Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21]Cl)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)CCCCCl)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N2CCCCC2=O)cc(C(C)(C)C)c1O
Yield: 80 %

Procedure:
N-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-chlorovaleramide (5.5 g: 16 mmol) in 25 ml of tetrahydrofuran was slowly added to 1.4 g (35 mmol) of 60% sodium hydride in mineral oil (washed twice with 25 ml portions of hexane) and 50 ml of tetrahydrofuran. The reaction mixture was stirred and gas evolution was observed. Seventeen hours later the mixture was concentrated to 20 ml, diluted with 50 ml of methylene chloride and washed successively with dilute 1N hydrochloric acid and dilute sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and concentrated to a solid (4.5 g). This solid was recrystallized from acetone to yield 3.9 g (12.8 mmol, 80%) of crystalline 1-(3,5-di-tert-butyl-4-hydroxyphenyl)piperidin-2-one, mp 212°-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=O)[CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH:30]1[C:40]2[C:41]3[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=3[CH:37]=[CH:38][CH:39]=2)[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]([N:30]5[C:40]6[C:41]7[CH:32]([CH2:33][C:34](=[O:42])[NH:35][C:36]=7[CH:37]=[CH:38][CH:39]=6)[CH2:31]5)=[O:26])[CH:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=C1CC2CNc3cccc(c32)N1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)O)c3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ccnc(C(=O)N4CC5CC(=O)Nc6cccc4c65)c3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
67 mg (0.17 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-carboxylic acid and 30 mg (0.17 mmol) 1,2,2a,5-tetrahydro-3H-pyrrolo[4,3,2-de]quinolin-4-one in 56 μL (0.40 mmol) TEA and 1.8 mL DMF were combined with 58 mg (0.18 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]([CH3:23])[C:21]([CH3:24])=[N:20][CH:19]=1>CN(C=O)C>[CH3:23][N:22]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:19][N:20]=[C:21]1[CH3:24]
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1ncc(CBr)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cnc(C)n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (764 mg, 5.4 mmol) was dissolved in anhydrous DMF (30 mL), then potassium carbonate (2.23 g, 16.1 mmol) and 5-(bromomethyl)-1,2-dimethyl-1H-imidazole (1.52 g, 8.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 20% DCM in MeOH to afford 2-{[(1,2-dimethyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (279 mg, 21% yield for 3 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 2.24 (s, 3H), 3.46 (s, 3H), 4.40 (s, 2H), 5.99 (s, 1H), 6.72 (s, 1H); LRMS (ES+) m/z 251 (50%, M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[CH3:16][O:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:16][O:17][CH2:18][CH2:19][O:1][C:2]1[C:3]([CH3:15])=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCCl
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1c([N+](=O)[O-])ccc(C(=O)OC)c1C
Temperature: 90 °C
Reaction time: 20 h
Yield: 106.3 %

Procedure:
Methyl 3-hydroxy-2-methyl-4-nitrobenzoate (1.55 g) and 2-chloroethyl methyl ether (1.8 g) were dissolved in anhydrous DMF (20 mL), and potassium carbonate (1.25 g) and potassium iodide (300 mg) were added, followed by stirring at 90° C. for 20 hours. To the reaction mixture, ethyl acetate (200 mL) was added, followed by washing twice with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain methyl 3-(2-methoxyethoxy)-2-methyl-4-nitrobenzoate (2.1 g) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[CH2:10]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Ba+2].[OH-]>CCO>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:22]=[CH:1][C:2]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:3])=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C1CCCCC1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(OCc2ccccc2)cc1)C1CCCCC1

