Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH:13]C(OCC2C=CC=CC=2)=O)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].CO.[ClH:26].CCOCC>[Pd]>[ClH:26].[OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH2:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(NNC(=O)OCc1ccccc1)Nc1ccc(O)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NNC(=O)Nc1ccc(O)c(O)c1

Procedure:
A solution of 5.03 g (15.85 mmol) of 2-[[(3,4-dihydroxyphenyl)amino]carbonyl]hydrazinecarboxylic acid, phenylmethyl ester in 250 ml of methanol containing 2.64 ml (31.70 mmol) of hydrochloric acid was hydrogenated in the presence of 0.5 g of 10% palladium on charcoal for 5 minutes. The catalyst was filtered off and the solvent was distilled off in vacuo to leave a solid which was stirred with a few ml of dry ether; yield after drying in vacuo: 3.36 g; melting point 170°-180° C., dec.
Reaction SMILES: [NH2:1][C:2]12[CH2:13][C:6]3([CH3:14])[CH2:7][C:8]([CH2:11][OH:12])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:23][C:24]([NH:1][C:2]12[CH2:13][C:6]3([CH3:14])[CH2:7][C:8]([CH2:11][OH:12])([CH2:10][C:4]([CH3:15])([CH2:5]3)[CH2:3]1)[CH2:9]2)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC12CC3(C)CC(N)(C1)CC(CO)(C2)C3
Solvent: C1CCOC1
Product: CC12CC3(C)CC(CO)(C1)CC(NC(=O)OCc1ccccc1)(C2)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 1-amino-3,5-dimethyl-7-hydroxymethyl adamantane (60 mg) in THF (3 mL) was added N-(benzyloxycarbonyloxy)-succinimide (74 mg) and the mixture was stirred at room temperature overnight. THF was removed and the residue was dissolved in ethyl acetate. The solution was washed with water and brine. The product was purified by thin layer chromatography eluting with ethyl acetate and hexane (1:4, v/v) to give a white solid (80 mg). 1H NMR (DMSO-d6, ppm): 7.33 (m, 5H, C6H5), 6.89 (brs, 1H, NH), 4.94 (s, 2H, OCH2), 4.32 (t, 1H, OH, J=5.7 Hz), 3.04 (d, 2H, CH2OH, J=5.7 Hz), 1.46 (dd, 6H), 1.04 (dd, 6H), 0.84 (s, 6H, 2×CH3).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:39])([F:38])[C:5]1[CH:6]=[CH:7][C:8]([N+:35]([O-])=O)=[C:9]([N:11]=[N:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])[C:14]=2[OH:34])[CH:10]=1.ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2.S(=O)(=O)(O)O>O.C(O)CCC.CCCCCCC.CC(O)CC>[F:3][C:4]([F:39])([F:38])[C:5]1[CH:6]=[CH:7][C:8]2=[N:35][N:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:14]=3[OH:34])[N:11]=[C:9]2[CH:10]=1
Reactant: COc1ccc(C(C)(C)c2cc(C(C)(C)C)cc(N=Nc3cc(C(F)(F)F)ccc3[N+](=O)[O-])c2O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCC(C)O
Solvent: O
Solvent: CCCCCCC
Product: COc1ccc(C(C)(C)c2cc(C(C)(C)C)cc(-n3nc4ccc(C(F)(F)F)cc4n3)c2O)cc1
Temperature: 90 °C

