of granulated lithium were added within 20 minutes to 100 ml (4 mol) of liquid ammonia at −37° C. The mixture was stirred until no more lithium floated (after approximately 15 minutes). A dark cyan solution of lithium in liquid ammonia was obtained. 6.34 g (92 mmol) of piperylene (=1,3-pentadiene) were added portion wise within 30 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 10.1 g (71 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (89.7% GC) were added with a dropping funnel to the reaction mixture at −37° C. within 30 minutes. The reaction mixture was held at −37° C. for about 1 hour. 14.0 g (126 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 30 minutes. The reaction mixture was subsequently stirred for 1 hour. 100 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 1.5 hours. 50 ml of water were added to the reaction mixture at 22° C., and the mixture was vigorously stirred until all salt was dissolved. The water layer was extracted once with 50 ml of n-hexane. The organic layer was dried over 5 g of anhydrous sodium sulfate. The solution was concentrated under reduced pressure (40° C., 60 mbar) and the crude product was analyzed by GC. 11.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 87.5% (yield 85.3% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([CH3:14])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:46]([C:48]1[CH:63]=[C:62]([C:64](=[NH:67])[NH:65]O)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]>CN(C=O)C.O1CCOCC1>[CH2:46]([C:48]1[CH:63]=[C:62]([C:64]2[N:67]=[C:11]([C:9]3[CH:8]=[C:7]([CH3:14])[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=3)[O:13][N:65]=2)[CH:61]=[C:60]([CH3:68])[C:49]=1[O:50][CH2:51][C@@H:52]([OH:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][OH:57])[CH3:47]
Reactant: Cc1cc(CC(C)C)nc(C(=O)O)c1
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)cc(CC(C)C)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reaction time: 1 h
Yield: 10 %

