Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH:8]([CH:20]1[CH2:25][C:24](=[O:26])[O:23][C:21]1=[O:22])=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCC.O>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[C:24](=[O:26])[CH2:25][CH:20]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:21]([OH:23])=[O:22]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: OCCNCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC=CC(CC(=O)N(CCO)CCO)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A 500 ml, two-neck flask was charged with 52.6 g (500 mmol) diethanolamine and 50 ml toluene. A temperature probe was placed into this solution through one of the necks of the flask and the flask was immersed into a water bath. A solution of 105.2 g (500 mmol) dodecenylsuccinic anhydride dissolved in 200 ml toluene was dripped into the magnetically stirred solution diethanolamine solution over a 40-minute period. Ice was added to the water bath as required to prevent temperature of the reaction mixture from getting above 25° C. The mixture was then stirred for another 2.5 hours at room temperature. The complete disappearance of the anhydride functional group was confirmed by infrared spectroscopy. The FTIR trace on this compound had significant absorptions at 2957, 2924, 2858, 1733, 1616, 1560, 1415, 1160, 1069, 969, and 728 wavenumbers. The solution was concentrated down to 50% solids in toluene and was then set aside for later use.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].O.NN>C(O)C>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH2:24])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(CCN3C(=O)c4ccccc4C3=O)CC2)c2ncccc2c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCc1cc(OC2CCN(CCN)CC2)c2ncccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.8 %

Procedure:
2-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-1H-isoindole-1,3(2H)-dione (for example, as prepared for Intermediate 30) (2.76 g, 6.03 mmol) was stirred under nitrogen in ethanol (40 ml) containing hydrazine monohydrate (commercially available, for example, from Aldrich) (0.71 ml, 15.1 mmol) at 80° C. for 2 h. The reaction was cooled with ice-water and filtered. The filter-cake was leached with ethanol and the combined filtrates were evaporated to an oil containing a white solid. This solid was mixed with DCM (about 20 ml) and filtered. The filter-cake was leached with more DCM and the combined filtrates were evaporated to give the title compound (2.07 g) as an oil: LCMS RT=2.32 min, ES+ve m/z 328 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd].[H][H]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1CNC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CN2C(=O)CNC2=O)cc1

Procedure:
The 3-(4-nitrobenzyl)hydantoin derivative as dissolved in methanol (about 10 ml per mmol of hydantoin derivative) and hydrogenated with palladium/carbon in a hydrogen atmosphere until reaction was complete. The catalyst was filtered off and the solvent was removed on a rotary evaporator. The 3-(4-aminobenzyl)hydantoin derivative was obtained.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[CH:1]([C:4]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CC(C)c1cc2ccccn2n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCC(=O)c1c(C(C)C)nn2ccccc12
Yield: 62.9 %

Procedure:
A mixture of 6.4 g (40 mmol) of 2-isopropylpyrazolo[1,5-a]pyridine, 3.7 g (40 mmol) of propionyl chloride and 400 mg of AlCl3 was stirred at RT in 5 ml of CS2 for 3 days. The mixture was quenched with saturated NH4Cl and extracted with EtOAc to provide 5.44 g of crude 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one, which was purified on a silica gel column to yield 700 mg of pure intermediate along with 3.53 g of starting material. 700 mg of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one was reacted with 600 μl of 1M t-BuOK in t-BuOH at −20° C. for 20 minutes, followed by the addition of 600 μl of isoamylnitrite at 0° C. and stirring at RT overnight. The mixture was quenched with saturated NH4Cl and extracted with EtOAc to provide 1.2 g of crude product, which was purified on a silica gel column to furnish 314 mg of (Z)-2-(hydroxyimino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one. Compound 1083.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:21]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])=[CH:20][N:19]=[CH:18]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([C:21]3[O:17][CH:18]=[N:19][CH:20]=3)[CH:23]=2)=[N:3][CH:4]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(-c2cnco2)c1
Product: Oc1cccc(Nc2nc(Nc3cccc(-c4cnco4)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-(1,3-oxazol-5-yl)aniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-(1,3-oxazol-5-yl)phenyl]-2,4-pyrimidinediamine. LCMS: purity: 76%; MS (m/e): 364 (MH+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[NH:7][C:5]=2[N:6]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[NH:7][C:5]3[N:6]=[C:2]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[S:3][C:4]=3[CH:9]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2cc3sc(Cl)nc3[nH]2)cc1
Reactant: C1COCCN1
Product: Fc1ccc(-c2cc3sc(N4CCOCC4)nc3[nH]2)cc1
Yield: 91 %