Procedure:
To a 2 L, five-necked flask equipped with a mechanical stirrer, 500 mL of 2-butanol and 8 g of sodium hydroxide pellets are charged and heated to 90° C. A solution of 50 g of the monoazo compound prepared in Example 12, 2.3 g of 2,3-dichloro-1,4-naphthoquinone and 300 mL of heptane is charged to the hot butanol solution over a three hour period. After the addition is complete, the reaction mass is stirred for an additional hour at reflux. To the reaction mass is then added, 100 mL of water and the pH is adjusted to 2 with 30% aqueous sulfuric acid. The aqueous layer is removed and the organic layer is washed once with 100 mL of saturated sodium chloride solution and twice with water. The desired product is crystallized from the solution yielding the title compound as a light yellow solid melting at 140° C. The structure is verified by 1Hnmr and mass spectroscopy analyses.
Reaction SMILES: C(N(CC)CC)C.[Br:8][CH2:9][C:10](Br)=[O:11].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[NH2:18]>O1CCCC1>[Br:8][CH2:9][C:10]([NH:18][C:17]1[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:15]([O:14][CH3:13])[CH:16]=1)=[O:11]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CBr)cc(OC)c1OC
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Add triethylamine (1.53 mL, 11.0 mmol) and bromoacetyl bromide (0.87 mL, 10.0 mmol) dropwise to a 0° C. solution of 3,4,5-trimethoxy-aniline (1.74 g, 9.5 mmol) in tetrahydrofuran (30 mL). Allow the reaction to warm to room temperature overnight. Filter the mixture, wash with tetrahydrofuran, and concentrate. Dissolve the resulting brown solid in chloroform, wash with 1N HCl, saturated aqueous sodium bicarbonate solution, brine; dry over magnesium sulfate; and concentrated. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 2.50 g of the title compound as an orange solid, 87% yield. 1H NMR: consistent with structure. MS (ion spray) 304 (M+).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=O.CN1C=C([N+:15]([O-:17])=[O:16])C=C([N+]([O-])=O)C1=O.N>>[N+:15]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([O-:17])=[O:16]
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: O=c1cccc[nH]1
Agent: N
Product: O=[N+]([O-])c1ccccn1

Procedure:
In addition, compounds referred to hereinbelow as 7e and 7f were synthesized by modifying the method described by Tohda et al, Nucleophilic Reaction upon Electron-Deficient Pyridone Derivatives X. One-Pot Synthesis of 3-Nitropyridines by Ring Transformation of 1-Methyl-3,5-dinitro-2-pyridone with Ketones or Aldehydes in the Presence of Ammonia, Bull. Chem. Soc. Jpn. 1990, 63, 2820–2827, for producing nitropyridine by using 3,5 dinitro-1-methyl-2-pyridone which produced the nitro compound 7e which was reduced to the amine 7f.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].CS(Cl)(=O)=O.Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:19])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(N)=O)nn1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C#N)nn1
Temperature: 0 °C
Yield: 126.4 %

Procedure:
To a solution of 6-[N-(5-chloro-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-pyridazine-3-carboxamide (example 18) (210 mg, 0.6 mmol) in pyridine (10 ml) at 0° C. was added methane sulfonyl chloride (0.5 ml, 0.6 mmol) and the mixture allowed to stir (gradually coming to an ambient temperature as the ice melts) for 60 hours. The solution was poured into 2 N hydrochloric acid (50 ml) over ice and the product extracted with diethyl ether (200 ml), washed with water (3×200 ml), dried over anhydrous magnesium sulphate and the solvent removed in vacuo to give the title compound as a brown gum (260 mg) which was used without further purification.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[CH:12]1([CH3:22])[CH2:17][CH2:16][CH:15]([CH:18]([CH3:20])[CH3:19])[CH:14](O)[CH2:13]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][CH:14]1[CH:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17][CH:12]([CH3:22])[CH2:13]1)=[O:4]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(O)C(O)c1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)C(O)c2ccccc2)C1

Procedure:
2.1 kg of hydroxyphenylacetic acid are esterified with 2.5 kg of (-)-menthol in 15 l of boiling toluene with the addition of 40 g of toluenesulphonic acid; the water of reaction is removed from circulation in a water separator. When water is no longer separated, the mixture is cooled, washed with 4 l of saturated NaHCO3 and twice with 4 l of water and concentrated to dryness in vacuo. The title compound is obtained as an oily residue.
Reaction SMILES: [C:1]1([CH2:7][S:8][C:9]2[N:10]=[C:11](Cl)[C:12]3[S:17][C:16]([NH2:18])=[N:15][C:13]=3[N:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23]>>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:20][CH:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23])=[N:10][C:9]([S:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:14][C:13]=2[N:15]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: CC(C)C(N)CO
Product: CC(C)C(CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 100 °C
Yield: 24.1 %

