Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([C@H:23](O)[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:33])[C@@H:13]([CH:23]([F:7])[C:24]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CCCc1ccccc1)[C@H](O)C(=O)N1CCOCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CCCc1ccccc1)C(F)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.3 %

Procedure:
(Diethylamino)sulfur trifluoride (2.0 ml, 15.2 mmol) was added to a ice cold solution of (R)-2-((S)-1-Hydroxy-2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid methyl ester (4a) (0.85 g, 2.5 mmol) in dry methylene chloride (15 ml) and the reaction mixture was stirred overnight while warming to room temperature. The reaction was quenched with aqueous NaHCO3 solution and extracted with methylene chloride. The organic extracts were dried over Na2SO4 and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as a off-white solid (230 mg). 1H NMR (CDCl3) δ 1.90–1.58 (m, 4H), 2.78–2.57 (m, 2H), 3.28–3.10 (m, 1H), 3.75 (s, 3H), 3.74–3.45 (m, 8H), 5.40–5.12 (m, 1H), 7.35–7.18 (m, 5H);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([Mg]CCCC)CCC.C([Li])CCC.[C:28]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>CCCCCCC.C1COCC1>[OH:33][C:28]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([OH:13])=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCCC1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: CCCC[Mg]CCCC
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(C3(O)CCCC3)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (600.0 mg, 0.002489 mol) in tetrahydrofuran (20 mL, 0.2 mol) was cooled below −20 Celsius under N2 atmosphere, and 1.0 M of dibutylmagnesium in heptane (1.3 mL) was slowly added to the solution while maintaining the temperature below −20 Celsius. Then n-butyllithium (2.5 M in hexane, 1.1 mL) was slowly added to the slurry while maintaining the temperature below −20 Celsius with effective stirring. After the mixture was stirred at −20 Celsius for 1 hour, a solution of cyclopentanone (0.264 mL, 0.00299 mol) in THF (20.0 mL) was added to the mixture. Then after stirring at −20 Celsius for 1 hour, the reaction was quenched with ammonium chloride and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, then dried over Na2SO4, and then filtered. The filtrate was concentrated. The residue was flash chromatographed on silica gel column with 30% ethyl acetate in hexanes to afford the desired compound. MS (ESI): 229.1 (M−OH−), 269.1(M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]#[C:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=2[CH3:19])=[CH:9][N:10]=1)[CH:5]=[N:6][OH:7]>C(Cl)(Cl)Cl.C(Cl)Cl.CO.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:11]=[C:12]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=3[CH3:19])[N+:6]([O-:7])=[CH:5]2)=[CH:9][N:10]=1
Reactant: Cc1c(F)cncc1C#Cc1cnc(Cl)cc1C=NO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cncc1-c1cc2cnc(Cl)cc2c[n+]1[O-]
Temperature: 60 °C
Yield: 67.5 %

Procedure:
A slurry of 2-chloro-5-((5-fluoro-4-methylpyridin-3-yl)ethynyl)isonicotinaldehyde oxime (400 mg, 1.38 mmol) in chloroform (10 mL) was treated with silver nitrate on silica gel (10% w/w, 357 mg, 0.210 mmol). The reaction mixture was heated at 60° C. for 2 hours and then diluted with DCM (20 mL) and methanol (5 mL), loaded on silica gel, and purified by flash chromatography (12 g, Silica, 0-10% methanol in dichloromethane). Desired fractions were combined and evaporated in vacuo to afford the title compound as an off-white solid (270 mg, 66% over two steps). 1H NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.40 (s, 2H), 8.01 (s, 1H), 2.12 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[C:9]1([C:15]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33]#[N:34])=[CH:27][CH:26]=2)=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.Cl>[C:9]1([C:15]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=[CH:32][C:33]3[NH:34][N:7]=[N:6][N:5]=3)=[CH:27][CH:26]=2)=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(=C(c1ccccc1)c1ccc(C=CC#N)cc1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(=C(c1ccccc1)c1ccc(C=Cc2nnn[nH]2)cc1)c1ccccc1