Procedure:
The title compound was prepared as described in General Method 2 using 17.40 g (138 mmol) of cyclohexyl methyl ketone, 29.26 g (138 mmol) of 4-benzyloxybenzaldehyde, 3.17 g of barium hydroxide (anhydrous), and 300 mL of 95% EtOH. The reaction was heated at reflux for eight hours. The crude product was recrystallized from EtOAc. The 25.85 g of product, contaminated with some 4-benzyloxybenzaldehyde, was taken on without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]C)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[Si](C)(C)C.Br.Br.[CH:29]12[CH2:35][CH:32]([NH:33][CH2:34]1)[CH2:31][NH:30]2.C(#N)C>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH:32]5[CH2:35][CH:29]4[CH2:34][NH:33]5)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NC2CNC1C2
Reactant: COC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of 1.0 g (3.4 mmole) of methyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 25 ml dichloromethane was added 0.6 ml (0.8 g, 4.2 mmole) of iodotrimethylsilane while stirring at room temperature under a blanket of nitrogen. The reaction was warmed to reflux and stirred overnight. An additional 0.23 ml (1.6 mmole) of iodotrimethylsilane was added and the solution was refluxed for another two hours, cooled to room temperature, and concentrated. The residue was taken up in 20 ml of acetonitrile. To this solution was added a mixture of 2.2 g (8.5 mmole) of 2,5-diazabicyclo[2.2.1]heptane, dihydrobromide, 2.7 g (17.9 mmole) 1,8-diazobicyclo[5.4.0]undec-7-ene and 20 ml acetonitrile. The reaction was refluxed for 2.5 hours then cooled to room temperature. The formed precipitate was filtered, washed with acetonitrile and ethyl ether, yielding 1.13 g (92%) of the title compound, mp 288°-290° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:29])([CH3:28])[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:28][C:19]([NH:29][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:18])[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CCN1CCOCC1
Product: CC(C)(CCN1CCOCC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1,1-dimethyl-3-morpholin-4-yl-propylamine (Example 35 d) as starting materials, MS (EI): m/e=388.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2Br)[CH:7]=[C:6]([NH2:16])[CH:5]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1B(O)O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:27]2[CH:28]=[C:29]([Br:32])[CH:30]=[CH:31][C:26]=2[O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:9]=1
Reactant: OB(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: COC(=O)c1cc(N)cc(C2=C(Br)CCC2)c1
Product: COC(=O)c1cc(N)cc(C2=C(c3cc(Br)ccc3OCc3ccccc3)CCC2)c1

Procedure:
Prepared by general procedure 3 but using 3-amino-5-(2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-(benzyloxy)-5-bromophenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
N-Hydroxyphthalimide (12.0 g) in 130 ml dimethyl sulphoxide is treated with anhydrous finely divided potassium carbonate (6.6 g), when the dark red colour of the anion develops. The mixture is then treated dropwise at room temperature with p-fluorobenzyl chloride (20 g) and the mixture is stirred overnight or until the red colour is discharged. The reaction mixture is poured into water, and the resultant crystalline product is filtered off. Recrystallisation from ethanol gives N-p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4 g, 82%), m.p. 156°-157° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([N:22]([CH3:24])[CH3:23])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[C:13]([NH:14][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]3[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=3)[CH:35]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([N:22]([CH3:23])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1ccccc1F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1-c1ccccc1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example J10) (271 mg, 0.78 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (194 mg, 0.65 mmol) according to the general procedure M. Obtained as a yellow solid (316 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]>>[Br:30][C:31]1[N:36]=[C:35]([C:37]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:38])[CH:34]=[CH:33][C:32]=1[F:40]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)CC[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 11 of Example 305, tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 6-bromo-5-fluoropicolinic acid were coupled to yield tert-butyl (3R,4R)-1-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate. LCMS (m/z): 510.0/512.0 (MH+); LC Rt=4.51 min.
Reaction SMILES: [CH3:1][C:2]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C@H:4]1[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5]1)[CH3:3]>CO.[Pd]>[CH3:3][C:2]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])([C@H:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:1]
Reactant: CC(C)(C)OC(=O)NC(C)(C)[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C)(C)[C@H]1CCNC1
Reaction time: 24 h
Yield: 114.3 %

Procedure:
To a solution of 1,1-dimethylethyl {1-methyl-1-[(3S)-1-(phenylmethyl)-3-pyrrolidinyl]ethyl}carbamate (5.85 g, 18.4 mmol) in MeOH (100 mL) was added Pd/C (5 g, 10%). The suspension was hydrogenated at 50 psi of H using a Parr shaker. After 24 h, the mixture was filtered and washed several times with MeOH. The filtrate was concentrated to afford the title compound (4.8 g, quantit.) as an oil, which was used without further purification: LC/MS (ES) m/e 229 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:14](I)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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[C:14]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
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: C1COCCO1
Solvent: O
Product: FC(F)(F)c1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Compound number 130 (i.e., 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylbenzimidazole was prepared as follows. A 250-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (400 mg, 1.15 mmol, 1.00 equiv), (4-chlorophenyl)boronic acid (359 mg, 2.30 mmol, 1.99 equiv), sodium carbonate (380 mg), dioxane (40 mL), Pd(PPh3)4 (67 mg), and water (10 mL) was placed in the flask. The resulting solution was stirred for 4 h at 100° C. in an oil bath. The mixture was cooled. The resulting solution was diluted with 100 mL of H2O. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×100 mL of brine (sat.). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30). This resulted in 34.9 mg (9%) of 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)([Cl:10])[Cl:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([Cl:9])[Cl:10])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: Cl
Solvent: CC(C)=O
Product: Clc1cc(C(Cl)Cl)cc(Cl)n1

