Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:21][C:22]1[N:26]([CH:27]2[CH2:33][C@H:32]3[N:34]([CH2:35][CH2:36][C:37]4([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[C@H:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:25]2[CH:49]=[CH:50][CH:51]=[CH:52][C:24]=2[N:23]=1>ClCCCl>[CH3:21][C:22]1[N:26]([CH:27]2[CH2:33][C@H:32]3[N:34]([CH2:35][CH2:36][C:37]4([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[CH2:38][CH2:39][N:40]([C:6]([C:3]5([C:1]#[N:2])[CH2:5][CH2:4]5)=[O:8])[CH2:41][CH2:42]4)[C@H:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:25]2[CH:49]=[CH:50][CH:51]=[CH:52][C:24]=2[N:23]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: N#CC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)C2(C#N)CC2)CC1

Procedure:
To a solution of 1-cyanocyclopropane-carboxylic acid (38.9 mg, 0.351 mmole) in 1 ml of DCE was added carbonyldiimidazole (38.0 mg, 0.234 mmole) and the mixture was stirred until gas evolution stopped. 2-Methyl-1-{(1R,5S)-8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole (50.0 mg, 0.117 mmole) was added and the resulting mixture was stirred overnight. The solvent was evaporated and the reaction mixture was flashed on silica using a gradient of 1-8% MeOH in CHCl3 to afford 1-[(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenyl-1-piperidinyl)carbonyl]cyclopropanecarbonitrile. MS ES+ 522 (M+H). 1H NMR (300 MHz, chloroform-d) δ ppm 1.6 (m, J=43.1 Hz, 6H), 1.9 (d, J=25.3 Hz, 10H), 2.4 (m, J=10.0 Hz, 4H), 2.6 (s, 3H), 3.3 (m, 3H), 3.5 (m, 1H), 4.1 (m, 2H), 4.7 (m, 1H), 7.3 (m, 8H), 7.7 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:13])[CH3:12])(=[O:3])[NH2:2].C1C(=O)N([Cl:26])C(=O)C1>CC(O)=O.O>[C:1]([C:4]1[CH:8]=[C:7]([Cl:26])[S:6][C:5]=1[NH:9][C:10](=[O:18])[C:11]([O:14][C:15](=[O:17])[CH3:16])([CH3:12])[CH3:13])(=[O:3])[NH2:2]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sccc1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C)(C)C(=O)Nc1sc(Cl)cc1C(N)=O
Temperature: 25 °C

Procedure:
Intermediate 10 (78.5 g, 291 mmol) is dissolved in AcOH (850 mL). To the resulting suspension, NCS (42.9 g, 320 mmol) is added. The mixture is stirred at room temperature, after which it is evaporated to give a slurry. This slurry is taken up in water to give a suspension that is filtered. Resulting precipitate is dried in the vacuum oven and used as such.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=O)=[CH:3][CH:2]=1.[NH3:26]>CO.CCOCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([NH2:26])=[O:17])=[CH:3][CH:2]=1
Reactant: COC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: NC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1

Procedure:
A solution of methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyrate (39 g, 120 mmol) in 600 mL of MeOH was saturated with NH3. The solution was periodically treated with additional NH3 over a 24 h period. The solution was degassed with a stream of nitrogen and the solution was concentrated to leave a yellow solid. The solid was, slurried in ether and filtered to leave the title compound: MS (M+H): 325 (base peak).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1)#[N:2].[Li+].[OH-].Cl>O1CCOCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31])[CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:14]2[NH:13][C:12]3[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=3[C:10]=2[CH:9]=1)#[N:2]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(OC(C)C)c(C#N)c3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.7 %

