Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15]Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].[Na]>CO.O>[CH2:1]([O:8][C:9]1[C:10]([CH2:15][O:18][CH3:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: ClCc1ncccc1OCc1ccccc1
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COCc1ncccc1OCc1ccccc1
Yield: 97 %

Procedure:
The solution of 41 g (0.18 mol) of 3-(benzyloxy)-2-(chloromethyl)pyridine in 100 ml of methanol is added to the solution of sodium methoxide, prepared by adding 5.2 g (0.23 mol) of sodium to 150 ml of methanol. After refluxing for 3 hours under nitrogen, the solution is concentrated to dryness. The oil obtained is taken up in water and extracted with ethyl acetate. The organic solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate, and then concentrated to dryness. 39 g (97%) of a brown oil are obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>CN(C=O)C>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2cnccc2n1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1,2,3,4-tetrahydroisoquinoline (55.6 μL, 0.431 mmol) and 1-(3dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) afforded the desired product as a white solid (79.1 mg, 95%): m.p. 98-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl.O>O1CCCC1>[CH3:12][O:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc(C=O)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-hydroxybenzaldehyde (1.0 g) in tetrahydrofuran (25 mL) was added sodium hydride (374 mg) at 0° C. and the mixture was stirred at 0° C. for 20 minutes. Methoxymethylchloride (0.92 mL) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was poured into cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:1→5:1) to give the title compound (1.36 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH2:20][CH3:21])=[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=2)[C:5]([Br:27])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(-c2nc(N)ncc2Br)[nH]c1-c1cc(Cl)ccc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxylate (450 mg, 1.21 mmol) in DMF (7.5 mL) was treated with N-bromosuccinimide (216 mg, 1.21 mmol). The mixture was stirred overnight at room temperature, then poured into water, extracted with EtOAc (2×30 mL). The separated organic phase was dried over sodium sulfate and the solvent evaporated. Crystallization from diethyl ether afforded the title compound (420 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16](=[O:24])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[C:25]([O:33][CH2:34][C@H:35](O)[CH2:36][OH:37])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[Si](C)(C)C)(C)C.O>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:25]([O:33][CH2:34][C@H:35]1[CH2:36][O:37][C:16]2([CH2:15][CH2:14][CH:13]([S:10](=[O:12])(=[O:11])[NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17]2)[O:24]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OC[C@H](O)CO)c1ccccc1
Reactant: CCOC(=O)C1=CC(=O)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: CC(C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OC[C@H](COC(=O)c1ccccc1)O2
Yield: 80.9 %

Procedure:
100 mg (0.27 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-oxo-1-cyclohexene-1-carboxylate obtained in Example 7 and 69 mg (0.35 mmol) of (R)-2,3-dihydroxypropyl benzoate were dissolved in 2 ml of dichloromethane and 0.19 ml (1.05 mmol) of isopropoxytrimethylsilane and 2 μl (0.014 mmol) of trimethylsilyl trifluoromethanesulfonate were sequentially added thereto with stirring under ice-cooling, followed by stirring at the same temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate 1:1), to give 121 mg of ethyl (2R)-2-benzoyloxymethyl-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as a pale yellow oil (yield: 81%).
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O>CS(C)=O.[Cl-].[Na+].O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[C:5]3[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])=[CH:15][CH:14]=1
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
5-Amino-1-(4-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (0.7398 g) was dissolved in dimethyl sulfoxide (35 ml), and to the solution was added CuCN (0.6065 g). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.792 ml) was added dropwise during 1.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 4 hours. After allowing to cool, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (100 g, CHCl3:methanol=25:1) and then by silica gel column (70 g, hexane:ethyl acetate=1:1) to give the title compound (0.1767 g, 23%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[CH2:19]([NH2:25])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1>O>[Cl:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:25][CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccco1
Reactant: Clc1ccc2nc(Cl)nc(-c3ccccc3)c2c1
Solvent: O
Product: Clc1ccc2nc(NCc3ccco3)nc(-c3ccccc3)c2c1
Yield: 83.4 %