Procedure:
To a solution of 6-isobutyl-4-methyl-pyridine-2-carboxylic acid (100 mg, 0.435 mmol) and DIPEA (169 mg, 1.31 mmol) in DMF (5 mL), TBTU (210 mg, 0.653 mmol) is added at 0° C. The mixture is stirred for 15 min at 0° C. before N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acet-amide (170 mg, 0.522 mmol) is added. Stirring is continued at 0° C. for 1 h. The reaction is quenched by adding water. The mixture is diluted with sat. aq. NaHCO3-solution and extracted with EA and two times with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated to give the crude hydroxy-amidine ester intermediate. This material is dissolved in dioxane (5 mL) and the mixture is stirred at 80° C. for 24 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol followed by prep. HPLC to give the title compound (21 mg) as a pale yellow oil; LC-MS: tR=1.00 min, [M+H]+=483.26; 1H NMR (CDCl3): δ 0.99 (d, J=6.8 Hz, 6H), 1.29 (t, J=7.5 Hz, 3H), 2.21 (hept, J=6.8 Hz, 1H), 2.36 (s, 3H), 2.48 (s, 3H), 2.72 (q, J=7.5 Hz, 2H), 2.79 (d, J=7.3 Hz, 2H), 3.47-3.55 (m, 1H), 3.74-3.92 (m, 3H), 4.16-4.24 (m, 3H), 7.18 (s, 1H), 7.23 (t br, J=5.8 Hz, 1H), 7.88 (s, 1H), 7.90 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][NH:12][CH3:13].CCN(CC)CC.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:21](=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CNCc1cc2ccccc2n1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
To a stirred solution of 1-methyl-2-(methylaminomethyl)-1H-indole (1.0 g, 5.7 mmole), from Preparation 1, and Et3N (0.9 mL, 6.4 mmole) in CH2Cl2 (50 mL) at 0° C. was added dropwise acryloyl chloride (0.51 mL, 6 mmole) over 5 minutes. The reaction was stirred at 0° C. for 1 hr, then was poured into ice water. The organic phase was separated, washed with brine, dried (MgSO4), and concentrated to dryness to give the title compound (1.19 g, 91%) as a yellow oil. This was used without further purification: TLC (silica gel, 50% EtOAc/hexanes) Rf=0.31.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[C:10]([N+:25]([O-:27])=[O:26])=[C:9](N)[CH:8]=2)[CH:4]=[N:3]1.[NH+]([O-])=[O:30].C([O-])(O)=O.[Na+]>[H+].[B-](F)(F)(F)F.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)[C:10]([N+:25]([O-:27])=[O:26])=[C:9]([OH:30])[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(N)c([N+](=O)[O-])c(NCc3ccc4ncccc4c3)n2)cn1
Reactant: O=[NH+][O-]
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [H+]
Solvent: O
Product: Cn1cc(-c2cc(O)c([N+](=O)[O-])c(NCc3ccc4ncccc4c3)n2)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a mixture of 6-(1-methyl-1H-pyrazol-4-yl)-3-nitro-N2-(quinolin-6-ylmethyl)pyridine-2,4-diamine (260 mg, 0.69 mmol) in HBF4 (5 mL) at 0° C. was added HNO2 (96 mg, 1.4 mmol) in H2O (0.5 mL). The reaction mixture was stirred at 0° C. overnight, then basified with aqueous NaHCO3 to pH=6-7. The resulting mixture was filtered. The filtrate was concentrated and purified by chromatography on silica gel to afford the title compound (200 mg). MS (m/z): 377 (M+1)+.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:14])[C@H:6]2[C:9]([O:12][CH3:13])([CH3:11])[CH3:10])[C@H:3]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:52]1[CH:57]=[CH:56][C:55]([SH:58])=[CH:54][CH:53]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C)C=O>[CH3:13][O:12][C:9]([C@@H:6]1[C:5](=[O:14])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:58][C:55]1[CH:56]=[CH:57][N:52]=[CH:53][CH:54]=1)=[C:3]2[C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)=[O:16])([CH3:11])[CH3:10]
Reactant: Sc1ccncc1
Reactant: COC(C)(C)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C)(C)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccncc3)C[C@H]12
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-(1-methoxy-1-methylethyl)-1-azabicyclo[3.2.0]heptane-2-carboxylate (450 mg) and 4-(N,N-dimethylamino)pyridine (14.6 mg) in methylene chloride (22.5 ml) was added a solution of N,N-diisopropyl-N-ethylamine (0.249 ml) in methylene chloride (2.241 ml) at -30° C. To the mixture was added further a solution of trifluoromethanesulfonic anhydride (0.211 ml) in methylene chloride (1.899 ml) at -30° C. After stirring for 30 minutes at the same temperature, a solution of 4-(N,N-dimethylamino)pyridine (2.9 mg) and N,N-diisopropyl-N-ethylamine (0.0498 ml) in methylene chloride (0.448 ml) and then a solution of trifluoromethanesulfonic anhydride (0.0422 ml) in methylene chloride (0.38 ml) were added thereto at -30° C. After stirring for 30 minutes at the same temperature a solution of N,N-diisopropyl-N-ethylamine (0.833 ml) in methylene chloride (7.497 ml) and a solution of pyridine-4-thiol (159.5 mg) in N,N-dimethylformamide (5.63 ml) were added successively thereto at -30° C. The resultant solution was stirred for 30 minutes at the same temperature and for additional 30 minutes at 0° C. The solvent was distilled off and the residue was dissolved in ethyl acetate, washed twice with water and a saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was filtered and evaporated. The residue was chromatographed on deactivated silica gel with 10% water (13.5 g), eluting with a mixture of benzene and acetone (100:1 to 6:1) to give 4-nitrobenzyl (5R, 6R)-6-(1-methoxy-1-methylethyl)-7-oxo-3-(4-pyridylthio)-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (379 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH3:23])[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][CH:15]4[C:14](=[O:24])[CH:13]=[CH:12][C@@:11]35[O:25][CH3:26].[Cl-].[NH4+].[OH-].[Na+]>O1CCCC1.C(OCC)C.[Cu](I)I>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:22]([CH3:23])[CH2:21][CH2:20][C@:16]45[C:17]=2[C:18]=1[O:19][CH:15]4[C:14](=[O:24])[CH2:13][C@@H:12]([CH3:1])[C@@:11]35[O:25][CH3:26]
Reactant: [Li]C
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(OC)[C@@H](C2)N(C)CC[C@]314
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c3c1OC1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)N(C)CC[C@]314
Reaction time: 0.17 h

Procedure:
To a suspension of copper iodide (10.49 g, 57.3 mmol) in dry tetrahydrofuran (50 ml) and diethyl ether (50 ml), cooled in an ice bath, methyl lithium (60 ml of a 1.84 molar solution, 0.11 mol) was added under a nitrogen atmosphere. After 10 minutes, a solution of 14-methoxycodeinone (14) (15.0 g, 45.8 mmol) in tetrahydrofuran (300 ml) was added and the mixture was stirred for another 3 hours. At the end of this period, a saturated solution of ammonium chloride (200 ml) was added slowly. This was followed by the addition of a 20% NaOH solution until the mixture was basic. The aqueous layer was separated and extracted with ethyl acetate (3×100 ml) whereupon the organic extracts were combined, washed once with water (100 ml), dried over MgSO4, filtered and evaporated to give crude (20). This material was recrystallized from ethanol to give 8 g (51% theory) of the title compound as a colorless solid, m.p. 204°-205° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]([CH3:35])[CH2:32][CH2:33][NH2:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:34][CH2:33][CH2:32][N:31]([CH3:35])[C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(N(C)CCN)cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1ccc(N(C)CCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-[N-(3,4-dimethoxyphenyl)-methylamino]-ethylamine analogously to Example 6.
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[O:7][CH:8]=1.[NH2:20][C@@H:21]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:22][C@H:23]([OH:42])[C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[O:41][N:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)Cl>CO>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([NH:20][C@@H:21]([CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:22][C@H:23]([OH:42])[C@@H:24]([NH:32][C:33]([O:35][CH2:36][C:37]1[O:41][N:40]=[CH:39][CH:38]=1)=[O:34])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:19])[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[O:7][CH:8]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)O)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)co1
Yield: 64 %

