Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[C:14]([C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][N:10]=1)#[N:16]
Reactant: CCN(CC)CC
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: N#Cc1cc(-c2ccccc2)ccn1

Procedure:
A solution of 1.90 g (11.1 mmol) of 4-phenylpyridine-N-oxide (available from Aldrich Chemical Co.), 4.8 ml (35 mmol) of sieve-dried triethylamine and 4.7 ml (35 mmol) trimethylsilylcyanide in 10 ml of sieve-dried acetonitrile was heated to 100° for 24 hours. The reaction mixture was cooled, quenched with 1 ml of H2O then added to 50 ml of H2O and extracted with three-25 ml portions of ethyl acetate. The organic extracts were combined, dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica gel, 1:4 EtOAc/petroleum ether) to give 2-cyano-4-phenylpyridine as a white solid. Recrystallization (EtOAc/petroleum ether) of the solid afforded 1.65 g (83%) of title nitrile as white crystals, m.p. 97°-98°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH:9]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=1.N1C=CN=C1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].Cl>CN(C=O)C>[O:1]([C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[CH:9]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][CH:7]=1)[Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34]
Reactant: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 128.9 %

Procedure:
To a solution of ethyl(2RS,3SR)-3-(4-hydroxyphenyl)-1-oxoindane-2-carboxylate (3.0 g, 10.2 mmol) in DMF (10 ml) under an argon atmosphere were added imidazole (1.72 g, 25.3 mmol) and t-butyldimethylchloro-silane (1.82 g, 12.1 mmol). The resulting mixture was allowed to stir at room temperature for 3 d, then was poured into dilute aqueous HCl and extracted with EtOAc (2×). The combined organic extracts were washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to provide the title compound (5.40 g) which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([CH2:18]O)[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[Cl:42][CH2:18][C:15]1[CH:14]=[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[O:17][N:16]=1
Reactant: OCc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)on1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC(F)(F)c1cc(-c2cc(CCl)no2)cc(C(F)(F)F)c1
Temperature: 75 °C

Procedure:
To a solution of {5-[3,5-bis(trifluoromethyl)phenyl]-3-isoxazolyl}methanol (Example 323B) (0.100 g, 0.32 mmol) in dry carbon tetrachloride (15 mL) was added PS-triphenylphosphine (0.292 g, 2.2 mmol/g, 0.64 mmol). The reaction was heated at 75° C. overnight. The resin was filtered and washed with carbon tetrachloride. Concentration in vacuo afforded the title compound, which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1C(=O)N([Cl:41])C(=O)C1>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]2[C:19]3[C:20]4[CH:33]=[CH:32][S:31][C:21]=4[C:22](=[O:30])[NH:23][C:24]=3[C:25]([Cl:41])=[CH:26][C:27]=2[O:28][CH3:29])[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCNC(=O)OC(C)(C)C)c(Cl)c1
Yield: 51.8 %