Procedure:
Ethyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (1.32 g, 3.05 mmol) was dissolved in dioxane (34 mL) and 1.0 M aqueous LiOH (9.16 mL, 9.16 mmol) was added. The reaction was stirred at room temperature for 6 h and then warmed to 35° C. and stirred for one additional hour. After cooling to room temperature, the reaction was acidified to pH 3 with 1.0 M HCl and partitioned between water and ethyl acetate. The organics were removed and the aqueous layer was extracted twice with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated to give the title compound (1.23 g). LCMS m/z=405.6 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (d, J=5.9 Hz, 6H), 2.03-2.13 (m, 1H), 2.35 (dd, J=15.9, 9.0 Hz, 1H), 2.58-2.77 (m, 4H), 3.41-3.51 (m, 1H), 4.79 (septet, J=5.9 Hz, 1H), 5.01 (s, 2H), 6.69 (dd, J=8.8, 2.4 Hz, 1H), 6.91 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 2.3 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 10.45 (s, 1H), 12.1 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19].Cl>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:5]=[O:6]
Reactant: CC(C)CI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(C=O)cc1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In 50 ml of N,N-dimethylformamide are suspended 5.0 g of 3,4-dihydroxybenzaldehyde, 10.0 g of potassium carbonate and 8.3 ml of isobutyl iodide. The suspension is stirred at 80° C. for 2 hours. The reaction mixture is added to a mixture of ethyl acetate and water, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 3.3 g of 3-hydroxy-4-isobutoxybenzaldehyde as a light yellow solid product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O>CO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][C:11]([CH2:28][C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[CH:12][N:13]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1cccs1
Reactant: COc1ccc(C2=NCCN=C2c2ccc(OC)cc2)cc1
Solvent: CO
Product: COc1ccc(-c2ncc(Cc3cccs3)nc2-c2ccc(OC)cc2)cc1

Procedure:
The same procedures as in Example 3 was repeated using 2,3-bis(p-methoxyphenyl)-5,6-dihydropyrazine and 2-thiophenealdehyde. 2,3-Bis(p-methoxyphenyl)-5-(2-thienylmethyl)pyrazine was obtained as colorless prisms, m.p. 89° C. (recrystallized from methanol). Physical properties of the product support a chemical structure of the below formula (XIII).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](SC)(OC(O)=S)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SnH](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC(OC(O)=S)(c1ccccn1)C1CN(C(=O)OC(C)(C)C)C1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Cc2ccccn2)C1
Temperature: 110 °C

Procedure:
To 428 mg (1.21 mmol) 3-(methylsulfanylthiocarboxyoxy-pyridin-2-yl-methyl)-azetidine-1-carboxylic acid tert-butyl ester in 15 mL dry toluene was added 6 mg (36 μmol) AlBN followed by 508 mg (1.69 mmol) nBu3SnH, and the mixture was heated under nitrogen at 110° C. for 2 hours. After evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 1:1 to EtOAc).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:16]([C:17]([O:19]C)=[O:18])=[C:15]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[C:14]4[CH:33]=[CH:34][CH:35]=[CH:36][C:13]=4[S:12]3(=[O:38])=[O:37])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Li+]>C1COCC1.CO.O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:16]([C:17]([OH:19])=[O:18])=[C:15]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=4)[C:14]4[CH:33]=[CH:34][CH:35]=[CH:36][C:13]=4[S:12]3(=[O:38])=[O:37])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)C1=C(c2cc(OC)c(OC)c(OC)c2)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C2=C(C(=O)O)N(Cc3ccc4c(c3)OCO4)S(=O)(=O)c3ccccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl 2-benzo[1,3]dioxol-5-ylmethyl-1,1-dioxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylate (0.28 g, 0.05 mmol) in THF/methanol/water (10 mL/3 mL/3 mL) was treated with lithium hydroxide (0.33 g, 7.78 mmol) and the reaction mixture stirred at room temperature overnight. The solution was diluted with ethyl acetate, washed with 1N HCl, brine, dried over magnesium sulfate, and the solvent evaporated. The foam was crystallized from methylene chloride/isopropyl ether; MS (CI) m/e 525.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(OC(C)(C)C)=O.Cl.O1CCOCC1>C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 160.9 %

