Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C@H:7]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:8][CH2:9][C@@H:10]([NH:14]C(OC(C)(C)C)=O)[CH:11]([CH3:13])[CH3:12].[ClH:35]>C(OCC)(=O)C>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH2:31][S:32][CH3:33])[NH:5][C:6](=[O:29])[C@H:7]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH:8][CH2:9][C@@H:10]([NH2:14])[CH:11]([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC[C@@H](N)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step C (0.74 g, 0.0015 mole) in ethyl acetate (25 ml) was treated with HCl gas at -25° C. for 30 min. The solution was stirred at room temperature for 1 hour and concentrated in vacuo to provide the title compound as a white solid (~0.79 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[Cl:15].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:17]([CH3:19])[CH3:18])=[CH:10][C:9]=1[Cl:15]
Reactant: CC(C)I
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)c(Cl)c1
Temperature: 60 °C
Yield: 81 %

Procedure:
A sample of K2CO3 (52.8 mmol, 7.4 g) was added to the 4-bromo-3-chloro-phenol (24 mmol, 5 g) in anhydrous DMF (100 mL) followed by the addition of 2-iodopropane (100 mmol, 10 mL). This stirred and heated at 60° C. overnight. The reaction was cooled, extracted into EtOAc (150 mL), washed with H2) (2 L), dried over MgSO4, and concentrated in vacuo, yielding 1-bromo-2-chloro-4-isopropoxybenzene as a brown oil (4.85 g, 81%). 1H NMR (CDCl3, 300 MHz): 7.35 (1H, d, J 8.7 Hz), 6.89 (1H, d, J 2.9 Hz), 6.57 (1H, dd, J 8.8 and 2.9 Hz), 4.38 (1H, m), 1.22 (6H, d, J 6.2 Hz.)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1(C=CC=CC1Cl)C(Cl)=O.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33]#[N:34]>ClCCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([C:31]1[N:27]([CH3:26])[C:28]([CH2:32][C:33]#[N:34])=[CH:29][CH:30]=1)=[O:21]
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: O=C(Cl)C1(Cl)C=CC=CC1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1c(CC#N)ccc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a cooled suspension of 16.6 g. (0.12 mole) aluminum chloride in 60 ml. 1,2-dichlorobenzoylchloride is added dropwise 23 g. (0.12 mole) m-chlorobenzoylchloride. The resulting suspension is added dropwise to a cooled solution of 15 g. (0.12 mole) 1-methylpyrrole-2-acetonitrile in 60 ml. 1,2-dichloroethane. The reaction mixture is stirred for about twenty minutes at room temperature and then heated and refluxed for three minutes. The reaction is terminated by pouring the mixture into ice acidified with 3N hydrochloric acid. The resulting two fractions are separated. The aqueous fraction is washed with chloroform. The organic fraction is then dried over anhydrous magnesium sulfate. The solvent is evaporated, and the resulting residue is triturated with cold methanol to yield a precipitate of the desired product which is filtered off and set aside. The methanol filtrate is concentrated in vacuo and the remaining oily residue is chromatographed on a column packed with neutral alumina using hexane, benzene and ether as the successive solvents. About 2.5 g. of the desired product are isolated by evaporation of the first few compound-bearing (ether) fractions. The solids are combined and recrystallized from methanol to yield about 3.6 g. of 5-(m-chlorobenzoyl)-1-methylpyrrole-2-acetonitrile, M.P. 122°-127° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[N:10][OH:11])[NH2:9])=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=O>C1(C)C=CC=CC=1.CC(O)=O>[C:13]([C:18]1[O:11][N:10]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=2)[N:9]=1)([CH3:17])([CH3:14])[CH3:12]
Reactant: NC(=NO)c1ccc(Cl)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(-c2ccc(Cl)nc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A mixture of 1.5 g (8.74 mmol) of 6-chloro-N′-hydroxypyridine-3-carboximidamide and 1.13 mL (9.18 mmol) of trimethylacetyl chloride in 15 mL of toluene is stirred for 1 hour at room temperature and then refluxed for 4 hours. The medium is filtered. The insoluble material formed is dissolved in 15 mL of AcOH and then heated at 60° C. for 5 hours. After cooling to room temperature, the medium is concentrated under reduced pressure and then purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc mixture (9/1). 0.39 g of 5-(5-tert-butyl-1,2,4-oxadiazol-3-yl)-2-chloropyridine is obtained in the form of a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][OH:6].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:3][C:4]([F:10])([CH:7]([F:9])[F:8])[CH2:5][O:6][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCC(F)(F)C(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)C(F)F)cc1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To sodium hydride (288 mg as 55-60% mineral oil dispersion, 6 mmol) in N,N-dimethylformamide (2 mL), a solution of 2,2,3,3-tetrafluoro-1-propanol (535 μL, 6 mmol) in N,N-dimethylformamide (8 mL) was added dropwise. The reaction mixture was stirred for thirty minutes at room temperature. Then, 4-fluorobenzaldehyde (429 μL, 4 mmol) was added slowly, and the reaction was heated to 80° C. for three hours. After cooling, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 674 mg of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde; 1H NMR (300 MHz, CDCl3) δ 9.93 (s, 1H), 7.88 (d, 2H), 7.06 (d, 2H), 6.06 (tt, 1H), 4.44 (tt, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH:11]([C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[CH2:12][CH:13]=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.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[CH:3]=[C:4]([NH:9][C:10](=[O:22])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=3)=[CH:17][CH:16]=2)[CH2:12][CH:13]=[CH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=CCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(Br)cc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2cccc(C#N)c2)cc1
Temperature: 90 °C
Yield: 43.9 %

