Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCOP(=O)(OCC)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: O=CO
Product: CCOP(=O)(OCC)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of diethyl 4-nitrophenylphosphonate (1.07 g, 4.13 mmol, 1.00 equiv), TEA (3 mL), Palladium carbon (0.025 g). This was followed by the addition of formic acid (2 mL) dropwise with stirring at room temperature. The resulting solution was heated to reflux for 3 hr. The reaction was then quenched by the addition of 5 mL, of water and the solids were filtered out. The resulting filtrate was extracted with 5×10 mL, of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. This resulted in 800 mg (85%) of diethyl 4-aminophenylphosphonate as a white solid.
Reaction SMILES: C[O:2][CH:3](Cl)Cl.[CH2:6]([Br:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Br:14][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:3]=[O:2])=[CH:10][CH:9]=1
Reactant: BrCCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of dichloromethyl methyl ether (62 ml) in methylene chloride (40 ml) was added titanium tetrachloride (75 ml) over 10 minutes under a nitrogen atmosphere at 4-5° C. Then, a solution of phenethyl bromide (85 ml) in methylene chloride (50 ml) was added thereto over 50 minutes at 5-7° C. and the mixture was stirred for 5 hours while gradually raising the temperature of the mixture to room temperature. Water (200 ml) was added to the reaction mixture over 1 hour and the mixture was extracted with chloroform (200 ml). The chloroform layer was washed with water, a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (167 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=20:1) to give 4-(2-bromoethyl)benzaldehyde (32.3 g) as a yellow solid, melting point 50-52° C.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([O-:4])=[O:3].[C:13](OCC)(=[O:19])[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>O.C(O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[CH2:12][C:13](=[O:19])[C:14]([OH:16])=[O:15]
Reactant: Cc1cccc([N+](=O)[O-])c1C
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
Sodium (3.802 g, 165.38 mmol, 2.5 eq) was added portionwise into ethanol (66 mL, 1M) at 0° C. Next, 3-nitro-ortho-xylene (10.00 g, 66.15 mmol, 1 eq) and diethyl oxalate (19.33 g, 132.23 mmol, 2 eq) were added. The mixture was stirred at room temperature for 18 hours and then refluxed for 10 minutes. 1N sodium hydroxide and water were added and the reaction was stirred for one hour. The ethanol was removed under vacuum. Water was added and the aqueous solution was acidified with concentrated hydrochloric acid to ph~2. The mixture was extracted with methylene chloride. The extracts were dried (magnesium sulfate) and concentrated to give the title compound (9.0 g, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 76.3 %

Procedure:
A mixture of methyl piperidine-4-carboxylate (2.70 g), 1-fluoro-4-nitrobenzene (6.00 g) and triethylamine (6.80 g) in acetonitrile (60 mL) was refluxed overnight, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (3.80 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:11][O:12][C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 150 °C
Yield: 37.4 %

Procedure:
To a solution of 4-fluoronitrobenzene (0.70 g, 4.96 mmol) in THF (8 mL) was added piperadine-4-carboxylic acid methyl ester (0.71 g, 4.96 mmol) and diisopropylethylamine (0.66 g, 5.11 mmol). The mixture was heated in a microwave oven at 150° C. for 1.5 hr. The resulting mixture was extracted with ethyl acetate and hydrochloric acid (0.2 N). The organic layer was washed with brine and concentrated sodium bicarbonate solution. After the evaporation of solvents, the residue was purified through a Biotage flash column chromatography using ethyl acetate and hexanes (1:1 ratio) to give a yellow solid as 1-(4-nitrophenyl)-piperidine-4-carboxylic acid methyl ester (490 mg). 1H-NMR is consistent with the structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H].O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=C1COCCN1c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1ccc(N2CCOCC2=O)cc1
Temperature: 40 °C

