Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:11]3[NH:12][C:13](=[O:22])[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CN(C=O)C>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:26][C:27]#[N:28])[C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]n2c(-c3ccccc3)nnc2cc1-c1ccccc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCOc1nn2c(-c3ccccc3)nnc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 3,7-diphenyl-1,2,4-triazolo[4,3-b]pyridazin-6-one (from Example 73, Step a) (0.4021 g, 1.39 mmol) in anhydrous DMF (20 ml) under nitrogen was added sodium hydride (60% dispersion in oil, 84.0 mg, 2.10 mmol) and the mixture was stirred at room temperature for 30 min,. then at 80° C. for 20 min. After allowing to cool, bromoacetonitrile (0.146 ml, 2.10 mmol) was added dropwise and the mixture was stirred at room temperature for 14 h. The mixture was then partitioned between ethyl acetate (100 ml) and water (100 ml), adding saturated aqueous NaCl to aid in the separation of the layers. The aqueous layer was extracted further with ethyl acetate (2×100 ml) and the combined organic extracts were dried (Na2SO4), and evaporated in vacua. The residue was purified by flash chromatography (silica gel 2% MeOH/CH2Cl2) to afford 0.4566 g (100%) of the title compound as a buff solid: 1H NMR (360 MHz, CDCl3) δ5.11 (2 H, s), 7.52-7.63 (8 H, m), 8.12 (1 H, s), 8.45 (2 H, m); MS (ES+) m/e 328 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17](=[O:19])[CH3:18])[CH:13]=2)[N:8]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(C(C)=O)cc2c1=O
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(F)cc2)c2ccc(C(C)=O)cc2c1=O
Temperature: 100 °C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
A suspension of ester compound 8 (0.6 g, 2.3 mmol) 4-fluorophenylmethyl chloride (0.97 g, 6.8 mmol) and anhydrous K2CO3 (0.44 g, 6.8 mmol) in dry DMF (20 mL) was stirred for 18 hours at 100° C. After this time the mixture was poured into water (100 mL) and the solid that precipitated was filtered, washed with water, ethanol and light petroleum ether, in turn, and finally dried under IR lamp to give compound 9 (0.75 g, 95%); mp 207-209° C. (washed with dry ethanol).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.C(N(CC)[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])C>C1COCC1>[Si:8]([O:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[CH:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Reactant: CCN(CC)C(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 1.25 h
Yield: 65 %

Procedure:
To a stirred solution of the (4-bromobenzyloxy)-(tert.-butyl)-dimethylsilane (24.94 g, 82.8 mmol) in THF (420 mL) at −78° C. was added dropwise a 1.6 M solution of nBuLi in hexane (62 mL, 99.2 mmol) over a 1 h period. After stirring the mixture at the same temperature for 75 min, a solution of N,N-diethyltrifluoroacetamide (19.19 g, 113 nmol) in THF (60 mL) was added dropwise over 1 h. Following the addition the mixture at −78° C. for a further 75 min before the reaction was quenched with an aqueous solution of NH4Cl. Ether was added and the organic layer was extracted 3 times with ether (3×300 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuum. The resulting pale yellow liquid was distillated in vacuo to give the 1-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-2,2,2-trifluoroethanone (65%) as a colorless liquid; b.p. 170-180° C. (10 torr), 1H NMR (CDCl3): δ 0.12 (s, (CH3)2Si), 0.96 (s, CH3)3C), 4.83 (s, CH2), 7.50 (d, J=8.2 Hz, C6H4), 8.05 (d, J=8.2 Hz, C6H4); 13C NMR (CDCl3): δ −5.4 (CH3Si), 18.3 (C(CH3)3), 25.8 (C(CH3)3), 64.2 (CH2O), 116.7 (q, J=289.7 Hz, CF3), 126.2 (C6H2), 128.6 (C6H2), 130.2 (C6H2), 150.1, (C6H2), 180.2 (q, J=34.5 Hz, CO).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:38][Si:39]([CH3:46])([CH3:45])[CH2:40][CH2:41][O:42][CH2:43]Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:43][O:42][CH2:41][CH2:40][Si:39]([CH3:46])([CH3:45])[CH3:38])[C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCc4ccccc4)cc3)nc2n(CCC)c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3ccc(OCc4ccccc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (1.2 g, 2.9 mmol) and potassium carbonate (1.19 g, 8.6 mmol), were taken in DMF (15 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (1.52 ml, 8.6 mmol) was added drop wise at 0° C. and mixture was stirred at room temperature for 20 hours. The mixture was cooled to 10° C. and diluted with water, extracted with ethyl acetate. The organic layer was washed with saturated brine solution and dried over Na2SO4. Solvent was removed and residue obtained was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (1.12 g, 71%).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>O>[CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:22][S:50]([C:47]1[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=1)(=[O:52])=[O:51])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 4 °C

