Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH3:17]>>[CH:9]([C:17]1[CH:16]=[CH:3][CH:2]=[CH:1][C:6]=1[N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:15])[CH3:10]
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CCO
Product: CC(C)c1ccccc1-n1c(-c2ccccc2)nc2ccccc21
Temperature: 25 °C

Procedure:
Intermediate 1 (1.5 g, 2.1 mmol) and 142-isopropylphenyl)-2-phenyl-1H-benzo[d]imidazole (2 g, 6.4 mmol) were mixed with 30 ml of ethanol in a three-neck flask under nitrogen. The mixture was heated up to reflux for 24 hours. After cooled to room temperature, the precipitate was collected by filtration. The product was purified by column chromatography using 1:2 dichloromethane and hexanes as eluent. 0.7 g of desired product was obtained after purification.
Reaction SMILES: C1COCC1.[CH:6]1([C:9](=[O:12])[CH2:10][CH3:11])[CH2:8][CH2:7]1.[C:13]([O:20][CH2:21][CH3:22])(=[O:19])[C:14]([O:16]CC)=O>C(OCC)C>[CH:6]1([C:9](=[O:12])[CH:10]([CH3:11])[C:14](=[O:16])[C:13]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][CH2:7]1
Reactant: CCC(=O)C1CC1
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C(=O)C1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
165 mL of an 1 M solution of bis(trimethylsilyl)lithiumamid in THF (166 mmol, 1.10 eq.) were brought forward in 500 mL of diethyl ether and cooled down to −78° C. 14.8 g of 1-cyclopropylpropan-1-one 1-12-1 was dissolved in 100 mL of diethyl ether and added dropwise at −78° C. The mixture was stirred for one hour at −78° C. and then 24.5 mL of diethyl oxalate was added dropwise. The cooling bath was removed and the mixture was stirred for 24 hours at rt. 500 mL of aqueous 1M hydrogen chloride solution was added and the mixture was extracted with DCM, dried over a silicone filter sulfate and concentrated in vacuo to provide 27.2 g (137 mmol, 91%) of the target compound as crude product. The crude product was used for the following step without further purification.
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.COC1C=NC2C(C=1)=CC=CC=2>C(COC)OC>[CH3:2][Sn:3]([CH3:5])([CH3:4])[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: COc1cc2ccccc2nc1Br
Reactant: C[Sn](C)(C)Cl
Agent: COc1cnc2ccccc2c1
Agent: [Na]
Solvent: COCCOC
Product: COc1cc2ccccc2nc1[Sn](C)(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3.00 g (131 mmol) of sodium are introduced in a sealed Schlenck-type apparatus under argon inert gas into 3 ml of DMEabs. (=absolute dimethoxyethane). The sodium is cut into very small pieces and, before being added to the reaction solution washed with DMEabs to remove any adhering paraffin. During addition of the sodium to the reaction solution, the DMEabs. slightly foams. The reaction solution is then cooled to -10° C. using an ice/common salt mixture. 0.83 g (4.18 mmol) of trimethyltin chloride is added to this solution. After a reaction time of 2 hours, the reaction solution is colorless, milky and cloudy. After a total of 3 hours, the reaction solution has become milky, cloudy and green. This can be considered as an indication of the formation of sodium trimethylstannate. Excess sodium is removed from the reaction solution under argon via a D-2 Schlenck-type frit. 0.35 g (1.45 mmol) of 2-bromo-3-methoxyquinoline (20) dissolved in 3 ml of DMEabs. is added dropwise to the filtered cloudy green reaction solution. Upon dropwise addition of the educt, the reaction solution spontaneously turns blood red. After a short time, the reaction solution has a brown color. After 30 minutes, the reaction solution finally turns beige. The solution is stirred at -10° C. for a total of 3 hours, during which the color of the reaction solution no longer changes. After the reaction is complete, the product mixture is filtered through a D-4 frit to remove the precipitate. The precipitate is washed with DMEabs. without vacuum, the runoff being dark brown. A colorless solid remains in the frit. Upon evaporation of the filtrate in a rotary evaporator, a dark-brown oil is obtained whose composition is analyzed by 1H-NMR spectroscopy. Explicit purification of the product is omitted due to the sensitivity to hydrolysis. The product content is determined by spectroscopy. The hydrolysis product 3-methoxyquinoline can be detected as a by-product of this reaction. This finding is confirmed by the 1H-NMR experiments described below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][CH2:32][Cl:33].CN(C=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][Cl:33])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCCBr
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Temperature: 40 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
A suspension of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (20.00 g), K2CO3 (10.37 g), KI (1.04 g), 1-bromo-3-chloropropane (7.50 mL) and DMF (150 mL) was stirred at 40° C. for 6 h. The reaction mixture was poured into water and filtered. The filter residue was purified by a silica gel column chromatography (eluting agent: EA) to give the title compound as pale yellow liquid (22.05 g, 89.00%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 396.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.01 (m, 2H), 3.68 (t, J=4.2 Hz, 2H), 4.00 (s, 3H), 4.10 (t, J=4.2 Hz, 2H), 6.80 (s, 1H), 7.16 (s, 1H), 7.26 (s, 1H), 7.30 (s, 1H), 7.47 (s, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [CH3:1]I.[CH3:3][C:4]1([CH3:14])[CH2:11][C:10]2([CH3:12])[CH:7]([CH2:8][CH2:9]2)[C:6](=[O:13])[CH2:5]1.[Cl-].[NH4+]>[Mg].CCOCC>[CH3:1][C:6]1([OH:13])[CH2:5][C:4]([CH3:14])([CH3:3])[CH2:11][C:10]2([CH3:12])[CH:7]1[CH2:8][CH2:9]2
Reactant: CI
Reactant: CC1(C)CC(=O)C2CCC2(C)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)CC(C)(O)C2CCC2(C)C1
Yield: 96.7 %

