Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](O)=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:21])=O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([Cl:21])=[O:14])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)Cl)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid (4 g, 16.93 mmoles) in toluene (70 ml) and dimethylformamide (10 ml) cooled in an ice bath, oxalyl chloride (4.30 g, 33.87 mmoles) is dropped. The mixture is maintained under stirring at 0° C. for 1 hour then the temperature is let reach the room value and it is left for 2 hours. The solvent is removed at reduced pressure and the raw product is used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20].[I-:27].[Na+].CC(=O)CC>CCOCC>[I:27][CH2:2][CH2:3][C@H:4]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20]
Reactant: [I-]
Reactant: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCI)c1ccccc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A dry 1-L R.B. flask was charged (R)-3-chloro-1-phenyl-1-(2-methyl-4-((tert-butoxycarbonyl)oxy)phenoxy)propane (18.00 g, 47.80 mmol), sodium iodide (90.0 g, 600 mmol) and 2-butanone (550 mL). The reaction flask was protected from light. The reaction mixture was stirred at reflux temperature under nitrogen for 16 hours. The mixture was cooled to room temperature and poured into ether (1 L). The insoluble inorganic salts (white precipitate) were removed by filtration. The filtrate was concentrated under reduced pressure and the crude residue was dissolved in diethyl ether (1 L). The ethereal layer was washed with cold saturated sodium bisulfite solution (2×200 mL), water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to flash chromatography, eluting with 20% ethyl acetate in hexane to provide 20.5 grams (91%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c([N+](=O)[O-])c2)CC1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
A suspension of 350 mg of 2-amino-6-chloro-3-nitropyridine, 744 mg of N-(tert-butoxycarbonyl)piperazine and 552 mg of potassium carbonate in 4 ml of N-methylpyrrolidone was stirred in nitrogen atmosphere for 15 minutes at 160° C. The suspension was cooled to room temperature, to which 10 ml of water was added. Whereupon formed solid was recovered by filtration, washed with hexane and dried to provide 323 mg of the title compound.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH:11]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22](OCC)=[O:23])[CH2:10]3)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[C:4]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:13]3[C:12]4[NH:37][C:22](=[O:23])[C:18]5[N:17]([CH:21]=[CH:20][N:19]=5)[C:11]=4[CH2:10][C:9]=3[CH:8]=2)[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: CCOC(=O)c1nccn1C1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Yield: 66.1 %

Procedure:
8-Phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one can be obtained in the following way: a mixture of 17 g of ethyl 1-(5-phthalimidomethyl-1oxoindan-2yl)imidazole-2-carboxylate and 153 g of ammonium acetate in 355 ml of glacial acetic acid is heated at reflux for 16 hours. The reaction mixture is cooled to a temperature in the region of 20° C. The precipitate is filtered on sintered glass, rinsed with distilled water to neutral pH and then washed with acetone. After drying under vacuum (1 mbar) at 80° C., 10 g of 8-phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a brown solid (1H NMR spectrum in d6-DMSO, T=300K, δ in ppm: 4.00 (2H, s, CH2), 4.83 (2H, s, NCH2), 7.47 (1H, d, J=7 Hz, arom. CH), 7.55 (2H, d, J=7 Hz, arom. CH), 7.80 (1H, d, J=7 Hz, arom. CH), between 7.85 and 8.00 (4H, m, phthal. H), 12.30 (1H, broad s, NH)).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[BH4-].[Na+].CC(O)=O>CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCCc2c(Br)cncc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC1CCCc2c(Br)cncc21
Temperature: 0 °C
Yield: 92 %

Procedure:
A suspension of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (intermediate A-2 [C]) (2.135 g, 9.44 mmol) in MeOH (18.9 mL) was cooled to 0° C. and treated with NaBH4 (357 mg, 9.44 mmol) in 5 portions over 30 min. The reaction was stirred for ¾ h at 0° C., then AcOH was added dropwise until a pH ˜5-6 was obtained and the reaction mixture was evaporated. The residue was diluted with water and poured into aq. sat. NaHCO3-solution, then extracted with EtOAc (3×). The organic layers are washed once with aq. sat. NaHCO3 and aq. 10% NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was precipitated with CH2Cl2/n-pentane to afford the title compound (1.98 g, 92%) as dark brown viscous oil. MS: 227 (M+, 1Br).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[O:20]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)C(Br)c1ccc(I)cc1
Solvent: CO
Product: COC(=O)C(Oc1ccccc1)c1ccc(I)cc1

Procedure:
In a similar manner as in Example 29, 14.2 g of methyl α-bromo-α-(p-iodophenyl)acetate is reacted with 4.70 g of phenol in methanol to yield a white to light pink solid, mp 68°-71° C. Recrystallization from petroleum ether yields the product as white crystals, mp 72.5°-74° C.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[NH:13][C:12]3=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH3:24])[C:12]3=[O:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)c2cc(Oc3ccc([N+](=O)[O-])cc3)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2C1=O
Reaction time: 8 h
Yield: 82.9 %