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl) amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino) carbonyl)-L-alanine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl) methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 92:8 CH2Cl2 :CH3OH, the desired compound (Rf 0.48, 92:8 CH2Cl2 :CH3OH) in 64% yield. 1H NMR (DMSO-d6) δ 1.08 (d, 3 H), 1.24 (d, 6 H), 1.50 (m, 2 H), 2.82 (s, 3 H), 3.0 (m, 1 H), 4.25 (s, 2 H), 4.60 (d, 1 H), 5.05 (s, 2 H), 6.20 (br d, 1 H), 6.32 (d, 1 H), 7.20 (m, 11 H), 7.50 (br d, 1 H), 7.78 (s, 1 H), 8.51 (d, 1 H). Mass spectrum: (M+H)+ =661.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:11]1[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:27]=[C:26]([N:39]2[CH:44]3[CH2:45][CH2:46][CH:40]2[CH2:41][O:42][CH2:43]3)[N:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH:40]12[N:39]([C:26]3[N:25]=[C:24]([N:11]4[C@@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH2:14][C@H:10]4[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[N:29]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=4)[N:27]=3)[CH:44]([CH2:45][CH2:46]1)[CH2:43][O:42][CH2:41]2
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc([N+](=O)[O-])cc2)nc(N2C3CCC2COC3)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc(N)cc2)nc(N2C3CCC2COC3)n1
Yield: 54.6 %

Procedure:
A suspension of palladium on charcoal (10%, 50 mg) and 8-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (0.55 g, 1.2 mmol) in tetrahydrofuran (20 mL) was stirred under a balloon of hydrogen overnight. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as a tan foam (0.42 g, 80%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.Cl[S:27]([C:30]1[CH:42]=[CH:41][C:33]2[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:32]=2[CH:31]=1)(=[O:29])=[O:28]>C(Cl)Cl>[CH:31]1[C:32]2[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[O:34][C:33]=2[CH:41]=[CH:42][C:30]=1[S:27]([NH:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1N
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (II-1) (251 mg, 1.00 mmol) was dissolved in methylene chloride (8 ml) and triethylamine (0.238 ml, 2.00 mmol) was added thereto under a nitrogen atmosphere. To the mixture was added 2-chlorosulfonyldibenzofuran (350 mg, 1.31 mmol) under ice-cooling, and the mixture was stirred for 30 min and allowed to warm up to room temperature. The reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:4)) and recrystallized from n-hexane (10 ml) to yield methyl (Z)-7-[(1S, 2R, 3R, 4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (342 mg, 0.710 mmol). Yield 71%, mp 115-116° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH:11]([N:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16]1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]1[CH2:40][C@H:39]([NH2:41])[C:37](=[O:38])[NH:36][CH2:35][CH2:34]1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][CH:11]([N:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16]1)[C:12]([NH:41][C@H:39]1[CH2:40][CH2:33][CH2:34][CH2:35][NH:36][C:37]1=[O:38])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(C(=O)O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Reactant: N[C@H]1CCCCNC1=O
Solvent: CN(C)C=O
Product: O=C(CC(C(=O)N[C@H]1CCCCNC1=O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Yield: 67.2 %