Procedure:
5-Phenylmethylthio-7-chloro-thiazolo[4,5-d]pyrimidin-2-ylamine (WO 00/09511) (100 mg, 0.32 mmol) and DL-2-amino-3-methyl-1-butanol (253 μL, 2.3 mmol) were suspended in anhydrous tetrahydrofaran (4 mL) and the reaction tube was capped. The solution was heated at 100° C. for 24 hours and was then allowed to cool down to room temperature. The solvent was evaporated in vacuo and the crude product was flash chromatographed on silica (eluent—ammonia:ethanol:dichloromethane, 1:8:91) followed by a second chromatography (gradient eluent—ammonia ethyl acetate: dichloromethane, 1:59:40 to 1:99:0) resulting in 29 mg (24% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Cl.C(#N)C>O>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:7]2[C:6](=[O:22])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:29][CH:31]4[CH2:32][O:33]4)=[CH:3][CH:4]=3)[O:9][CH:8]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: ClCC1CO1
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A mixture of 7-hydroxy-3′,4′-dimethoxyisoflavone (2, 0.30 g, 1 mmol), K2CO3 (0.41 g, 3 mmol), epichlorohydrin (0.3 g, 3 mmol) and acetonitrile (30 mL) was refluxed with stirring for 4 hrs (TLC monitoring). The mixture was evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus formed was collected, purified by column chromatography (MeOH/CH2Cl2=1:100), and crystallized from EtOH to give the title compound 4 (0.25 g, 70% yield). M.p.: 161-162° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12]O)[N:3]=[CH:4][CH:5]=1.P(Br)(Br)[Br:15].C([O-])(O)=O.[Na+]>C1COCC1>[Br:15][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: OCc1ccccc1-n1nccn1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCc1ccccc1-n1nccn1
Temperature: 70 °C
Yield: 56.3 %

Procedure:
To a stirred solution of (2-(2H-1,2,3-triazol-2-yl)phenyl)methanol (37 mg, 0.209 mmol) in THF (1 mL), PBr3 (0.024 mL, 0.251 mmol) was added and the mixture was heated at 70° C. for 20 min. The mixture was cooled to rt, poured into saturated aqueous NaHCO3 solution and extracted with dichloromethane (2×). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash-column chromatography over silicagel (eluent: gradient 10%-100% ethyl acetate/heptane) to yield the title compound (28 mg, 54%). [1H NMR (400 MHz, DMSO-d6) ♀ ppm 8.17 (s, 2H), 7.69 (ddd, J=7.59, 3.58, 1.63 Hz, 2H), 7.53 (dqd, J=14.74, 7.51, 7.51, 7.51, 1.63 Hz, 2H), 4.96 (s, 2H); LCMS RtA=1.02, [M+H]+=238.2/240.2].
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].O.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[N:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[C:5]([CH2:6][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])[CH:4]=1
Reactant: O=Cc1ccc[nH]1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccn1Cc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A suspension of 60% NaH (3.28 g) in THF (400 ml) was cooled to 0° C. under nitrogen atmosphere, and thereto was added pyrrol-2-carbaldehyde (7.81 g) in portions. To the mixture was added a solution of the above crude bromo compound in toluene, and the mixture was stirred at room temperature for 0.5 hour, and stirred at 40° C. for one hour, and further stirred at 50° C. for 2 hours. The mixture was cooled to room temperature, and poured into water, and extracted with ethyl acetate. The extract was washed with a saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=3/1→2/1→1/1) to give 1-(3-quinolylmethyl)-1H-pyrrol-2-carbaldehyde (10.5 g, 54%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[C:16](C1C=C(C)C=C(C)C=1O)(C)(C)C.C(C1C=C(CC)C=C(C(C)(C)C)C=1O)(C)(C)C.C(C1C=C(CCCC)C=C(C(C)(C)C)C=1O)(C)(C)C.C(C1C=C(CC(C)C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C2C=C(C)C=C(C3CCCC3)C=2O)CCCC1.C(C1C=C(C)C=C(CCCCCCCCCCCCCCCCCC)C=1O)CCCCCCCCCCCCCCCCC.C1(C2C=C(C3CCCCC3)C=C(C3CCCCC3)C=2O)CCCCC1.C(C1C=CC=CC=1O)(C)(C)C.C(C1C=C(COC)C=C(C(C)(C)C)C=1O)(C)(C)C>>[C:11]([C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: CC(C)(C)c1ccccc1O
Agent: CC(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCCCCCCCCCCCCCCCCc1cc(C)cc(CCCCCCCCCCCCCCCCCC)c1O
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-di-tert-butylphenol; 2-tert-butyl-4,6-dimethylphenol; 2,6-di-tertbutyl-4-ethylphenol; 2,6-di-tert-butyl-4-ethylphenol; 2,6-di-tert-butyl-4-n-butylphenol; 2,6-di-tertbutyl-4-isobutylphenol; 2,6-dicyclopentyl-4-methylphenol; 2-(α-methylcyclohexyl)-4,6-dimethylphenol; 2,6-dioctadecyl-4-methylphenol; 2,4,6-tricyclohexylphenol; 2,6-di-tert-butyl-4-methoxymethylphenol o-tert-butylphenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[OH:16])[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:27]>[Ag]=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:15]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[O:16][CH3:27])[CH2:11][O:10][C:9]1([CH3:25])[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C#CC(O)c2ccc(Cl)cc2)COC1(C)C
Reactant: CI
Agent: O=[Ag]
Product: COC(C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 70 °C
Yield: 76 %