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
To a solution of aluminum chloride (1.82 g, 13.5 mmol) in THF (20 mL) at 0° C. was added sodium azide (1.77 g, 27 mmol) and then nitrile (4b) (888 mg, 2.65 mmol). The mixture was stirred 10 min and heated to reflux. After refluxing overnight, the mixture was diluted with 1N HCl, and extracted with EtOAc. The combined organic layers were washed with water, brine and then dried (MgSO4). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, 10–20% methanol/CH2Cl2) to give tetrazole (4c) as a white solid (700 mg, 70%): 1H NMR (CDCl3) δ 7.63 (d, J=16.5 Hz, 1H), 7.39–7.11 (m, 12H), 6.98 (d, J=16.5 Hz, 1H), 6.91 (d, J=8.4 Hz, 2H), 2.48 (q, J=7.3 Hz, 2H), 0.94 (t, J=7.3 Hz, 3H); ESI m/z: 377 (M−H−, 100%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]([CH3:26])[C:12](=[O:25])[N:13]([C:15]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=3[CH3:24])[CH2:14][C:8]2=[CH:7][N:6]=1)(=O)=O.[CH3:27][N:28]([CH3:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>CO>[CH3:27][N:28]([CH3:36])[C:29]1[CH:30]=[C:31]([NH:32][C:5]2[N:10]=[C:9]3[N:11]([CH3:26])[C:12](=[O:25])[N:13]([C:15]4[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=4[CH3:24])[CH2:14][C:8]3=[CH:7][N:6]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(Nc3cccc(N(C)C)c3)nc2N(C)C1=O
Temperature: 130 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 7-methanesulfonyl-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (148 mg, 0.39 mmol) and 3-dimethylaminoaniline (530 mg, 3.9 mmol) is stirred for 1 hour at 130° C. The mixture is cooled down to room temperature and suspended in methanol. The precipitate is collected and washed with methanol to give 7-(3-dimethylamino-phenylamino)-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (98 mg, 58%) as a yellow solid.
Reaction SMILES: CC(OC)(C)C.O.[CH3:8][CH:9]([CH3:21])[C:10]([O:12][CH:13]([O:17][C:18]([CH3:20])=[S:19])[CH:14]([CH3:16])[CH3:15])=[O:11].FC(F)(F)[C@@H](C1C2C(C=C3C=1C=CC=C3)=CC=CC=2)O>C(O)CO>[CH3:8][CH:9]([CH3:21])[C:10]([O:12][C@@H:13]([O:17][C:18]([CH3:20])=[S:19])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Agent: O[C@H](c1c2ccccc2cc2ccccc12)C(F)(F)F
Solvent: OCCO
Solvent: COC(C)(C)C
Solvent: O
Product: CC(=S)O[C@H](OC(=O)C(C)C)C(C)C
Reaction time: 5 h
Yield: 70 %

Procedure:
A mixture of MTBE (990 mL) and water (10 mL) was stirred for 5 h until a clear solution was obtained. To this solution was added 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (50 g), prepared as described in Gallop et al., U.S. Pat. No. 7,227,028, and a non-covalent complex of porcine liver esterase (PLE), with methoxypolyethylene glycol (mPEG) (5 wt %, 75 g) prepared according to the method described by Heiss and Gais, Tetrahedron Lett., 1995, 36, 3833-3836; and Rupport and Gais, Tetrahedron Asymmetry, 1997, 8(21), 3657-3664. The resulting suspension was stirred at room temperature and the reaction periodically monitored by 1H-NMR using the chiral solvating agent (R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol. After ca. 48 h, 1H-NMR indicated that only one enantiomer remained in the reaction mixture at which time the reaction was quenched by filtration through a pad of CELITE®. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) then brine, and dried over anhydrous sodium sulfate (Na2SO4). After removing the solvent in vacuo, the title compound (12) was isolated as a single S-enantiomer (as determined by HPLC using a chiral column) in 70% yield. The absolute configuration was established by: (i) conversion to compound (20b) (see Step B); (ii) reaction of (20b) with R-baclofen to afford 4-{[(1S)-isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid; and (iii) correlation with the product formed in Example 18 of Gallop et al., U.S. Pat. No. 7,227,028. 1H NMR (CDCl3, 400 MHz): δ 0.96 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (hept, J=7.2 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H). 1H NMR with chiral solvating agent, (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: δ 0.98 (d, J=6.8Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 1.19 (d, J=7.2 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=7.2 Hz, 1.5H), 2.01-2.09 (m, 1H), 2.34 (s, 1.5H), 2.444 (s, 1.5H), 2.591 (hept, J=7.2 Hz, 0.5H), 2.59 (hept, J=6.8 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.70 (d, J=5.2 Hz, 0.5H).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][NH:21][CH2:20][CH2:19]2>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH2:22][N:21]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:20][CH2:19]2
