Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 100.5 %

Procedure:
A mixture of 18.0 g of 6-hydroxy-2-methylbenzoxazole, 36.6 g of 1-bromohexadecane, 24.0 g of potassium carbonate and 120 ml of N,N-dimethylformamide was stirred at 90° C. for 4.5 hours. The reaction solution was filtered to remove solids and the filtrate was poured into 500 ml of methanol to precipitate crystals. These crystals were collected by filtration. 45.0 g of 6-hexadecyloxy-2-methylbenzoxazole was obtained.
Reaction SMILES: C(O[C:4](=S)[S:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Br:16])[CH:7]=1)C.[OH-].[K+].[CH2:20](Br)C.C([O-])([O-])=O.[K+].[K+]>O.CCO>[Br:16][C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([S:5][CH2:4][CH3:20])[CH:7]=1
Reactant: CCBr
Reactant: CCOC(=S)Sc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1cc(Br)cc(C(F)(F)F)c1
Yield: 45.3 %

Procedure:
Dithiocarbonic acid S-(3-bromo-5-trifluoromethyl-phenyl) ester O-ethyl ester (3.3 g, 10.3 mmoles) was dissolved into 30 mL of EtOH, 10 mL of H2O, and was sealed under nitrogen. To this stirring mixture was added KOH (2.8 g, 50 mmoles) and this mix was stirred at reflux (under nitrogen) for 12 hours. After this period the reaction mixture was evaporated in vacuo and combined with 50 mL of water. The pH was adjusted to <2 using 6N HCl and the resulting mixture was extracted with diethyl ether (3×50 mL). The combined ethereal layer was washed with brine and dried over anhydrous MgSO4. Following evaporation in vacuo the crude thiol was dissolved into 50 mL of acetone. Ethyl bromide (1.5 mL, 20.1 mmoles) and K2CO3 (5 g, 36.2 mmoles) were added, and the mixture was stirring at ambient temperature (under nitrogen) for 6 hours. After this period the mixture was gravity filtered, and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-1% EtOAc/Hexane) to yield 1-bromo-3-ethylsulfanyl-5-trifluoromethyl-benzene (1.33 g, 45% yield) as a yellowish liquid. 1H-NMR (CDCl3): δ 7.56 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 3.0 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:30])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: C1CCNC1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2- one (Example 96) (219 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (157 mg, 64%).
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].CON(C)[C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:13]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:12]=1)=[O:10].Cl>C1COCC1>[C:9]([C:11]1[CH:15]=[C:14]([C:16]2[CH:30]=[CH:29][C:19]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[N:13]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:12]=1)(=[O:10])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: COc1ccc(-n2nc(C(=O)N(C)OC)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(=O)C(C)C)cc2-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 0.76M solution of isopropyl magnesium bromide in THF (8.5 ml) was added dropwise to a solution of tert-butyl {4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]benzyl}carbamate (1 g) in THF (10 ml) at 10–15° C. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a mixture of 1M HCl and ice. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with AcOEt/n-hexane=20%, 25%, then 10% MeOH/CHCl3. The combined pure fraction was concentrated in vacuo to give tert-butyl {4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate (318 mg) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[N:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH2:16][CH2:15]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[O:10])[CH:5]=[N:4][CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(O)c1cncc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cncc(Cl)n1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.18 g (1.1 mmol) 6-chloro-pyrazine-2-carboxylic acid, 0.15 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 3.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 1 h at RT. The reaction mixture was mixed with water and stirred for 5 min. The precipitated solid was filtered, washed with water and dried.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:14]1[CH2:15][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]([C:1]([O:9][CH3:10])=[O:8])[CH2:13]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C\C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccccc2)CC1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.02 %