Procedure:
A mixture of 275 mg of 2,6-dichloro-4-phenylquinazoline (compound No. II-2) and 486 mg of furfurylamine was stirred at 85° C. for 40 minutes and then poured into 50 ml of water. The mixture was extracted with ethyl acetate, and the resultant extract was washed with water and then concentrated. The resulting residue was recrystallized from ethanol to obtain 280 mg of the titled compound. Mp.142.0° C. 1H NMR (CDCl3): 4.77 (2H, d, J=5.6 Hz), 5.70 (1H, br. t, J=5.6 Hz), 6.29-6.32 (2H, m), 7.36 (1H, dd, J=1.8, 0.9 Hz), 7.53-7.70 (7H, m), 7.78 (1H, d, J=2.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][OH:22])=[N:17][O:16][N:15]=2)[O:5][CH:6]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][S:24]([O:22][CH2:21][CH2:20][NH:19][C:18]1[C:14]([C:9]2[N:8]([CH2:7][C:4]3[O:5][CH:6]=[C:2]([Br:1])[CH:3]=3)[C:12](=[O:13])[O:11][N:10]=2)=[N:15][O:16][N:17]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nonc2NCCO)n1Cc1cc(Br)co1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (7.7 g, 21 mmol, containing also some of the corresponding bromo-compound) in ethyl acetate (100 mL) was added methanesulfonyl chloride (0.96 mL, 12 mmol) in one portion. The reaction was stirred for 5 minutes and triethylamine (1.6 mL, 11 mmol) was added, also in one portion. After stirring for 30 minutes, additional methanesulfonyl chloride (0.4 mL, 5 mmol) was added, followed 5 minutes later by triethylamine (0.58 mL, 4.2 mmol). After 15 minutes, the reaction was quenched with the addition of water (100 mL). The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers washed with brine (100 mL). After drying over sodium sulfate, the solvent was removed in vacuo to give the desired product (9.3 g, 100%). LCMS calculated for C12H13BrN5O7S (M+H)+: m/z=449.8, 451.8. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1H), 6.73 (t, J=6.2 Hz, 1H), 6.68 (s, 1H), 5.08 (s, 2H), 4.37 (m, 2H), 3.59 (q, J=5.8 Hz, 2H), 3.16 (s, 3H).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:54]=[CH:53][C:36]([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:47][C:46]([C:48](O)=[O:49])=[C:45]([CH3:51])[CH:44]=3)[C:39]2=[O:52])=[CH:35][CH:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1>>[CH3:51][C:45]1[CH:44]=[C:43]([N:40]2[CH2:41][CH2:42][N:38]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:54][CH:53]=3)[C:39]2=[O:52])[S:47][C:46]=1[C:48](=[O:49])[NH:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 75 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-(tert-butoxycarbonylamino)benzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a beige solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.53 (d, J=4.5 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.27 (dd, J=7.8, 4.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.51 (br s, 1H), 6.08 (br s, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.40 (s, 2H), 3.82-3.73 (m, 2H), 3.45-3.37 (m, 2H), 2.50 (s, 3H), 1.51 (s, 9H); MS (ES+) m/z 522.5 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[NH2:16][CH2:17][CH2:18][C:19]1C=C[C:23]([OH:24])=[C:21](O)[CH:20]=1.[ClH:27].O1C=CC=C1CCN>>[ClH:27].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([NH:16][CH2:17][CH2:18][C:19]1[O:24][CH:23]=[CH:21][CH:20]=1)[CH2:10]2)(=[O:3])[CH3:2]
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Agent: Cl
Agent: NCCc1ccco1
Product: CC(=O)Nc1cccc2c1CCC(NCCc1ccco1)C2