Procedure:
To 0.97 g. (0.04 g. atom) of magnesium in a 250 ml. 3-necked round bottomed flask fitted with dropping funnel, magnetic stirrer, and nitrogen inlet was added 25 ml. of ether. Then 5.0 g. (0.035 mole) of methyl iodide in 100 ml. of ether was added from a dropping funnel at such a rate that reflux was maintained as the Grignard reagent was formed. After all the methyl iodide was added, the solution was stirred and refluxed for an additional 1 hour. Then 4.98 g. (0.03 mole) of 4,4,6-trimethylbicyclo[4.2.0]octane-2-one was added in 75 ml. of ether over 30 minutes. After all of the ketone was added, the solution was stirred for an additional 1 hour and then 50 ml. of saturated aqueous ammonium chloride was added. The layers were separated and the aqueous layer was extracted twice with 50 ml. portions of ether. The combined ether layers were dried over sodium sulfate and concentrated in vacuo to yield a solid which was sublimed. The recovered product was 5.3 g. (0.029 mole, 97% yield) of 2,4,4,6-tetramethylbicyclo[4.2.0]octane-2-ol. m.p. 54° - 55° C. nmr: (deuterochloroform): 0.92δ (S-34); 1.02δ (S-34); 1.13δ (S-34); 1.21δ (S-34); 1.28δ - 2.25δ (complex multiplets10H). IR: 3610 cm-1.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([CH2:16][OH:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:20].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.CCOCC>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]([OH:20])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1onc(-c2ccccc2)c1C(F)(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CCOCC
Product: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)methanol (5.24 g, 21.6 mmol) in acetone (75 mL) at room temperature (immersed in a water bath) was added Jones' Reagent (43.8 mL, 53.9 mmol) via addition funnel slowly over 1.5 h. The dark reaction mixture was stirred at room temperature overnight. By HPLC, the reaction was 93% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. After 1 h, the reaction was 95% complete. After an additional 3 h, the reaction was 96% complete. An additional 0.5 equivalents (9 mL) of the Jones' Reagent was added. The reaction mixture was stirred for an additional 2.5 h. By HPLC, the reaction was 97% complete. Isopropyl alcohol (6 mL) was added, and the mixture was stirred for 90 min, resulting in a dark green precipitate. The mixture was diluted with ether (600 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite (5×100 mL), and the organic layer was collected. The aqueous layer was back-extracted with ether (2×100 mL). By HPLC, there was no additional product in the aqueous layer. The combined organic layers were washed with water (100 mL), washed with a saturated aqueous solution of brine (100 mL), and dried over anhydrous sodium sulfate. The aqueous layer was back-extracted with ether (100 mL), and the organic layer was added to the previous organic layers. The solution was concentration under reduced pressure to give 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid as an off-white solid. The solid was diluted with dichloromethane (200 mL), washed with a 2% aqueous solution of sodium hydrogen sulfite, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (3.84 g, 14.93 mmol, 69.3% yield) as a pale yellow solid. The product was 96% pure by HPLC with a ret. time=1.60 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=258.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5](=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:18][NH:19][NH2:20]>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:19]([CH3:18])[N:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(C=Cc1ccccc1)c1cccc(O)c1
Reactant: CNN
Solvent: CCO
Product: CN1N=C(c2cccc(O)c2)CC1c1ccccc1
Yield: 96.9 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was charged 1.0 g (0.0045 moles) of 3'-hydroxychalcone, and 25 mls of absolute ethanol. To this solution was then added 0.21 g (0.0045 moles) of methyl hydrazine in one portion. The reaction was then heated to reflux for two hours, then cooled. The solvent was removed under reduced pressure to afford 1.1 g of 3-(3-hydroxylphenyl)-1-methyl-5-phenyl-2-pyrazoline as a thick brown oil in 97% yield
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Br:18])C(OCC)=O)C.[OH-].[K+]>O>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(Cc1ccccc1Br)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccccc1Br
Temperature: 80 °C