Procedure:
To a solution of dimethyl maleate (4.00 g) in CH2Cl2 (100 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq) followed by a solution of TFA in CH2Cl2 (0.1 eq, 1 M) dropwise at 0° C. under N2. The reaction mixture was heated to room temperature and stirred for 6 h, washed with water followed by brine. The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 3:1 (v/v) PE/EA) to yield the title compound (6.62 g, 86.02%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 278 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.70-2.75 (m, 2H), 3.12-3.17 (m, 1H), 3.30-3.33 (m, 2H), 3.66 (s, 6H), 7.24-7.31 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C[O+](C)C.[CH3:28][C:29]1[C:30]([C:34]([NH:36][NH2:37])=O)=[N:31][S:32][CH:33]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:34]([C:30]3[C:29]([CH3:28])=[CH:33][S:32][N:31]=3)=[N:36][N:37]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: Cc1csnc1C(=O)NN
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1csnc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)c(F)c1Cl)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[(2,4-Dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (90 mg, 0.309 mmol) was suspended in dichloromethane (DCM) (1.5 mL) before treating with trimethyloxonium tetrafluoroborate (57.8 mg, 0.371 mmol) and stirring for 16 hours at RT under argon before adding 4-methyl-3-isothiazolecarbohydrazide (I129)(58.3 mg, 0.371 mmol) and stirring for 4 hours. Adding 1-butanol (1.500 mL) then removing the DCM by evaporation before heating at 110° C. for 3 hours. As LCMS indicated that some start material remained, the reaction mixture was left heating for a further 17 hours. The reaction was worked up by diluting with DCM (30 ml) and washing with saturated sodium bicarbonate solution (30 ml). The aqueous layer was extracted with DCM (2×20 ml), the combined extracts were washed with brine (20 ml), dried (MgSO4), filtered and evaporated to afford a brown gum, 120 mg. The gum was purified by MDAP, the desired fraction isolated and the solvent evaporated to afford a white solid. The solid dried over the weekend in the vac oven at 40° C. to afford an off white solid of desired product in 22 mg.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85° C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])(O)=[O:2].C([NH2:23])=O>[Cl-].[Na+].O>[F:15][C:14]([F:17])([F:16])[C:13]([C:12]1[NH:23][C:1](=[O:2])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([I:10])[CH:9]=2)[N:11]=1)([OH:19])[CH3:18]
Reactant: CC(O)(C(=O)Nc1ccc(I)cc1C(=O)O)C(F)(F)F
Reactant: NC=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(O)(c1nc2ccc(I)cc2c(=O)[nH]1)C(F)(F)F

Procedure:
A solution of N-(2-carboxy-4-iodophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (5 g) and formamide (5 mL) was stirred and heated at 190°-200° C. for 3 hours. The cooled reaction mixture was poured into brine (150 mL) and extracted with ethyl acetate. The ethyl acetate solution was dried (Na2SO4) and evaporated. Chromatography, eluting with ethyl acetate, gave the title compound (2.86 g) as a white solid; mp 205°-207° C.; NMR: 1.75 (s,3), 7.48 (d,1), 7.5 (s,1), 8.13 (d,1), 8.42 (s,1), 12.05 (s,1); MS: m/z=385(M+1). Analysis for C11H8F3IN2O2 : Calculated: C, 34.40; H, 2.10; N, 7.29; Found: C, 34.48; H, 2.09; N, 7.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of t-butyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-4-methylpentanoate (10.0 g, 27.92 mmol) in dimethylformamide (250 mL) at room temperature is added 3-picolyl chloride hydrochloride (4.81 g, 29.32 mmol) followed by sodium hydride (2.79 g, 69.80 mmol, 60% in oil). The reaction mixture is stirred at room temperature for 48 hours. The mixture is quenched with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (45% ethyl acetate/hexanes) to provide t-butyl 2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)-amino]-4-methylpentanoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[C:7]([NH2:13])[CH:6]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:17]=1[CH:18]=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]([CH3:12])[C:18]([C:17]3[C:16]([Cl:15])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:24])=[N:13][C:7]=2[CH:6]=1)=[O:14])[CH3:2]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(NC)c(N)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1c(Cl)cccc1Cl)n2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-4-methylaminobenzoic acid ethyl ester (388 mg) and 2,6-dichlorobenzaldehyde (350 mg) in DMSO (4 mL) was added Yb(OTf)3 (50 mg) and the solution was stirred at room temperature for 24 h. More Yb(OTf)3 was added and stirring was continued for 24 h. This process was repeated another two times. The reaction mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by flash chromatography using a gradient of ethyl acetate/CH2Cl2 (0% to 25%) to give 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid ethyl ester as a beige solid, mp=164-166° C.; MS (m/z) 349 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][CH:6]([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21].[Br:22]Br.O.S(=O)(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:10]2[O:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:9]=2[C:8]2[CH2:7][C:6]([Br:22])([CH2:17][CH2:18][CH3:19])[C:5](=[O:20])[C:4]=2[C:3]=1[CH3:21]
Reactant: CCCC1Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Reactant: BrBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(Br)Cc2c3c(c(C)c(C)c2C1=O)OC(C(=O)O)C3
Yield: 78.4 %

