Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)Nc1ccccc1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (4.6 g, 0.037 mole) was added dropwise (slowly) to a stirred and chilled (10°-15° C.) solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.035 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of aniline (3.5 g, 0.038 mole) and triethylamine (7.6 g, 0.076 mole) in anhydrous dimethylformamide (75 ml). The reaction was stirred at room temperature overnight, poured into water (500 ml), allowed to precipitate, and filtered. The filter cake was twice suspended in potassium bicarbonate solution (250 ml) and filtered. The filter cake was washed with water, air dried, and recrystallized from ethanol, giving 4.74 g (37%) of off-white needles, mp 211°-212° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5].C(N(CC)CC)C>O>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH:2]=[O:1]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Temperature: -65 °C
Reaction time: 0.42 h
Yield: 100 %

Procedure:
A solution of oxalyl chloride (4.68 g, 0.037 mol) in dry CH2Cl2 under argon atmosphere was cooled to-65° C. A solution of dimethyl sulfoxide (DMSO) (5.33 ml) in CH2Cl2 (17 ml) was added rapidly, dropwise, to the cooled oxalyl chloride solution. After stirring for 7 minutes at -65° C., a 10 ml CH2Cl2 solution of (E,E)-farnesol (7.0 g, 0.032 mol) was added over 10 minutes to the reaction solution at -65° C.: a precipitate formed upon the addition of approximately half of the farnesol solution. After the addition of the farnesol solution was completed, the reaction was stirred at -65° C. for 25 minutes, and then 22.4 ml (0.16 mol) of triethylamine was added over 10 minutes. After stirring for an additional 15 minutes at -65° C., the reaction was warmed to room temperature, and then diluted with water (~200 ml). The resulting aqueous layer was extracted several times with CH2Cl2. The combined organic layers were washed once with saturated aqueous NaCl solution once with 1% HCl, once with 5% Na2CO3 solution and once with saturated aqueous NaCl solution. The resulting organic layer was dried over MgSO4 to give 7.05 g (100%) of a clear oil after filtration and solvent removal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH2:8][OH:9])[CH:7]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: Cc1ccc(Br)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1ccc(Br)cc1C=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of INT 29 (19.3 g, 96 mmol) in dioxane (800 mL) was added manganese dioxide (50.2 g, 577 mmol). The reaction mixture was stirred at 80° C. for 3 h. The mixture was filtered over Celite and the filtrate was concentrated to give INT 30.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)[C:5]([O:7][CH3:8])=[O:6].O.C[N+]1([O-])CC[O:22]CC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[O:22])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CON=C(C(=O)OC)c1ccccc1CBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1C=O
Yield: 58.1 %

Procedure:
20 g (0.070 mol) of methyl 2-(bromomethyl)phenylglyoxylate O-methyloxime, 32 g (0.237 mol) of N-methylmorpholine N-oxide monohydrate and 300 ml of CCl4 are mixed and heated to reflux. After refluxing for 9 hours, the mixture is filtered, and the organic phase is washed with water and with 2 N hydrochloric acid, dried and concentrated. The residue is recrystallized from pentane. 9.0 g of product (58%) are obtained as colorless crystals.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1Br)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>COCCOC>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:37])[F:36])[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 84.3 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid-t-butyl ester (5.1 g, 16.71 mmol) in DME (60 ml)/2M Na2CO3 (29.25 ml, 58.50 mmol) was treated with 2-trifluoromethoxyphenylboronic acid (5.16 g, 25.08 mmol), and Pd[PPh3]4 (3.87 g, 3.33 mmol) in a microwave oven at 150° C. for 15 min. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with 1N NaOH and brine, then dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 8-10% ethyl acetate/hexanes gradient to afford 4.65 g of colorless oil (t-butyl ester). This material was dissolved in 4N HCl/dioxane (40 ml) and stirred at 60° C. for 2 h and then at rt overnight. Concentration under reduced pressure afforded the product as colorless oil (4.17 g, 24%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][C:2]1=[O:8].CC(O)=O.CN.Cl.[BH3-][C:17]#[N:18].[Na+]>CO>[CH3:17][NH:18][CH:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:8])[CH2:3]1
Reactant: O=C1CCNC(=O)C1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC1CCNC(=O)C1
Reaction time: 2 h
Yield: 81 %