Procedure:
Starting from 0.61 g (0.0031 mol) of 5-acetylamino-2-tetralone and 0.9 g (0.006 mol) of 2 (2-furyl)ethylamine-hydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 0.8 g (77.1% of theory) and with a melting point of 256° C., which increases to 257° C. after recrystallisation from methanol/ether.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:32]([O:38][CH2:39][CH3:40])(=[O:37])[CH2:33]C([O-])=O.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:33][C:32]([O:38][CH2:39][CH3:40])=[O:37])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of 2.65 g (10 mmoles) of 6-benzyloxycarbonylaminohexanoic acid and 1.62 g (10 mmoles) of commercial 1,1'-carbonyldiimidazole in 25 ml of anhydrous tetrahydrofuran was stirred for 15 minutes at room temperature. To the reaction mixture was added a suspension of 6.18 g (40 mmoles) of a white powder of magnesium enolate of monoethyl malonate (prepared from 5.28 g of monoethyl malonate and 972 mg of magnesium) in 50 ml of anhydrous tetrahydrofuran. The mixture was stirred for 2 hours at room temperature. After addition of 50 ml of 1N hydrochloric acid and stirring for 10 minutes, the reaction mixture was extracted 3 times with 50 ml of chloroform. The chloroform layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline, then dried over anhydrous sodium sulfate and freed from the solvent by distillation. The residue was passed through a column of 100 g "Silica Gel 60" (Merck & Co.) and eluted with chloroform (20 g fraction size). Fractions No. 43 to No. 105 were combined and evaporated to dryness to yield 2.35 g (70% yield) of ethyl 8-benzyloxycarbonylamino-3-ketooctanoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:16](OCC)[O:17]CC)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:16]=[O:17])=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CCOC(OCC)c1cc(-c2ccccc2)c(C(=O)OC)s1
Solvent: C1COCCO1
Solvent: O=CO
Product: COC(=O)c1sc(C=O)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of 5-Diethoxymethyl-3-phenyl-thiophene-2-carboxylic acid methyl ester (5.07 g, 15.82 mmol) in dioxane (25 ml) was cooled to 0° C. (ice bath). 95% formic acid (50 ml) was added dropwise and the mixture was stirred at 0° C. for 30 min and then at rt for 60 min. The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (3.50 g, 90% yield).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH:45][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)[C@H](C)NC(=O)N(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of acetylalanylalanylproline (3 mmole) and N-methylmorpholine (3 mmole) in dry tetrahydrofuran (110 ml) at -20° to -25° C. is added isobutyl chloroformate (3 mmole) and stirred at -20° C. for 10 minutes. A solution of 2-azaalanylalanine ethyl ester (3 mmole) in tetrahydrofuran (15 ml) is added dropwise. The resulting mixture is allowed to warm to room temperature over a period of 1 hour and stirred overnight. The precipitate is filtered off and the filtrate is concentrated to dryness. Chromatography on silica gel (70 gm) and elution with 8% methanol in chloroform gives acetylalanylalanylprolyl-2-azaalanylalanine ethyl ester.
Reaction SMILES: ClC(OCC)=O.N[C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=1.COC(=O)CC1C=CC([NH2:28])=CC=1>>[C:12]([NH2:28])(=[O:13])[C:11]1[CH:16]=[CH:17][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCOC(=O)Cl
Product: NC(=O)c1ccccc1

Procedure:
Converting 3,4-dialkoxy benzoic acid to anhydride by adding ethyl chloroformate thereto, and reacting the anhydride with methyl 4-aminobenzoate or 4-aminophenyl acetic acid methylester, to produce a benzamide compound;
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[CH3:18][C:19]1([CH3:30])[C@H:24]2[CH2:25][C@@H:20]1[CH2:21][CH2:22][C@H:23]2[CH2:26][C:27](O)=[O:28]>>[CH3:18][C:19]1([CH3:30])[C@H:24]2[CH2:25][C@@H:20]1[CH2:21][CH2:22][C@H:23]2[CH2:26][C:27]([NH:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1)=[O:28]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Nn3nc(-c4ccccc4)c4ccsc4c3=O)[C@@H]1C2

Procedure:
The product from Example 29B and 2-[(1S,2S,55)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid (Eigenmann, G. W.; Arnold, R. T. JACS 1959, 81, 3440-2) were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (d, J=9.76 Hz, 1H) 1.08 (s, 3H) 1.20 (s, 3H) 1.39-1.66 (m, 1H) 1.76-2.05 (m, 5H) 2.20-2.46 (m, 4H) 7.45-7.65 (m, 4H) 7.71 (dd, J=7.63, 1.83 Hz, 2H) 8.35 (d, J=5.19 Hz, 1H) 11.46 (s, 1H); MS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C.CCOC(C)=O>[CH:22]1([CH2:21][N:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([OH:1])[C:3]2=[O:13])[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1cc[nH]c(=O)c1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(CC2CC2)c(=O)c1O
Temperature: 80 °C
Yield: 25.5 %

Procedure:
To a solution of Intermediate 1B (250 mg, 1.370 mmol) in DMF (2 mL) was added cesium carbonate (1.12 g, 3.41 mmol) and (bromomethyl)cyclopropane (553 mg, 4.09 mmol). The reaction was heated at 80° C. for 3 h. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in a small amount of DCM and charged to a 24 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 11 (82 mg, 0.350 mmol, 25.3% yield) as an oil. HPLC/MS (Method D) RT=1.64 min, [M+1]+ 238.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (1H, d, J=7.28 Hz), 6.30 (1H, d, J=7.03 Hz), 4.21 (2H, q, J=7.03 Hz), 3.65-3.66 (2H, m), 1.29 (1H, m), 1.19 (3H, t, J=7.04 Hz), 0.78 (2H, m), 0.61 (2H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3]/[C:2]/1=[N:7]/[NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11].[ClH:15].C(OC)(C)(C)C>CO>[ClH:15].[F:11][C:10]([F:13])([F:12])[C:9]1[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][C:2]2=[N:7][N:8]=1
Reactant: O=C(N/N=C1/CNCCN1)C(F)(F)F
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CO
Product: FC(F)(F)c1nnc2n1CCNC2
Temperature: 55 °C
Yield: 90.7 %