Procedure:
A stirred suspension of 4,5-dimethyl-6-oxo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (14 g., 0.00486 mole) in acetic acid (15 ml.) is treated with a solution of bromine (0.8 g., 0.005 mole) in acetic acid (5 ml.) during a three minute period. The reaction mixture is poured into water (100 ml.) containing sodium bisulfate (1 g.), extracted with ether, washed with water, dried over magnesium sulfate and the ether distilled at reduced pressure affording an oil which on trituration with cyclohexane affords 4,5-dimethyl-6-oxo-7-bromo-7-propyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid (1.4 g., 78%) as a white solid which melts at 78°C. and is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][NH:24][C:23]2=[O:27])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][N:24]([C@H:12]([CH3:13])[C@:9]3([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])[O:10][CH2:11]3)[C:23]2=[O:27])=[CH:20][CH:21]=1
Reactant: O=c1[nH]ccn1-c1ccc(Cl)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(-c2ccc(Cl)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 12 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.80 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.78 g of 1-(4-chlorophenyl)-2(1H,3H)-imidazolone, 0.18 g of 1-(4-chlorophenyl)-3-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]- 2(1H,3H)-imidazolone was obtained as a colorless viscous oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:8])[CH3:7])(=[NH:3])[CH3:2].C(=O)(O)[O-].[Na+].Br[CH2:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([CH3:30])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=O>C(#N)C.ClCCl>[CH3:2][C:1]1[N:4]([NH:5][C:6](=[O:8])[CH3:7])[CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH3:30])[C:22]=2[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:3]=1
Reactant: Cc1ccc(-c2c(C(=O)CBr)cnn2C)cc1
Reactant: CC(=N)NNC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)Nn1cc(-c2cnn(C)c2-c2ccc(C)cc2)nc1C
Temperature: 80 °C

Procedure:
N′-Ethanimidoylacetohydrazide (147 mg, 1.28 mmol) and sodium bicarbonate (99%, 181 mg, 2.13 mmol) were added to a solution of 2-bromo-1-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone (250 mg, 0.853 mmol) in acetonitrile (9 mL), and the mixture was heated at 80° C. for 3 hours. The reaction was allowed to cool to room temperature, and was then diluted with dichloromethane and filtered through Celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (Eluant: 10% methanol in dichloromethane) to provide the product as a yellow oil. Yield: 236 mg, 0.763 mmol, 89%. LCMS m/z 310.5 (M+1). 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 2.10 and 1.77 (2 s, 3H), 2.25 and 2.36 (2 s, 3H), 2.44 and 2.46 (2 s, 3H), 3.69 and 3.72 (2 s, 3H), 6.21 (s, 1H), 7.22-7.33 (4H, m, assumed; partially obscured by solvent peak), 7.96 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])=O)[CH3:12].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:28]([C:27]([O:26][CH2:24][CH3:25])=[O:32])=[C:29]([CH3:30])[NH:31][C:16]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21])=[O:23])[CH3:12]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: CCOC(=O)/C=C(/C)N
Reactant: COc1ccc(C=O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccc(OC)cc1
Yield: 45 %

Procedure:
After heating a solution of 5.7 g of 4-methoxybenzaldehyde, 7.9 g of γ-acetoxyacetoacetic acid ethyl ester and 5.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol for 20 hours, the mixture is cooled and the precipitate is filtered off and recrystallised from ether. White crystals of melting point 89°-90° C., yield: 45%
Reaction SMILES: [CH2:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCc1nc2ccccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2ccccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a three-neck 250 mL round-bottom flask equipped with a thermometer, dropping funnel, and efficient magnetic stir bar was added compound 4 (27.8 g, 0.10 mole), anhydrous sodium acetate (10.0 g) and glacial acetic acid (130 mL). Bromine (16.0 g, 0.10 mole) dissolved in acetic acid (10 mL) was added dropwise to the above solution at 40° C. for 1-2 h. After addition was complete, the mixture was poured into water (1500 mL) and stirred for 1-2 h at room temperature. The precipitated product, 2-(1′-bromopropyl)-3-benzylquinazolin-4-one (5) was isolated by filtration, washed with warm water to remove traces of acetic acid, and rinsed with a small amount of isopropanol. Drying yielded compound 5 (33.0 g, 92%).