Procedure:
Piperidine-2,4-dione (2.0 g, 25.126 mmol, 1.0 eq.) was dissolved in MeOH (20 ml); AcOH (0.1 ml) and CH3NH2.HCl (2.37 g, 35.398 mmol, 2.0 eq.) were added and stirring was carried out for 2 hours at RT. NaCNBH3 (3.29 g, 53.097 mmol, 3.0 eq.) was added in portions at 0° C. and the mixture was stirred for 14 hours at RT. After monitoring by TLC, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was used in the next stage without being purified further. Yield: 81% (1.814 g, 14.173 mmol)
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.3 g, 1.085 mmol) in dry DCM (20 mL) were added tert-butyl 4-(aminooxy)piperidine-1-carboxylate 26 (0.29 g, 1.302 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.22 g, 1.63 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.63 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 4-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 27 (0.5 g, 98%) as a clear thick oil.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CN(C)C=O.O>[CH2:1]([CH:3]([C:6]1[C:14]2[N:13]([CH2:30][C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CC(C)OC(=O)CBr
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1cccc2c1n(CC(=O)OC(C)C)c(=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (23.2 g, 76.2 mmol) in N,N-dimethylformamide (120 mL) was added potassium carbonate (11.6 g, 83.9 mmol) and isopropyl bromoacetate (10.9 mL, 83.9 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 mL). The organic layer was washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude tert-butyl 4-(1-ethylpropyl)-3-(2-isopropoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]C)=O.[NH2:11][C:12]([NH2:14])=[S:13].[OH-].[K+]>C(O)C.O>[SH:13][C:12]1[N:11]=[C:7]([OH:9])[C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[N:14]=1
Reactant: NC(N)=S
Reactant: COC(=O)C1CCCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1nc(S)nc2c1CCC2
Yield: 26.4 %

Procedure:
To a solution of the methyl 2-oxocyclopentanecarboxylate (40 g, 281 mmol) and thiourea (21 g, 281 mmol) in ethanol (200 ml) was added KOH (20 g, 356 mmol) in water (120 ml). The mixture was refluxed for 12 hour. The solvent was removed and the residue was quenched with concentrated HCl (25 mL). The precipitate was filtered, washed with water and dried to afford the 2-mercapto-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (12.5 g, 26%). MS (APCI+) [M+H] +168.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([C:14](OCC)=[O:15])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>C(O)C>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of ethyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate (2 g, 7 mmol) in ethanol (70 mL) in an ice bath was added sodium borohydride (1.06 g, 28 mmol) portionwise. The resulting mixture was stirred at room temperature for 1.5 hours, which was then quenched with saturated ammonium chloride aqueous solution. Solvent was removed from the mixture under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was then dried over sodium sulfate, and solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:Hexanes=2:3) to afford {5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl}methane-1-ol.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([OH:17])[C:14]=2[CH3:16])[O:9][C:5]2([CH2:8][CH2:7][CH2:6]2)[CH2:4]1.[BH4-].[Na+].O>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(O)(=O)C>[NH2:1][CH2:2][C:3]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([OH:17])[C:14]=2[CH3:16])[O:9][C:5]2([CH2:6][CH2:7][CH2:8]2)[CH:4]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(O)(CN)CC1(CCC1)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)C(CN)=CC1(CCC1)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A solution of 4-(aminomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol (277 mg) in DCM (10 mL) was slowly added to sodium borohydride (200 mg) in 4 mL of TFA-acetic acid, 1:1 at 0° C. The mixture was stirred at 0° C. for 2 h then poured into water and separated the DCM. The DCM was dried and evaporated. The residue was purified by silica gel column eluting with 7.5% MeOH in DCM to give 4-(aminomethyl)-5,7,8-trimethylspiro[chromene-2,1′-cyclobutan]-6-ol (55 mg). 1H-NMR (300 MHz, CDCl3): δ=6.12 (s, 1H), 3.78 (s, 2H), 2.34-1.70 (3s+m, 18H) ppm. 13C-NMR (75 MHz, CDCl3): δ146.59, 145.56 137.14, 128.02, 124.51, 123.45, 120.62, 117.21, 76.24, 45.56, 36.07, 14.65, 12.85, 12.56, 12.33 ppm. MS: (m/z): 260 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=O)[CH:12]=[O:13]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[NH:9][C:12](=[O:13])[CH:11]=[N:10]2
Reactant: O=CC(=O)O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCO
Product: O=c1cnc2cc(Cl)c(Cl)cc2[nH]1
Yield: 90.4 %

