Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[OH:25]>>[OH:25][C:17]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:16]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-5-nitrophenol, N-(2-hydroxy-4-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[Na].[C:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Br)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][S:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Oc1ccccc1CBr)c1ccccc1
Reactant: Sc1nc2cnccc2[nH]1
Agent: [Na]
Product: O=C(Oc1ccccc1CSc1nc2cnccc2[nH]1)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 3 using 6.79 g (0.045 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine, 1.14 g (0.0495 g atom) of sodium and 13.09 g (0.045 mol) of 2-(bromomethyl)phenyl benzoate. Purification of the crude material (12.75 g) by HPLC gave a product which on recrystallization from ethyl acetate had a m.p. 129°-132° C.
Reaction SMILES: Br.[CH2:2]([C:4]1([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14]C)[CH:10]=2)[C:5]1=[O:16])[CH3:3]>O>[CH2:2]([C:4]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[C:5]1=[O:16])[CH3:3]
Reactant: CCOC(=O)CC1(CC)CCc2cc(OC)ccc2C1=O
Agent: Br
Solvent: O
Product: CCC1(CC(=O)O)CCc2cc(O)ccc2C1=O
Yield: 83.5 %

Procedure:
Aqueous HBr (70 mL) was added to 4A (7 g, 24.13 mmol) and the reaction mixture was refluxed for 4 h. The reaction mixture was then brought to room temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified using flash chromatography using 40% ethyl acetate in hexanes to afford the title compound (5 g, 83.6%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 12.0 (s, 1H), 10.3 (s, 1H), 7.8 (d, J=8.4 Hz, 1H), 6.7 (d, J=7.4 Hz, 1H), 6.6 (s, 1H), 3.0 (m, 1H), 2.7 (m, 2H), 2.4 (m, 2H), 1.9 (m, 1H), 1.7-1.5 (m, 2H), 0.9 (t, J=7.6 Hz, 3H). ESI-MS m/z=247 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[CH3:45])=[C:34]([NH2:46])[CH:33]=1.Cl>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:47])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]2[CH3:45])=[C:34]([NH:46][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(N)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COC(=O)c1ccc(N[C@@H]2CCCC[C@H]2C)c(NC(=O)Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of 4.46 g of 2-thienyl-acetic acid in 80 ml of dry DMF 1.94 g of HOAT, 6.56 g of EDC and 9 ml of DIPEA were added at 0° C. After 30 min 7.48 g of 3-Amino-4-((1R,2R)-2-methyl-cyclohexylamino)-benzoic acid methyl ester were added, followed by the addition of 9 ml of DIPEA and the reaction was stirred at rt for 16 h. The reaction was then poured into water, brought to pH3 by the addition of 2 M aqueous hydrochloric acid and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 9.52 g (86%) of 4-((1R,2R)-2-Methyl-cyclohexylamino)-3-(2-thiophen-2-yl-acetylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: CO[C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[CH2:22]([Al+]CC(C)C)[CH:23](C)C.C([Mg]Br)=C>C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([NH:5][CH:4]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([OH:20])[CH:22]=[CH2:23])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)C[Al+]CC(C)C
Agent: C=C[Mg]Br
Agent: [H-]
Solvent: Cc1ccccc1
Product: C=CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.6 %

Procedure:
A solution of 10.25 g (36.7 mmol) of N-(t-butyloxycarbonyl)phenylalanine methyl ester in 60 ml of toluene was cooled to -78° C. under inert atmosphere and treated dropwise over a period of 45 min with 35 ml (52.5 mmol) of diisobutylaluminum hydride in toluene. The resulting solution was stirred for 5 min, treated with 200 ml (200 mmol) of vinylmagnesium bromide, and allowed to warm to 0° C. for 16 h. The solution was subsequently quenched cautiously with methanol, treated with-aqueous Rochelle salts, stirred for a few min, and filtered. The residue was digested several times with ethyl acetate and filtered; and the combined filtrates were washed with saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography using 20% ethyl acetate in hexane gave 5.46 g (54%) of the pure desired compound as a mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:10]([NH:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[C:7]([Br:9])[CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)cc(Br)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Brc1cc(Br)cc(NCc2ccccc2)c1
Yield: 69.5 %