Procedure:
A 4-neck 2 litre round bottom flask with equipped with a reflux condenser, thermometer and stirrer, is charged with 230 g (0.70 mol) of 2-(2-Bromo-benzyl)-malonic acid diethyl ester and placed in an oil bath. A solution of 225.8 g (4.02 mol) potassium hydroxide in 225 ml water is slowly added with stirring. The reaction temperature is carefully monitored and the addition of the potassium hydroxide solution is interrupted as soon as a significantly exothermic reaction starts. The temperature may rise up to 80° C. The remaining potassium hydroxide solution is added as soon as the initial reaction starts to subside. It may happen that no change in temperature is observed while adding the potassium hydroxide solution. If this happens, the reaction mixture is carefully and slowly heated to 80° C. The exothermic reaction may suddenly start. As soon as the initial reaction starts to subside, the reaction mixture is heated to 100° C. and stirred for 6 h at this temperature.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1.N1C=CC=C1C(O)=O.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[O:13]=[C:10]1[NH:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:25]2[CH2:24][CH2:23][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26]2)[CH2:12][O:11]1
Reactant: O=C1NC(c2ccccc2Br)CO1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]I
Agent: O=C(O)c1ccc[nH]1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C2COC(=O)N2)CC1
Temperature: 90 °C
Yield: 64.9 %

Procedure:
A mixture of 4-(2-bromophenyl)oxazolidin-2-one (497 mg, 2.05 mmol), 1H-pyrrole-2-carboxylic acid (137 mg, 1.23 mmol), tert-butyl piperazine-1-carboxylate (765 mg, 4.11 mmol), copper(I) iodide (117 mg, 0.616 mmol) and K3PO4 (1.74 g, 8.21 mmol) in DMSO (15 mL) was heated at 90° C. for 8 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (hexane/EtOAc, 1:1) to give tert-butyl 4-(2-(2-oxooxazolidin-4-yl)phenyl)piperazine-1-carboxylate (462 mg, 65%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][CH:32]([CH3:36])[C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:33]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:34])[CH:32]([CH3:36])[CH3:31]
Reactant: CC(C)C(=O)O
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 42.2 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol), 2-methylpropanoic acid (50 μL, 0.544 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (104 mg, 0.544 mmol), 1-hydroxybenzotriazole (73 mg, 0.544 mmol), triethylamine (76 μL, 0.544 mmol) and N,N-dimethylformamide (5 ml) as starting materials and in the same manner as in Example 380, the title compound (74 mg, 42%) was obtained as a pale-green powder.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH2:34][OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[CH2:32][CH2:33][CH:34]=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1O[C@@H](CCCO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: C[C@@H]1O[C@@H](CCC=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To solution of 3-(2,3,4-tri-O-benzyl-α-L-fucopyranosyl)propanol (8.4 g, 17.62 mmol) in CH2Cl2 (100 mL) at 0° C. was added Dess-Martin periodinane (11.21 g, 26.4 mmol). The resulting mixture was allowed to stir at 0° C. for 1 hr and then at rt for 2 hr. TLC indicates still some starting alcohol present so further Dess-Martin periodinane (5 g, 11.8 mmol) added and the mixture was stirred at rt for additional 2 hr. The resulting mixture was washed with sat'd NaHCO3 (3×150 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue purified by flash chromatography on silica gel (220 g), eluting with 0-80% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, J=6.6, 3H), 1.82 (m, 1H), 2.06 (m, 1H), 2.40-2.58 (m, 2H), 3.80 (m, 2H), 3.84 (m, 1H), 3.90 (m, 1H), 3.99 (dt, J=10.9, 3.8, 1H), 4.55 (d, J=11.8, 1H), 4.65 (d, J=11.8, 1H), 4.70 (t, J=12.0, 2H), 4.79 (dd, J=12.0, 9.2, 2H), 7.28-7.40 (m, 15H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1)=[O:6].CC1C=C(C)C=C(C)C=1S([NH:29]O)(=O)=O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:11]([NH2:29])[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: Cc1cc(C)c(S(=O)(=O)NO)c(C)c1
Reactant: CCOC(=O)c1ccc(C(=O)OC)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(=O)OC)n1N
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 90 mg) was added to a solution of 1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester (100 mg) in N,N-dimethylformamide (2 mL) and the resulting mixture was stirred for 5 minutes. 2,4,6-Trimethyl-benzenesulfonylhydroxylamine (prepared from 0.5 g of mesitilene oxamate as described in JOC 1973, 1239) was then added and the mixture was stirred for 5 minutes. The reaction mixture was then quenched by addition of water and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 90/10) to afford 100 mg of 1-amino-1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester 5-methyl ester.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]1[NH:8][C:7](=[O:9])[CH2:6]1.[CH2:12]=[O:13]>>[OH:13][CH2:12][N:8]1[CH:5]([C:4]#[C:3][Si:2]([CH3:10])([CH3:1])[CH3:11])[CH2:6][C:7]1=[O:9]
Reactant: C=O
Reactant: C[Si](C)(C)C#CC1CC(=O)N1
Product: C[Si](C)(C)C#CC1CC(=O)N1CO
Temperature: 25 °C
Yield: 75 %