Procedure:
A solution of 1-O-octadecyl-3-O-trityl-glycerol (173.51 g, 295.63 mmol) in 895 mL water-free pyridine is added dropwise to a solution of p-toluenesulfonyl chloride (88.49 g, 464.15 mmol) in 670 mL water-free pyridine with constant stirring. The reaction mixture is kept at ambient temperature (20-23° C.) for two days. Diethyl ether (2.8 L) is added, and the organic phase is washed six times with water, twice with 0.5 N HCl (500 mL each), twice with diluted aqueous sodium carbonate, and then washed with water until neutral. After drying the organic phase over sodium sulfate, the solvent is removed under vacuum. The residue is triturated with isopropanol (1140 mL) with stirring until the product crystallizes. After cooling to 4° C., the product, 1-O-octadecyl-2-O-p-toluenesulfonyl-3-O-trityl-glycerol, is isolated by filtration, washed with isopropanol and dried under vacuum. Yield: 190.14 g (86.91%); m.p. 56-58° C.; Rf value (TLC on silica gel 60) of 0.38 with benzene as the developing solvent; and Rf value of 0.74 with benzene/methanol (50/2).
Reaction SMILES: [CH3:1][S:2][CH:3]1[CH:8]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][CH:5]([CH3:12])[CH2:4]1.[OH:13]O>C(O)(=O)C>[CH3:1][S:2]([CH:3]1[CH:8]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][CH:5]([CH3:12])[CH2:4]1)=[O:13]
Reactant: OO
Reactant: CSC1CC(C)CCC1C(C)C
Solvent: CC(=O)O
Product: CC1CCC(C(C)C)C(S(C)=O)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
p-Menth-3-yl methyl sulphide, prepared as in Part A (1.5 g., 8 mmoles), hydrogen peroxide (1 ml. of 30% solution) and glacial acetic acid (25 ml.) were stirred at room temperature for 17 hours. The mixture was then poured into ferrous sulphate solution and extracted with ether. The ether extracts were washed with sodium carbonate solution and then dried (MgSO4). Removal of the solvent left an oil which was purified by column chromatography and distillation to give p-menth-3-yl methyl sulphoxide, b.p. 88°/0.03 mm. (Found C, 65.3; H, 10.9. C11H22OS requires C, 65.4; H, 10.9%).
Reaction SMILES: O1CCOCC1.[C:7](O)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[N:17]1([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:7]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:18][CH2:19]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Yield: 23 %

Procedure:
To a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride were added 1.2 g of benzoic acid and 3.0 g of 5-(1-piperazinylcarbonyl)oxindol hydrochloride. To this mixture, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide dissolved in 5 ml of methylene chloride was added dropwise at 10° to 20° C. under ice-cooling externally with stirring. Then, the mixture was stirred for 3.5 hours at the same temperature. Crystals which precipitated were filtered off, and the filtrate was concentrated to dryness under reduced pressure. The resultant residue was dissolved in 100 ml of methylene chloride, and the organic layer was washed, in turn, with 5% aqueous hydrochloric acid solution, 5% aqueous sodium hydrogen carbonate solution, and water, and dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled off and the residue was recrystallized from methanol to give 0.79 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21]([O-])=[O:22]>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C([O-])c1ccc(N2CCOCC2)c(Cl)c1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)c(Cl)c3)cc2)cc1

Procedure:
Compound 617 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 3-chloro-4-morpholinobenzoate. [M+H]+ calcd for C24H23ClN3O3: 436.14; found: 435.97.
Reaction SMILES: [H-].[Na+].[ClH:3].[CH3:4][O:5][C:6]1[C:18]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10]=2[CH:9]=[CH:8][C:7]=1[O:19][CH3:20].Br[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[ClH:3].[CH2:22]([N:13]1[CH2:12][CH:11]2[CH:15]([CH2:16][CH2:17][C:18]3[C:6]([O:5][CH3:4])=[C:7]([O:19][CH3:20])[CH:8]=[CH:9][C:10]=32)[CH2:14]1)[CH2:23][CH3:24]
Reactant: COc1ccc2c(c1OC)CCC1CNCC21
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CC2CCc3c(ccc(OC)c3OC)C2C1
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
A slurry of NaH (0.68 g, 50% in oil, 14.1 mmole, washed 3 times with hexane) and 68 mL dry DMF was stirred under N2 at room temperature as a solution of the compound of example 5 (free base) (3.0 g, 12.9 mmole) in 20 mL dry DMF was added dropwise. The reaction mixture was stirred for 1.5 hr. at room temperature, then 1-bromopropane (1.3 mL, 14.1 mmole) was added dropwise. The reaction mixture was stirred for 1 hr at room temperature, and for 18 hrs. at 30°-35° C. The reaction mixture was evaporated to dryness, water was added and the solution was extracted 3 times with CH2Cl2. The combined CH2Cl2 layers were washed with water, brine, dried (MgSO4), filtered, evaporated, and converted to the HCl salt to yield 2.0 g (50%) gray glass; M+ 246.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH-].[K+]>C(O)C.O.Cl>[C:14]([O:13][C:11]([NH:10][C:9]1[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccc(Cl)cc2)sc1C(=O)O