Procedure:
To (S)-4-[3-(4-chloro-phenyl)-3-hydroxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.10 g) was added dropwise iodomethane (5.27 ml). To the resulting yellow solution was added silver oxide (5.89 g) and the mixture was heated at 70° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[3-(4-chloro-phenyl)-3-methoxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.44 g, 76%) as a colourless oil. MS (ISP): 399.2 ([{37Cl}M+NH4]+), 397.2 ([{35Cl}M+NH4]+).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:10]([OH:12])=[O:11].[CH2:17](O)[CH3:18]>C(OCC)C.O>[Br:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([F:16])[CH:15]=1)[C:10]([O:12][CH2:17][CH3:18])=[O:11]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(F)cc(Br)c1
Temperature: 25 °C

Procedure:
Sulphuric acid (0.5 mL) was added to a stirring solution of 3-bromo-5-fluorobenzoic acid (473 mgs, 2.16 mmol) in ethanol (10 mL) and refluxed for 17 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether and water. The ether layer was washed with 5% sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to dryness to give the title compound as a brown oil. (506 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]3[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=3[O:22][C:21]([CH3:31])([CH3:30])[N:20]=2)=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:24]3[CH:25]=[CH:26][C:27]([NH:29][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][C:23]=3[O:22][C:21]([CH3:31])([CH3:30])[N:20]=2)=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)N=C(c2ccc(Cl)cc2)c2ccc(N)cc2O1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)N=C(c2ccc(Cl)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methanesulfonyl chloride (55 μL) and pyridine (85 μL) were added dropwise to a solution of 4-(4-chlorophenyl)-2.2-dimethyl-2H-1,3-benzoxazin-7-ylamine (a compound of Reference Example 1, 101 mg) in chloroform (8 mL) and said mixture was stirred at room temperature for 2 days. The reaction solution was purified by column chromatography on silica gel (Chromatorex NH-silica gel, FUJI SILYSIA CHEMICAL LTD., Solvent: chloroform/methanol=100/0 to 90/10) and the obtained powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (112 mg) as a colorless powder.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][C:11]=1/[CH:15]=[CH:16]\[S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C(C)(C)C)(C)C.Cl.O.C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:8][CH2:9][C:10]1[S:14][CH:13]=[N:12][C:11]=1/[CH:15]=[CH:16]\[S:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1scnc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1scnc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
5-t-Butyldimethylsilyloxymethyl-4-((Z)-2-tritylthioethen-1-yl)thiazole (392 mg) was dissolved in 10 ml of THF, 0.7 ml of 5 N-aqueous hydrochloric acid was added to the solution, and the mixture was stirred at room temperature for 2 hr. Brine was added to the reaction solution, and the mixture was adjusted to pH 8 by the addition of sodium bicarbonate water. The mixture was extracted twice with ethyl acetate, followed by washing with brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. Ethyl acetate (5 ml) and 5 ml of hexane were added to the residue, and the resultant solid was collected by filtration to give 180 mg of the title compound.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[H-].[Na+].CS(O[CH:38]1[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C:40](=[O:51])[CH2:39]1)(=O)=O>O>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:20]=[N:19][N:18]([CH:38]4[CH2:43][CH2:42][NH:41][C:40](=[O:51])[CH2:39]4)[CH:17]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1=O