Procedure:
126 mg (0.50 mmol) of 2-chloro-5-(4-fluorophenyl)-4H-pyrrolo[2,3-d]thiazole are suspended in 2 ml of morpholine in a microwave vessel and irradiated at 130° C. for 2 h and subsequently purified directly by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1/1), giving 139 mg (0.45 mmol, 91%) of 5-(4-fluorophenyl)-2-morpholin-4-yl-4H-pyrrolo[2,3-d]thiazole as beige crystals; m.p. 240-248;
Reaction SMILES: [Cl:1][CH:2]([C:6](=[O:8])[CH3:7])[C:3]([NH2:5])=[O:4].[C:9](Cl)(=[O:11])[CH3:10]>C(OC(=O)C)(=O)C>[C:9]([NH:5][C:3](=[O:4])[CH:2]([Cl:1])[C:6](=[O:8])[CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: CC(=O)C(Cl)C(N)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NC(=O)C(Cl)C(C)=O

Procedure:
A solution of 2-chloro-3-oxobutyramide (1 g) in acetic anhydride (5 ml) containing acetyl chloride (1 ml) was heated in a 100° oil bath for 2 hours. Excess reagent was evaporated under reduced pressure and the residue was vacuum distilled in a kugelrohr apparatus. The distilled product crystallized to give a colorless solid with mp 54°-8°; ir (Nujol) 3200 and 1700 cm-1 (broad); nmr (CDCl2) 2.28 (CH3), 2.47 (CH3), 5.53 (CH), and 9.7 ppm (NH), (a weaker set of singlets corresponding to the enol appears at 2.23, 2.52, and 8.7 ppm); mass spectrum m/e 43 (100%), 93, 135, and 177 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3](=O)[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O.[NH2:19][C:20]1[CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]([OH:29])=[CH:22][CH:21]=1>C(O)(=O)C>[C:2]([C:3]1[N:19]([C:20]2[CH:21]=[CH:22][C:23]([OH:29])=[C:24]([C:25]([OH:27])=[O:26])[CH:28]=2)[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=1)([CH3:18])([CH3:17])[CH3:1]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: CC(C)(C)C(=O)CC1C(=O)CCc2ccccc21
Solvent: CC(=O)O
Product: CC(C)(C)c1cc2c(n1-c1ccc(O)c(C(=O)O)c1)CCc1ccccc1-2