Procedure:
The same procedure as described above was used in a scale up reaction where 3,5-dibromoaniline (273) (3.85 g, 15.35 mmol), benzaldehyde (274) (1.61 g, 15.35 mmol), Na(OAc)3BH (6.47 g, 30.7 mmol), AcOH (1.11 g, 18.42 mmol) and DCE (38 mL) were used. After 3 h reaction and purification (flash chromatography), benzyl-(3,5-dibromo-phenyl)-amine (275) (3.64 g, 10.67 mmol) was obtained in 69.6% isolated yield.
Reaction SMILES: [OH-].[K+].[I:3]I.[F:5][C:6]([F:17])([F:16])[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][CH:8]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[F:17][C:6]([F:5])([F:16])[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([I:3])=[N:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: II
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
Potassium hydroxide (73 mg, manufactured by Wako Pure Chemical Industries, Ltd.) and iodine (330 mg, manufactured by Kanto Chemical Co., Inc.) were added to a solution of 6-(trifluoromethyl)-1H-indazole (121 mg) synthesized according to the literature (Shoji, et al., Tetrahedron Lett., 2004, 45, 1769-1772) in N,N-dimethylformamide (6.5 mL, manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred for 3 hours at room temperature. An aqueous solution of sodium thiosulfate (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×20 mL), washed with brine (40 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 169 mg of the title compound. LC-MS: HPLC retention time 4.46 minutes, m/z 313 (M+H), condition B-1.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[CH2:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27]C)=[CH:22][CH:21]=1)[CH:17]([CH3:19])[CH3:18].[CH3:30][O:31][CH:32](OC)[O:33]C.S(=O)(=O)(O)O>>[CH3:30][O:31][C:32]([CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=1)[CH3:27])=[O:33]
Reactant: COC(OC)OC
Reactant: CCC(=O)c1ccc(CC(C)C)cc1
Agent: O=S(=O)(O)O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 6 h
Yield: 79 %

Procedure:
To a suspension of iodobenzene diacetate (322 grams(g), 1.0 mol) in a solution of p-isobutylpropiophenone (190 g, 1.0 mol) in trimethylorthoformate (109 ml, 1.0 mol) was added, dropwise, concentrated sulfuric acid (about 96% H2SO4, 10.7 ml, 0.2 mol) at 3° C. with stirring over 40 minutes. The resulting reaction mixture was stirred 6 hours at 0° C. to 15° C. The ensuing reaction was quenched by adding 200 ml deionized water. HPLC (high performance liquid chromatography) analysis of the resulting reaction product, comparing to an external standard, demonstrated 79% yield of ibuprofen methylester. The mixture obtained can be separated into an aqueous phase and an organic phase, followed by isolation of purified ibuprofen methyl ester from the organic phase by column chromatography or distillation. Alternatively, the crude ester can be hydrolyzed by treating with 50% aqueous sodium hydroxide, followed by extraction of the resulting aqueous phase with heptane. Acidification of the aqueous phase and recrystallization of the solid precipitate yields high-purity ibuprofen.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9](OS(C)(=O)=O)[CH2:10]2)=[O:5])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:19]=[N+:20]=[N-:21])[CH2:10]2)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C2CCC1CC(N=[N+]=[N-])C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
To a solution of 3-methanesulfonyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.74 g, 6.28 mmol) in DMF (62 mL) was added sodium azide (813 mg, 12.5 mmol) portion-wise. The mixture was heated to 100° C., stirred for 5 hrs, cooled, and diluted with ethyl acetate. The solution was washed three times with water, sodium bicarbonate, brine; dried over Na2SO4, filtered, and concentrated to provide a yellow oil (1.42 g). 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.1 Hz, 3H), 1.68 (m, 4H), 1.91 (m, 2H), 2.01 (m, 2H), 3.73 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 4.34 (m, 2H); MS (ESI+Q1MS) m/z 225 [M−H]+
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[S:1]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCCCCCc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OCCCCCc1ccccc1

