Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:27](OC(C1C2C=CC(O)=CC=2OC=1)=O)[CH3:28].BrCC1CC1>>[CH:2]1([CH2:1][O:3][C:4]2[CH:26]=[CH:25][C:7]3[C:8]([CH2:11][O:12][C:13]4[CH:21]=[CH:20][CH:19]=[C:18]5[C:14]=4[CH:15]=[C:16]([C:22]([OH:24])=[O:23])[NH:17]5)=[CH:9][O:10][C:6]=3[CH:5]=2)[CH2:28][CH2:27]1
Reactant: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Reactant: CCOC(=O)c1coc2cc(O)ccc12
Agent: BrCC1CC1
Product: O=C(O)c1cc2c(OCc3coc4cc(OCC5CC5)ccc34)cccc2[nH]1

Procedure:
4-(6-cyclopropylmethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (30b) is synthesized analogous to 30a from 6-Hydroxy-benzofuran-3-carboxylic acid ethyl ester (26) and bromomethyl cyclopropane.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[O:11]=[C:12]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]1.Cl.CN(C)CCCN=C=NCC.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][N:34]([CH3:33])[C:17]([CH:14]1[CH2:15][CH2:16][C:12](=[O:11])[CH2:13]1)=[O:19]
Reactant: CNOC
Reactant: O=C1CCC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 1-hydroxybenzotriazole (7.91 g, 58.5 mmol), 3-oxo-1-cyclopentanecarboxylic acid (5.00 g, 39.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.22 g, 58.5 mmol) in 44 mL DCM under nitrogen was added N,O-dimethylhydroxylamine hydrochloride (5.71 g, 58.5 mmol) followed by triethylamine (8.16 mL, 58.5 mmol) in portions. The reaction mixture became warm and was cooled with an ice bath for the remainder of TEA addition, then stirred at ambient temp under nitrogen for 2 d. The reaction mixture was concentrated in vacuo, and taken up in EA (300 mL), washed with water, sat'd aq. Sodium bicarbonate, brine, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo, to give (rac)-N-methoxy-N-methyl-3-oxocyclopentanecarboxamide as a yellow oil which was used without further purification. 1H NMR (400 MHz, CDCl3-d) δ ppm 3.74 (s, 3 H), 3.41-3.61 (m, 1 H), 3.23 (s, 3 H), 2.52-2.64 (m, 1 H), 2.34-2.50 (m, 2 H), 2.08-2.31 (m, 3 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][O:6][C:7]1[C:8]([CH:23]=C)=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.CC1C=CC=C(C)N=1.I([O-])(=O)(=O)=[O:43].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:8]1[C:7]([O:6][CH2:5][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:3][CH:2]([CH3:1])[CH3:33])=[CH:22][C:11]2[N:12]([CH3:21])[C:13](=[O:20])[C:14]3[C:19]([C:10]=2[CH:9]=1)=[CH:18][CH:17]=[N:16][CH:15]=3)=[O:43]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(C)C[C@@H](COc1cc2c(cc1C=O)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
A mixture of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-9-vinyl-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (300 mg, 0.664 mmol) (prepared as described in Example 46, Part A) osmium tetroxide (2.5% in 2-methyl-2-propanol) (4.17 μl, 0.013 mmol), and 2,6-dimethylpyridine (0.155 mL, 1.329 mmol) in 1,4-dioxane (5 mL) and water (2 mL), cooled to 0° C., was stirred for 15 min. Sodium metaperiodate (568 mg, 2.66 mmol) was added and the reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was filtered through diatomaceous earth (Celite®), eluting with EtOAc. The EtOAc layer was washed with saturated aqueous NaHCO3, H2O, then brine. The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/petroleum ether) to afford (S)-tert-butyl (1-((9-formyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (160 mg, 0.353 mmol, 53% yield) as a gummy solid. LC/MS (ESI) m/e 454.1, [(M+H)+, calcd for C25H32N3O5, 454.2].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:26]#[C:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: ClCCl
