Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](C=O)[CH:2]=1.[CH2:9]([NH2:11])[CH3:10]>C(Cl)(Cl)Cl>[N:1]1[CH2:2][C:3](=[N:11][CH2:9][CH3:10])[CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cccnc1
Reactant: CCN
Solvent: ClC(Cl)Cl
Product: CCN=C1C=CC=NC1
Yield: 101.2 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (1 g, 9.3 mmol) and ethylamine (661 mg, 10.2 mmol, 70% wt in water) was strirred at room temperature for 18 h. The reaction mixture was diluted with chloroform (20 mL) and dried over anhydrous K2CO3. The solution was filtered and the solvent was evaporated to afford N-(3-pyridylidene)-ethylamine (XVII) 1.15 g (92%), which was used immediately without further purification. 1H NMR (CDCl3): δ 8.82 (s, 1H), 8.60 (d, 1H), 8.28 (s,1H), 8.10 (m, 1H), 7.4-7.3 (m, 1H), 3.78-3.62 (q, 2H), 1.38-1.22 (t, 3H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Br[CH2:5][CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>>[CH2:1]([NH:3][CH2:5][CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCN
Product: CCNCC(OCC)OCC

Procedure:
Ethylamine (38 grams) and 1-bromo-2,2-diethoxyethane (20 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux overnight. After this time the mixture was washed with aqueous sodium hydroxide and the organic phase separated from the aqueous phase. The organic phase was then distilled to yield the desired product N-ethyl-N-(2,2-diethoxyethyl)amine as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([C:38]3[CH:39]=[CH:40][C:41](=[O:44])[NH:42][N:43]=3)=[CH:19][CH:20]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]n2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Yield: 13.4 %