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 5-phenyl-1-pentanol. The oil obtained was further purified by chromatography using a column with methylene chloride as eluting agent. Evaporation of appropriate fractions gave a viscous oil which solidified on standing. The solid was recrystallized from ethyl ether-petroleum ether (bp range 30°-60° C.) to give the title compound as white solid, mp 63°-66° C. in 60% yield.
Reaction SMILES: [Br:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4C=C[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:4][CH:3]=1.BrC1C=CC(CN2C3C=CC(O)=CC=3N=C2CC(C)(C)C(OCC)=O)=CC=1.ClCC1[S:69]C2C=CC=CC=2N=1>>[S:69]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]1[CH2:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH2:6][C:5]3[CH:37]=[CH:38][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]([CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:9][C:10]=2[CH:15]=1
Reactant: ClCc1nc2ccccc2s1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Agent: CCOC(=O)C(C)(C)Cc1nc2cc(O)ccc2n1Cc1ccc(Br)cc1
Product: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Br)cc1

Procedure:
The title compound was prepared using analogous conditions to those described for ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate using ethyl 3-(1-(4-bromobenzyl)-5-hydroxy-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate and 2-(chloromethyl)benzo[d]thiazole. MS (ESI): mass calcd. for C29H28BrN3O3S, 577.10; m/z found, 578.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1)=S.[N:15]#[C:16][NH2:17].[Pb]>>[C:16]([NH:17][C:3]([NH:2][CH3:1])=[N:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][CH:11]=1)#[N:15]
Reactant: CNC(=S)NCCSCc1cncs1
Reactant: N#CN
Agent: [Pb]
Product: CNC(=NCCSCc1cncs1)NC#N

Procedure:
The reaction of N-methyl-N'-[2-(5-thiazolylmethylthio)ethyl]thiourea with lead cyanamide by the procedure of Example 3(b) gives the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:24])[N:10]([O:25]CC2C=CC=CC=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:24])[N:10]([OH:25])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following the procedure of Example 32, hydrogenation of 1-benzyl-3-benzyloxy-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example A-3, 110 mg, 0.247 mmol) and 10% Pd/C (15 mg) in MeOH (2 mL) and ethyl acetate (3 mL) afforded 67 mg, of the title compound as a solid, mp 219-220° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[C@H:23]([CH2:24][CH2:25][CH:26]2[O:31]CCO[CH2:27]2)[C@H:22]([N:32]=[N+:33]=[N-:34])[C:21]1=[O:35])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S(=O)(=O)(O)O.C(O)(=O)C>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][O:13][P:14]([CH2:19][N:20]1[C@H:23]([CH2:24][CH2:25][C:26](=[O:31])[CH3:27])[C@H:22]([N:32]=[N+:33]=[N-:34])[C:21]1=[O:35])([O:16][CH2:17][CH3:18])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(CN1C(=O)[C@@H](N=[N+]=[N-])[C@H]1CCC1COCCO1)OCCC(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOP(=O)(CN1C(=O)[C@@H](N=[N+]=[N-])[C@H]1CCC(C)=O)OCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A suspension of cis-1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-(3-ethylenedioxybutyl)-2-azetidinone (0.10 g.) in 10% aqueous sulfuric acid (8 ml.) and glacial acetic acid (1 ml.) is heated with stirring at 50° for 2 hrs. The mixture is cooled to room temperature and extracted with methylene chloride (3×15 ml.) The combined extracts are washed with brine (2×10 ml.), dried with magnesium sulfate, filtered, and evaporated in vacuo to yield 60% of cis-1-(benzyloxycarbonyldiethylphosphono)methyl-3-azido-4-(3-oxobutyl)-2-azetidinone as a light brown oil. NMR (CDCl3) δ: 1.27 (m, O--CH2 --CH3); 2.13 (s, CH3); 4.12 (m, O--CH2CH3 and H4); 4.72 (d, J=5.5 Hz, H3); 5.23 (s, OCH2 φ); 7.35 (φ). IR (film) μ: 4.70 (N3); 5.61 (β-lactam); 5.70 (ester); 5.82 (C= O) M+ (Calc. 466) Found 466.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:11][C:10]([CH2:12][CH2:13][CH3:14])=[N:9][C:8]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[CH2:31][CH2:30][C:29]([N+:37]([O-:39])=[O:38])=[CH:28]2>C1COCC1>[CH3:36][O:35][C:34]1[CH:33]=[C:32]2[C:27](=[CH:26][C:25]=1[O:24][CH3:23])[CH:28]([C:7]1[O:11][C:10]([CH2:12][CH2:13][CH3:14])=[N:9][C:8]=1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[CH:29]([N+:37]([O-:39])=[O:38])[CH2:30][CH2:31]2
Reactant: COc1cc2c(cc1OC)CCC([N+](=O)[O-])=C2
Reactant: CCCc1nc(COC2CCCCO2)c(Br)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1nc(COC2CCCCO2)c(C2c3cc(OC)c(OC)cc3CCC2[N+](=O)[O-])o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
n-Butyllithium (2.5M in hexane, 10 mmol) was added to a solution of the compound from step 29c (2.70 g, 8.88 mmol) in 40 mL of THF cooled to -78° C. The resulting yellow solution was stirred for 30 min at -78° C., and a solution of 1,2-dihydro-6,7-dimethoxy-3-nitronaphthalene (2.227 g, 9.48 mmol), from Example 1b, precooled to -78° C., was added via cannula. The reaction was stirred for 2 hours at -78° C., then the reaction was quenched by the addition of 10 mL of satd. NH4Cl. After warming to room temperature, the organic layer was separated, and the aqueous layer was extracted with 2×50 mL of methylene chloride. The organics were combined, dried over MgSO4 and concentrated. The crude product was dissolved in 45 mL of methanol and treated with 8 mL of triethylamine. This solution was stirred for 15 hours at room temperature. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel, eluting with 30-60% ethyl acetate in hexane, to afford after removal of the solvent and drying, 3.64 g (89% yield) of the title product as an oil. MS: 461 (M+H)+. NMR showed a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])(O)=O.[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Yield: 91.3 %