Procedure:
Ethyl acetate (1.5 mL) was added to 100 mg of Boc-Tyramine-PEM (α,γ-mixture) obtained in Reference Example 3 to suspend the compound, and then 4 N HCl/dioxane (0.5 mL) was added thereto. The mixture was stirred for one hour at room temperature. A precipitate thus obtained was filtered with a Kiriyama funnel and dried in a vacuum, and thus 93 mg of Tyramine-PEM (α,γ-mixture) was obtained. The compound is thought to be a dihydrochloride salt, based on yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([NH:41][C@@H:42]([CH2:46][C:47]#[N:48])[C:43]([OH:45])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:49][C@@H:50]([CH2:67][C:68]1[CH:73]=[CH:72][C:71]([O:74][CH3:75])=[CH:70][CH:69]=1)[C:51]([NH:53][C@@H:54]([CH2:61][C:62]1[CH2:66][CH2:65][CH2:64][CH:63]=1)[C:55]([C@@:57]1([CH3:60])[CH2:59][O:58]1)=[O:56])=[O:52]>CN(C=O)C.O.CCOC(C)=O>[C:47]([CH2:46][C@H:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:36])[CH3:37])[C:43]([NH:49][C@@H:50]([CH2:67][C:68]1[CH:69]=[CH:70][C:71]([O:74][CH3:75])=[CH:72][CH:73]=1)[C:51]([NH:53][C@@H:54]([CH2:61][C:62]1[CH2:66][CH2:65][CH2:64][CH:63]=1)[C:55]([C@@:57]1([CH3:60])[CH2:59][O:58]1)=[O:56])=[O:52])=[O:45])#[N:48]
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC#N)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](CC#N)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Sequentially HATU (1.21 g, 3.20 mmol) and DIEA (1.35 mL, 7.8 mmol) were added to a 0° C. solution of (S)-2-(tert-butoxycarbonylamino)-3-cyanopropanoic acid and (S)-2-amino-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)propanamide (TFA salt, 2.1 mmol) in DMF (20 mL). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added. The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:2) to afford tert-butyl ((S)-3-cyano-1-(((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyl oxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (590 mg, 45% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.[C:34]([O:37][CH2:38][C:39]1[NH:40][CH:41]=[C:42]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[C:43](=[O:45])[CH:44]=1)(=[O:36])[CH3:35].[CH2:56](O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>O1CCCC1>[C:34]([O:37][CH2:38][C:39]1[CH:44]=[C:43]([O:45][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:42]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)=[CH:41][N:40]=1)(=[O:36])[CH3:35]
Reactant: COc1ccc(COc2c[nH]c(COC(C)=O)cc2=O)cc1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2cnc(COC(C)=O)cc2OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A solution of triphenylphosphine (39.3 g, 150 mmol) in tetrahydrofuran (600 ml) was treated at 0° C. with bis(1-methylethyl) (E)-1,2-diazenedicarboxylate (30 ml, 152 mmol). After 10 minutes [5-({[4-(methoxy)phenyl]methyl}oxy)-4-oxo-1,4-dihydro-2-pyridinyl]methyl acetate (33.5 g, 110 mmol) (for a synthesis, see WO2004058144, Example 60(c)) was added. After 10 minutes benzyl alcohol (12.4 ml, 120 mmol) was added and the mixture was stirred overnight. Evaporation and chromatography on silica eluting with 20-50% ethyl acetate in hexane afforded an oil (26.3 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH2:34][OH:35])[N:33]=[C:29]4[N:28]=[C:27]([C:36](=[O:39])[NH:37][OH:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:42][O:43][C:44]([CH3:60])([CH3:59])[C:45]([NH:47][NH:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=1)=[O:46]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]([C:45](=[O:46])[NH:47][NH:48][C:49](=[O:58])[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=2)([CH3:59])[CH3:60])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH2:34][OH:35])[N:33]=[C:29]4[N:28]=[C:27]([C:36](=[O:39])[NH:37][OH:38])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(C(=O)NO)nc5nc(CO)nn45)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(C(=O)NO)nc4nc(CO)nn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (50 mg) (0.082 mmol) and 34 mg (0.11 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 4 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the solvent is removed at room temperature. The residue is treated with water. The precipitated product is filtered off under suction and washed in succession with water and diethyl ether. There are obtained 50 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[CH:7][C:6]=2[CH:13]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([Cl:16])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc2cc(Cl)ccc2o1

Procedure:
A solution of 5-chloro-1-benzofuran-2-carboxylic acid (827 mg, 42 mmol) in thionyl chloride (4 mL) was refluxed over night. The solvent was removed in vacuo to give the 5-chloro-1-benzofuran-2-carbonyl chloride in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([NH:21]C(OC(C)(C)C)=O)[CH:18]=[CH:17][N:16]4[C:29]=3[CH3:30])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl>C(O)C>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][CH2:12][C:13]3[N:14]=[C:15]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][N:16]4[C:29]=3[CH3:30])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(NC(=O)OC(C)(C)C)ccn12
Agent: Cl
Solvent: CCO
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2cc(N)ccn12
Yield: 39.8 %