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: COc1ccc2c(c1)CCNC2
Product: COc1ccc2c(c1)CCN(c1ccc(C#N)c3ccccc13)C2
Yield: 19 %

Procedure:
The title compound (7 mg, 19% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 6-methoxy-3,4-dihydro-1H-isoquinoline (76 mg, 0.468 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([I:19])=[C:8]1I.CC[Mg+].[Br-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:11][CH:10]([CH2:17]1)[N:9]1[C:5]2=[N:6][C:7]([I:19])=[CH:8]1
Reactant: Fc1cc2c(cc1Br)-c1nc(I)c(I)n1C1CC2C1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: Fc1cc2c(cc1Br)-c1nc(I)cn1C1CC2C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 9-bromo-10-fluoro-3,4-diiodo-2,5-diazatetracyclo[11.1.1.0[2,6]. 0[7,12]]pentadeca-3,5,7,9,11-pentaene (252 g, 462.45 mmol, 1.00 equiv) in tetrahydrofuran (2000 mL), followed by the addition of EtMgBr (163 mL, 1.05 equiv, 3 M) dropwise with stirring at −40° C. over 30 min. The resulting solution was stirred at −40° C. for 30 min, quenched by the addition of 200 mL of NH4Cl (sat) and extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of water and 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 173 g (89%) of 9-bromo-10-fluoro-4-iodo-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene as a red solid.
Reaction SMILES: N1CCCCC1.C=O.[CH3:9][CH:10]([CH3:27])[CH2:11][C@@H:12]([C:24]([OH:26])=[O:25])[CH:13]([C:21](O)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)(C)C>[C:17]([O:16][C:14]([C:13]([C@@H:12]([CH2:11][CH:10]([CH3:27])[CH3:9])[C:24]([OH:26])=[O:25])=[CH2:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)C[C@@H](C(=O)O)C(C(=O)O)C(=O)OC(C)(C)C
Agent: C=O
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: C=C(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)O
Reaction time: 8 h
Yield: 74.3 %

Procedure:
7.8 ml of piperidine and 20 ml of a 40% aqueous formaldehyde solution were added to a solution of 6.0 g of 1-tert.butyl dihydrogen 4-methyl-1(RS),1,2(R)-pentanetricarboxylate in 80 ml of isopropyl alcohol and the mixture was stirred overnight under a nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in ethyl acetate. The ethyl acetate phase was washed in succession with 1M aqueous hydrochloric acid, warm water and brine and the dried over anhydrous magnesium sulphate. The solvent was evaporated to give 3.94 g of 2(R)-[1-(tertbutoxycarbonyl)vinyl]-4-methylvaleric acid in the form of a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([O:25]C)=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:6]=1[CH3:38])=[O:4].CO.[OH-].[Li+].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:27])[N:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=[C:8]2[N:7]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=2)[C:6]=1[CH3:38])=[O:4]
Reactant: COC(=O)Cn1nc2n(c1=O)C(c1ccc(C#N)cc1)C(C(=O)OC)=C(C)N2c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution of Intermediate 16 (108 mg, 0.21 mmol) in THF (1 mL), was added MeOH (1 mL) followed by lithium hydroxide (3 M in water, 68 μL, 0.21 mmol). The reaction mixture was stirred at RT for 2 hours, and then lithium hydroxide (3 M in water, 27 μL, 0.08 mmol) was added. After a further 1 hour stirring at RT, the reaction mixture was made acidic by addition of 1 M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a white solid (100 mg).