Procedure:
A mixture of 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile (150 mg, 0.31 mmol), 6-chloropyridazin-3-(2H)-one (62 mg, 0.47 mmol), Pd(Ph3P)2Cl2 (15 mg), and aq. Cs2CO3 solution (2 mL, 2M) in 1,4-dioxane (10 mL) was stirred at reflux for 2 h. When the reaction was finished, the mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative TLC to give 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (18.9 mg, 15%). LC-MS Method 2 tR=1.053 min, m/z=457.3; 1H NMR (CDCl3): δ1.16 (s, 3H), 1.25 (s, 3H), 1.38 (d, 3H), 2.21 (s, 2H), 2.24 (m, 1H), 2.40 (m, 2H), 2.86 (m, 1H), 5.61 (m, 1H), 6.86 (m, 2H), 6.95 (m, 1H), 7.29 (m, 5H), 7.32 (m, 2H), 7.56 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+].[CH3:24][CH2:25][OH:26]>>[CH2:25]([O:26][C:12]1[CH:13]=[C:14]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)[C:5]2[C:6](=[O:11])[NH:7][C:8]3[C:4]=2[C:3]=1[C:2]([F:1])=[CH:10][CH:9]=3)[CH3:24]
Reactant: CCO
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (19.8 mg, 0.05 mmol) in EtOH (5 mL) was added NaH (Aldrich, 60%, 0.1 g, 2.5 mmol) in portions at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was heated under reflux for 2 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, 50% ethyl acetate in hexanes) to afford 5-ethoxy-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 3.0 mg, 20.1%).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:10][C:9]1([CH3:14])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)Oc2ccccc2O1
Temperature: 25 °C
Yield: 37840.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 10.0 grams (0.091 mole) of catechol in 100 mL of toluene and 100 mL of acetone was stirred and 0.01 gram (catalyst) of para-toluenesulfonic acid was added in one portion. Upon completion of additon the reaction mixture was warmed to reflux where it was maintained during a 48 hour period. After this time the reaction mixture was cooled to ambient temperature, then it was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:31][C:29]2[S:30][C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:33]=[CH:32][C:27]=3[N:28]=2)=[O:17])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Product: COc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 6-methoxybenzo[d]thiazol-2-amine (99 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methoxybenzo[d]thiazol-2-yl)benzamide as an off-white solid. Yield: 89 mg (35%). 1H-NMR: 8.57 (s, 1H), 8.37 (d, J=8 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.77-7.66 (m, 2H), 7.63 (d, J=2.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.07 (dd, J=8.5, 2.5, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.5 Hz, 2H), 3.83 (s, 3H), 2.92 (t, J=8.5 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH:9]=1)[CH3:2].[CH3:11][N:12]([CH3:15])[CH:13]=O>>[CH3:11][N:12]([CH:15]=[C:6]1[C:5](=[O:10])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH2:8][CH2:7]1)[CH3:13]
Reactant: CN(C)C=O
Reactant: CCOC1=CCCCC1=O
Product: CCOC1=CCCC(=CN(C)C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3.4 g (0.02 mmol) of 2-ethoxycyclohex-2-en-1-one were dissolved in 30 mL of dry dimethylformamide and 30 mL (0.05 mmol) of dimethylformamide dimethyl acetale were added. The solution was stirred at 60° C. for 2 hours. The solvent was then evaporated under vacuum, the residue triturated with diethyl ether and collected by filtration to give 6.6 g of the title compound (80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:11][CH2:10]1
Reactant: CCOC(=O)Cl
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-methoxyphenyl)piperazine (30 g) in dichloromethane (500 ml) are added triethylamine (22.9 ml) and ethyl chloroformate (15.8 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is concentrated under reduced pressure, diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure to give ethyl 4-(2-methoxyphenyl)piperazine-1-carboxylate. (2) To a solution of the above product (5 g) in conc. sulfuric acid (18 ml) is added conc. nitric acid (1.31 ml) at 0° C., and the mixture is stirred at around 10° C. for 2 hours. The reaction solution is poured into cold water, and the pH value thereof is adjusted to pH 3 with 2M aqueous sodium hydroxide solution. The resulting precipitates are collected by filtration to give ethyl 4-(2-methoxy-5-nitrophenyl)piperazine-1-carboxylate. (3) The above product (5 g) is dissolved in a mixture of methanol (50 ml) and tetrahydrofuran (50 ml), and thereto is added 2M aqueous sodium hydroxide solution (50 ml), and the mixture is heated under reflux for 18 hours. The reaction solution is diluted with water and ethyl acetate, and the organic layer is washed with saturated brine, dried over magnesium sulfate. To the organic layer is added a 30% solution of hydrogen chloride in ethanol, and the resulting precipitates are collected by filtration to give the title compound (3.52 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=O)=[CH:4][CH:3]=1.Cl.[NH2:13][C:14]1[N:18]([NH2:19])[C:17]([CH3:20])=[N:16][N:15]=1.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]=[N:19][N:18]3[C:17]([CH3:20])=[N:16][N:15]=[C:14]3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1nnc(N)n1N
Reactant: O=CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc2nc(-c3ccc(Cl)cc3)cnn12

Procedure:
A solution of 7.8 g. of p-chlorophenylglyoxal, 6.3 g. of 3,4-diamino-5-methyl-4H-1,2,4-triazole hydrochloride and 1.7 g. of sodium hydroxide in 90 ml. of 67% acetic acid is heated on a steam bath for 1/2 hour. Water is added and heating is continued until yellow crystals separate. These crystals are collected by filtration and washed with hot ethanol, giving the desired product as a yellow solid, m.p. 240° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][C@H:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:36](=[O:37])[CH2:35][O:34][C:31]1=[O:33]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N)C1
Reactant: CC(=O)OCC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(Cl)cc(Cl)cc2[C@H](c2ccccc2N2C(=O)COC2=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (300 mg, enantiomer B, preparation as described in WO2004085404) was dissolved in absolute THF (10 ml) and admixed at room temperature with stirring with sodium hexamethyl-disilazide solution (0.5 ml; 2 M in THF). After 30 min, acetoxyacetyl chloride (77 μl) was added and the mixture was stirred at room temperature for 2 h. Subsequently, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate/water and basified with sodium hydrogencarbonate solution, and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 380 mg of the desired product were obtained. 40 mg thereof were dissolved in acetonitrile/water, acidified with 0.1 N hydrochloric acid and freeze-dried.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([OH:34])=[CH:28][CH:27]=2>>[CH3:23][C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][C:29]([O:34][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:28][CH:27]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 39.5 %