Procedure:
Following General Procedure H, tert-butyl 2-chloro-4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethylcarbamate (127 mg, 0.26 mmol) was reacted with NCS (43 mg, 0.312 mmol) to afford the desired product (70 mg, 52%) as a yellow solid: ESI MS m/z 519 [C25H24Cl2N2O4S+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6]Br.[C:17]([NH:20][C@H:21]([C:32]([OH:34])=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)(=[O:19])[CH3:18]>>[C:17]([NH:20][CH:21]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[C:32]([O:34][CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=1)=[O:33])(=[O:19])[CH3:18]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Following the method of Example 1, 3,5-bistrifluoromethylbenzyl bromide (6.16 g) and N acetyl-L-tryptophan (4.92 g) gave the title compound which was recrystallised from ethyl acetate/petroleum ether (3.7 g), m.p. 147°-148° C. 1H NMR (360 MHz, CDCl3) δ8.01 (1H, s), 7.83 (1H, s), 7.61 (1H, s), 7.51 (1H, d, J=8 Hz), 7.32 (1H, d, J=8 Hz), 7.17 (1H, t, J=7 Hz), 7.09 (1H, t, J=7 Hz), 6.91 (1H, d, J=2 Hz), 5.98 (1H, s), 5.13 (1H, d, J=13 Hz), 5.06 (1H, t, J=13 Hz), 4.96 (1H, t, J=6 Hz), 3.31 (2H, m), 1.98 (1H, s); Found: C, 56.08; H, 3.79; N, 5.74. C22H18N2F6O3 requires C, 55.84; H, 3.84; N, 5.93%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](SC)[N:6]3[C:14](=[O:24])[N:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:33])[N:6]3[C:14](=[O:24])[N:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Br)cc2c2nn(-c3ccc(C)cc3)c(=O)n12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
To a solution of 7a (0.534 g, 1.33 mmol) in 60 mL of CH2Cl2 was added (77%) m-CPBA (0.597 g, 2.67 mmol) and mixture was stirred at room temperature for 6 h. A white precipitate was slowly formed. Saturated solutions of aqueous Na2S2O3 (20 mL) and NaHCO3 (20 mL) were subsequently added and the mixture was stirred vigorously for 30 min. The precipitate was filtered off, washed several times with water and heated in a mixture of 25 mL ethyl alcohol and 25 mL of water at reflux for 30 min. The mixture was cooled to rt. and filtered to give 8a as a white solid (0.488 g, 99%). mp: 369° C.;
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1c(F)cccc1F
Yield: 81.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,6-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.1 g, 82%) as crystals.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:31]=[CH:30][N:14]3[C:15](=[O:29])[C:16](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(O)=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:31]=[CH:30][N:14]3[C:15](=[O:29])[C:16](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(O)nc3c2)n1
Yield: 168 %

Procedure:
tert-Butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (15 mg) was treated with formic acid (1 ml) in the dark for 1 hour, and added with toluene. The solvent was evaporated under reduced pressure to obtain the title compound (22 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH:20]([CH3:22])[CH3:21])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([N:8]([CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C@H:7]([CH:20]([CH3:21])[CH3:22])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine t-butyl ester (4.38 g, 13.0 mmol) in dimethylformamide (200 mL) is added 3-picolyl chloride hydrochloride (2.3 g, 14.0 mmol) followed by potassium carbonate (17.94 g, 130.0 mmol). The reaction mixture is stirred at room temperature for 2 days. The mixture is then diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate) to give t-butyl 2(R)-[N-[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanoate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[N+:38]([C:41]1[CH:42]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N+:38]([C:41]1[CH:46]=[C:45]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=2)[CH:44]=[CH:43][CH:42]=1)([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC1(C)OB(c2cccc([N+](=O)[O-])c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc([N+](=O)[O-])c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 96.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (291 mg, 0.500 mmol), 3-nitrophenyl boronic acid pinacol ester (187 mg, 0.750 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (35.4 mg, 0.0500 mmol) and 2M Na2CO3 (0.500 mL, 1.00 mmol) in DMF (4.00 mL) was heated at 160° C. under microwave irradiation for 1 hour under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3) and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=1:4→1:2) to afford desired product (289 mg, 96.2%) as yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.45 (s, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.07-8.00 (m, 2H), 7.91-7.86 (m, 1H), 7.47-7.36 (m, 3H), 7.34-7.26 (m, 1H), 7.22-7.12 (m, 3H), 6.98 (d, J=7.3 Hz, 1H), 6.90-6.69 (m, 2H), 6.62 (dd, J=7.8, 4.6 Hz, 1H), 5.77-5.09 (m, 1H), 2.65-2.31 (m, 4H), 2.28-2.07 (m, 1H), 1.99-1.82 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1cccc(O)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2ccc(C#N)cc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 4-cyanobenzyl bromide (40 mmol, 7.84 g), methyl 3-hydroxybenzoate (40 mmol, 6.08 g) and potassium carbonate (60 mmol, 8.29 g) in 50 mL DMF was stirred at 60° C. overnight and the solution was cooled to room temperature. To it was added dilute citric acid followed by ethyl acetate. The organic layer was separated, washed with brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give a solid. The solid was washed with ether two times to give 6.2 g (60%) product. NMR (DMSO-d6): δ7.88 (d,2H);7.66(d,2H);7.58 (m, 2H); 7.46 (t, 1H); 7.32 (dd, 1H); 5.30 (s, 2H); 3.84 (s, 3H).
Reaction SMILES: C(OC([N:8]([C@H:20]([CH2:43][O:44][Si](C)(C)C)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>ClCCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[OH:44][CH2:43][C@@H:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:42]=[CH:41][CH:40]=[CH:39][C:33]=2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1ccccc1NC(=O)Nc1ccc(C[C@@H](CO[Si](C)(C)C)N(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1ccccc1NC(=O)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-((2S)-2-hydroxy-3-phenoxypropyl)amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate (10.0 mg) in 1,2-dichloroethane (100 μl) was added trifluoroacetic acid (100 μl) and the solution was stirred at room temperature for 30 minutes. The solvent was removed by evaporation to give ethyl 2-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]-carbonyl]amino]benzoate trifluoroacetate (10.3 mg) as a white foam.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-])([OH:10])=[O:9].[C:12]([O:15][CH2:16][CH2:17][C:18]([N+:38]([O-:40])=[O:39])([N+:35]([O-:37])=[O:36])[CH2:19][NH:20][CH2:21][C:22]([N+:32]([O-:34])=[O:33])([N+:29]([O-:31])=[O:30])[CH2:23][CH2:24][O:25][C:26](=[O:28])[CH3:27])(=[O:14])[CH3:13]>>[C:26]([O:25][CH2:24][CH2:23][C:22]([N+:32]([O-:34])=[O:33])([N+:29]([O-:31])=[O:30])[CH2:21][N:20]([N+:8]([O-:10])=[O:9])[CH2:19][C:18]([N+:38]([O-:40])=[O:39])([N+:35]([O-:37])=[O:36])[CH2:17][CH2:16][O:15][C:12](=[O:14])[CH3:13])(=[O:28])[CH3:27]
Reactant: CC(=O)OCCC(CNCC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCCC(CN(CC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (315 ml) was stirred in an ice bath to maintain a temperature of 20°-23° C. during the slow addition of 95 ml of 90 percent nitric acid. The solution was then cooled to 5° C. while 3,3,7,7-tetranitro-5-azanonane-1,9-diol-1,9-diacetate was added in portions with good stirring. The solution was stirred at ambient temperature overnight before it was poured into ice water. The mixture was stirred for one hour and the solid (66.5 g, 97 percent, mp 87°-89° C.) was removed by filtration. A recrystallized sample (CH2Cl2 /hexane) had mp 88°-89° C.; 1H NMR (CDCl3): δ2.09 (s, 3H), 3.00 (t, 2H), 4.35 (t, 2H), 5.20 (s, 2H).
Reaction SMILES: O[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH3:18])[CH:12]([NH:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]1=[O:39])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].N1C=CC=CC=1.S(Cl)([Cl:48])=O>O1CCCC1.O1CCOCC1>[Cl:48][CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][CH3:18])[CH:12]([NH:19][C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:11]1=[O:39])[C:3]([O:5][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:4]
Reactant: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(O)C(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC#CCSC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1C(Cl)C(=O)OC(C)(C)C