Procedure:
To an Argon-purged solution of 2-(4-bromophenyl)-pent-4-enoic acid (3,5-dichloro-phenyl)-amide (1.5 g, 3.7 mmol) in toluene/EtOH (2:1 v/v, 30 mL) was added 3-cyanophenylboronic acid (0.99 g, 6.7 mmol, 1.8 eq), Pd(PPh3)4 (160 mg, 0.44 mmol, 12%), and a solution of Na2CO3 (2.12 g, 20 mmol, 5.4 eq) in 10 mL of water. The reaction mixture was heated at 90° C. for 16 h. The mixture was partitioned between EtOAc (50 mL) and 10% NaHCO3 (50 mL) and the organic phase separated. The organic phase was washed with 10% NaHCO3 (30 mL) and saturated brine (30 mL), dried (Na2SO4), and concentrated. Chromatography on silica gel (20% EtOAc/hexanes) gave 2-(3′-cyano-biphenyl-4-yl)-pent-4-enoic acid (3,5-dichloro-phenyl)-amide as a yellow oil (685 mg, 44%). 1H NMR (300 MHz, CD3OD): δ 7.93 (m, 2H), 7.81 (m, 2H), 7.66 (m, 4H), 7.49 (m, 2H), 7.12 (t, 1H), 5.89 (m, 1H), 5.21 (m, 2H), 3.76 (t, 1H), 3.11 (m, 1H), 2.73 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:27]1[C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]2[C:36]([O:38][C:39](=O)[C:29]=2[CH:28]=1)=[O:37]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:36](=[O:37])[C:30]2[C:29](=[CH:28][CH:27]=[C:32]([C:33]([OH:35])=[O:34])[CH:31]=2)[C:39]1=[O:38]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4ccc(F)c(F)c4)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(F)c4)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)-5-(3,4-difluorophenyl)benzoxazole (63 mg, 0.18 mmol) and 1,2,4-benzenetricarboxylic anhydride (35 mg, 0.18 mmol) the title compound was obtained (25 mg, 27%). 1H NMR (DMSO) δ 8.53(dd, 1H), 8.42(m, 3H), 8.18(m, 2H), 7.94(m, 2H), 7.79(dd, 1H), 7.60(m, 3H), 3.95(s, 3H). MS 527 m/z (M+H)+.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([OH:19])=O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>O1CCCC1>[Br:1][C:2]1[O:6][C:5]([C:7]2[N:15]([CH2:16][C:17]([NH2:22])=[O:19])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Agent: N
Solvent: C1CCOC1
Product: NC(=O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.9 %

Procedure:
A mixture of 2-(5-bromo-2-furanyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.90 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. The reaction mixture was cooled in a dry ice/acetone bath, and liquid ammonia (50 ml) was added. The mixture was allowed to warm to room temperature and was stirred for 2 days under nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was recrystallized from hot methanol and dried under high vacuum at 40° C. to give 2.23 g (38%) of title compound, mp. >250° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:25]=[CH:26][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccccc2Oc2ccc(N)cc2)cc1
Yield: 77.4 %