Procedure:
This compound was prepared by General Method 1 from 2-amino-5-nitrophenol (6.0 g, 39 mmol), NaHCO3 (7.8 g, 93 mmol), and chloroacetyl chloride (3.58 mL, 45 mmol) to afford 6.91 g (91%) of 7-nitro-2H-1,4-benzoxazin-3(4H)-one. Data for 7-nitro-2H-1,4-benzoxazin-3(4H)-one: Rf 0.44 (11.5:1 CH2Cl2:MeOH); 1H NMR (400 MHz, DMSO-d6) δ 11.3 (br s, 1H), 7.90 (dd, 1H, J=8.7, 2.6), 7.76 (d, 1H, J=2.5), 7.06 (d, 1H, J=8.7), 4.73 (s, 2H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:29]=[CH:28][C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:26][CH3:27])=[C:20]([C:23]([OH:25])=O)[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:10][C:9]=2[CH3:30])=[O:6])[CH2:3][CH2:2]1.Cl.[O:32]([NH2:34])[CH3:33]>>[CH3:33][O:32][NH:34][C:23]([C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:26][CH3:27])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[CH:28]=[CH:29][C:8]([NH:7][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:6])=[C:9]([CH3:30])[CH:10]=1)=[O:25]
Reactant: CON
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(C)c3)c2cc1C(=O)O
Agent: Cl
Product: CONC(=O)c1cc2c(Oc3ccc(NC(=O)NC4CC4)c(C)c3)ccnc2cc1OC
Yield: 21.74 %

Procedure:
4-(4-((Cyclopropylamino)carbonyl)amino-3-methylphenoxy)-7-methoxy-6-quinolinecarboxylic acid (30 mg, 0.0736 mmol) and methoxylamine hydrochloride (0.0123 ml) were used for reaction in the same manner as Example 458, and after purification by NH silica gel column chromatography (ethyl acetate:methanol=10:1), the obtained crystals were suspended in ethanol, diluted with hexane, filtered out, washed with hexane and dried by aspiration to obtain the title compound (7 mg, 0.0160 mmol, 21.74%) as light yellow crystals.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][OH:7])=[N+:2]=[N-:3].[H-].[Na+].N[C@H:11]([C:23]([OH:25])=[O:24])CC1C=C2C(C=CC=C2)=CC=1.ClCC([O-])=O.[Na+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:1]([CH2:4][CH2:5][CH2:6][O:7][CH2:11][C:23]([OH:25])=[O:24])=[N+:2]=[N-:3]
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: [N-]=[N+]=NCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])CCl
Agent: [Br-]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCOCC(=O)O
Yield: 574 %