Procedure:
60 g (0.27 mol) of 4-(4-nitrophenyl)-3-morpholinone (VII) are suspended in 480 g of ethanol, admixed with 3 g of palladium on activated carbon (5%) and contacted with 5 bar of hydrogen at 80° C. for one hour. After hydrogenation has ended, the suspension is admixed with 80 g of ethanol and 270 g of water and heated to 40° C., and the catalyst is filtered off. The solution is concentrated under reduced pressure and the remaining solid is dried to constant weight at 50° C. under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(COc1ccc(F)cc1)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
A solution of p-fluorophenol (28.1 g., 0.25 mole) is DMF (30 ml.) is added dropwise to a suspension of hexane (2 × 30 ml.)-prewashed sodium hydride (50% oil dispersion, 12.5 g., 0.26 mole) in DMF (120 ml.). The resulting mixture is stirred at room temperature for 10 minutes, treated with bromoacetaldehyde diethyl acetal (49.3 g., 0.25 mole) and finally heated on a steam bath for 4 hours. The reaction mixture is allowed to come to room temperature and the precipitated sodium bromide is filtered off. DMF is then removed on a rotary evaporator, the oil residue is diluted with acetone (100 ml.) and another quantity of sodium bromide is precipitated which again is removed by filtration. The filtrate is then concentrated on a rotary evaporator leaving an oil residue which is vacuum distilled at 85°/0.05 mm to yield the desired product as colorless oil (46.7 g., 0.205 mole, 82%). Ir (neat) 3.4~3.5, 6.21, 6.64, 8.00, 8.25, 8.83, 9.32, 12.08, 13.20μ; pmr (CCl4) δ 1.17 (6H, t J=7.5Hz), 3.57 (2H, q, J=7.5 Hz), 3.61 (2H, q, J=7.5 Hz), 3.85 (2H, d, J=5Hz), 4.68 (1H, t, J=5Hz), 6.6-7.1 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH:7][NH2:8])=[O:6])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10]>C(Cl)Cl>[O:10]=[C:9]1[O:6][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[N:7][NH:8]1
Reactant: O=C(Cl)Cl
Reactant: CC1(C(=O)NN)CC1
Solvent: ClCCl
Product: CC1(c2n[nH]c(=O)o2)CC1

Procedure:
85 gm of 1-methylcyclopropane carboxylic acid hydrazide was added to methylene chloride on a 3-neck 2-liter round bottom flask. The system was first cooled to 0°-5° C. and 590.5 gm of a 12.5% solution of phosgene added dropwise over a period of time. The system was then heated at reflux for 7 hours. The methylene chloride was removed by stripping. The product was washed with petroleum ether and filtered to give 66.6 gm of 5-oxo-2-(1'-methylcyclopropyl)-1,3,4-oxadiazoline as light brown crystals, melting point 68°-70° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:19][S:20]([O:12][CH:10]1[CH2:11][N:8]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)(=[O:22])=[O:21]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -20 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
A 100 mL flask was charged with 1-diphenylmethylazetidin-3-ol (1.5 g, 6.27 mmol) and pyridine (15 mL). The solution was cooled to −20° C. and methane sulfonyl chloride (0.73 mL, 9.4 mmol) was added dropwise. The reaction mixture was stirred at −20° C. for 1 h and then left 3 days at 4° C. The solution was poured on ice and the resulting precipitate was filtered, washed 3 times with H2O and 3 times with pentane. The solid was dried under reduced pressure to give the title compound (1.92 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:13]2[CH2:16][CH:15]([OH:17])[CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH:12]([N:13]1[CH2:16][CH:15]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Methane sulphonyl chloride (0.5 mL, 6.43 mmol) was added to a solution of 1-(diphenylmethyl)-3-hydroxyazetidine (1.38 g, 5.77 mmol) and Et3N (0.9 mL, 6.46 mmol) in toluene (10 mL) at 0° C. The reaction mixture was stirred and warmed to room temperature overnight. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (100 mL). The organic layer was dried over MgSO4 and concentrated to give pale yellow oil (756 mg, 41%) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: CO
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 100 °C
Yield: 95 %

Procedure:
2-amino-3-nitrobenzoic acid 1 (5 g, 27.4 mmol) was dissolved in methanol (100 mL) and con H2SO4 was added. The mixture was heated at 100° C. for 12 h, concentrated to dryness and suspended in H2O (50 mL). The mixture was extracted with CH2Cl2 (50 mL), dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography to give 11 (5.1 g, 95% yield).
Reaction SMILES: CS([Cl:5])(=O)=O.CCN(CC)CC.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH2:20]O>C(Cl)Cl>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH2:20][Cl:5]
Reactant: COc1ccc([N+](=O)[O-])c(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(CCl)c1
Yield: 94.9 %

Procedure:
MsCl (1.9 mL, 24 mmol) was added to Et3N (4.5 mL, 32 mmol) and 5-methoxy-2-nitrobenzyl alcohol (1.48 g, 8.1 mmol) in CH2Cl2 (80 mL) and the ni-xture kept at reflux for 12 h. The solution was cooled, washed with dilute HCl (2N, 2×50 mL), dried (Na2SO4), concentrated, and filtered through a short column of silica (eluting with 9:1 petroleum ether:EtOAc) to give 5-methoxy-2-nitrobenzyl chloride as a yellow liquid (1.55 g, 95%). 1H N (CDCl3) δ 8.17 (d, J=9.1 Hz, 1 H, H-3), 7.20 (d, J=2.8Hz, 1 H, H-6), 6.93 (dd, J=9.1, 2.8 Hz, 1 H, H-4), 5.03 (s, 2 H, ArCH2Cl), 3.93 (s, 3 H, ArOCH3); 13C NMR (CDCl3) δ 163.7 (C-2), 140.7, 135.5, 128.2, 116.5, 113.7 (C-1,3,4,5,6), 56.1 (OCH3), 43.7 (CH2Cl); MS (EI) m/z 201 [70%, M+ (35Cl)], 184 (100%), 166 (60%, M - Cl), 156 (50%), 106 (70%); HRMS (EI) Calcd. for C8H8ClNO3 203.0163 (35Cl). Found 203.0165.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C(Cl)(Cl)Cl.C(O)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Clc1cnc2ccc(Br)cc2n1
Yield: 58 %

Procedure:
Heat benzene-1,2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethyl ester (20 mL) in ethanol (100 mL) at 120° C. for 18 h. Cool, filter the resulting precipitate, and wash with dry ether to give 1H-quinoxalin-2-one (6.7 g). Dissolve 1H-quinoxalin-2-one in acetic acid (300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h. Filter the resulting crystals and wash with ether to afford 7-bromo-1H-quinoxalin-2-one (7.2 g). Reflux 7-bromo-1H-quinoxalin-2-one in POCl3 (30 mL) for 18 h. Remove POCl3 in vacuo, dissolve the product in 3:1 chloroform/isopropyl alcohol, and wash the organic phase with saturated sodium bicarbonate. Dry over sodium sulfate and purify by silica gel flash chromatography eluting with dichloromethane to 10% methanol/90% dichloromethane to afford the title compound as a yellow solid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:23][CH:24]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)[C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.O=S(Cl)Cl>C(Cl)Cl>[C:11]1([C:9]2[N:10]=[C:6]([CH:5]3[CH2:4][CH2:3][CH2:2][N:23]3[CH:24]3[C:32]4[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[O:7][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc2c1CCC2NC(CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1CCC2N1CCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 57.8 %

Procedure:
To a solution of 1-[[4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.27 g) in CH2Cl2 (5 ml) was added SOCl2 (1 ml) at 0° C. After being stirred for 17 hours at room temperature, the solvent was evaporated in vacuo and the residue was dissolved in DMF (5 ml). To the mixture was added K2CO3 (2.07 g). After being stirred for 1 day at room temperature, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-2,3-dihydro-4-methoxy-1H-indene (0.15 g).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([OH:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[N:4]=1)[CH3:2].[OH-].[K+:38]>C(O)C>[CH2:1]([C:3]1[S:7][C:6](=[N:8][C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]([O-:18])=[O:17])=[O:10])[N:5]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:33][N:34]=[N:35][N:36]=3)=[CH:24][CH:25]=2)[N:4]=1)[CH3:2].[K+:38]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)O)CCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=NC(=O)C2=C(C(=O)[O-])CCC2)s1