Procedure:
Using an analogous procedure to that described in Example 34, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (110 mg, 0.34 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,3-dimethyl-5-hydroxyindole (66 mg, 0.41 mmol), (Arch. Pharm. 1972, 305, 159). The crude product was purified by column chromatography eluting with methanol/methylene chloride (1/9) followed by 3M ammonia in methanol/methanol/methylene chloride (5/15/80) to give 4-(2,3-dimethylindol-5-yloxy)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (60 mg, 40%).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](=[NH:8])[O:5][CH2:6][CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:8]=[C:4]([O:5][CH2:6][CH3:7])[C:3]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:2]=1[Cl:1])=[O:19]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1cccc(Cl)c1Cl
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1cccc(Cl)c1Cl

Procedure:
starting from ethyl 2,3-dichlorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2,3-dichlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(2,3-dichlorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 86°-88° C.;
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O>C1COCC1>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([I:12])=[C:7]([CH:11]=1)[CH2:8][OH:9]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1I
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Trifluoromethyl-2-iodobenzoic acid (50 g, 158 mmol) is dissolved in anhydrous THF (200 mL) and cooled in an ice-salt bath until the temperature reaches −5° C. Borane-THF complex is added dropwise as a 1.0 M solution in THF (350 mL, 350 mmol) at −5° C. After addition is complete, the reaction mixture is slowly warmed to room temperature and stirred for 12 hours. Water (40 mL) is carefully added dropwise (foaming) and the reaction mixture stirred for 30 minutes. Additional water (350 mL) is added and the mixture is concentrated by rotary evaporator to remove most of the THF. Additional water (250 mL) is added to form a precipitate, which is isolated by filtration to give 5-trifluoromethyl-2-iodobenzyl alcohol (m.p. 81–82° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:11][C:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[OH:1])=[O:12]
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: COC(OC)N(C)C
Product: COc1ccc(C(=O)C=CN(C)C)c(O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(2-hydroxy-4-methoxyphenyl)ethane-1-one (20 g, 120 mmol) and N,N-dimethylformamide dimethylacetal (23 g, 181 mmol) was stirred at 90° C. for 2 hours. After cooling to room temperature the reaction mixture provided a yellow precipitate, which was washed with ethyl acetate (3×30 ml), water (2×50 ml), and dried under reduced pressure to yield 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one (9) as the trans isomer; MS 222.1 (M+H)
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:4][C:3]=1[CH3:21].[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH2:19][C:17]1[S:18][C:14]([C:12]2[O:11][N:10]=[C:9]([C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[C:3]([CH3:21])[CH:4]=3)[N:13]=2)=[CH:15][CH:16]=1)[CH3:24]
Reactant: CNC
Reactant: Cc1cc(-c2noc(-c3ccc(C=O)s3)n2)cc(C)c1O
Product: Cc1cc(-c2noc(-c3ccc(CN(C)C)s3)n2)cc(C)c1O

Procedure:
The title compound is prepared from 5-[3-(4-hydroxy-3,5-dimethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-thiophene-2-carbaldehyde and dimethylamine according to Method B; LC-MS: tR=0.75 min; [M+1]+=330.05.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:39])=[C:34](B(O)O)[CH:35]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: Cc1ccc(F)cc1B(O)O
Product: Cc1ccc(F)cc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1C[C@H](O)[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 290 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 248.1) and 5-fluoro-2-methylphenylboronic acid to afford a white solid. HPLC (Condition 10) tR=6.25 min, UPLC-MS (Condition 11) tR=1.08 min, m/z=508.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.90 (s, 2H) 1.95/2.06 (s, 3H) 2.76-3.00 (m, 1H) 3.04-3.25 (m, 2H) 4.09-4.21 (m, 1H) 4.76-4.90 (m, 2H) 7.08-7.17 (m, 1H) 7.25-7.35 (m, 4H) 7.81-7.97 (m, 3H) 8.74 (s, 1H) 10.07-10.17 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:31]=[C:30]([CH3:32])[C:14]([O:15][CH:16]4[CH2:19][CH:18]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[CH2:17]4)=[C:13]([CH3:33])[CH:12]=3)[O:8][C:6]=2[N:7]=1.[CH3:34][S:35]([O-:37])=[O:36].[Na+]>CN(C)C=O>[CH3:34][S:35]([C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:31]=[C:30]([CH3:32])[C:14]([O:15][CH:16]4[CH2:19][CH:18]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[CH2:17]4)=[C:13]([CH3:33])[CH:12]=3)[O:8][C:6]=2[N:7]=1)(=[O:37])=[O:36]
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cnc(S(C)(=O)=O)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1