Procedure:
A suspension of N′-((Z)-piperazin-2-ylidene)-trifluoroacetohydrazide (41 g) in methanol (170 mL) is stirred and heated to about 55° C. Hydrogen chloride (21 mL) is added to the reaction mixture and stirred for about 2 hours. The solution is cooled to 20° C. and methyl tert-butyl ether (423 mL) is added to it. The solution is further cooled to 0° C. and stirred for about 1 hour. The solid is filtered, washed with mixture of ethanol and methyl tert-butyl ether (82 mL) and dried at about 45° C. to afford the title compound. (Yield: 90.7%)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@@H:12]([CH3:26])[C@@H:13]([CH3:25])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:7][C:6]=1[O:27][CH3:28].C[O-].[Na+].[N+:32]([C:35]1[NH:36][CH:37]=[CH:38][N:39]=1)([O-:34])=[O:33]>>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH2:14][C@H:13]([CH3:25])[C@H:12]([CH3:26])[CH2:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:36]3[CH:37]=[CH:38][N:39]=[C:35]3[N+:32]([O-:34])=[O:33])=[C:6]([O:27][CH3:28])[CH:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCBr)c(OC)c2)cc1OC
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OCCn3ccnc3[N+](=O)[O-])c(OC)c2)cc1OC
Yield: 52.7 %

Procedure:
The Standard Procedure 2 was followed by use of 9a (38.2 mg, 0.0849 mmol, 1.0 equiv), sodium methoxide (10.1 mg, 0.187 mmol, 2.2 equiv), and 2-nitroimidazole (6b, 19.2 mg, 0.170 mmol, 2.0 equiv). After workup and purification with column chromatography (80% EtOAc in hexanes as eluant), 10b (21.6 mg, 0.0447 mmol) was obtained in 53% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.79 (d, J=6.8 Hz, 3H, CH3), 0.81 (d, J=6.8 Hz, 3H, CH3), 1.72-1.73 (m, 2H, 2×CH), 2.23-2.32 (m, 2H, 2×ArCH), 2.68-2.74 (m, 2H, 2×ArCH), 3.73 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.30 (t, J=4.6 Hz, 2H, CH2N), 4.80 (t, J=4.8 Hz, 2H, CH2O), 6.59-6.70 (m, 5H, 5×ArH), 6.75-6.77 (m, 1H, ArH), 7.13 (s, 1H, nitroimidazole C5-H), 7.34 (s, 1H, nitroimidazole C4-H); 13C NMR (CDCl3, 100 MHz) δ 16.04, 16.16, 38.69, 38.88, 39.05, 39.21, 49.64, 55.59, 55.72, 55.81, 68.30, 110.92, 112.16, 112.87, 115.24, 120.84, 121.02, 127.51, 128.03, 134.26, 136.84, 144.64, 145.10, 146.97, 148.60, 149.68; IR (neat) 2924 (s), 2853 (s), 1590 (w), 1539 (m), 1516 (s), 1456 (w), 1361 (s), 1261 (s), 1235 (s), 1030 (s) cm−1; HRMS (FAB) m/z calcd for C26H34N3O6 (M+H)+: 484.2448. found: 484.2457.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO.[S:6](Cl)([C:9]1[CH:17]=[CH:16][C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>O>[CH2:1]([NH:3][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[CH:16][CH:17]=1)(=[O:7])=[O:8])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN
Solvent: O
Solvent: CO
Product: CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 79 %

Procedure:
To a 40-mL vial with magnetic stir bar at 25° C. was added the Ethylamine solution (0.91 g, 20 mmol, 1.3 mL, 70% w/v in water, 4.5 eq.) and methanol (5 mL). The reaction vial was cooled to 0° C. The Nosyl chloride (1.0 g, 4.5 mmol, 1 eq.) was added portion-wise keeping the temperature between 0-5° C. and stirring continued ×15 min. after addition was complete. Water (10 mL) was then added. A precipitate began to form immediately. Stirring was continued at 0° C.×30 minutes. The material was collected by filtration, rinsed with water, and dried thoroughly in vacuo to afford 827 mg (79% yield). LCMS (ESI) 231 (M+H); 229 (M−H).