Procedure:
The mixture of 2-amino-6-[2-(3-methyl-7-tertbutoxycarbonylaminoimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.8 g) and conc. hydrochloric acid (0.9 ml) in ethanol (20 ml) was heated under refluxed for 1 hour. The mixture was ice-cooling and the isolated precipitate was collected by filtration. To a precipitate was added a mixture of ethyl acetate, tetrahydrofuran and water, and the mixture was adjusted to pH 8.5 with 20% aqueous potassium carbonate solution with salting-out technique. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was triturated with a solution of ethyl acetate and diethyl ether, and the precipitate was collected by filtration to give 2-amino-6-[2-(7-amino-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.24 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([Si:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[Si:12]([O:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.2 %

Procedure:
Into a 250-mL round-bottom flask was placed a solution of piperidin-4-ol (4 g, 39.55 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), TEA (12 g, 118.59 mmol, 3.00 equiv) and tert-butyl(chloro)diphenylsilane (16 g, 58.21 mmol, 1.47 equiv). The resulting solution was stirred for 16 h at room temperature. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). Purification afforded 1.1 g (8%) of 4-[(tert-butyldiphenylsilyl)oxy]piperidine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.[CH2:13]([NH:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:14].C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CCCCNCC
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)c1cc(C)nc(Cl)c1[N+](=O)[O-]

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (1 g, 4.83 mmol), N-ethylbutylamine (0.75 mL, 5.55 mmol), and N,N-diisopropylethylamine (1 mL, 6 mmol) were stirred at 25° C. for 24 h and at reflux for 5 h. Then the mixture was stripped in vacuo and the residue was partitioned between EtOAc (75 mL), and water (50 mL). The organic layer was washed with water (30 mL), brine (30 mL), dried (MgSO4) and stripped in vacuo. The residue was chromatographed on silica gel (10%) EtOAc/hexanes eluent) to give the two regiomers 270 mg and 840 mg. The major regioisomer was characterized as the 4-adduct by nOe NMR experiments. minor: NMR (CDCl3) 6.56 (s, 1H), 3.30-3.42 (m, 4H), 2.38 (s, 3H), 1.49-1.59 (m, 2H), 1.23-1.35 (m, 2H), 1.15 (t, 3H, J=7.3 Hz), 0.92 (t, 3H, J=7.0 Hz); major: NMR (CDCl3) 6.52 (s, 1H), 3.28 (q, 2H, J=7.0), 3.18 (dd, 2H, J1 =7.3 Hz, J2 =8.1 Hz), 2.44 (s, 3H), 1.49-1.60 (m, 2H), 1.24-1.37 (m, 2H), 1.17 (t, 3H, J=7.3 Hz), 0.94 (t 3H, J=7.3 Hz).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
A 218 mg (5.45 mmol) portion of sodium hydride was added to 12 ml of DMF solution containing 0.99 g (3.64 mmol) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, and the mixture was stirred at room temperature for 30 minutes, mixed with 0.52 ml (5.45 mmol) of methyl bromoacetate and again stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the thus obtained oily material was purified by a silica gel column chromatography (200 cc; elution by ethyl acetate-hexane=1:3) to obtain 0.96 g of the title compound (77% in yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][C:10]([O:12][CH:13]([CH2:18][O:19][CH2:20][CH3:21])[CH2:14][O:15][CH2:16][CH3:17])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33])(=[O:25])=[O:24]>>[C:1]([O:5][C:6]([N:8]([O:9][C:10]([O:12][CH:13]([CH2:14][O:15][CH2:16][CH3:17])[CH2:18][O:19][CH2:20][CH3:21])=[O:11])[S:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[S:23]([CH3:22])(=[O:25])=[O:24])(=[O:34])=[O:33])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCOCC(COCC)OC(=O)ONC(=O)OC(C)(C)C
Product: CCOCC(COCC)OC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
1-({[(tert-Butoxy)carbonyl]({[(1,3-diethoxypropan-2-yl)oxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene (102) is prepared from 2-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}-1,3-diethoxypropane and 2-methylsulfonyl benzene sulfonyl chloride according to Scheme 11. (2.3 g, 47%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (2H, ddd, 12.2, 7.5, 1.5 Hz), 7.84 (2H, m), 5.06 (1H, quin, 5.1 Hz), 3.68 (4H, t, 4.9 Hz), 3.48-3.61 (4H, m), 1.43 (9H, s), 1.27 (3H, t, 7.2 Hz), 1.19 (3H, t, 6.9 Hz).