Procedure:
4,5-Dichloro-1,2-phenylenediamine (25 g, 141.2 mmol) was suspended in 780 ml EtOH, and 13 g (142.0 mmol) of glyoxylic acid (HO2CCOH/H2O) was added. The mixture was heated at reflux for 3 hours, and then cooled and filtered, yielding 27.45 g of 6,7-dichloroquinoxalin-2-one as a solid. The product (25 g, 116.3 mmol) and 230 ml (911.7 mmol) of phosphorus oxychloride (POCl3) were stirred at reflux (100° C.) for 3 hours. The mixture was cooled and ice/H2O added. The resulting brown/grey solid was filtered, and dried in an oven, yielding approximately 25 g of 2,6,7-trichloroquinoxaline
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:27]Br.[OH-].[Na+]>C(Cl)(Cl)Cl.O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[C:14]([Br:27])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2)CC1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 4-(1-phenyl-methylene)-piperidine-1-carboxylic acid tert-butyl ester (30.0 g, 0.11 mol) in CHCl3 (300 mL) containing K2CO3 (22.5 g, 0.16 mol) was added a solution of Br2 (5.9 mL, 0.16 mol) in CHCl3 (50 mL) at 0° C. over 1 h. The mixture was allowed to stir for 1 h at room temperature and then it was diluted with water, the layers were separated and the aqueous phase extracted with CH2Cl2. The combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated. The residue was dissolved in MeOH (300 mL) and a solution of NaOH (75 g, 1.88 mol) in H2O (250 mL) was slowly added, followed by another 100 mL of MeOH to maintain homogeneity. The mixture was heated at 40° C. for 4 hours and then most of the MeOH was removed in vacuo and the mixture was extracted with EtOAc (×3). The combined organic layers were washed, (H2O, brine), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (SiO2/hexane-EtOAc, 4:1) to afford the product (36.2 g, 94%) as a yellow-orange solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].Cl[C:14]1C=CC=CC=1C(C)C(O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: CC(C(=O)O)c1ccccc1Cl
Reactant: COc1ccccc1CC(=O)O
Product: COc1ccccc1C(C)C(=O)O
Yield: 39 %