Procedure:
4-(2-Trimethylsilylethynyl)-2-azetidinone (485 g) and paraformaldehyde (261 g) was heated at 135° C. for 45 minutes. The resulting mixture was cooled to room temperature and purified with column chromatography on silica gel (CH2Cl2: EtOAc=8:2) to give N-hydroxymethyl-4-(2-trimethylsilylethynyl)-2-azetidinone (429 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:13](Cl)(=[O:15])[CH3:14].C(OCC)C>O1CCCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:9]([CH3:12])(=[O:11])=[O:10])=[C:6]([NH:8][C:13](=[O:15])[CH3:14])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Br)cc1N
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(Br)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of 5-bromo-2-methanesulfonyl-phenylamine (5.7 g, 19.5 mmol) in dry tetrahydrofuran (30 mL) at 25° C. was treated with acetyl chloride (6.28 g, 80 mmol). The resulting solution was stirred overnight at 25° C., at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×100 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a brown solid. The brown solid was treated with diethyl ether (50 mL) and hexanes (50 mL). The white solid was collected by filtration and washed with hexanes (50 mL) to afford N-(5-bromo-2-methanesulfonyl-phenyl)-acetamide (4.55 g, 80%) as a white solid: mp 157-160° C.; EI-HRMS m/e calcd for C9H10BrNO3S (M+) 290.9565, found 290.9560.
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br

Procedure:
Alternatively, the starting material II may be prepared by reacting 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (prepared as disclosed by Krapcho et al, J. Med. Chem., 6, 544 (1963)) with N-bromosuccinimide to form 3-bromo-2-phenyl-1,5-benzothiazepin-4(5H)-one which is then reacted with cuprous cyanide in the presence of a solvent such as dimethylformamide to form the 1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarbonitrile starting material.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]1[CH2:17][C:16](=[O:18])[O:15][C:13](=[O:14])[CH2:12]1>C1(C)C=CC=CC=1>[CH3:10][CH:11]([CH2:17][C:16](=[O:18])[NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][C:13]([OH:15])=[O:14]
Reactant: NCCc1ccccc1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: Cc1ccccc1
Product: CC(CC(=O)O)CC(=O)NCCc1ccccc1

Procedure:
A solution of 2-phenylethylamine (6.3 ml) in dry toluene (50 ml) was added dropwise to a stirred solution of 3-methylglutaric anhydride (6.4 g) in dry toluene (250 ml) at 0° under a nitrogen atmosphere. After complete addition the mixture was heated at reflux temperature for 3 hours. The solution was evaporated and the residual oil triturated with ether (150 ml). The solid was filtered and dried to give the sub-title intermediate (3.3 g), mp 78°-80°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][C:12]1[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:14][C:15](Cl)=[N:16][C:17]=1[CH3:18].C(N(CC)CC)C.C(O)C(O)C>ClCCl>[CH3:11][C:12]1[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[CH3:30])=[N:14][C:15]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[O:9][CH3:10])=[N:16][C:17]=1[CH3:18]
Reactant: COc1cc(F)ccc1N
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CC(O)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccccc3C2C)n1
Temperature: 140 °C
Yield: 74.9 %

Procedure:
A reaction mixture of 4-fluoro-2-methoxy-aniline(0.155 g, 1.10 mmol), 5,6-dimethyl-2-chloro4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.24 lg, 0.84 mmol), triethylamine(0.15 ml, 1.1 mmol) and propyleneglycol (2 ml) was heated to 140° C. for 5 hours, cooled to a room temperature, diluted with dichloromethane(10 ml), and then washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/N-hexane=1/1) to give 0.247 g of the titled compound. (Yield 75.2%)