Product: CN1Cc2c(C#Cc3ccccc3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 20 hours with 1.12 g (11 mmol) of phenylacetylene, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 20 ml of diethylamine. The reaction mixture was diluted with methylene chloride and washed twice with water. The organic phase was dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(phenylethynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 205°-206°.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a solution of 2-hydroxy-2-methylpropanoic acid (500 mg, 4.80 mmol) in dry THF (10 ml), NaH (60% dispersion in mineral oil, 192 mg, 4.80 mmol) was added portionwise at 5° C. The resulting mixture was stirred 1 hour at RT. The solvent was removed, the residue was suspended in dry DMF (7 ml), and (bromomethyl)benzene (821 mg, 4.80 mmol) was added followed by a catalytic amount of KI. The reaction was heated under microwave irradiation at 100° C. for 3 hours. After cooling, the solvent was evaporated and the residue was partitioned between water and EtOAc; the organic phase was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc/petroleum ether=1/1) affording benzyl 2-hydroxy-2-methylpropanoate as a yellow liquid (773 mg, 3.98 mmol, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[CH:16])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.I[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(N)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:16]#[C:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:21][CH:22]=1
Reactant: Nc1ccc(I)cc1
Reactant: C#CCCN1CCC(Cc2ccc(Cl)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1ccc(C#CCCN2CCC(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 11.7 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-1-(but-3-yn-1-yl)piperidine (318 mg, 1.21 mmol) and 4-iodoaniline (265 mg, 2.19 mmol) in 10 mL of butylamine is added 70 mg of Pd(PPh3)4. The resulting solution is allowed to reflux for 24 hr. The solvent is evaporated in vacuo and the residue is purified by flash chromatography giving the title product as a brown oil (50 mg, 12%): 1H NMR (CDCl3) 1.24 (m, 2 H), 1.44 (m, 1 H), 1.58 (m, 2 H), 1.96 ( m, 3 H), 2.15 (m, 2 H), 2.55 (m, 4 H), 2.89 (m, 2 H), 3.75 (bs, 2 H), 6.53 (d, J=6.0 Hz, 2 H), 7.05 (m, 2 H), 7.20 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8]CC)=[O:7].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C)(C)Oc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(Oc1cc([N+](=O)[O-])ccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-nitrophenoxy)-2-methylpropionate (compound obtained in Reference Example 62(1); 332 mg) in tetrahydrofuran (1 mL)-ethanol (2 mL) was added an aqueous 5N sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 6N HCl (3 mL) and the mixture was extracted with diethylether. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2-(2-bromo-5-nitrophenoxy)-2-methylpropionic acid (297 mg) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19].C1(=O)[NH:25]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.C(OCC)(=O)C.C1(=O)NC(=O)C2=CC=CC=C12.[K]>[NH2:25][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(CBr)c([N+](=O)[O-])c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccc(CN)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.9 %

Procedure:
A mixture of compound 65b (1.08 g, 3.11 mmol) and potassium phthalimide (0.634 g) in DMF (10 mL) was stirred at rt overnight. Additional potassium phthalimide (0.063 g) was added and stirring was continued for 4 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried, and concentrated. The residue was dissolved in ethanol (20 mL) and hydrazine (0.34 mL) was added. The reaction mixture was refluxed for 1 h, and then cooled and filtered. The filtrate was concentrated to give compound 65c (1.04 g). ESI-MS m/e 282 (M+1).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[C:14](=[S:16])=[S:15].Br[CH2:18][CH2:19][CH2:20]Br>CN(C)C=O>[S:15]1[CH2:20][CH2:19][CH2:18][S:16][C:14]1=[C:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5]
Reactant: S=C=S
Reactant: BrCCCBr
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)C(C(C)=O)=C1SCCCS1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2,4-pentanedione (10.5 ml) in dimethylformamide (200 ml) was added potassium carbonate (42.5 g) then carbon disulfide (9.3 ml). To the resulting mixture was added 1,3-dibromopropane, dropwise over 40 min. The mixture was stirred at ambient temperature under a nitrogen atmosphere for 20 hrs. then ice/water (200 ml) was added and the suspension was stirred for 1 hr. The solid was collected by filtration, washed with water and then recrystallised from ethanol to give the sub-title compound as a solid (23.3 g).