Procedure:
A mixture of 15.2 g. (0.062 mole) of 1-(3,3-dimethyl-2-oxobutyl)-2-tetralone, 9.5 g. (0.062 mole) of 5-aminosalicylic acid, and 50 ml. of glacial acetic acid was heated under reflux under nitrogen for 1.5 hours, cooled and filtered. The collected solid was washed with acetic acid and petroleum ether and then recrystallized from acetonitrile to provide 10.4 g. (46%) of off-white crystals, m.p. 258°-260°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=1)[CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][N:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1)[CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N(CC)CCc2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CCc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-[N-(2-(2-benzyloxyphenyl)ethyl)-N-ethylamino]benzoate was dissolved in a solution of methanol (20 ml) and tetrahydrofuran (20 ml). To this solution was added aqueous 2N sodium hydroxide (10.5 ml) and the mixture heated at reflux for 24 hours; cooled and the volume reduced by evaporation to half the original volume. Water (20 ml) was added and the mixture acidified with acetic acid. The resulting solid was filtered and dried under vacuum at 60° C. to give the title product (950 mg) m.p. 175° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([OH:17])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2].Br[CH2:29][C:30]1[O:34][C:33](=[O:35])[O:32][C:31]=1[CH3:36]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:15]([O:17][CH2:36][C:31]1[O:32][C:33](=[O:35])[O:34][C:30]=1[CH3:29])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1oc(=O)oc1CBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OCc1oc(=O)oc1C
Yield: 5.3 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (19) (1.5 g, 3.5 mmol) dissolved in 15 mL of anhydrous toluene was reacted with 1.4 g (7.0 mmol) of commercially available 5-bromomethyl-4-methyl-1,3-dioxolen-2-one in the presence of 1.4 g (5.3 mmol) of silver carbonate (Ag2CO3). After work-up and further purification by mass-guided preparative HPLC, 0.1 g (5.3% yield) of the title compound (48a) was obtained as a colorless, viscous oil. Rf=0.62 (EtOAc/MeOH=19:1). MS (ESI) m/z 538.14 (M+H)+, 560.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Cl:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1>C1COCC1>[Cl:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:2][C:1]#[N:3])=[CH:13][CH:12]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCc1ccc(CCl)cc1
Temperature: -78 °C
Yield: 145.5 %

Procedure:
Acetonitrile (0.30 mL, 5.7 mmol) was added to a solution of n-butyllithium (2.4 m in hexanes, 1.96 mL, 4.7 mmol) in dry THF (5 mL) at −78° C. and stirred for 45 min. solution of α,α′-dichloro-p-xylene (2.485 g, 14.2 mmol) in dry THF at −78° C. was added to give a yellow, cloudy solution. The mixture was stirred at −78° C. for an additional hour and quenched with saturated aqueous NaCl (30 mL) before warming to room temperature. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organic extracts were dried over MgSO4 and concentrated to a white solid (2.45 g). The product was purified by column chromatography on silica gel (10:1-EtOAc:Hex) to give the desired nitrile (1.49 g, 60%) as a light yellow syrup. 1H NMR (300 MHz, CDCl3) δ7.37 (d, 2H, J=8.1 Hz), 7.24 (d, 2H, J=8.1 Hz), 4.58 (s, 2H), 2.96 (t, 2H, J=7.4 Hz), 2.62 (t, 2H, J=7.4 Hz).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:39][CH2:40][C:41]([C:44](OC)=[O:45])([CH3:43])[CH3:42])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[CH2:17][C:16](=[O:38])[NH:15]2)[CH:13]=1.O>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:39][CH2:40][C:41]([CH3:43])([CH3:42])[CH2:44][OH:45])=[C:12]([CH:14]2[C:19]3([C:27]4[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH:18]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[CH2:17][C:16](=[O:38])[NH:15]2)[CH:13]=1
Reactant: COC(=O)C(C)(C)COc1ccc(Br)cc1C1NC(=O)CC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Br)ccc2OCC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
LiAlH4 (11.4 mg, 0.3 mmol) was suspended in THF in ice bath, then a solution of racemic (2′R,3R,4′S)-2′-[5-bromo-2-(2-methoxycarbonyl-2-methyl-propoxy)-phenyl]-6-chloro-4′-(5-chloro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione prepared in Example 262d (63 mg, 0.1 mmol) in THF (2 mL) was added slowly. The reaction mixture was stirred at room temperature for 10 min, water (1 mL) was added and the resulting mixture was filtered. The filtration was concentrated and the residue was purified by Prep-HPLC to give the title compound as a white solid (Yield: 31 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].[CH2:21](O)[CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:21][CH2:22][OH:23])(=[O:10])=[O:11]
Reactant: OCCO
Reactant: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCO)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
A solution of 3-(2-methoxyphenylsulfonyloxy)-5-methylphenol (245 mg, 0.83 mmol, prepared in step b of example 8), ethylene glycol (0.23 mL, 4.1 mmol), 1,1'-(azodicarbonyl)dipiperidine (420 mg, 1.66 mmol) and anhydrous tetrahydrofuran (6 mL) was cooled to 0° C. under nitrogen. Tri-n-butylphosphine (0.41 mL, 1.66 mmol) was added dropwise over 2.5 minutes. The mixture was stirred at 0° C. for 5 hours, then more 1,1'-(azodicarbonyl)dipiperidine (210 mg) and tri-n-butylphosphine (0.21 mL) were added. The reaction was stirred overnight at ambient temperature, then more 1,1'-(azodicarbonyl)dipiperidine (420 mg) and tri-n-butylphosphine (0.41 mL) were added. The mixture was stirred overnight at ambient temperature, then diethyl ether (50 mL) was added and the mixture was filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography through silica gel (3:2 ethyl acetate/hexane) to give the title compound as a colorless oil (190 mg, 67%). 1H-NMR (300 MHz, CDCl3) δ 7.82 (dd, 1H, J=1.7, 7.9 Hz), 7.62 (ddd, 1H, J=1.8, 7.4, 8.4 Hz), 7.09 (dd, 1H, J=0.8, 8.4 Hz), 6.99-7.05 (m, 1H), 6.60-6.61 (m, 1H), 6.53-6.55 (m, 1H), 6.46-6.48 (m, 1H), 4.02 (s, 3H), 3.89-4.01 (m, 4H), 2.25 (d, 3H, J=0.6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H18O6S: 361.1 (M+Na). Found: 360.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: C1COCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CN1CCOCC1
Yield: 38.3 %