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNC(=O)C4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An 8-mL resealable tube was charged with (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.050 g, 0.15 mmol) and N,N-dimethylformamide (2 mL). Sodium hydride (60% dispersion in mineral oil, 0.012 g, 0.50 mmol) was added, and the resulting mixture stirred for 15 min at room temperature. tert-Butyl 4-(methylsulfonyloxy)-2-oxopiperidine-1-carboxylate (0.141 g, 0.48 mmol) was added, and the resulting mixture stirred overnight at 50° C. The reaction mixture was cooled to room temperature and water (10 mL) was added. The aqueous phase was separated and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RPC18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (13% to 60% acetonitrile in 8 min; flow rate: 20 mL/min); Detector, UV254&220. This afforded (2S)-methyl 5-cyclobutoxy-2-methyl-6-(1-(2-oxopiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.0091 mg, 14%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.17-1.20 (m, 3H), 1.29-1.40 (m, 1H), 1.40-1.51 (m, 1H), 1.58-1.68 (m, 1H), 2.03-2.19 (m, 4H) m 2.22-2.35 (m, 3H), 2.41-2.49 (m, 1H), 2.92-2.99 (m, 1H), 3.32-3.48 (m, 2H), 3.78 (s, 3H), 4.12-4.22 (m, 1H), 4.50-4.60 (m, 1H), 4.78-4.88 (m, 1H), 7.25-7.33 (m, 2H), 7.87 (s, 1H), 8.05 (s, 1H). MS (ESI, pos. ion) m/z 439 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:12][CH2:13][O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:32][O:33][NH2:34]>>[CH3:32][O:33][N:34]=[C:1]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:12][CH2:13][O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CON
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(C)=O)ccc32)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(C)=NOC)ccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine. The two (Z) and (E) compounds are not separated.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:5].C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:1][CH:2]([CH3:13])[CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:21])=[CH:10][CH:11]=1)=[O:5]
Reactant: Cc1ccc(C(=O)CC(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Heat a mixture of 3,4′-dimethylbutyrophenone (3 g, 17.02 mmol), NBS (3.787 g, 16.18 mmol), and AIBN (70 mg, 0.425 mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Cool to ambient temperature and filter the mixture. Concentrate the filtrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (9:1) to provide the title compound as oil (2.802 g, 65%). GC-MS m/z: 255 (M+).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH3:16]>O>[C:5]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH3:16])(=[O:7])[CH3:6]
Reactant: Cc1ccc(F)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C
Temperature: 25 °C

Procedure:
139 ml (150.4 g; 1.473 molecules) of acetic anhydride were added in one portion to a hot (35° ) stirred mixture of 90.0 g (0.719 molecule) of 2-amino-4-fluorotoluene (1) in 513 ml of water. The temperature rose to 73° and a solid separated out (by precipitation). The mixture was cooled to ambient temperature and the solid was recovered on a filter, washed with water (525 ml), then dried in vacuo at 80°, yield: 115.7 g (96.2%); m.p.: 127°-128°. The material was still transformable.