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:10]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[CH:34](Br)[CH:35]=O)[CH:29]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46][C:47]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[S:44][CH:45]=1)[C:28]2=[O:70])=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C.N1C=CC=CC=1>[CH:10]([O:23][C:24]([C:26]1[N:27]2[CH:30]([S:31][CH2:32][C:33]=1[C:34]1[S:8][C:1]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:35]=1)[CH:29]([NH:38][C:39](=[O:69])[C:40](=[N:66][O:67][CH3:68])[C:41]1[N:42]=[C:43]([NH:46][C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[S:44][CH:45]=1)[C:28]2=[O:70])=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC(=S)c1cccnc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4cccnc4)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Thionicotinamide (0.28 g) and pyridine (0.16 g) are added to a solution of the syn isomer of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the two diastereoisomers) (1.66 g) in tetrahydrofuran (20 cc) and the mixture is heated at 50° C. for 90 minutes. The reaction mixture is subsequently cooled to 0° C. and then treated successively with methanesulphonyl chloride (0.23 g) and triethylamine (0.56 cc). After 30 minutes at 0° C., the reaction mixture is poured into a mixture of a saturated solution of sodium bicarbonate (200 cc) and ethyl acetate (100 cc); the organic phase is decanted, washed with distilled water (150 cc) and with a saturated solution of sodium chloride (150 cc) and then dried over magnesium sulphate. The residue obtained after evaporation of the solvent to dryness under reduced pressure (4 kPa) at 40° C. is chromatographed on a column (height: 30 cm, diameter: 1.5 cm) containing silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.5 bar (50 kPa) with a mixture of cyclohexane and ethyl acetate (30/70 by volume) and 50 cc fractions being collected. Fractions 18 to 26 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-[2-(pyridin-3-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.18 g) in the form of a beige powder.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[CH3:18][NH2:19]>CO>[CH3:18][NH:19][C:3]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: CN
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Solvent: CO
Product: CNC(=O)c1cc2c(cn1)[nH]c1ccccc12
Yield: 43 %

Procedure:
12 g of β-carbolin-3-carboxylic acid methyl ester is suspended in 130 ml of methanol; 130 ml of 40% aqueous methylamine is added thereto and the whole is boiled at reflux for 2 hours. After cooling, the mixture is suction-filtered. By extraction with 300 ml of hot methanol and crystallization from dimethylformamide/hexane, the β-carbolin-3-carboxylic acid N-methylamide of melting point 264°-266° C. is isolated from the filter residue in 43% yield.
Reaction SMILES: [OH:1][C:2]12[CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[Li+].CC([N-]C(C)C)C.[CH2:17]([N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])=O>C1COCC1>[N:5]12[CH2:8][C:2]([O:1][C:25](=[O:26])[N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: O=C(Cl)N(Cc1ccccc1)c1ccccc1
Reactant: OC12CCN(CC1)C2
Agent: CC(C)[N-]C(C)C
Agent: O=C[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OC12CCN(CC1)C2)N(Cc1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 1.3 %

Procedure:
In a two necked flask under nitrogen, 3 ml of THF and 150 mg (1.33 mmoles) of 4-hydroxy-1-azabicyclo[2.2.1]heptane were placed. The suspension was cooled to −60° C. and 0.7 ml (1.46 mmoles) of LDA was added dropwise. After the addition the temperature was allowed to rise to 0° C. and was kept during two hours. A solution of 295 mg (1.20 mmoles) of benzylphenylcarbamoyl chloride in 2 ml of THF was added in 30 minutes. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was extracted with dichloromethane and water. The organic layer was extracted with 2N HCl and the aqueous layer basified with 8N NaOH and extracted with dichloromethane. The organic layers were dried over anhydrous Na2SO4 and evaporated. The oil obtained (162 mg) was purified by HPLC-MS to obtain 4.86 mg (0.015 mmoles) 1.3% of a pure product as a formate, structure confirmed by 1H-NMR.