Procedure:
The titled compound was prepared from o-methoxyphenylacetic acid in 39% yield in the same manner as the preparation of 2-(2-Chlorophenyl)propionic acid in Example 184a.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)C(=O)[O:18][N:17]=2)=[N:13][O:14][N:15]=1.[S:30](N)([NH2:33])(=[O:32])=[O:31].N1C=CC=CC=1.[OH-].[Na+]>C(O)(=O)C>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]([C:12]2[C:11]([CH2:10][CH2:9][NH:8][S:30](=[O:32])(=[O:31])[NH2:33])=[N:15][O:14][N:13]=2)=[N:17][OH:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: NCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Reactant: NS(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: NS(=O)(=O)NCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of 3-[4-(2-aminoethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4h)-one trifluoroacetate (23.0 mg, 53.0 mmol), sulfamide (15.0 mg, 160 mmol) and pyridine (1.0 mL) was heated at 120° C. for 3 min in a microwave. To the reaction solution was added 0.5 mL 1 N NaOH and stirred for 30 min. The reaction solution was then acidified with acetic acid and purified by preparative LCMS to give the desired product (12 mg, 46%). MF=C11H12ClFN6O4S; LCMS calculated for C11H13ClFN6O4S (M+H)+: m/z=379.0. 1H NMR (400 MHz, DMSO-d6): d 11.52 (s, 1 H), 10.45 (s, 0.1 H), 9.05 (s, 0.1 H), 8.98 (s, 1 H), 7.95 (m, 0.1 H), 7.32 (m, 0.2 H), 7.15 (t, J=9.0 Hz, 1 H), 7.00 (dd, J=6.5 Hz, 2.7 Hz, 1 H), 6.76 (t, J=5.9 Hz, 1 H), 6.65 (m, 1 H), 6.59 (s, 2H), 3.29 (m, 2 H), 3.07 (t, J=7.2 Hz, 2 H);
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(N(CC)C(C)C)(C)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][C:22](=[O:23])[CH2:21][Br:20]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(NC(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a stirred solution of 2,4,6-trimethylaniline (1 g, 7.40 mmol) in methylene chloride (25 mL) at -50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound (1.51 g, 80%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12]I>O1CCCC1>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1cccnc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cccnc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (2-bromopyridin-3-yl)methanol (20 g, 106.37 mmoles) in 140 mL of tetrahydrofuran is added 60% sodium hydride in mineral oil (6.38 g, 155.5 mmol) at 0° C. under nitrogen atmosphere. Solution is stirred at 0° C. for 30 minutes. Methyl iodide (7.95 mL, 127.6 mmol) is added over the solution and the mixture is stirred at room temperature overnight. The mixture is quenched by addition of water and the crude is extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate and solvent evaporated in vacuo to afford 2-bromo-3-(methoxymethyl)pyridin in a 98% yield that is used with no further purification. MS (m/z): 202 (M+1), 204 (M+3).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH:19]4[CH2:27][CH2:26][CH:22]3[CH2:21][CH2:20]4)[C:17]=2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:11]([CH3:35])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH:19]4[CH2:27][CH2:26][CH:22]3[CH2:21][CH2:20]4)[C:17]=2[O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])=[C:11]([CH3:35])[CH:10]=1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(CC3)C2C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(O)cc(C)c1C1=C(OC(=O)C(C)(C)C)C2C3CCC(CC3)C2C1=O

Procedure:
To a solution of 2,2-dimethylpropionic acid 2-(4-benzyloxy-2,6-dimethylphenyl)-3-oxo-3a,4,5,6,7,7a-hexahydro-3H-4,7-ethanoinden-1-yl ester (2.8 g, 0.006 mol) in methanol (250 ml) is added 10% palladium on carbon (0.50 g), and the suspension is stirred under a 4 bar hydrogen pressure for 5 hours. The reaction mixture is then filtered through a pad of diatomaceous earth and the filtrate is evaporated under reduced pressure. The crude product is triturated with diethyl ether to afford 2,2-dimethylpropionic acid 2-(4-hydroxy-2,6-dimethylphenyl)-3-oxo-3a,4,5,6,7,7a-hexahydro-3H-4,7-ethanoinden-1-yl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[CH3:9][NH:10][O:11][CH3:12].N1C=CC=CC=1>C(Cl)Cl.CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([N:10]([CH3:9])[O:11][CH3:12])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: CON(C)C(=O)CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 4-chlorobutanoyl chloride (5.64 g, 40.0 mmol) and a N,O-dimethylhydroxylamine hydrochloride (3.91 g, 40.0 mmol) in CH2Cl2 (80 mL) at 0° C., was added pyridine (7.2 ml, 88.0 mmol) in CH2Cl2 (30 mL). This mixture was kept stirring at 0° C. for 1 h, then warmed to rt. The reaction mixture then diluted with Et2O (200 mL), washed with saturated 1N HCl (2×), saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless oil (6.28 g, 95%). MS (ES+) m/e 166 [M+H]+.