Procedure:
A solution of 1a (1.37 g, 3.73 mmol) in ethanol (20 mL) was mixed with KOH (627 mg, 11.2 mmol) in water (20 mL). The resultant mixture was heated at 60° C. for 1 h, diluted with HCl (50 mL, 1N) and extracted with ethyl acetate (60 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated to afford compound 1b as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31]C)=[C:6]([C:8]2([CH2:11][C:12]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH3:25])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:31])=[C:6]([C:8]2([CH2:11][C:12]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH3:25])=[N:20]4)[CH2:9][CH2:10]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(C)ccc23)C(F)(F)F)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc2c(NCC(O)(CC3(c4cc(F)ccc4O)CC3)C(F)(F)F)cccc2n1
Reaction time: 1 h

Procedure:
Analogously to Example 38, 395 mg (0.88 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-methylquinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol is reacted with 4.30 ml (4.3 mmol) of a 1 M boron tribromide solution in 8.0 ml of dichloromethane. After one hour at 0° C., the reaction is halted. The subsequent recrystallization from ethyl acetate, acetone and methanol yields 257 mg (67% of theory) of the product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=2)[CH:8]=1)=[O:6]
Reactant: Fc1cccc(CBr)n1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(F)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 49 mg (0.18 mmol) of 3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one, 8 mg (0.21 mmol) of 60% sodium hydride, 40 mg (0.21 mmol) 2-bromomethyl-6-fluoro-pyridine and 0.8 mL of N,N-dimethylformamide. Yield: 28 mg of a white solid: LC-MSD, m/z for C24H19FN2O2 [M+H]+=387.3; HPLC retention time: 2.6 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][F:21]>CN(C=O)C>[F:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: COc1ccc(C=O)cc1O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCCF
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (10.0 g, 66.0 mmol, 1.0 equiv; commercially available) in anhydrous DMF (40 mL) was added K2CO3 (13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2 mg, 72.0 mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. The K2CO3 was removed by filtration and the organic phase concentrated under reduced pressure. To the residue was added a sat. solution of NaCl (100 mL) and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and the product crystallized from a mixture of isopropanol/diethyl ether to yield 12.69 g (97%) of the title compound. 1H NMR (300 MHz, DMSO): δ 3.89 (s, 3H), 4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 9.84 (s, 1H). MS (ISP): 198.6 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(F)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-fluorophenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][Si:17]([CH3:46])([CH3:45])[C:18]1[CH:19]=[C:20]([CH:38]=[C:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[C:21](NC1C=CC(C=CC(OCC)=O)=C(F)C=1)=[O:22]>>[CH3:42][Si:41]([CH3:44])([CH3:43])[C:39]1[CH:38]=[C:20]([CH:19]=[C:18]([Si:17]([CH3:46])([CH3:45])[CH3:16])[CH:40]=1)[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F
Reactant: CCOC(=O)/C(C)=C/c1ccc(N)cc1
Product: CCOC(=O)/C(C)=C/c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 27 %

Procedure:
Using BTMB (1.95 g) and Compound 13a (1.8 g), Compound 13b (910 mg, 27%) was obtained as a yellow solid in the same manner as Compound 2b was synthesized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH:19]=[O:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)c1nc(COCC=O)n(C)c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nc(COCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
In ethanol (6 ml)was dissolved 220 mg (0.59 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-ylmethoxy]acetaldehyde (24a), followed by addition of 45 mg (1.2 mmol)of sodium borohydride, and the mixture was stirred for 15 minutes. The reaction mixture was weakly acidified with acetic acid. A saturated aqueous sodium hydrogen carbonate solution was added to neutralize again, and the mixture was extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was fractionated by silica gel chromatography (ethyl acetate). The product was recrystallized from n-hexane to give 144 mg of 2-{[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy}ethanol (25a)(yield 65%). mp 89-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:14][CH2:15][C:16]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.0 g, 3.14 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.70 g, 2.4 mmol) were combined in dimethylformamide (8 mL) and cooled to 0° C. The reaction was treated with sodium hydride (115 mg, 4.8 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 1.6 g (96%). 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.39 (s, 1H), 7.34-7.37 (m, 4H), 7.25-7.28 (m, 2H), 4.35 (s, 2H), 3.75-3.77 (m, 2H), 3.41 (s, 2H), 3.01-3.06 (m, 2H), 2.19-2.22 (m, 2H), 1.83-1.89 (m, 2H), 1.44 (s, 9H). Mass spec.: 530.21 (MH)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[O:12]1[C@@H:14]([CH2:15][CH3:16])[CH2:13]1>CN(C=O)C.O>[OH:12][C@@H:14]([CH2:15][CH3:16])[CH2:13][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]1=[O:11]
Reactant: CC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To 1,2-Benzenedicarboximide (4.29 g) in DMF (10 ml), (S)-(−)-1,2-epoxybutane (2.1 g) was added followed by K2 CO3 (4.03 g) and heated at 60° C. for 48 h. The reaction was diluted with water, extracted with EtOAc, dried and solvent removed to give the subtitle compound as a white solid, 1.8 g.