Reaction SMILES: COC(=O)[C:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[CH:5]N(C)C.[CH3:18][NH:19][C:20](=[O:28])[CH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1.[CH3:29][OH:30].[H-].[Na+]>CN(C)C=O>[OH:30][C:29]1[N:19]([CH3:18])[C:20](=[O:28])[C:21]([C:22]2[S:23][CH:24]=[C:25]([CH3:27])[N:26]=2)=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1
Reactant: CO
Reactant: CNC(=O)Cc1nc(C)cs1
Reactant: COC(=O)C(=CN(C)C)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(-c3nc(C)cs3)c(=O)n(C)c2O)cc1
Temperature: 0 °C

Procedure:
Methyl-3-dimethylamino-2-(4-methoxyphenyl)propenoate (1.6 g), N-methyl-2-(4-methylthiazol-2-yl)acetamide (1 g) and methanol (0.28 cm3) were dissolved in N,N-dimethylformamide (30 cm3) and cooled to 0° C. under N2. Sodium hydride (60% suspension in oil, 0.28 g) was added and the mixture heated at 80° C. for 18 h. The mixture was cooled, partitioned between ethyl acetate (200 cm3) and water (200 cm3). The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (3×100 cm3) which was dried (MgSO4) and evaporated. The crude solid was recrystallised from ethyl acetate/ether to yield pure 6-hydroxy-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one (0.3 g). δH (250 MHz; CDCl3); 2.37 (3H, s), 3.48 (3H, s), 3.83 (3H, s), 6.37 (1H, s), 6.92 (2H, d, J 8.7 Hz), 7.33 (1H, s) and 7.53 (2H, d, J 8.7 Hz); m/z (ESP+) 329 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH2:24][C:25]([O:27][CH3:28])=[O:26])([NH:8][C:9]([C:11]2[O:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:3]1.[CH3:29][I:30]>>[I-:30].[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:4]1([NH:8][C:9]([C:11]2[O:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:5][CH2:6][CH2:7][N+:2]([CH3:29])([CH3:1])[CH2:3]1
Reactant: COC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCCN(C)C1
Reactant: CI
Product: COC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCC[N+](C)(C)C1
Product: [I-]

Procedure:
According to the method described in example 2a, methyl 2-(1-methyl-3-(5-phenethyl-furan-2-carboxamido)piperidin-3-yl)acetate was reacted with methyl iodide to give the title compound as a white solid (quantitative). MS ESI 399.2 [M]+, calcd for [C23H31N2O4]+ 399.21.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH:18]([C:20]([CH2:22][CH3:23])=[O:21])=[CH2:19].N12CCCN=C1CCCCC2>O1CCCC1.CCOC(C)=O>[CH2:1]([C:5]1([CH2:19][CH2:18][C:20](=[O:21])[CH2:22][CH3:23])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[C:11]=2[CH3:14])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: C=CC(=O)CC
Reactant: CCCCC1Cc2c(ccc(OC)c2C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC1(CCC(=O)CC)Cc2c(ccc(OC)c2C)C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of 2-butyl-5-methoxy-4-methyl-1-indanone (100 mg, 0.43 mmol) in tetrahydrofuran (0.43 mL) was treated with ethyl vinyl ketone (EVK, 0.064 mL, 0.646 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.013 mL, 0.086 mmol). The resulting solution was stirred under a nitrogen atmosphere and heated in an oil bath at 60° C. After 24 hour, more EVK (0.064 mL) and DBU (0.013 mL) were added and the solution was heated an additional 24 hours at 60° C. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) containing 2N HCl (1 mL). The organic phase was washed with brine (5 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide crude 2-butyl-5-methoxy-4-methyl-2-(3-oxopentyl)-1-indanone.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(Cl)=[S:14]>C1COCC1>[SH:14][C:13]1[O:12][C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=2[N:1]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: S=C(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(S)oc2c1