Procedure:
A solution of N-bromosuccinimide, dibromomethane (3.56 g, 20 mmol) and methyl-2-methylbenzoate (3.04 g, 20 mmol) in 30 mL CHCl3 was refluxed for 4 h. The solvent was evaporated and the residue was purified by column chromatography, with EtOAc:hexanes, 1:5, as eluant, yielding (3.496 g, 76%) of 2-bromomethyl-benzoic acid methyl ester. A solution of 2-bromomethyl-benzoic acid methyl ester (368 mg, 2 mmol) and morpholine (174 mg, 2.0 mmol) in 8 mL DMF with 1 mL HCl (2 N) was refluxed overnight. The solvent was evaporated in vacuo and the residue was purified by column chromatography with EtOAc:hexanes, 1:4, yielding (180 mg, 38%) 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester. The title compound was prepared from 2-(morpholin-4-ylmethyl)-benzoic acid methyl ester, hydrazine and then 3-trifluoromethyl-benzaldehyde in two steps by procedures similar to Example 29. 1H NMR (CDCl3): 8.46 (s, 1H), 8.02 (m, 2H), 7.96 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.45 (m, 2H), 7.22 (m, 1H), 3.82 (t, J=4.8 Hz, 4H), 2.64 (t, J=4.8 Hz, 4H).
Reaction SMILES: C([Li])CCC.[C:6]1([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.CN(C)[CH:23]=[O:24]>CCCCCC.CCOCC>[N:16]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[C:14]([CH:23]=[O:24])=[CH:13][CH:12]=[CH:11]3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C=O
Reactant: c1ccc2c(N3CCCC3)cccc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cccc2cccc(N3CCCC3)c12
Temperature: -20 °C