Procedure:
In a 3 l round-bottomed flask equipped with a magnetic stirrer bar, reflux condenser and dropping funnel was placed 64.20 g (0.182 mol) of 1,2-bis(4-nitrophenoxy)benzene (SI-319), 700 mL ethanol and 2 g 5% palladium on charcoal. The mixture was brought to boil when 200 mL of hydrazine hydrate was added dropwise during a period of 1.5 hours. The mixture was refluxed for a further 3 hours. The hot mixture was then filtered over a filter agent and left to 10 crystallize. The next day the crystals were separated and the liquid volume reduced to 400 mL, from which an additional crop of crystals was filtered off. The combined crystalline product was recrystallized twice from methanol/water (3:1) to yield 41.2 g of off-white crystals. By reducing the liquid volume a second crop of 5.7 g of crystals was obtained (overall yield 88.17% theoretical). Melting point 135-136° C. Elemental analysis: Calc: C, 73.95%, H, 5.51%, 9.59%; Found: C, 74.10%, H, 5.62%, 9.77%.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[OH:28][C@H:29]1[CH2:33][NH:32][C@H:31]([C:34]([O:36][CH3:37])=[O:35])[CH2:30]1.CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([N:32]1[CH2:33][C@H:29]([OH:28])[CH2:30][C@H:31]1[C:34]([O:36][CH3:37])=[O:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C1(c2ccccc2OC)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 13 h
Yield: 76.8 %

Procedure:
To a suspension of 2.28 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one, which is the compound described in Preparation 1.1 of Brochure No. WO01/55130, and the compound obtained in Step 4-1 (8.15 mmol) in CHCl3 (23 ml) was added dropwise 4.49 g of Et3N over 2 minutes under ice cooling, then, the reaction mixture was stirred at room temperature for 13 hours. An aqueous solution of 5% K2CO3 was added to the reaction solution, and the resulting mixture was stirred for 15 minutes. liquid separation was performed, and the aqueous layer was extracted with CHCl3 extraction. The combined organic layer was washed with saturated brine, then, dried over MgSO4, the drying agent was separated by filtration, then, the solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc) to obtain 2.37 g of a diastereoisomer mixture of the title compound (colorless amorphous).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:18]=[CH:17][C:13]3[CH:14]=[N:15][S:16][C:12]=3[CH:11]=2)=[N:7][N:6]=1)(=O)=O.C([O-])(=O)C.[NH4+:23].CO>C(Cl)Cl>[S:16]1[C:12]2[CH:11]=[C:10]([C:8]3[S:9][C:5]([NH2:23])=[N:6][N:7]=3)[CH:18]=[CH:17][C:13]=2[CH:14]=[N:15]1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3cnsc3c2)s1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: Nc1nnc(-c2ccc3cnsc3c2)s1
Temperature: 140 °C
Yield: 70.3 %

Procedure:
A mixture of 6-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)benzo[d]isothiazole (0.16 g, 0.54 mmol) and excess ammonium acetate (1.93 mL, 26.9 mmol) was heated in a microwave-safe reaction vessel at 140° C. for 30 minutes under microwave irradiation. The mixture was cooled, 5% MeOH in DCM (with NH3) was added, and the mixture was adsorbed onto silica gel. The residue was purified by flash column chromatography (DCM—10% MeOH in DCM) to obtain the desired product as an off-white solid (89 mg, 71%). LCMS (API-ES) m/z (%): 235.3 (100%, M+H+); 1H-NMR (400 MHz, CD3OD) δ ppm 9.02 (s, 1 H) 8.49 (s, 1 H) 8.25 (d, J=8.53 Hz, 1 H) 7.98 (d, J=9.03 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13]Cl)[CH:11]=1>CS(C)=O.CCOC(C)=O>[Br:6][C:7]1[CH:8]=[N:9][N:10]([CH2:12][CH2:13][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: COCCN
Reactant: ClCCn1cc(Br)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COCCNCCn1cc(Br)cn1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-methoxyethanamine (8.9 mL, 102.06 mmol) and chloride 75 (7.13 g, 34.02 mmol) in DMSO (20 mL) was heated at 60° C. 5 h. The mixture was then cooled to room temperature, diluted with EtOAc, washed with aqueous sodium bicarbonate, water and brine. The organic phase was further extracted with 1N HCl and the acid extract was collected and basified with 2N NaOH (pH˜11). The basic aqueous solution was extracted with DCM, the DCM extract was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford title compound 76 (8.44 g, 99%) as brown foam. MS (m/z): 248.04 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[N:12]([CH3:27])[C:11]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: COS(=O)(=O)OC
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, m.p. 128°-130° C.;
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6](=[O:20])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH2:9][N:7]1[CH2:8][CH:4]([CH:1]([OH:3])[CH3:2])[CH2:5][C:6]1=[O:20]
Reactant: COc1ccc(CN2CC(C(C)=O)CC2=O)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2CC(C(C)O)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-acetyl-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (1.5 g, 7.2 mmol) in MeOH (15 mL), NaBH4 (400 mg, 10.8 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour then diluted with water and extracted with EtOAc. The organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 1-(2,4-dimethoxybenzyl)-4-(1-hydroxyethyl)pyrrolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 7.10-7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.67-3.70 (m, 1H), 3.06-3.46 (m, 2H), 2.03-2.50 (m, 3H), 1.26-1.42 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C15H22NO4 [M+H]+ 280. found 280.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Br:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([N:30]3[CH2:29][CH2:28][N:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([Br:20])[CH:22]=4)[CH2:32][CH2:31]3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: Brc1cccc(N2CCNCC2)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(c1ccc(-c2ccc(Cl)cc2)o1)N1CCN(c2cccc(Br)c2)CC1
Yield: 92 %