Reaction time: 4 h

Procedure:
To a stirred solution of methyl 4-amino-3-hydroxybenzoate (4.45 g, 26.6 mmol) in THF (250 ml) at room temperature, thiophosgene (2.4 mL, 32 mmol) was added slowly via a syringe pump over a period of 1 hr. After stirring for 4 hr, excess thiophosgene was quenched by addition of a saturated aqueous solution of NH4Cl (100 mL), and the THF was removed by evaporation under reduced pressure. More water was added, and the aqueous mixture was extracted with EtOAc (3×). The Combined organic phase was washed with brine, dried (MgSO4), concentrated in vacuo to give Compound 4 as a tan solid. LC-MS, M+1=210
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].C(=O)([O-])[O-].[K+].[K+].[C:18](OCC)(=[O:26])[C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[C:18]([OH:26])=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11]1
Reactant: NNc1cc(F)ccc1F
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)n(-c2cc(F)ccc2F)n1
Temperature: 0 °C
Yield: 61.1 %

Procedure:
To a solution of (2,5-difluorophenyl)hydrazine hydrochloride (25.0 g) in ethanol (500 mL) were added potassium carbonate (38.3 g) and diethyl but-2-ynedioate (23.6 g). After refluxing for 18 hr, the mixture was cooled to 0° C. and acidified with 6 mol/L hydrochloric acid. Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixed solvent of ethyl acetate and diisopropyl ether, and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound as a pale-yellow solid (yield 22.7 g, yield 61%).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][C@@H:6]([C:18](O)=[O:19])[CH2:5]1)=[N+:2]=[N-:3].ClC(OCC(C)C)=O.CN1CCOCC1>C(COC)OC>[N:1]([C@@H:4]1[C@@H:9]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:8][CH2:7][C@@H:6]([CH2:18][OH:19])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C[C@@H]1N=[N+]=[N-]
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C[C@@H]1N=[N+]=[N-]
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
(1R,3S,4S)-3-Azido-4-(N-tert-butoxycarbonyl-amino)cyclohexane-1-carboxylic acid (1.86 g) was dissolved in dimethoxyethane (20 ml), and to the solution isobutyl chloroformate (1.02 ml) and N-methylmorpholine (860 mg) were added at −15° C. The mixture was stirred for 10 minutes at the same temperature. The hydrochloride of N-morpholine deposited was separated by filtration, and an aqueous solution (4 ml) of sodium borohydride (370 mg) was added to the filtrate to stir the mixture for 10 minutes. After water was added, and the solvent was distilled off under reduced pressure, the residue was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane 1:1) to obtain the title compound (1.35 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH2:15][C:16]([NH:18][C:19]1([C:27]([O:29]C)=O)[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]1)=[O:17].CN(C)C(=O)C.CC(C)([O-])C.[K+].[ClH:43]>O>[Cl:43][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:15]1[C:16](=[O:17])[NH:18][C:19]2([CH2:20][CH2:21][C:22]([F:25])([F:26])[CH2:23][CH2:24]2)[C:27]=1[OH:29]
Reactant: Cl
Reactant: COC(=O)C1(NC(=O)Cc2cc(-c3ccc(Cl)cc3)ccc2Cl)CCC(F)(F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1NC2(CCC(F)(F)CC2)C(O)=C1c1cc(-c2ccc(Cl)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.20 g (5.74 mmol) of the compound from Example 8A were initially charged in a solution of 14 ml of DMA (N,N-dimethylacetamide), a solution of 9 ml of DMA and 1.69 g (2.5 eq.) of potassium tert-butoxide was added dropwise at 20° C. and the mixture was stirred at room temperature for 4 h. The mixture was poured into 200 ml of water and the reaction was adjusted to pH 2 using concentrated aqueous hydrochloric acid, and the resulting residue was filtered off with suction. Purification by flash column chromatography (silica gel; ethyl acetate/n-hexane 1:1) gave 1.50 g (52% of theory) of the title compound of melting point m.p. 156° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].O.[CH2:14]([OH:17])[CH2:15][OH:16]>>[Cl:8][C:6]1[C:5]([O:16][CH2:15][CH2:14][OH:17])=[N:4][C:3]([F:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: OCCO
