Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]1(OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>COCCOC.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>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OB(O)Oc1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
1.75 g (0.01 mole) of 3-chloro-4-fluoronitrobenzene and 0.013 mole of phenylboric acid were dissolved in 70 mL of 1,2-dimethoxyethane under argon. Then, 0.5 g (0.0005 mole) of tetrakis(triphenylphosphine)palladium and 13 mL of 2N potassium carbonate solution were added, and the reaction mixture was heated to 80° C. At the end of the reaction, the reaction mixture was poured into 100 mL of ethyl acetate. The organic phase was extracted with dilute sodium hydroxide solution and then dried over magnesium sulfate. The solvent was distilled off from a rotary evaporator, and the residue was purified [by column chromatography] on silica gel using hexane/toluene (10:1) [as the eluent].
Reaction SMILES: O[C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([CH3:12])[CH2:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH2:4]1
Reactant: CCOC(=O)C1(O)CCC(C)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CCC(C)c2ccccc21
Yield: 93 %

Procedure:
The compound from Example 27 (42 g, 0.18 mole) and p-toluenesulfonic acid (6 g) were dissolved in 500 mL toluene and heated at reflux for 30 minutes with removal of water (Dean-Stark trap). The solution was cooled and washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and evaporated. The residual syrup was chromatographed on silica gel (0-3% ethyl acetate in heptane) to give the title compound in 93% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:4]([CH2:5][NH:15][CH3:14])[C:3]=1[OH:13]
Reactant: O=Cc1cc([N+](=O)[O-])cc(F)c1O
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc([N+](=O)[O-])cc(F)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.5 %

Procedure:
To a solution of 17C (2.65 g, 14.32 mmol) in MeOH (100 mL), methylamine (33% in EtOH, 1.960 mL, 15.75 mmol) was added dropwise and stirred rt for 1 h. The reaction mixture was cooled to 0° C., sodium borohydride (0.596 g, 15.75 mmol) was added portionwise and the mixture was stirred at rt for 1 h. The reaction was quenched with 0.5 N HCl, extracted with EtOAc (3×20 mL), washed with water, brine, dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography to give 27A (3.8 g, 18.98 mmol, 133% yield) yellow solid. MS (ESI) m/z: 201.2 (M+H)+.
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (20 mL) was added a solution of 4-(trifluoromethyl)phenyl isocyanate (0.41 g, 2.2 mmole) in dry dichloromethane (3 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. The resulting mixture was concentrated on a rotary evaporator and then partitioned between dichloromethane and 2N aqueous HCl. The organic layer was dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (15% ethyl acetate/hexane) to yield the title compound as a yellow solid (0.67 g, 91% yield), mp=78–81° C.; MS (−) ESI m/z=366 (M−H)−; [α]-D (25)=+24.2° (c=1, EtOH).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:17](/B(O)O)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22].[ClH:26]>CCOCC>[ClH:26].[CH:17](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:18]\[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCC/C=C/B(O)O
Reactant: COCCCNc1ccc2ncc(Br)n2n1
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCOC)nn12
Yield: 54 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (43 mg, 54%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.53 (d, J=9.7 Hz, 1H), 7.42 (s, 1H), 6.78 (dt, J=16.1, 7.0 Hz, 1H), 6.64-6.58 (m, 2H), 3.53 (t, J=6.2 Hz, 2H), 3.44 (t, J=6.2 Hz, 2H), 3.35 (s, 3H), 2.30-2.26 (m, 2H), 1.97-1.92 (m, 2H), 1.53-1.40 (m, 4H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 157.1, 139.2, 133.2, 130.0, 121.0, 120.6, 117.8, 114.3, 71.4, 59.0, 40.0, 34.3, 32.3, 29.4, 23.3, 14.3; HPLC tR=12.3 min, 98.6%; ES-MS: (M+H)=289 m/z.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]1=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]2[C:17]([C:2]3[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[C:3]=3[NH:16]2)=[CH:18][C:19]=1[CH3:20]
Reactant: O=C(O)C1CCCC(Br)C1=O
Reactant: Cc1ccc(N)cc1Cl
Product: Cc1cc2c3c([nH]c2cc1Cl)C(C(=O)O)CCC3