Procedure:
5-(4-Chlorophenyl)-2-furoic acid (Australian Journal of Chemistry, 26, 1147 (1973))(6.67 g; 0.03 mole) was refluxed in benzene (100 ml) with thionyl chloride (4.5 ml) for 1.5 hours. After removal of the excess thionyl chloride, the remaining acid chloride in benzene was added dropwise with stirring and cooling to a mixture of N-(3-bromophenyl)-piperazine (7.23 g; 0.03 mole) and triethylamine (4.5 ml, ca. 0.03 mole) in benzene (100 ml). After stirring for 1 hour at room temperature, the mixture was shaken with water (100 ml). The separated benzene phase was further washed with saturated salt solution, then evaporated to give an oil which readily crystallised. The product was recrystallised from ethyl acetate/60°-80° C. petroleum ether (1/3 v /v) to yield 1-[5-(4-chlorophenyl)-2-furoyl]-4-(3-bromophenyl)-piperazine (12.3 g) m.p. 130° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=O>>[F:23][C:24]1[CH:25]=[C:26]([C:27]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[C:10]([CH3:11])[C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[N:1]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Reactant: O=C(Cl)c1cccc(F)c1
Agent: NC(=O)c1ccccc1
Product: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Yield: 73 %

Procedure:
The general procedure described in Example 10 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and 3-fluoro-benzoyl chloride as acid chloride [B], which gave the title compound (2.1 g, 73%), [M+H]=271.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][N:6]1[C:2]([CH3:1])=[N:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5]1
Reactant: CCOC(=O)c1n[nH]c(C)n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C)n(Cc2cccc(Br)c2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
To a solution of ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (1.0 g, 6.44 mmol) and 1-bromo-3-(bromomethyl)benzene (1.77 g, 7.08 mmol) in THF (32 mL), K2CO3 (1.78 g, 12.88 mmol) was added. The mixture was stirred at 50° C. for 18 h, and then the reaction was filtered under vacuum. The solvent was removed under reduced pressure and the crude product was purified on a Biotage pre-packed silica gel column (EtOAc:Hexane 12% to 100% EtOAc) to afford ethyl 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (1.25 g, 60%) as a viscous oil. MS (ES+) C13H14BrN3O2 requires: 323, 325 found: 324, 326 [M+H]+(1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH:22]=[CH2:23])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:24])[C:11]([C:25]([O:27]CC)=[O:26])=[CH:10]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([CH:22]=[CH2:23])[C:15]([F:21])=[C:16]([F:20])[C:17]=2[F:19])[C:12](=[O:24])[C:11]([C:25]([OH:27])=[O:26])=[CH:10]1
Reactant: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2-c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 69.8 %

Procedure:
2 g of the product of Example C are refluxed for 2 hours in a mixture of 15 ml of glacial acetic acid, 1.5 ml of water and 0.7 ml of concentrated sulphuric acid. The product is filtered off with suction at room temperature, washed with water and dried. 1.3 g of the title compound are obtained (71% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccccc3Cl)cc1CC2
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2ccc(Nc3ccccc3Cl)cc2CCc2ccc(O)cc21
Temperature: 0 °C

Procedure:
0.2 g (0.55 mmol) of 2-(2-chloroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one is dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are added and the mixture is refluxed for 6 h. The solution is hydrolyzed with 200 g of ice and the precipitate is filtered off. The product is obtained in the form of a white powder.