Procedure:
A solution of 200 mg of benzyl 3-[4-(5-chlorooxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]cyclobutanecarboxylate and 48 mg of sodium methylsulfinate in 4 ml of N,N-dimethylformamide was heated in a microwave reactor at 100° C. for 60 min. At room temperature, the mixture was filtered and then washed with DMF. The filtrate was concentrated and the resulting residue was purified by preparative HPLC. This gave 71 mg (32%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][OH:11].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F>>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:11][C:15]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=1[C:13]([F:12])([F:24])[F:25]
Reactant: Cn1c([N+](=O)[O-])cnc1CO
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
m.p. 153° C, from 1-methyl-2-hydroxymethyl-5-nitro-imidazole and 2-trifluoromethyl-4-nitro-fluorobenzene.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O.O>[C:17]([O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])[CH3:18]
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzoin 23 (2.0 g, 9.40 mmol) was dissolved in acetic anhydride (15 mL, 158.70 mmol) followed by the addition of two drops of sulfuric acid which resulted in a pale yellow color. The reaction mixture was then stirred under a nitrogen atmosphere at room temperature (72 h) while monitoring its progress by TLC. The reaction mixture was then dissolved in water and extracted with dichloromethane (3×40 mL). The dichloromethane layer was then dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and removal of the solvent by rotary evaporation, the product was found to be of acceptable purity as evidenced by 1H NMR and TLC, Rf: 0.2 (hexane/ethyl acetate, 2:1): mp 83-85° C. (Lit. 85-87° C.).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:6][CH:5]=1.[CH3:22]O>>[CH3:22][C:19]1[C:10]([CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([Br:3])=[CH:5][CH:6]=2)=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13]
Reactant: CO
Reactant: COC(=O)c1ccccc1COc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1COc1ccc(Br)cc1
Reaction time: 8 h
Yield: 84 %

Procedure:
A 2 mol/L aqueous sodium hydroxide solution (250 mL) was added to a methanol (1 L) solution of methyl 2-(4-bromophenoxymethyl)-benzoate (139 g, 432 mmol), and the mixture was stirred overnight while heating under reflux. Methanol was distilled off under a reduced pressure, and a 6 mol/L hydrochloric acid was added to the residue obtained to precipitate the crystals, and the precipitated crystals were collected by filtration, and sufficiently washed with water. The crystals were dried over phosphorus pentoxide at 50° C., to give 112 g (84%) of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)Cc1ccccc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a 250 mL round bottom flask, 5.0046 g (23.2729 mmol, 1.0 eq) of 2-(Bromophenyl)acetic acid was dissolved in 100 mL of clean, dry MeOH under N2 atmosphere. This solution was cooled to 0° C. using a wet ice bath and stirred for five minutes. To the stirring solution was added 2.55 mL (34.9093 mmol, 1.5 eq) of thionyl chloride dropwise over a period of five minutes. The reaction was then allowed to stir overnight, gradually warming to room temperature. The following morning, the solvent was removed under reduced pressure. The resultant deep yellow oil was taken up in 50 mL of DCM. The solution was then washed with 50 mL of saturated NaHCO3 (aq) solution. The organic layer immediately became colorless. The layers were separated and the organic layer was washed with brine (1×30 mL) and then dried over Na2SO4. The solution was decanted and then solvent was removed under reduced pressure. A clear oil was isolated. LCMS (m/e): 230 (M+H); 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.69 (s, 3H) 3.82 (s, 2H) 7.10-7.25 (m, 1H) 7.26-7.40 (m, 2H) 7.58 (d, J=7.91 Hz, 1H).