Reaction SMILES: C([NH:4][CH:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=N)N.N[C@@H](CCC[N:35]=[C:36]([NH2:38])[NH2:37])C(N[C@@H](CC1C=CC=CC=1)C(O)=O)=O.N[C@@H](CC1C=CC(CN=C(N)N)=CC=1)C(O)=O.NC(CC1C=CC=CC=1)C(NN)=O.N[C@@H](CC1C=CC=CC=1)C(N[C@@H](CCCN=C(N)N)C(NC1C=CC2C(=CC=CC=2)C=1)=O)=O.CC([C@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)CCCNC(N)=N)=O)CCCNC(N)=N)=O)CC1C2C=CC=CC=2NC=1)=O)CS)=O)CC1C=CC=CC=1)=O)CCCNC(N)=N)=O)C(N[C@H](C(N[C@H](C(N[C@H](C(NCC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N)=O)CCCNC(N)=N)=O)CS)=O)CCCCN)=O)CCCNC(N)=N)=O)CC1C=CC(O)=CC=1)=O)CS)=O)CC1C=CC=CC=1)=O)=O)CCCNC(N)=N)=O)CC1C=CC(O)=CC=1)=O)CS)=O)C>>[NH:37]([C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@@H:5]([C:13]([OH:15])=[O:14])[NH2:4])=[CH:12][CH:11]=1)[C:36]([NH2:38])=[NH:35]
Reactant: N=C(N)NC(Cc1ccccc1)C(=O)O
Reactant: NC(N)=NCCC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CS)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CS)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(=N)N)C(N)=O
Agent: N=C(N)NCCC[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: NC(N)=NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)Nc1ccc2ccccc2c1
Product: N=C(N)Nc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
N-guanyl-dl-phenylalanine; (2S)-2-[[(2S)-2-amino-5-(diaminomethylideneannino)pentanoyl]amino]-3-phenylpropanoic acid, known as arginylphenylalanine; (2S)-2-amino-3-[4-[(diaminomethylideneamino)methyl]phenyl]propanoic acid; 2-amino-3-phenylpropanehydrazide; (2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-(diaminomethylideneamino)-N-naphthalen-2-ylpentanamide; and polyphemusin I or II.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=1[CH3:29]>CN(C=O)C.O>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=2)=[CH:23][C:22]=1[CH3:29]
Reactant: COC(=O)CCc1cccc(O)c1
Reactant: Cc1cc(CCl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To flask containing methyl 3-(3-hydroxyphenyl)propanoate (available from Aagile Labs Division of Tyger Scientific) (0.25 g, 1.387 mmol) and cesium carbonate (0.5876 g, 1.804 mmol) in DMF (8 mL), was added 1.2 (0.3654 g, 1.665 mmol). The resulting mixture was then stirred overnight. The reaction was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and then purified by combiflash (0 to 20% EtOAc/hexane) to provide 1.3 (0.4575 g, 90.78% yield). MS ESI (pos.) m/e: 382.0 (M+H2O)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]([CH3:22])[CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:21]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:1][C:8](=[CH2:22])[CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:21]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)CCCn1c(=O)oc2ccccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CCCn1c(=O)oc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Potassium tert-butoxide (3.5 g, 31.2 mmol) was gradually added to a mixture of methyltriphenylphosphonium bromide (11 g, 30.8 mmol) in THF (100 ml) while cooling in an ice-bath, and the mixture was stirred for 20 minutes. To which a solution of 3-(4-oxopentyl)-3H-benzoxazol-2-one (5.6 g, 25.6 mmol) in THF (10 ml) was gradually added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to afford 3-(4-methyl-4-pentenyl)-3H-benzoxazol-2-one (3.4 g, yield 61%) as a colorless oil.