Procedure:
A slurry of 5-(4-nitrophenoxy)isoindoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 mmol) and NaH (0.13 g, 5.27 mmol) in DMF (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mmol). The resulting mixture was stirred at room temp. overnight, then was cooled to ° C. and treated with water (10 mL). The resulting solids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindoline-1,3-dione as a bright yellow solid (0.87 g, 83%): TLC (35% EtOAc/65% hexane) Rf0.61.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1(C)C=CC=CC=1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: Oc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCN[C@H]3CC[C@H](O)CC3)cc2)nc1

Procedure:
Heat a mixture of the phenol (121.2 mg, 0.52 mmol), 6-chloronicotinamide (121.0 mg, 0.77 mmol), and K2CO3 (213.5 mg, 1.55 mmol) in 3:1 DMF/toluene (6.0 mL) at 165° C. for 3 hours. Quench the reaction with a small amount of H2O and concentrate to dryness, using xylenes to remove DMF azeotropically. Dissolve the residue in MeOH and filter. Concentrate the filtrate and purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH, to afford the title compound (79.1 mg, 43%): MS ES+ 356.0 (M+H)+, HRMS calcd for C20H26N3O3 356.1974 (M+H)+, found 356.1959, time 0.34 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=5.81 min, 100% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[C:14]([CH2:16]C(O)=O)#[N:15].C(O)(=O)CCCCCC.NC1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[CH2:16][C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: N#CCC(=O)O
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CCCCCCC(=O)O
Solvent: Nc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(CC#N)=CCC2
Yield: 87 %

Procedure:
There are introduced into a 670 litre reactor 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene in the presence of 11.0 kg of aniline. The mixture is heated at reflux. When all the starting substrate has disappeared, the solution is cooled and filtered. The precipitate obtained is washed with toluene and then the filtrate obtained is washed with a 2N sodium hydroxide solution and subsequently with water until neutral. After removal of the solvent by evaporation, the resulting solid is recrystallised from an ethanol/water (80/20) mixture to give the title product in a yield of 87% and with a chemical purity exceeding 99%.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[CH2:22][N:23]=[C:24]=[O:25]>C(O)C>[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[CH2:22][NH:23][C:24]([N:8]1[CH2:9][CH2:10][C:11]2[NH:3][CH:4]=[N:5][C:6]=2[CH2:7]1)=[O:25]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a mixture of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.55 mmol), ethanol (10 mL) and triethylamine (1.10 mL, 7.89 mmol), 2,4-dichlorobenzyl isocyanate (0.52 g, 2.57 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was distributed between water (20 mL) and ethyl acetate (75 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in diethylether (50 mL) and the crude product was filtered off. Recrystallization from acetone (25 mL) gave 0.30 g (37%) of the title urea as a colourless solid.
Reaction SMILES: [C:1]1([CH2:17][OH:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>CN(C=O)C.ClCCl>[Br:19][CH2:20][C:21]([O:18][CH2:17][C:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)=[O:22]
Reactant: OCc1ccc2ccc3cccc4ccc1c2c34
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CBr)OCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 23 °C
Reaction time: 17 h
Yield: 100.6 %