Procedure:
Under the conditions of Example 7(a), 10 g. of the ethyl ester of 3-bromo-2-oxocyclohexanecarboxylic acid is reacted with 3-chloro-4-methylaniline to obtain the ethyl ester of 7-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid and the ethyl ester of 5-chloro-6-methyl-1,2,3,4-tetrahydrocarbazole-1-carboxylic acid, which are separated by chromatography.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:10]([C:16](Cl)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:8]=2)[CH:7]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)C(Cl)C(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
5-Fluoropyridine-2-amine (1 g, 8.92 mmol) and ethyl 2,3-dichloro-3-oxopropanoate (39.6 g, 10.7 mmol, 5% in benzene) were added to a flask along with 75 mL of ethanol and stirred overnight at ambient temperature. The material was purified on Silica gel using methanol and ethyl acetate (Rf=0.4 in 5% MeOH/ethyl acetate) to provide 110 mg of the desired compound as a waxy solid, 95% pure by LC. MS (ES+APCI) m/z=209.2 (M+H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@H:12]1[CH2:15][C@H:14]([OH:16])[CH2:13]1.F[C:18]1[C:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1.C(OCC)(=O)C>CN(C=O)C>[O:27]1[CH2:28][CH2:29][CH:24]([C:23]2[C:18]([O:16][C@H:14]3[CH2:13][C@H:12]([C:4]4[NH:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[N:3]=4)[CH2:15]3)=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:26]1
Reactant: Fc1ncccc1C1CCOCC1
Reactant: O[C@H]1C[C@H](c2nc3ccccc3[nH]2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnc(O[C@H]2C[C@H](c3nc4ccccc4[nH]3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.049 g, 1.2 mmol) was added to a solution of trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol) in DMF (1.5 mL) under argon and the mixture was stirred for 45 min at RT. 2-Fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.58 mmol) was added and the mixture was stirred for 16 h at 110° C. Ethyl acetate was added and the mixture was washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 2-(trans-3-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)-1H-benzo[d]imidazole (37 mg, 0.11 mmol, 18% yield) as a white solid. [M+1]: 350.3. IC50 (uM) 0.01041.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH3:14])([CH3:13])[C:5]1=[O:15])(=O)C>S(=O)(=O)(O)O.C1COCC1.CCOCC>[CH3:13][C:6]1([CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:15]
Reactant: CC(=O)N1C(=O)C(C)(C)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)C(=O)Nc2ccccc21
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A solution of N-acetyl dimethyl oxindole (500 mg, 2.5 mmol) in 3 N sulfuric acid solution (7 mL) and THF (7 mL) was refluxed for 4 h. After cooling to room temperature, the reaction mixture was diluted with ether. The ethereal layer was washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 30% EtOAc in hexanes) to give dimethyl oxindole as a red solid (228 mg, 57%).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:15]([C:13]2[O:12][C:11]([CH3:24])=[C:10]([CH2:9][OH:8])[CH:14]=2)=[N:27][CH:28]=1
Reactant: COc1ccc(Br)nc1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
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: COCCOC
Solvent: O
Product: COc1ccc(-c2cc(CO)c(C)o2)nc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (1.9 g), 2-bromo-5-methoxypyridine (2.0 g), tetrakis(triphenylphosphine)palladium(0) (0.4 g), 2N aqueous sodium carbonate solution (7 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (10% ethyl acetate/hexane to 100% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.0 g, 65%) as a white crystal.
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][OH:5].Cl[CH2:7][C:8]([CH2:13]Cl)([CH2:11]Cl)[CH2:9][CH3:10]>C(O)C>[OH:5][CH2:4][CH2:3][S:2][CH2:7][C:8]([CH2:13][S:2][CH2:3][CH2:4][OH:5])([CH2:11][S:2][CH2:3][CH2:4][OH:5])[CH2:9][CH3:10]
Reactant: OCCS
Reactant: CCC(CCl)(CCl)CCl
Agent: [Na]
Solvent: CCO
Product: CCC(CSCCO)(CSCCO)CSCCO

