Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25]Br>>[Br:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([Br:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCc1cc(Br)cc(Br)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Br)cc(Br)c2)c1
Yield: 75.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (395 mg, yield: 75.6%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1.C([O-])(O)=O.[Na+]>O.C(O)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To 892 g of fuming sulfuric acid, containing 25-27% of SO3, 100 g (0.6 m) of terephthalic acid are added at 20-23° C., under stirring, then 46 g (0.5 m) of 1,3,5-trioxane are added portionwise thereto at about 15° C. At the end of the addition, the mixture is heated 2 hours at 130-133° C. whereby a dark, clear solution is obtained. When the reaction is complete, as shown by a HPLC control, the mixture is cooled to 20-22° C. and 210 g of glacial acetic acid are slowly added thereto, without exceeding the temperature of 23-25° C. The mass is cooled to −5-0° C. and 1800 ml of cold deionized water are added thereto. During this operation the temperature rises to 43-45° C. At the end of the addition, the mixture is kept 1 hour under stirring at 23-25° C., then it is filtered, the solid is washed with deionized water abundantly and suspended, still wet, in 1200 ml of deionized water at room temperature. To the suspension thus obtained, about 1550 g of a 7% solution of NaHCO3 are added to a constant pH of 7,6-7,8. The mixture is filtered on Celite®, washing with deionized water. The pH of the filtrate is brought to about 1 by slow addition of about 120 ml of 35% hydrochloric acid at 22-25° C. The suspension is kept 1 hour under stirring at 22-25° C., then it is filtered and washed with deionized water abundantly. The product is dried in vacuo at about 50° C. to give 81 g of 5-carboxyphthalide with a titer (HPLC)>94% and purity (HPLC)>95%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>CN1CCCC1=O>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][N:3]=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=1)([O-:14])=[O:13]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3)nccc12
Yield: 97.8 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-2 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 500 mg, 2.30 mmol), and 4-(trifluoromethyl)aniline (772 mg, 4.70 mmol) in N-methylpyrrolidinone (3 mL) to afford 750 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.94 (d, J=8.4 Hz, 1H), 8.53 (d, J=7.2 Hz, 1H), 8.26 (d, J=6.3 Hz, 1H), 8.06 (d, J=9.0 Hz, 2H), 8.33 (t, J=7.8 Hz, 1H), 7.66 (m, 3H); MS (m/z): 334.19 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=1)(=[O:5])=[O:4].B(Br)(Br)Br.CO>C(Cl)Cl>[F:17][C:2]([F:1])([F:18])[S:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1)(=[O:4])=[O:5]
Reactant: COc1cccc(CCNS(=O)(=O)C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(NCCc1cccc(O)c1)C(F)(F)F
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of 12.5 g (0.044 mol) of 1,1,1-trifluoro-N-[2-(3-methoxyphenyl)ethyl]methanesulfonamide in 150 ml of methylene chloride is cooled to -40° C. A solution of boron tribromide in methylene chloride (90 ml, 0.09 mol) is added from a dropping funnel and the mixture is allowed to warm to room temperature. The solution is concentrated in vacuo to obtain a residue, which is rapidly added to 50 ml of methanol. The solution is concentrated in vacuo to obtain 11.8 g (100%) of an oil, MS (CI) 270 (M+H). The product is used without further purification in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:18][C:19]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:20]=1[C:21](OCC)=[O:22].C(N(CC)C(C)C)(C)C>C(O)C>[Cl:30][C:27]1[CH:26]=[C:20]2[C:19]([CH2:18][N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH:8]([CH3:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=3)[C:21]2=[O:22])=[CH:29][CH:28]=1
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Cl)cc3C2=O)cc1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
A mixture of tert-butyl 2-(4-aminophenyl)propanoate (0.24 g, 1.08 mmol), ethyl 2-(bromomethyl)-5-chlorobenzoate (0.25 g, 0.901 mmol) and N,N-diisopropylethylamine (0.14 g, 1.08 mmol) in ethanol (5 mL) was heated in a sealed tube at 100° C. overnight. After this time, the mixture was cooled with an ice bath and the solids collected by filtration to afford tert-butyl 2-(4-(6-chloro-1-oxoisoindolin-2-yl)phenyl)propanoate (0.18 g, 55%) as a white solid: mp 169-171° C.; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J=2.5 Hz, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.56 (dd, J=8.0, 2.0 Hz, 1H), 7.45 (d, J =8.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 4.84 (s, 2H), 3.63 (m, 1H), 1.45 (d, J=7.5 Hz, 3H), 1.41 (s, 9H); ESI MS m/z 404 [M+H+CH3OH]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:38]([CH:35]3[CH2:37][CH2:36]3)=[O:39])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)C1CC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)C1CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with cyclopropanecarbonyl chloride (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H37N2O2Cl2 [(M+H)+] 563.2227, observed 563.2224.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[CH2:21]=[O:22].Cl>O1CCCC1>[OH:22][CH2:21][C:11]1[O:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)=[CH:13][CH:12]=1
Reactant: FC(F)(F)c1cccc(-c2ccco2)c1
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
2-(3-Trifluoromethylphenyl)-furan (J. Chem. Soc. (C) 1968, 2737 and Acta Chem Scand. 24, 2379 (1970))(21.2 g; 0.1 mole) was stirred in tetrahydrofuran (100 ml), cooled to -40° C. and n-butyl lithium (0.1 mole, solution in hexane) was added dropwise. After stirring for 1 hour at -40° C., paraformaldehyde (3.3 g; 0.11 mole) was added gradually. The mixture was stirred at -40° C. for 30 minutes, then the temperature was allowed to rise. At 10° C. an exothermic reaction set in and the temperature gradually rose to 40° C. (over 10 minutes), then gradually fell back to 20° C. After stirring for further 1 hour the clear brown solution was poured onto ice/water, adjusted to pH ca 4 with dilute hydrochloric acid and extracted via ethyl acetate. The dried acetate extract (MgSO4) was evaporated to give a brownish yellow viscous oil which was distilled in vacuo to give 2-hydroxymethyl-5-(3-trifluoromethylphenyl)-furan as a colourless liquid b.p. 125° C./0.5 mm., (16.2 g), which on standing gave crystals, m.p. 45° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([OH:26])=[O:25])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:27]O>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[S:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CO
Product: COC(=O)CS[C@@H]1CCC[C@H]1Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The compound of Example 5 (1.0 g, 0.0025 mole) was dissolved in methanol (35 ml) and hydrogen chloride gas was bubble into the solution for 10 minutes. Nitrogen gas was bubbled into the reaction solution to remove most of the dissolved hydrogen chloride, and then the reaction mixture was poured into water (150 ml). The mixture was extracted twice with 100 ml of diethyl ether, and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The product was purified by silica gel chromatography. The structure was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([CH2:11]Br)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1NC(=O)OC(C)(C)C.BrC1C=CC=CC=1[C:30]#[N:31]>COCCOC.C([O-])(O)=O.[Na+].CCOCC>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:30]#[N:31])=[CH:2][C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1-c1oc2ccc(CBr)cc2c1Br
Reactant: N#Cc1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
Intermediate 1 (20 g) was added to a stirred solution of 2-bromobenzonitrile (10.34 g) and tetrakistriphenylphosphine palladium (0) (1.5 g) in DME (200 ml) and 8% aqueous NaHCO3 (50 ml) at reflux under nitrogen. Further catalyst (1.5 g) was added and the reaction was heated overnight. The reaction was cooled to room temperature and diluted with ether (200 ml). The organic layer was separated, washed with water (3×100 ml) and dried. Filtration and evaporation gave a white solid which was purified by chromatography eluting with System A (1:9) to give the title compound (10.58 g) as a white solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: COC(=O)c1ccccc1S
Reactant: CCSc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 14 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-ethylthiopyridine (1.02 g, 6.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give precipitated crystals, which were recrystallized from ethanol to give the titled compound (0.26 g, 14%)
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=[C:6]([C:8]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:18])[CH3:10])[CH:7]=1.[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][C:32](Cl)=[N:31][CH:30]=1.N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][C:32]([O:17][C:14]2[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=3)([OH:23])[C:19]([F:21])([F:22])[F:20])=[C:12]([Cl:18])[CH:13]=2)=[N:31][CH:30]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cc(Cl)c(=O)n(C)c1)C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(Cl)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to Example 163, 3-chloro-5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 221, step 5) was reacted with methyl-6-chloro-4-(trifluoromethyl)-nicotinate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as an off-white solid. MS (m/e)=599.1 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:35](OC)(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1([C:5]2[N:6]=[CH:7][C:2](/[CH:37]=[CH:36]/[CH:35]=[O:38])=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(-n2cccn2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C/C=C/c1ccc(-n2cccn2)nc1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A solution of the compound from step A (450 mg, 2.01 mmol) and tri(o-tolyl)phosphine (123 mg, 0.40 mmol) in DMF (8 mL) was cooled to 0° C. and purged with nitrogen for 15 min. TEA (0.56 mL, 4.02 mmol) and methyl acrylate (0.36 mL, 4.00 mmol) were added and purging was continued for 5 min. Palladium acetate (45 mg, 0.20 mmol) was added and the flask was stoppered and heated to 120° C. for 24 h. The cooled reaction mixture was diluted with ether (50 mL) and washed with water (2×25 mL) and brine (25 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 356 mg (77%) of the title compound. MS 230 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:11]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[N:8]=[CH:9]2)([CH3:18])[CH3:17])=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride (0.65 g) in dichloromethane (20 ml). The solution was cooled to 0° C. and benzenesulphonyl chloride (0.27 g) in dichloromethane (10 ml) was added dropwise with stirring. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 3 hours. The mixture was washed with water, sodium bicarbonate solution and then dried, filtered and evaporated to give a yellow oil which was dissolved in alcohol and treated with ethereal hydrogen chloride. The resulting salt was hygroscopic and so was converted back to the free base by treatment with aqueous sodium hydroxide solution to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]-propyl}imidazol-4-yl)ethyl]benzenesulphonamide as an oil.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH2:31][O:32][CH3:33])[NH:15][C:14]2=[O:34])=[O:12])=CC=1)([O-])=O.[C:35]1([C:41]2([C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[N:13]([C:11](=[O:12])[NH:50][CH2:49][CH2:48][CH2:47][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:51]3[S:52][CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45]2)[C:14](=[O:34])[NH:15][C:16]=1[CH2:31][O:32][CH3:33])=[O:28]
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: NCCCN1CCC(c2ccccc2)(c2cccs2)CC1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3ccccc3)(c3cccs3)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (29 mg, 0.06 mmol) in 2 ml of CH2Cl2 was added 3-(4-phenyl-4-thiophen-2-yl-piperidin-1-yl)propylamine (20 mg, 0.07 mmol) and the resulting solution was stirred for 2 h at 25° C. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5% MeOH/CHCl3) to yield 25 mg (64%) of the desired product which was converted to a HCl salt and recrystallized from EtOAC-Et2O to afford 22 mg of the product as a white solid: mp 157-159° C.; Anal. Calc. For C33H36F2N4O5S requires C, 58.6; H, 5.33; N, 8.29. Found: C, 57.3; H, 5.45; 7.90.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(NC(C)=O)cc1C(=O)OCC