Procedure:
n-Butyllithium (14.7 ml of a 1.7 M solution in hexane) was added dropwise to a stirred solution of 1-(1-naphthyl)pyrrolidine (25.00 mmol, 5.00 g) in dry ether (50 ml) at −20° C. under argon. After 48 hours a solution of dry N,N-dimethylformamide (6.2 ml, 75.00 mmol) in ether (10 ml) was added dropwise at −78° C. to the reaction mixture. The mixture was allowed to warm to −20° C. over 4 hours, then quenched with a solution of methanol (15 ml) and allowed to warm to room temperature. The reaction mixture was diluted with ether (100 ml), washed with water (3×150 ml) and with brine (150 ml), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography using dichloromethane as eluent to afford the aldehyde which was crystallized from hexane.
Reaction SMILES: [NH2:1][O:2]S(O)(=O)=O.[F:7][C:8]1[C:13]([CH:14]2[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)=O.C(OCC)(=O)C>[F:7][C:8]1[C:13]([CH:14]2[CH2:19][CH2:18][C:17](=[N:1][OH:2])[CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: NOS(=O)(=O)O
Reactant: O=C1CCC(c2cccnc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: ON=C1CCC(c2cccnc2F)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A suspension of aminooxysulfonic acid (0.35 g, 3.11 mmol) in 96% formic acid (2.5 mL) was added dropwise to a solution of 4-(2-fluoropyridin-3-yl)cyclohexanone (0.50 g, 2.59 mmol) in 96% formic acid (2.5 mL) at room temperature. The solution was stirred for 15 min, then warmed to 40° C. for 2 h, then cooled 0° C. Ethyl acetate (10 mL) was added and the mixture was neutralized by the dropwise addition of 10 N aqueous sodium hydroxide solution (10 mL) followed by saturated aqueous sodium bicarbonate. The resulting biphasic mixture was separated, the aqueous layer was extracted with ethyl acetate (2×), and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 4-(2-fluoropyridin-3-yl)cyclohexanone oxime. [M+1]=209.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[N:11]=1.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[N:11]=1
Reactant: [H][H]
Reactant: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCCc1nc(-c2ccccc2N)co1

Procedure:
Combine 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester (3.0 g, 10.3 mmol) with Pd/C (5%, 450 mg) and Pd/black (50 mg) in THF (150 mL) and react with hydrogen (init. 40 psi) in a Parr® apparatus. When reduction is complete, filter the mixture through Celite® and concentrate the filtrate. Drying allows for recovery of crude 4-[4-(2-amino-phenyl)-oxazol-2-yl]-butyric acid methyl ester (2.36 g, 88%). MS (ES): (M+1)+ 261.2 m/z.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[F:1]
Reactant: CC(=O)Nc1cccc(F)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(F)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-(3-Fluoro-2-methylphenyl)acetamide (39 mmol) in acetic acid (50 mL) was added bromine (40 mmol) in dropwise fashion. After stirring at rt for 2 days, the precipitated product was filtered, washed with water, and dried under high vacuum. N-(4-Bromo-3-fluoro-2-methylphenyl)acetamide was obtained as a white solid.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].F[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=1>O1CCCC1>[F:32][C:28]1[N:27]=[C:26]([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH3:2])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(c1ccccn1)c1ccccn1
Reactant: Fc1cccc(F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(c1ccccn1)(c1ccccn1)c1cccc(F)n1

Procedure:
26.8 g (145 mmol) of 2,2′-(ethane-1,1-diyl)dipyridine were dissolved in 400 ml of tetrahydrofurane. A solution of 32 g (160 mmol) of potassium hexamethyldisilazide in 240 ml tetrahydrofuran was added. Meanwhile the solution coloured to dark red. After stirring for one hour 16.8 g (145 mmol) of 2,6-difluoropyridine was added in one batch. The mixture was heated under reflux for 1 hour.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][C:12](=[O:14])[C:5]2[C:6]([C:9]([OH:11])=O)=[CH:7][O:8][C:4]=2[CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9]([C:6]2[C:5]3[C:12](=[O:14])[CH2:13][CH:2]([CH3:1])[CH2:3][C:4]=3[O:8][CH:7]=2)=[O:11])=[CH:18][CH:17]=1
Reactant: CC1CC(=O)c2c(C(=O)O)coc2C1
Reactant: Nc1ccc(F)cc1
Product: CC1CC(=O)c2c(C(=O)Nc3ccc(F)cc3)coc2C1

Procedure:
Starting from 6-methyl-4-oxo-4,5,6,7-tetrahydro-benzofuran-3-carboxylic acid and 4-fluoroaniline, General Procedure B provided the title compound: