Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C1(C=CC(O)=CC=1)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])=[CH:5][CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(O)cc1
Agent: Oc1ccc(O)cc1
Product: COc1ccc(Oc2ccc(C)cc2[N+](=O)[O-])cc1

Procedure:
4-Methoxy-phenol was reacted with 1-fluoro-4-methyl-2-nitrobenzene according to the procedure from Example 122a substituting 4-methoxy-phenol for hydroquinone to provide the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][NH2:23]>C(O)(C)C>[CH3:22][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(c1ccccn1)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: CN
Solvent: CC(C)O
Product: CNc1ccc(C2(C(=O)c3ccccn3)CC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 231d from [1-(4-chloro-3-nitro-phenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone and methylamine in isopropanol.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2([F:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:11](I)=[CH:10][N:9]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>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.CC#N>[Cl:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2([F:29])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[C:11]([C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:10][N:9]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CNc2cc(Cl)ncc2I)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2cnc(Cl)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
MeCN (0.72 mL) and 0.5M aqueous sodium carbonate (0.24 mL, 1.5 eq.) were added to a mixture of tert-butyl 4-((2-chloro-5-iodopyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (37 mg, 0.079 mmol), 4-methoxyphenylboronic acid (11.97 mg, 0.079 mmol), and tetrakis(triphenylphosphine)palladium(0) (4.55 mg, 3.94 μmol) in a 0.5 mL microwave reaction vial. The sealed vial was heated at 100° C. for 20 mins by microwave irradiation. The volatiles were removed in vacuo. The residue was dissolved in dichloromethane and loaded onto a 12+S Biotage silica column. Chromatography, eluting with a gradient of EtOAc in hexanes, gave tert-butyl 4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol, 48%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH2:20][CH2:21][OH:22]>C1COCC1>[Si:5]([O:22][CH2:21][CH2:20][CH2:19][C:15]1[S:14][CH:18]=[CH:17][N:16]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1nccs1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1nccs1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
TBDMS-Cl (10.74 g, 71.2 mmol) and imidazole (5.38 g, 76.8 mmol) were added to a solution of 3-thiazol-2-yl-propan-1-ol (10.0 g 69.8 mmol) in THF (350 mL). Stirring was continued at rt overnight. The reaction mixture was partitioned between aq. sat. NH4Cl and Et2O. The aq. layer was extracted again with Et2O, the combined org. extracts were dried over MgSO4, filtered, and solvents were removed in vacuo. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound as an orange oil (13.00 g, 72%). LC-MS: tR=1.05 min, ES+: 258.24.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([CH2:16]C(O)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCNCC1
Product: Oc1ccc(C=Cc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 0.2 h

Procedure:
A portion (244.24 grams, 2.0 moles) of 4-hydroxybenzaldehyde, phenylacetic acid (272.30 grams, 2.0 moles) and piperidine (51.6 milliliters) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere. Heating commences and after 12 minutes and at 93° C., a solution forms. After a total of 27 minutes, the reaction temperature reaches 150° C. and is held therein. After 2 hours at the 150° C. temperature, a solution of sodium carbonate (40.0 grams) in deionized water (800 milliliters) is added to the reactor over a 3 minute period while stirring and heating are maintained. After 10 minutes of mixing with heating, stirring ceases and the aqueous layer is decanted from the reactor. The solid product remaining in the reactor is recovered and dissolved in a solution of sodium hydroxide (100.0 grams) in deionized water (2400 milliliters) which has been heated to 90° C. The resultant solution is held for 16 hours at 4° C. and the resultant crystalline precipitate which forms is recovered by filtration. The crystals are suspended in deionized water (1600 milliliters) which is stirred and then acidified to a pH of one by addition of aqueous concentrated hydrochloric acid. The resultant crystalline product is recovered by filtration, then washed on the filter with deionized water (two 250 milliliter portions). The product recovered on the filter is dried at 80° C. under a vacuum of 2 mm Hg to a constant weight of 87.1 grams of white crystalline powder. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product reveals the presence of the expected hydroxyl group O--H stretching absorbance centered at 3416 cm-1 (broad), the ethylene C--H out-of-plane deformation at 965 cm-1, the C--H out-of-plane vibration at 819 cm-1 for the para substituted aromatic ring and the C--H out-of-plane vibration at 746 and 686 cm-1 for the monosubstituted aromatic ring. High pressure liquid chromatographic analysis of the 4-hydroxystilbene product using a uv detector set at 254 nm reveals a single sharp peak. Proton magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [OH-].[K+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)=[O:9].[CH2:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)C>CO>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[C:25]1[CH2:26][CH2:27][N:22]([CH3:20])[CH2:23][CH:24]=1)=[O:9]
Reactant: O=C(Nc1ccc2[nH]ccc2c1)c1ccco1
Reactant: CCN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccco4)cc23)CC1
Temperature: 0 °C
Yield: 48.3 %

Procedure:
To a solution of 0.868 gm (15.5 mMol) potassium hydroxide in 8 mL methanol were added 1.0 gm (4.42 mMol) 5-(2-furoyl)amino-1H-indole and 0.774 mL 1-ethyl-4-piperidone and the solution was stirred at reflux for 18 hours. The reaction mixture was cooled to ambient and then diluted with ice/water. The resultant precipitate was collected and dried under vacuum. This solid was purified by radial chromatography (2 mm silica), eluting with a gradient of dichloromethane containing 5-7.5% methanol and 0.5-1.0% ammonium hydroxide. The product was then crystallized from ethyl acetate to give 0.715 gm (48.3%) of the title compound as a bright yellow powder.
Reaction SMILES: O.C(O)(=O)C.[CH3:6][O:7][C:8]1[C:20]([N+]([O-])=O)=[CH:19][C:11]2[O:12][C:13]([CH3:18])([CH2:15][CH2:16][CH3:17])[O:14][C:10]=2[CH:9]=1>C(O)C>[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:11]2[O:12][C:13]([CH3:18])([CH2:15][CH2:16][CH3:17])[O:14][C:10]=2[CH:9]=1
Reactant: CCCC1(C)Oc2cc(OC)c([N+](=O)[O-])cc2O1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCC1(C)Oc2ccc(OC)cc2O1
Reaction time: 0.5 h

Procedure:
A suspension of 50 g of hydrogen-reduced iron powder in 150 ml of ethanol, to which 7 ml of water and 5 ml of acetic acid have been added, is heated under reflux. 0.08 mole (20.3 g) of 5-methoxy-6-nitro-2-methyl-2-propyl-1,3-benzodioxole is added portionwise. Heating is continued for 30 minutes after the end of the addition. The reaction mixture is filtered while boiling. 25 ml of a 7N solution of hydrochloric acid is added to the filtrate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:12][N:13]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncnc2ccccc12
Reactant: CNCCOc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCOc1ccccc1)c1ncnc2ccccc12
Reaction time: 7 h
Yield: 88.3 %

Procedure:
To a solution of 2.5 g (0.015 mole) of 4-chloroquinazoline in benzene were added 2.3 g (0.015 mole) of N-methyl-N-phenoxyethylamine and 1.5 g (0.015 mole) of triethylamine. The mixture was then refluxed, with stirring, for 7 hours. After completion of the reaction, the benzene was removed by evaporation. Water was added to the residue and the mixture was extracted with chloroform and the extract was dried. The chloroform was removed by evaporation and the resulting oil was purified by column chromatography through silica gel (eluted with a 1:1 by volume mixture of benzene and ethyl acetate) to give 3.7 g (88%) of the desired Compound No. 4 in the form of a pale yellow liquid having a refractive index nD27 1.6329.
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.[F:11][C:12]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:13]=1[O:14][C:15]([CH3:20])([CH3:19])[C:16](O)=[O:17].O.NN.C(N(CC)CC)C>C(#N)C>[F:11][C:12]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:13]=1[O:14][C:15]([CH3:20])([CH3:19])[C:16]([NH:7][NH2:8])=[O:17]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(Oc1ccc(F)cc1F)C(=O)O
Agent: NN
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccc(F)cc1F)C(=O)NN
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
HOBt (1.76 g) and WSC•monohydrochloride (2.49 g) were added to a solution of 2-(2,4-difluorophenoxy)-2-methylpropanoic acid (2.34 g) in acetonitrile (27 ml), followed by stirring at room temperature for one hour. This solution was added dropwise to a solution of hydrazine monohydrate (3.25 g) and triethylamine (3.0 ml) in acetonitrile (20 ml) under ice cooling, followed by stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=98:2) to obtain 2-(2,4-difluorophenoxy)-2-methylpropanohydrazide (1.74 g).
Reaction SMILES: [NH2:1][C:2]1(C#N)[CH2:7][C:6]([Cl:8])=[C:5]([F:9])[C:4](=[O:10])[N:3]1[CH3:11].Cl>C(O)=O>[Cl:8][C:6]1[C:7]2[C:4](=[O:10])[NH:3][CH:2]=[N:1][C:2]=2[N:3]([CH3:11])[C:4](=[O:10])[C:5]=1[F:9]
Reactant: CN1C(=O)C(F)=C(Cl)CC1(N)C#N
Agent: Cl
Solvent: O=CO
Product: Cn1c(=O)c(F)c(Cl)c2c(=O)[nH]cnc21
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Combine 2-amino-5-fluoro-4-chloro-1-methyl-6-oxo-1,6-dihydropyridine-carbonitrile (33.0 g, 0.164 mol) and 99% formic acid (264 mL, 8 volumes) in a dried vessel. Heat to 70° C. When a solution is formed, add concentrated aqueous hydrochloric acid (165 mL, 5 volumes). After 20 hours, add another portion of concentrated aqueous hydrochloric acid (35 mL) and heated at 70° C. for another 4 h. Then cool the reaction mixture to the ambient temperature and add ice-water (350 mL, 10 volumes). Cool in an ice bath to give a solid. After 30 minutes, collect the solid by filtration, rinse with water (2×30 mL), and dry in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ12.96 (s, 1H), 8.35 (s, 1H). 3.61 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ157.7 (d, J=4.4 Hz), 154.6 (d, J=26.4 Hz), 151.2 (d, J=2.2 Hz), 149.9, 146.4 (d, J=242 Hz), 125.0 (d, J=16.9 Hz), 99.94, 29.8; 19F NMR (376 MHz, DMSO-d6) δ−133.8; MS (M+H)+m/z calcd 230.0. found 230.0.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12]>CN(C=O)C>[CH2:12]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:11]=[CH2:10]
Reactant: CCOC(=O)CO
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl hydroxyacetate was added dropwise to a slurry of NaH (1.1 eq) in DMF at 0° C. and the resulting mixture was stirred at RT for 2 h. After cooling to 0° C., allylbromide (1.1 eq) was added dropwise via syringe and the reaction mixture was stirred at RT for 2 h, quenched by careful addition of sat. aq. NH4Cl and partitioned between Et2O and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the title compound as pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 5.91 (m, 1H), 5.30 (dd, J 17.2, 1.5, 1H), 5.24 (dd, J 10.6, 0.6, 1H), 4.23 (q, J 2.1, 2H), 4.10 (d, J 5.7, 2H), 4.08 (s, 2H), 1.29 (t, J 7.08, 3H).
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C(=O)C2=CC=CC=C12.O.NN>C(Cl)Cl.CO>[NH2:5][O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)/C=C/CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C/CON
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a solution of tert-butyl 4-phthalimidooxycrotonate (20.0 g) in methylene chloride (140 ml) was added a solution of hydrazine monohydrate (5.0 g) in methanol (10 ml) with stirring, and the stirring was continued at ambient temperature for 15 minutes. The insoluble substance was collected by filtration and washed with methylene chloride. The washings and the filtrate were combined and then extracted three times with 5% hydrochloric acid. After the combined extracts were washed with diethyl ether, thereto was added methylene chloride, followed by adjusting to pH 7.5 with 28% aqueous ammonium hydroxide. The separated methylene chloride solution was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave an oil of tert-butyl 4-aminooxycrotonate (11.03 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:17][CH2:18][N:19]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:20][CH2:21]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCNCC2)c1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(C3CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of a mixture of 4-methyl-2-(5-piperidin-4-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester and methyl ester (68b) (55 mg, 0.12 mmol) in 1,2-dichloroethane (1.0 mL) was added cyclohexanone (0.014 mL, 0.14 mmol) and sodiumtriacetoxyborohydride (33 mg, 0.16 mmol). The mixture was stirred for 14 h at room temperature. The reaction was quenched with water and extracted with dichloromethane. The organic was washed with saturated aqueous NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 2-[5-(1-cyclohexyl-piperidin-4-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester and methyl ester. Calcd for C31H40F3NO2 (M+H) 516.65, Found 516.3 (methyl ester) and Calcd for C32H42F3NO2 (M+H) 530.68, Found 530.2 (ethyl ester).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) (5.4 g, 20.1 mmol), benzotriazol-1-yloxytris(dimethylaminop)phosphonium hexafluorophosphate (14.22 g, 32.15 mmol), and tert-butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in methylene chloride (20 mL) was treated with triethylamine (8.4 mL, 60.3 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane) to yield 7.10 g (81%) tert-butyl 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate as a white foam. HRMS: calcd for C23H33ClN2O4, 436.2129; found (ESI_FT), 437.21996.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][C@@H:12]([CH3:33])[C:13]([NH:15][CH:16]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]=2[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2)=[O:14]>C1(C)C=CC=CC=1>[CH3:24][N:21]1[C:22](=[O:23])[CH:16]([NH:15][C:13]([C@@H:12]([O:11][C:9](=[O:10])[NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:33])=[O:14])[C:17]2[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=2[C:19]2[CH:28]=[CH:27][CH:26]=[CH:25][C:20]1=2
Reactant: C[C@H](O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Reactant: O=C=NCc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H](OC(=O)NCc1ccccc1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 100 °C