Reaction time: 16 h

Procedure:
A solution of diethyl 4-aminophthalate (660 mg) in methylene chloride (40 mL) at 0° was treated with pyridine (0.25 mL) and acetyl chloride (0.22 mL). The reaction mixture was allowed to warm to 23° and stirred for 16 h. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and methylene chloride. The organic layer was washed with water, 2N hydrochloric acid and brine, dried (MgSO4) and evaporated. The residue was dissolved in ethyl acetate, which upon standing afforded the title compound as white crystals (350 mg). M.p. 118°-121°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Br)cc2)CCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: OCC1(c2ccc(Br)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To a solution of 1-(4-bromophenyl)cyclobutanecarboxylic acid (300 mg, 1.20 mmol) in 1,4-dioxane (5 mL) was added borane dimethylsulfide complex (0.24 mL, 2.4 mmol) dropwise at 0° C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was quenched with methanol (20 mL). The organic solvents were removed under reduced pressure to give a residue, which was dissolved in ethyl acetate, then washed with brine. The organic phase was concentrated to give [1-(4-bromophenyl)cyclobutyl]methanol (170 mg, 62% yield) as a yellow oil which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[N:16][O:17][C:11]=3[C:10]3[S:18][CH:19]=[CH:20][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:40])=[C:35]([CH:39]=1)[C:36](Cl)=[O:37]>ClCCl>[O:17]1[C:11]2[C:10]3[S:18][CH:19]=[CH:20][C:9]=3[N:8]([C:6]([C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:36](=[O:37])[C:35]4[CH:39]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=4[CH3:40])=[CH:3][CH:4]=3)=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=[N:16]1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2CCc3cnoc3-c3sccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2CCc3cnoc3-c3sccc32)cc1

Procedure:
As described for Example 1, a solution of 2 mmol of 5,6-dihydro-6-(4-aminobenzoyl)-4H-isoxazolo [5,4-d]thieno[3,2-b]azepine and 5 mmol of triethylamine is reacted with 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane under argon for 16 hours to give the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:14][CH2:15][CH3:16])[C:5](=[O:13])[N:6]([CH2:9][CH:10]([OH:12])[CH3:11])[C:7]=1[NH2:8].[C:18](O)(=O)[CH3:19]>>[OH:12][CH:10]([CH3:11])[CH2:9][N:6]1[C:7]2[N:8]=[C:18]([CH3:19])[NH:1][C:2]=2[C:3](=[O:17])[N:4]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:13]
Reactant: CCCn1c(=O)c(N)c(N)n(CC(C)O)c1=O
Reactant: CC(=O)O
Product: CCCn1c(=O)c2[nH]c(C)nc2n(CC(C)O)c1=O

Procedure:
About 15 g of 5,6-diamino-1-(2-hydroxypropyl)-3-propyl-2,4-(1H, 3H)-pyrimidinedione as an oil was refluxed for one hour in 50 ml of acetic acid. The solution was evaporated and the residue was dissolved in water. Active carbon was added and filtered off. To the filtrate 25 ml of 5-N NaOH was added and the solution was refluxed for 30 minutes. Hydrochloric acid was added until acid reaction and the received crystals were filtered off and recrystallized from 200 ml of water. Yield 2.7 g. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.[C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:37])[CH:35]=[CH2:36]>CO.ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:36][CH2:35][C:34]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: O=c1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN1CCC(Nc2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1
Temperature: 70 °C

Procedure:
To a solution of 6-(bis(4-chlorophenyl)methyl)-4-(piperidin-4-ylamino)quinolin-2(1H)-one (200 mg) in methanol (0.3 mL) and dichloromethane (0.3 mL) was added a solution of t-butyl acrylate (1.80 mL; 1.57 g) in methanol (0.8 mL) and dichloromethane (0.4 mL) in 1 min. The reaction was heated to 70° C. for 24 hr. The reaction was cooled to room temperature and concentrated. The resulting residue was purified by silica column (ISCO) (5% MeOH/CH2Cl2) to yield tert-butyl 3-(4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-1,2-dihydroquinolin-4-yl)amino)piperidin-1-yl)propanoate.