Reactant: Fc1nc(F)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOc1nc(F)c(Cl)cc1Cl

Procedure:
To a solution of 12 grams (0.065 mole) of 3,5-dichloro-2,6-difluoropyridine in 35 milliliters of ethylene glycol was added over a 10 minute period 2.7 grams of anhydrous sodium hydroxide in 40 milliliters of ethylene glycol. The reaction mixture was maintained at ~70° C. with agitation for 10 minutes, cooled and poured into water. The insoluble material is removed by filtration and the filtrate extracted with methylene chloride and dried. The solid 2-(3,5-dichloro-6-fluoro-2-pyridyloxy) ethanol product was crystallized from hexane and recovered in a yield of 9 grams (61 percent of theoretical). The product melted at 65°-67° C. and was found by analysis to have carbon, hydrogen, chlorine and nitrogen contents of 37.4, 3.1, 31.5 and 6.4 percent, respectively, as compared with the theoretical contents of 37.2, 2.7, 31.4 and 6.2 percent, respectively, calculated for the above-named compound.
Reaction SMILES: C1C(C(N)=N)=CC=C(O[CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH2:23])=[NH:22])=[CH:19][CH:20]=2)C=1.[CH:24]1[C:29]([C:30]([NH2:32])=[NH:31])=[CH:28][C:27](Br)=[C:26]([O:34][CH2:35][CH2:36]COC2C=CC(C(N)=N)=CC=2Br)[CH:25]=1.C1C(C(N)=N)=CC=C(OCCCCCCOC2C=CC(C(N)=N)=CC=2)C=1>N[C@H](C(O)=O)CC(C)C>[CH:28]1[C:29]([C:30]([NH2:32])=[NH:31])=[CH:24][CH:25]=[C:26]([O:34][CH2:35][CH2:36][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH2:23])=[NH:22])=[CH:17][CH:16]=2)[CH:27]=1
Reactant: N=C(N)c1ccc(OCCCOc2ccc(C(=N)N)cc2)cc1
Reactant: N=C(N)c1ccc(OCCCOc2ccc(C(=N)N)cc2Br)c(Br)c1
Agent: CC(C)C[C@H](N)C(=O)O
Agent: N=C(N)c1ccc(OCCCCCCOc2ccc(C(=N)N)cc2)cc1
Product: N=C(N)c1ccc(OCCCCCOc2ccc(C(=N)N)cc2)cc1

Procedure:
Efflux pump inhibitory activity of propamidine, dibromopropamidine, and hexamidine was confirmed in Leu-Nap accumulation assays. The uptake of Leu-Nap (100 μg/ml) by PAM1723 (FIGS. 10A, C, and E) or PAM1626 (FIGS. 10B, D, and F) cells was studied in the presence of various concentrations of propamidine (0 μg/ml to 160 μg/ml), dibromopropamidine (0 to μg/ml to 40 μg/ml), and hexamidine (0 μg/ml to 40 μg/ml), respectively. All three compounds were capable of completely inhibiting the MexAB-OprM-mediated efflux of Leu-Nap from the strain overexpressing this pump. The rate of Leu-NAp uptake into PAM1626, and PAM1723, in the presence of 160 μg/ml propamidine, 20 μg/ml of dibromoproapmidine, and 20 μg/ml of hexamidine was the same.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9]N1C(=O)CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In methylene chloride (200 ml) was dissolved 2-fluoroaniline (51.0 g) and, under cooling at 0° C. and stirring N-bromosuccinimide (81.7 g) was added in small installments over a period of an hour. The mixture was further stirred for 20 minutes, after which it was washed with cold water and dried over anhydrous sodium sulfate. The methylene chloride layer was concentrated and the resultant oil was distilled under reduced pressure. By the above procedure, there was obtained 2-fluoro-4-bromoaniline as an oil boiling at 75°-80° C./0.3 mmHg.