Procedure:
A solution of 3-azidopropanol (70.1 g, 0.693 mol) in 100 mL of THF was added dropwise, in a period of 1.5 hours, to a mechanically stirred suspension of NaH (60% in mineral oil, 30.5 g, 0.763 mol) in 250 mL of THF. During the addition of 3-azidopropanol, a gentle reflux was maintained. This was followed by addition of solid Nal (10.4 g, 69.3 mmol), and tetrabutylammonium bromide (22.3 g, 69.3 mmol), and sodium chloroacetate (88.8 g, 0.763 mol). The reaction mixture was heated at reflux temperature for 19 hours, cooled, quenched initially with 20 mL of water (added dropwise) and then with 700 mL of water, washed with EtOAc (3×200 mL), acidified with concentrated HCl to pH=2, and extracted with dichloromethane (6×100 mL). The combined dichloromethane extracts were dried (MgSO4), and the solvent was removed in vacuo to give 63.3 g (58%) of the title compound as a yellow viscous oil. The crude product was used in the next step after spectral characterization.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.N1C=CC=CC=1.Cl.[CH3:48][C:49]([CH:52]1[CH2:57][CH2:56][CH2:55][NH:54][CH2:53]1)([OH:51])[CH3:50]>C(#N)C>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:54]2[CH2:55][CH2:56][CH2:57][CH:52]([C:49]([OH:51])([CH3:50])[CH3:48])[CH2:53]2)=[O:16])=[CH:7][CH:8]=1
Reactant: CC(C)(O)C1CCCNC1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(O)C1CCCN(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
5-[4-(Trifluoromethyl)phenyl]isoxazole-4-carboxylic acid (30 mg, 0.12 mmol) was dissolved in acetonitrile (1.5 mL) followed by the addition of o-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (52 mg, 0.16 mmol), pyridine (60 μL, 0.72 mmol) and 3-(1-methyl-1-hydroxyethyl)piperidine hydrochloride (25 mg, 0.14 mmol), and stirred at 60° C. for 30 min. The residue was purified on reversed phase HPLC to yield the title compound (23 mg). HRMS (ESI, pos. ion) m/z calcd for C19H21F3N2O3: 382.1504, found 382.1502.
Reaction SMILES: [C:1]([N:4]1[CH:13](C(O)=O)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=O)[CH3:2].[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20]>C(OC(=O)C)(=O)C>[CH3:22][O:21][C:19]([C:18]1[C:17]([C:23]([O:25][CH3:26])=[O:24])=[C:1]([CH3:2])[N:4]2[C:13]=1[CH2:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5]2)=[O:20]
Reactant: CC(=O)N1Cc2ccccc2CC1C(=O)O
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1ccccc1C2
Temperature: 67.5 °C

Procedure:
A mixture of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (3.00 g, 13.6 mmol) and dimethyl acetylenedicarboxylate (2.84 g, 20 mmol) in acetic anhydride (25 mL) was heated at 65-70° C. for 1.5 hours. The reaction mixture was then cooled and evaporated under reduced pressure to dryness. The residue was recrystallized from methanol to give 3-methyl-5,10-dihydropyrrolo[1,2-b]-isoquinoline-1,2-dicarboxylic acid dimethyl ester, 3.29 g, (80.2%); mp 152-154° C.; 1H NMR (DMSO-d6) δ 2.40 (3H, s, Me), 3.70 (3H, s, COOMe), 3.72 (3H, s, COOMe), 4.18 (2H, s, CH2), 5.06 (2H, s, CH2), 7.29-7.32 (2H, m, 2×ArH), 7.35-7.39 (2H, m, 2×ArH); m/z 299.0 (M+H)+. Anal. Calcld. for C17H17NO4: C, 68.22; H, 5.72; N, 4.68. Found: C, 68.29; H, 5.77; N, 4.67.