Procedure:
To 300 parts of ethanol were successively added 6.9 parts of metallic sodium, 23.4 parts of 2-mercaptoethanol and 18.9 parts of 1,1,1-tris(chloromethyl)propane in this order, and the resulting mixture was heated under reflux. Thereafter, the deposited sodium chloride was removed, and the solution was concentrated to obtain 1,1,1-tris(2-hydroxyethyl-thiomethyl) propane. This compound was added to 50 parts of chloroform, and 45 parts of thionyl chloride was dropped into the resulting mixture. Subsequently, the mixture was heated under reflux, and then the solvent chloroform and unreacted thionyl chloride were removed by distillation under reduced pressure. The residual oily substance was poured into ice water and extracted with ether, and the ether extract was dehydrated over anhydrous sodium sulfate and then freed from the solvent by distillation to obtain 1,1,1-tris(2-chloroethylthiomethyl)propane. To this compound were successively added 0.3 part of phosphoric acid and 60 parts of 30% aqueous hydrogen peroxide, and the resulting medium mixture was heated under reflux and then cooled to deposit 1,1,1-tris(2-chloroethylsulfonylmethyl)propane. The deposited compound was recovered by filtration and dissolved in 200 parts of acetone, and the resulting acetone solution was incorporated with 30 parts of triethylamine and then stirred at room temperature to deposit triethylamine hydrochloride. This hydrochloride was removed, and the acetone solution was concentrated to deposit white solids. The solids were recrystallized from ethanol-acetone to obtain 1,1,1-tris(vinylsulfonylmethyl)propane.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][O:31][CH2:32][CH2:33]Br>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:33][CH2:32][O:31][CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: COCCBr
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-methoxyethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 2-bromoethyl methyl ether following General Procedure H.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10](O)=[O:11].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[C@@H:4]([CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])[C@@H:3]1[C:10]([Cl:16])=[O:11]
Reactant: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 77 %

Procedure:
Into 50 ml of water were dissolved 11.0 g of sodium hydroxide, followed by the addition of 50.0 g of ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate and about 100 ml of ethanol as a solvent. This mixture was stirred at room temperature for one day. To the reaction mixture was further added a solution of 8.0 g sodium hydroxide in 15 ml of water and the mixture was stirred at room temperature for two days. The resultant reaction mixture was distilled under reduced pressure to remove ethanol and extracted with diethyl ether to recover the unreacted ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate. Then, the alkaline aqueous layer was acidified by the addition of hydrochloric acid and extracted with diethyl ether. The etheral layer was dried over anhydrous magnesium sulfate and distilled to remove diethyl ether. By the above procedure there were obtained 45.2 g of cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylic acid. To 45.2 g of the carboxylic acid were added 131 g of thionyl chloride and 150 g of benzene and the mixture was heated under reflux overnight. The reaction mixture was then distilled under reduced pressure to remove the low-boiling fraction. The resultant residue was purified by distillation under reduced pressure to obtain 37.2 g of cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylic acid chloride which displayed the following NMR spectrum [yield 77% based on the ethyl cis, trans-2,2-dimethyl-3-(2,2,2-trichloroethyl) cyclopropanecarboxylate].
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]N1C(=O)CCC1=O>C(O)(=O)C>[Br:18][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1cc(C(F)(F)F)nc(-c2ccccc2)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2)nc(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
To a solution of 1.0 g (3.94 mmol) of 2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone and 20 mL of glacial acetic acid was added 1.0 g (5.6 mmol) N-bromosuccinimide and the mixture was left to stir at room temperature for 16 h. The reaction was poured onto ice water and vacuum filtered, washing well with water. The crude product was recrystallized from ethyl acetate to yield 1.05 g (83.5%) of 5-bromo-2-phenyl-6-trifluoromethyl-4(3H)-pyrimidinone, as a white solid. 1H-NMR (d6DMSO)δ7.6 (3H, m); 8.15 (2H, m).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:8][C:7](=[S:9])[C:6]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:5]2[N:4]=1.[OH-].[Na+].I[CH3:20]>>[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:20])[C:6]2=[C:10]([CH3:16])[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[N:5]2[N:4]=1
Reactant: CI
Reactant: CCCc1nc(C)c2c(=S)[nH]c(N)nn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc(C)c2c(SC)nc(N)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine-4(3H)-thione, hydrochloride (0.65 g.) in a slight excess of 2N sodium hydroxide was treated with iodomethane (0.4 g.) and the mixture was stirred 2 hours at room temperature. The solid was collected and crystallised from aqueous ethanol and had m.p. 139°-140°. Its hydrochloride melted at 207°-208°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[CH3:14][S:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([S:15][CH3:14])=[CH:17][CH:18]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CSc1nc(Cl)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2cc(C(F)(F)F)nc(SC)n2)cc1
Reaction time: 24 h
Yield: 84 %