Procedure:
To a solution of 73 grams (0.275 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine dissolved in 125 milliliters of acetone was added a solution of 108 grams (0.48 mole) of stannous chloride hydrate and 40 milliliters of concentrated hydrochloride acid in 500 milliliters of acetone. The mixture was refluxed for 2.0 hours. The solid which formed was separated by filtration and three fourths of the solvent was thereafter removed by evaporation. The remainder of the reaction mixture was diluted with water and the oil phase which formed, removed by extraction with hexane. The 2,6-dichloro-4-(dichloromethyl)pyridine product was dried and recovered from the solvent by evaporation of the solvent. The product had a boiling point of 123°- 126° C. at 1.6 millimeters of mercury.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Reactant: CCCCCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCCCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.70 ml (5.0 mmol) of 1-heptanal in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=4/1) to yield 1.82 g (87.3%, yellow oily substance) of the desired product.
Reaction SMILES: N1C=CN=C1.[CH3:6][CH:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:8][OH:9].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[O:9]([CH2:8][CH:7]([CH3:6])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)[Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)Cc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of imidazole (27.2 g) in DMF (100 ml) was added to a stirred solution of 2-methyl-3-(4-bromophenyl)propanol (37.4 g) and tert-butyldimethylsilyl chloride (28.9 g) in dry DMF (100 ml) at 0° C. The reaction mixture was allowed to stir, warming to ambient temperature, over 21 hours and was then poured onto ice (500 g). The reaction mixture was extracted with diethyl ether (3×500 ml), the combined organic layers were dried (MgSO4) and the solvent was evaporated to give 1-(tert-butyldimethylsiloxy)-2-methyl-3-(4-bromophenyl)propane as a yellow oil (53.3 g), mass spectrum (+ve CI): 343 (M+H)+.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[C@@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@H:15]([OH:23])[CH2:14][N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][NH:9][C:10]([C@H:12]1[C@@H:17]2[O:18][C:19]([CH3:21])([CH3:22])[O:20][C@@H:16]2[C@H:15]([OH:23])[CH2:14][N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](O)[C@H]3OC(C)(C)O[C@H]3[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](O)[C@H]3OC(C)(C)O[C@H]3[C@@H]2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
The above compound (7) (278 mg) was dissolved in ethyl acetate (15 mL) and 10% Pd—C (38 mg) was added, and then the mixture was stirred under a hydrogen atmosphere room temperature for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel medium pressure column chromatography (chloroform:methanol=50:1→30:1→10:1) and then freeze-dried to obtain the titled compound (205 mg) as a colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:21][CH2:22]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Yield: 85.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-3-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4 g), the title compound (7 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][O:13][C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(OCc1ccc(-c2ccc(Cl)cc2)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(=O)O)c1ccccc1
Yield: 47.7 %

Procedure:
A solution of ethyl 2-[4-(4-chlorophenyl)benzyloxy]-2-phenylpropionate (7.9 g.) in methanol (100 ml.) containing potassium hydroxide (11.0 g.) was heated under reflux for 2 hours and then evaporated. The residue was partitioned between water (100 ml.) and ether (30 ml.). The aqueous phase was separated and acidified with 4 N-hydrochloric acid to pH 2-3 and extracted with ether (3×30 ml.). These ether extracts were washed with water, dried (MgSO4) and evaporated. The residue was crystallised by treatment with a mixture of ethyl acetate and hexane to give 2-[4-(4-chlorophenyl)-benzyloxy]-2-phenylpropionic acid, (3.5 g.), m.p. 125°-126° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[C:21](O)=[O:22]>>[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[OH:27])[C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:22]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(Nc1ccccc1-c1cc2ccccc2[nH]1)c1ccc(O)c(O)c1
Yield: 54 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-dihydroxybenzoic acid in 54% yield following procedure 1. The product was chromatographed on silica. 100% Purity by LC/MS (230 DAD), Mass-spec (M+H+)=345.83, 1H NMR (MeOH-d4): 6.645 s (1H), 6.80 d, 8 Hz (1H), 7.02 t, 8 Hz (1H), 7.12 td, 8.1 Hz (1H), 7.23 dd, 8.1 Hz (1H), 7.33–7.36 m (2H), 7.39–7.42 m (2H), 7.52 d, 7 Hz (1H), 7.65 dd, 8.1 Hz (1H), 7.94 d, 8 Hz (1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH2:20]2>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH2:20]2
Reactant: Brc1cccc2c1CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2c(Br)cccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.