Procedure:
According to the procedure described in Example 8(a), 2(RS)-(3-biphenyl4-yl-1H-imidazol-1-yl)-succinic acid 4-benzyl ester (1.20 g, 2.82 mmol) and L-α-amino-ε-caprolactam (469 mg, 3.67 mmol) was coupled in DMF with pyBOP to furnish 1.02 g (67%) of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid benzyl ester.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[C:16]([O:18][C:19](=[O:24])[C:20]=2[CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Cl.CCCCCC.C(OCC)(=O)C>C(O)C>[OH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[C:16]([O:18][C:19](=[O:24])[C:20]=2[CH:21]([CH3:22])[CH3:23])=[O:17])[CH2:13][CH2:14]1
Reactant: CC(C)C1=C([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)C(=O)OC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)C1=C([C@H]2CC[C@H](O)CC2)C(=O)OC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2-(trans-4-t-butyldimethylsilyloxycyclohexyl)-3-isopropylmaleic anhydride (263 mg, 0.745 mmol) in ethanol (7 mL) was added concentrated. hydrochloric acid (83 mg, 0.84 mmol), and the mixture was left standing at 50° C. for 30 min. The reaction mixture was directly concentrated, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 1:1) to give 179 mg (quantitative) of the title compound as a solid.
Reaction SMILES: O1CCC[CH2:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:10]#[N:11].CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][O:17][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:2])[C:14]=1[O:15][CH3:16])[C:10]#[N:11]
Reactant: COc1cc(C#N)cc(Br)c1OC
Reactant: C1CCOC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C#N)cc(C)c1OC
Temperature: 100 °C
Reaction time: 4 h

Procedure:
50 mg [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) and 5 mL tetrahydrofuran was stirred for 10 min at ambient temperature before 500 mg 3-bromo-4,5 dimethoxybenzonitrile, 0.1 mL trimethylboroxine and 0.85 g cesium carbonate as a solution in 1 mL water were added. The suspension was stirred at 100° C. for 4 h and then diluted with water and ethyl acetate. The phases were separated and the water phase was extracted with additional ethyl acetate (×2). The organic phases were combined, dried over magnesium sulfate and concentrated. The residue was purified with silica gel chromatography (SiO2: cyclohexane/ethyl acetate 9:1 to 7:3) to provide 4.17.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-]=[N+]=[N-].[Na+].C([O:18][C:19](=[O:38])[C@@H:20]1[CH2:24][C@H:23]([N:25]=[N+]=[N-])[CH2:22][N:21]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])C.[OH-].[Na+]>N1C=CC=CC=1.CN(C=O)C.O.CO>[C:34]1([CH3:37])[CH:33]=[CH:32][C:31]([S:28]([N:21]2[CH2:22][C@@H:23]([NH2:25])[CH2:24][C@H:20]2[C:19]([OH:38])=[O:18])(=[O:30])=[O:29])=[CH:36][CH:35]=1
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1S(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](N)C[C@H]2C(=O)O)cc1

Procedure:
Trans-4-hydroxy-L-proline was treated with EtOH and HCl gas, and the mixture was evaporated to give trans-4-hydroxy-L-proline ethyl ester hydrochloride. This product was treated with TsCl in pyridine to give, after aqueous workup, N-(toluene-4-sulfonyl)-trans-4-(TsO)-L-proline ethyl ester. This product was treated with NaN3 in DMF and H2O to give, after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-cis-4-azido-L-proline ethyl ester. This product was treated with NaOH in CH3OH and H2O to give, after acidification, extraction, drying with MgSO4, filtration and evaporation, N-(toluene-4-sulfonyl)-cis-4-azido-L-proline. This product was treated with 10% Pd on C in THF, AcOH and H2O, and the mixture was shaken under 50 psi H2. The mixture was filtered through Celite and evaporated to give N-(toluene-4-sulfonyl)-cis-4-amino-L-proline. This product was treated with Boc2O and Et3N in t-BuOH and H2O to give, after evaporation, acidification, extraction, drying with MgSO4, filtration, and evaporation, N-(toluene-4-sulfonyl)-cis-4-(t-butoxycarbonylamino)-L-proline. This product was treated with HCl.Phe-O-t-Bu, BOP, arid NMM in DMF to give, after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-cis-4-(t-butoxycarbonylamino)-Pro-Phe-O-t-Bu. This product was treated with TFA to give after evaporation the trifluoroacetate salt of the title compound as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH2:14]([NH2:16])[CH3:15].C([O-])([O-])=O.[Na+].[Na+].O>C(OCC)(=O)C.C(Cl)Cl>[CH2:14]([NH:16][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH3:15]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 161.2 %

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (140 g, 361 mmol) in ethyl acetate (250 mL) was added dropwise at room temperature to a mixture of 70% aqueous ethylamine (50 mL, 630 mmol), ethyl acetate (100 mL), Na2CO3 (67 g, 632 mmol), and water (250 mL). The reaction mixture was stirred for 4 h (TLC monitoring, CH2Cl2). The organic layer was separated, washed with water, with a solution of citric acid, dried with Na2SO4, and evaporated. The residue solidified into a white crystalline mass. The latter was triturated with hexane, filtered off, and dried to give 134 g (92%) of the product.