Procedure:
To 206 mg of 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarboxylic acid, 8.3 ml of a 0.05N potassium hydroxide solution in ethanol and 50 ml of ethanol were added, followed by heating over water bath to dissolve completely. From the resulting solution, the solvent was distilled off under reduced pressure. To the residue, ethanol was added and the solid so precipitated was collected by filtration. The solid was dried under reduced pressure, whereby 180 mg of the title compound was obtained.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C@@H:16]([CH3:27])[CH2:15][NH:14]2.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>ClCCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:26])[C:22]([F:23])([F:25])[F:24])[C@@H:16]([CH3:27])[CH2:15][N:14]2[C:31]([CH:28]1[CH2:30][CH2:29]1)=[O:32]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)C1CC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
N,N-Diisopropylethylamine (0.486 mL, 2.79 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.300 g, 0.928 mmol) and cyclopropanecarbonyl chloride (0.126 mL, 1.39 mmol) in 1,2-dichloroethane (6.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-25% ethyl acetate-hexane) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.355 g, 98%) as a yellow oil. MS (ESI, pos. ion) m/z 435, 437 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(Cl)Cl>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[N:3]1
Reactant: Clc1noc2ccccc12
Reactant: NCCCCO
Solvent: ClCCl
Product: OCCCCNc1noc2ccccc12
Temperature: 80 °C
Reaction time: 96 h
Yield: 93.3 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (0.08 mol), 4-amino-1-butanol (0.24 mol) and KI (1 g) was stirred for 4 days at 80° C. The reaction mixture was cooled, dissolved in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%) of 4-(1,2-benzisoxazol-3-ylamino)-1-butanol (interm. 1). b) Thionyl chloride (0.048 mol) was cooled to 0° C. A solution of intermediate (1) (0.048 mol) in CHCl3 (20 ml) was added dropwise and the reaction mixture was stirred overnight at RT. The solvent was evaporated. The residue was washed with water. The reaction mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered, and the solvent was evaporated, yielding 10.4 g of ON—(4-chloro-butyl)-1,2-benzisoxazol-3-amine (interm. 2).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].C[O-].[Na+].[C:17](=[O:19])=[O:18]>CN(C)C(=O)C>[CH:10]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:13])[C:17]([OH:19])=[O:18])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O
Temperature: 90 °C
Yield: 23 %

Procedure:
This acid was prepared according to the procedure of W. H. Meek et al. J. Chemical and Engineering Data, 14(3), 388, (1969). To a solution of 2,6-diisopropylphenol (Aldrich cat. # D12660-8) (37.0 ml, 0.20 mol) in anhydrous N,N-dimethylacetamide (150 ml) was added sodium methoxide (16.2 g, 0.30 mol). Carbon dioxide was passed through the mixture throughout the subsequent reaction period. The mixture was heated with stirring and the solvent was slowly distilled out during 2 hours of the period until the pot temperature reached to 180° C. The mixture was allowed to continue stirring at 180° C. for another 1.5 hours and then cooled to 90° C. The flow of carbon dioxide was discontinued and water (400 ml) was added. The mixture, after further cooled to room temperature, was washed with toluene (4×60 ml) and then treated with conc. hydrochloric acid in an ice-water bath to pH 3. The resulting mixture was extracted with diethyl ether (2×150 ml); the ether extract was washed with brine (100 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 3,5-diisopropyl-4-hydroxybenzoic acid (10.4 g, 23%). Rf 0.5 (silica gel, 50% diethyl ether/hexane). MS (CI, CH4): m/z 223 M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(OC2CCNCC2)nc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1
Yield: 73.6 %

Procedure:
5-Chloro-2-(piperidine-4-yloxy)-pyridine (2.13 g; 10 mmol) (preparation of this compound was made as described in WO 99-GB2801), diisopropylethylamine (2.20 ml; 12.5 mmol) and Methanesulfonyl chloride (1.56 ml; 10.1 mmol) gave 2.14 g (74%) of the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.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>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Yield: 50.2 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.37 mmol), 4-bromobenzaldehyde (62 mg, 0.34 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system gave the title compound (52 mg, 46% yield): >95% purity by LCMS, ESI-MS: 305.2 (M+H+). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.00 (d, 2H), 7.95 (d, 2H), 7.46 (d, 2H), 7.19 (d, 1H), 7.16 (s, 1H), 2.63-2.58 (m, 1H), 1.94-1.76 (m, 4H), 1.53-1.42 (m, 4H), 1.38-1.25 (m, 2H). MS (ESI) m/z: Calculated: 304.38; Observed: 305.2 (M++1).