Procedure:
Benzylisocyanate (13.3 mg, 0.1 mmol) was added to a solution of (S)-2-hydroxy-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide (30 mg, 0.1 mmol) in Toluol (1 ml) and heated to 100° C. for 1 week. The solvent was evaporated and the residue was dissolved in DMF (0.5 ml). The title compound, MS: m/e=444.4 (M+H+) (29 mg, 67%), was isolated from this mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5–95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 30 ml/min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4].[CH2:21]([O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27])[CH3:22]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:26](=[O:27])[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:29])[C:7]([Cl:12])=[C:8]([Cl:11])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1c(Cl)c(Cl)c(Cl)n1NCc1ccccc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)N(Cc1ccccc1)n1c(Cl)c(Cl)c(Cl)c1C(=O)OC
Yield: 52.6 %

Procedure:
A mixture of 1-benzylamino-3,4,5-trichloro-1H-pyrrole-2-carboxylic acid methyl ester (394 mg, 1.18 mmol) and chlorocarbonyl-acetic acid ethyl ester (227 μL, 1.77 mmol) in dioxane (5 mL) was stirred under reflux for 30 min; then the reaction mixture was cooled and the solvents were removed, the residue was directly silica gel column purified to give the desired product (278 mg) as colorless syrup. ESI (m/z): 447 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8](=O)[CH3:9].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH:8](=[N:7]/[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])\[CH3:9]
Reactant: CC=O
Reactant: CC(C)(C)[S@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C/C=N/[S@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.2 %

Procedure:
In a flask (R)-2-methyl-propane-2-sulfinic acid amide (4.00 g, 33.0 mmol) was dissolved in CH2Cl2 (14.0 mL). Acetaldehyde (16.7 mL, 297 mmol), MgSO4 (11.9 g, 99.0 mmol) and pyridinium tosylate (415 mg, 1.65 mmol) were added. The reaction mixture was stirred overnight at room temperature, filtered and concentrated to give 5.21 g of (R)-2-methyl-propane-2-sulfinic acid (E)-ethylideneamide as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH:13]([OH:15])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[C:24]([CH3:26])([CH3:25])[O:23][C:22]([CH3:28])([CH3:27])[C:21](=[O:29])[CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH:13]([O:15][C:19]3[C:24]([CH3:25])([CH3:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21](=[O:29])[CH:20]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(C)(C)C(Cl)=CC1=O
Reactant: CC(O)c1cnc(-c2ccc(Cl)cc2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OC1=CC(=O)C(C)(C)OC1(C)C)c1cnc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 1-[2-(4-chlorophenyl)thiazol-5-yl]ethanol (335 mg, 1.4 mmol) in anhydrous tetrahydrofuran (5 ml) under nitrogen is added sodium hydride, 60% dispersion in mineral oil, (48 mg, 1.2 mmol) and the resulting yellow suspension is allowed to stir at room temperature for 1 hour. A solution of 5-chloro-2,2,6,6-tetramethyl-6H-pyran-3-one (189 mg, 1 mmol) in anhydrous tetrahydrofuran (2 ml) is then added and reaction is allowed to stir at room temperature for 17 hours. The crude reaction mixture is purified by flash chromatography on silica gel to give 5-{1-[2-(4-chlorophenyl)thiazol-5-yl]ethoxy}-2,2,6,6-tetramethyl-6H-pyran-3-one (288 mg).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][N:10](C)[C:11](OC(C)(C)C)=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].C1(OC)C=CC=CC=1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>ClCCl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][NH:10][CH3:11])=[O:8])=[CH:19][CH:20]=1)#[N:2]
Reactant: CN(NC(=O)c1ccc(C#N)cc1)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNNC(=O)c1ccc(C#N)cc1

Procedure:
In a similar manner to Example 14, starting material step (b), the product of step (a) (2.2 g), anisole (2 ml), dichloromethane (20 ml) and TFA (27 ml) were reacted to give N-(4-cyanobenzoyl)-N'-methylhydrazine, trifluoroacetate salt (2.3 g), as a white solid: m.p. 131-134° C.; NMR Spectrum (DMSO-d6) 2.76 (3H, s), 8.00 (4H, s).