Procedure:
Pyrenemethanol (Pyr-OH) (109.6 mg, 0.47 mmol) in 1.0 mL DMF (anh) was treated with 180 μL TEA (anh, 1.29 mmol) and 2-bromoacetyl bromide (132.2 μL, 1.50 mmol) in 1 mL dichloromethane. The mixture was stirred at RT (˜23° C.) for 17 hours. After the solvent was evaporated, the crude product was purified by silica gel column (Hex/EtOAc=2/1) to give 167 mg final product as a yellow solid (yield 90%). 1H NMR (CDCl3, 500 MHz): δ 8.28-8.03 (m, 9H, ArH), 5.94 (s, 2H, ArCH2), 3.90 (s, 2H, CH2Br). ESI: 375, [M+Na]+.
Reaction SMILES: Cl.[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][NH:6][CH2:5]1.Cl[C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>>[CH3:2][O:3][C@H:4]1[C@@H:9]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7][N:6]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=2)[CH2:5]1
Reactant: Cc1cc(Cl)ncn1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CN(c2cc(C)ncn2)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
The same operation as in Example (158a) was performed using benzyl cis(±)-[3-methoxypiperidin-4-yl]carbamate hydrochloride obtained in Example (160a) (549 mg, 1.83 mmol), 4-chloro-6-methylpyrimidine (235 mg, 1.83 mmol) and diisopropylethylamine (709 mg, 5.48 mmol), to obtain the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].Cl.[O:15]1[C:19]([CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22])=[CH:18][CH:17]=[N:16]1>CO>[C:7]([NH:22][CH:21]([C:23]([OH:25])=[O:24])[CH2:20][C:19]1[O:15][N:16]=[CH:17][CH:18]=1)(=[O:9])[CH3:8]
Reactant: NC(Cc1ccno1)C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)NC(Cc1ccno1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
20 ml of pyridine and 20 ml of acetic anhydride were added to a solution of 12.45 g of 3-(5-isoxazolyl)-DL-alanine hydrochloride (prepared as described in Preparation 6) dissolved in 100 ml of methanol, whilst ice-cooling. The mixture was then stirred at room temperature for 8 hours, after which it was allowing to stand overnight. The mixture was then freed from the solvent by evaporation under reduced pressure. The residue was mixed with water and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, to afford 10.39 g (82.3%) of the title compound as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]=[O:26])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:26])[C:28]([F:30])([F:29])[F:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C=O)cc2=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(O)C(F)(F)F)cc2=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a semi-suspension of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-4-oxo-1,4-dihydropyridine-2-carbaldehyde (500 mg, 1.21 mmol) in THF (5 mL) at 0° C. was added (trifluoromethyl)trimethylsilane solution (5.3 mL of 0.5 mL solution in THF) followed by tetrabutylammonium fluoride solution (0.1 mL of a 1 M solution in THF). The reaction mixture was stirred at 0° C. for 1 h and then quenched by adding water. The quenched reaction mixture was then diluted with dichloromethane, washed with brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (24 g silica gel, linear gradient of 0 to 5% methanol in dichloromethane) afforded 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[NH:13][CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[N:13]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.11 g, 2.74 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.48 g, 2.28 mmol) in DMF (11.4 mL) at 0° C. The mixture was stirred at room temperature for 15 minutes and then bromomethylcyclopropane (0.26 mL, 2.74 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with water and extracted with AcOEt. The organic layer was separated, washed with brine, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-cyclopropylmethyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.32 g, 54% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1F.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Br:16]
Reactant: COC(=O)c1ccc(C(=O)OC)c(F)c1
Reactant: Oc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2Br)c1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoro-terephthalic acid dimethyl ester 2j (10 g, 47.1 mmol), 2-bromophenol 1j (6.0 mL, 51.8 mmol) and potassium carbonate (7.16 g, 51.8 mmol) in N,N-dimethylformamide (100 mL) was heated at 100° C. for 36 h. The mixture was allowed to cool to rt, then poured into cold dilute hydrochloric acid (0.5 N, 350 mL). The product was extracted into EtOAc, washed with water (4×) and brine (1×) and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel using dichloromethane as the eluant. The crude product was isolated (10.5 g) and used without further purification in the subsequent reaction. MS: m/z 365 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[CH:39]=[CH:38][S:37][CH:36]=3)[CH:30]=2)=[N:26][C:25]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:39]=[CH:38][S:37][CH:36]=4)[CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-3-ylphenyl)oxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.64 (dt, J=7.6 Hz, J=1.2 Hz, 1H), 7.56–7.55 (m, 1H), 7.48–7.39 (m, 3H), 7.23–7.14 (m, 5H), 6.96 (t, J=7.2 Hz, 1H), 6.83–6.81 (m, 4H), 4.24 (t, J=6.8 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t, J=6.4 Hz, 2H), 2.39 (s, 3H), 1.38 (s, 3H) 1.21 (t, J=7.2 Hz, 3H); MS (EI) 568.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.O>ClCCl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:2][CH:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(N)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OC
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Part A: To a stirred solution of dimethyl aminomalonate hydrochloride (25 gram, 0.136 mol) in dichloromethane (200 mL) triethylamine (41.4 mL, 2.2 molar equivalent) is added at 0° C. 4-Chlorobenzoyl chloride (23.8 gram, 0.136 mol) is slowly added and the resulting solution is allowed to stand at room temperature overnight. Water is added and the organic layer is separated. The water layer is extracted twice with dichloromethane. The collected organic layers are washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallised from methanol (400 mL) to give dimethyl 2-(4-chlorobenzoylamino)malonate (30.5 gram, 79% yield). Melting point: 146-148° C. 1H-NMR (200 MHz, CDCl3): δ 3.86 (s, 6H), 5.38 (d, J=6 Hz, 1H), 7.15 (br d, J˜6 Hz, 1H), 7.43 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Sc2ccccc2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Sc2ccccc2)cc(C)c1-c1csc(N)n1
Yield: 88.9 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(phenylthio)phenyl)ethanone (591.7 mg, 1.8 mmol, 1.0 equiv) and thiourea (134.3 mg, 1.8 mmol, 1.0 equiv) in EtOH (15.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(phenylthio)phenyl)thiazol-2-amine (483.7 mg, 1.6 mmol) as yellow solids in 88% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.33-7.38 (m, 2 H), 7.29-7.33 (m, 3 H), 7.06 (s, 2 H), 6.89 (s, 2 H), 6.38 (s, 1 H), 2.07 (s, 6 H); ESI-MS: m/z 313.8 (M+H)+.