Procedure:
A mixture of 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine (ButtPark Ltd, 2.86 g, 14.55 mmol), 4-(methylthio)phenylboronic acid (Aldrich, 2.83 g, 1.1 eq), tetrakistriphenylphosphine palladium (0) (0.2 g) and sodium carbonate (4.04 g, 2.6 eq) in DME (200 ml) and water (100 ml) was heated under reflux with stirring under N2 for 24 h. The reaction mixture was concentrated in vacuo and the resultant mixture partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and concentrated in vacuo to a purple solid. Purification by flash column chromatography with cyclohexane:ethyl acetate as (6:1) as eluant gave the title compound as a yellow crystalline solid (3.869, 84%).
Reaction SMILES: [N:1]1([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:23][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[CH2:2][CH2:3]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(Br)ccc32)CC1
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
A solution of compound 2 (2.0 g, 6.61 mmol) in dry DMF (10 mL) was treated with N-bromosuccinimide (1.17 g, 6.61 mmol) in DMF (10 mL) at 0° C. over a period of 30 min. The reaction was stirred at same temperature for 3.5 h. The reaction was diluted with water (200 mL) and product was extracted into ethyl acetate (3×25 mL). The combined ethyl acetate layer was washed with water (2×50 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 3 (2.5 g, 99%) as a syrup. 1H NMR (CDCl3) δ 7.13-7.10 (m, 2H), 6.27 (d, 1H, J=9.0 Hz), 4.28-4.20 (m, 2H), 3.50-3.40 (m, 1H), 3.35 (t, 2H, J=8.4 Hz), 2.93 (t, 2H, J=8.4 Hz), 2.75 (t, 2H, J=12.9 Hz), 1.78-1.72 (m, 2H), 1.60-1.49 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %) 381, 383 (MH+, 3), 325, 327 (100).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13](=[O:40])[C@@H:14]([N:22]2[C:26](=[O:27])[C@H:25]([CH2:28][C:29]3C=CC4C(=CC=CC=4)[CH:30]=3)[NH:24][C:23]2=[O:39])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[S:10][CH:11]=1)=[O:6]>>[CH3:3][O:4][C:5]([C:7]1[N:8]=[C:9]([NH:12][C:13](=[O:40])[C@@H:14]([N:22]2[C:26](=[O:27])[C@@H:25]([CH2:28][CH2:29][CH3:30])[NH:24][C:23]2=[O:39])[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[S:10][CH:11]=1)=[O:6]
Reactant: [H][H]
Reactant: COC(=O)c1csc(NC(=O)[C@H](CC2CCCCC2)N2C(=O)N[C@@H](Cc3ccc4ccccc4c3)C2=O)n1
Product: CCC[C@H]1NC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2nc(C(=O)OC)cs2)C1=O

Procedure:
In yet another embodiment of Compound A-1b, R3 is naphthyl and R4 is hydrogen. An example of such a compound is (S,S)-2-[[3-cyclohexyl-2-[2,5-dioxo-4-(naphthalen-2-yl)methylimidazolidin-1-yl]propanoyl]amino]thiazole-4-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]=[O:23])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:13][CH:12]=2.O1CCC[CH2:25]1.C[Mg]Br.C(OCC)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH:22]([OH:23])[CH3:25])=[N:10][C:11]2[C:16]([N:17]=1)=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:14]=[CH:13][CH:12]=2
Reactant: O=Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC(O)c1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring heterogeneous mixture of 3-(2-chlorophenyl)-5-(trifluoromethyl)-quinoxaline-2-carbaldehyde (0.2129 g, 0.632 mmol) in tetrahydrofuran (6.32 mL, 0.632 mmol) was added methylmagnesium bromide 3 M in diethyl ether (0.632 mL, 1.90 mmol) dropwise at 0° C. (started at 11:20 am), and the mixture was then stirred at room temperature. After 3 h, the reaction was quenched with saturated aq. NH4Cl (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown syrup. The brown syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 10 min as eluent to give 1-(3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethanol as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1 H, d, J=8.6 Hz), 8.31 (1 H, d, J=7.0 Hz), 8.05 (1 H, t, J=8.0 Hz), 7.48-7.71 (4 H, m), 5.33 (1 H, br. s.), 4.84 (1 H, br. s.), 1.28-1.55 (3 H, m); LC-MS (ESI) m/z 353.0 [M+H]+.