Procedure:
1-(1-Hydroxy-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one (0.44g) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (10ml) and the solution, under nitrogen, was cooled to -10°. Pyridine (0.2g) in dry dioxan (2.5ml) was added, followed by the dropwise addition of thionyl chloride (0.19ml) in dioxan (2.5ml) over 2-3 minutes. After a further 15 minutes the precipitated solid was filtered off and the filtrate evaporated to dryness. Dry toluene was added to the residue and decanted off from any solid. The organic solution was evaporated to dryness and re-evaporation from dry ether gave 1-(1-chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(but-2-ynylthio)azetidin-2-one as an amorphous solid (0.45g).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[C:39]([O:45][CH2:46]Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[C:39]([O:45][CH2:46][N:36]1[N:37]=[N:38][C:34]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[O:24][C:21]2([CH2:22][CH2:23][N:18]([C:16]([C:6]4[CH:5]=[C:4]([O:3][CH3:2])[C:13]5[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:17])[CH2:19][CH2:20]2)[CH2:32][C:31]3=[O:33])=[N:35]1)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the sodium salt (105 mg) obtained in Example 18 in 1.0 mL of DMF, was added pivaloyloxymethyl chloride (35.6 μl), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (4 times) and aqueous saturated sodium chloride solution, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel column chromatography (0.7% methanol/chloroform) to obtain the 2-isomer and 1-isomer. 2-Isomer (major product): 1H-NMR (CDCl3) δ: 8.69 (1H, d, J=2.4 Hz), 8.32 (1H, dd, J=2.4, 8.8 Hz), 7.77 (1H, dd, J=1.0, 8.3 Hz), 7.47 (1H, dd, J=7.7, 8.3 Hz), 7.20 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=7.7 Hz), 6.50 (2H, s), 4.64-4.56 (1H, m), 4.24-4.17 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.68-3.59 (1H, m), 3.40 (1H, td, J=12.9, 2.8 Hz), 2.88 (1H, d, J=16.6 Hz), 2.81 (1H, d, J=16.6 Hz), 2.28-2.20 (1H, m), 2.14-2.07 (1H, m), 2.01-1.88 (2H, m), 1.23 (9H, s). MS [M+H]+=615. 1-Isomer (minor product): 1H-NMR (CDCl3) δ: 8.30 (1H, d, J=2.4 Hz), 8.09 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.2, 1.0 Hz), 7.48 (1H, t, J=8.2 Hz), 7.25 (1H, d, J=8.2 Hz), 7.20 (1H, s), 7.08 (1H, d, J=8.8 Hz), 6.32 (1H, d, J=11.2 Hz), 6.29 (1H, d, J=11.2 Hz), 4.65-4.57 (1H, m), 4.28-4.20 (1H, m), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.59 (1H, m), 3.40 (1H, td, J=12.8, 2.9 Hz), 2.90 (1H, d, J=16.6 Hz), 2.84 (1H, d, J=16.6 Hz), 2.28-2.21 (1H, m), 2.14-2.07 (1H, m), 2.06-1.89 (2H, m), 1.28 (9H, s). MS [M+H]+=615.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([CH2:10][C:11]([O:13]CC)=O)[NH:9][C:5]=2[CH:4]=1.[C:19](#[N:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH2:22]>>[CH3:18][N:2]([CH3:1])[C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([CH2:10][C:11]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]#[N:27])=[O:13])[NH:9][C:5]=2[CH:4]=1
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)Cc1nc2ccc(N(C)C)cc2[nH]1
Product: CN(C)c1ccc2nc(CC(=O)Nc3ccccc3C#N)[nH]c2c1

Procedure:
The title compound was synthesized as described in Example 9, Method B using ethyl 2-[5-(dimethylamino)benzimidazol-2-yl]acetate and anthranilonitrile. LC/MS m/z 320.2 (MH+), Rf 1.68 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.C(O)(=O)C.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Yield: 29.9 %

Procedure:
A mixture of N-{4-[(Z)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}acetamide (2 g) and 10% palladium carbon (400 mg) in methanol (25 ml), tetrahydrofuran (25 ml) and acetic acid (18 ml) was stirred under 4 atm hydrogen at ambient temperature for 5 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate. The organic solution was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with n-hexane/ethyl acetate (1:2)→ethyl acetate as an eluent, and triturated with ethyl alcohol/ethyl ether to give N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (539.6 mg) as an off-white solid.