Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[N:3]=1.O1CCCC1.[CH:24]1([Mg]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[Cl-].[NH4+]>O1CCCC1>[CH:24]1([CH:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=3)[CH:5]=2)[OH:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C=O
Reactant: Br[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carbaldehyde (2.6 g) synthesized above in tetrahydrofuran (40 mL) was added dropwise 1M cyclohexylmagnesium bromide tetrahydrofuran solution (15 mL) at 0° C. After stirring at 0° C. for 1 hr, aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (2.0 g, 36%) as a colorless solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][C:9]=1[OH:15].[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>CC(C)=O>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:12][C:11]2[CH:13]=[CH:14][C:8]([Br:7])=[C:9]([OH:15])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
K2CO3 (3 eq) was added to a stirred mixture of 4-bromoresorcinol (0.35 M) and TsCl (1.2 eq) in acetone and the mixture stirred at 50° C. for 18 h. Volatiles were removed in vacuo and the residue partitioned between 6 N HCl (aq) and EtOAc. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound. The product was used in the next step without further purification. (ES+) m/z 343, 345 (M+H)+.
Reaction SMILES: [CH:1]([NH2:3])=O.[N+:4]([C:7]1[CH:8]=[C:9]([NH2:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=O)([O-:6])=[O:5]>O>[N+:4]([C:7]1[CH:8]=[C:9]2[C:10]([C:11]([OH:13])=[N:3][CH:1]=[N:16]2)=[CH:14][CH:15]=1)([O-:6])=[O:5]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Temperature: 160 °C
Reaction time: 7 h
Yield: 86.1 %

Procedure:
A mixture of formamide (7.91 g, 176 mmol) and 4-nitroanthranilic acid (4.00 g, 22.0 mmol) was warmed to 160° C. and stirred for 7 h then cooled to RT and stirred overnight. The mixture was diluted with H2O (30 mL) and stirred overnight. The brown solid was collected by filtration and dried to yield 7-nitroquinazolin-4-ol (3.62 g, 86% yield). 1H NMR (300 MHz, DMSO-d6): 8.38-8.33 (m, 2H), 8.27-8.23 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)nc1

Procedure:
In an analogous manner to that described in Journal of Medicinal Chemistry 33:2087–2093 (1990), the reaction of 4-fluorobenzylalcohol instead of benzylalcohol with 2-chloro-5-nitropyridine yields the 2-(4-fluoro-benzyloxy)-5-nitro-pyridine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]([F:17])=[C:4](Cl)[N:3]=1.O.[NH2:20][NH2:21]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:5]([F:17])=[C:4]([NH:20][NH2:21])[N:3]=1
Reactant: NN
Reactant: CN(Cc1ccncc1)c1nc(Cl)nc(Cl)c1F
Solvent: O
Solvent: CS(C)=O
Product: CN(Cc1ccncc1)c1nc(Cl)nc(NN)c1F
Temperature: 50 °C
Yield: 23.1 %

Procedure:
2,6-Dichloro-5-fluoro-N-methyl-N-(4-pyridinylmethyl)-4-pyrimidinamine (0.3516 g, 1.23 mmol) was dissolved in 5 mL of DMSO and hydrazine monohydrate (0.36 mL, 7.4229 mmol). The reaction vessel was pressure sealed and heated to 50° C. for 2.5 hours. The reaction mixture was then purified by RP-HPLC to provide 2-chloro-5-fluoro-6-hydrazino-N-methyl-N-(4-pyridinylmethyl)-4-pyrimidinamine as a wine colored solid (0.0803 g, 23%). LCMS: (M+H)+=283.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[C:8]([CH3:10])[CH:9]=1)=[O:4].O.N>[Zn].C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c(Br)s1
Agent: N
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)cs1
Yield: 90.6 %

Procedure:
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml), and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (3.47 g). A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g), zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (30 ml), and 1N aqueous sodium hydroxide (15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:3]([C:6]1[C:11]([CH2:12][OH:13])=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4]>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[S:3]([C:6]1[C:11]([CH:12]=[O:13])=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4]
Reactant: CN(c1ccccc1)S(=O)(=O)c1ncccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(c1ccccc1)S(=O)(=O)c1ncccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A mixture of 3-hydroxymethylpyridine-2-sulfonic acid methylphenylamide (0.25 g), chloroform (20 mL) and manganese (IV) oxide (3.9 g) was stirred at room temperature for 2 hours. The mixture was treated with additional manganese (IV) oxide (1.6 g) and stirred at room temperature for a further 2 hours. The mixture was filtered through hyflo and the filtrate was concentrated under reduced pressure to afford the title compound (0.10 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[C:6]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: Cc1cccc2c1CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2c(C)cccc2C1=O
Yield: 67 %

Procedure:
A solution of 13.0 g of 4-methyl-1-indanone, 19.2 ml of 3-buten-2-ol and 170 mg of p-toluenesulfonic acid in 170 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 12.0 g (67%) of (RS)-2-(2-buten-1-yl)-4-methyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH:10]=1.[C:24]1([CH3:33])[C:25]([C:30](Cl)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.C1(C2C=CC=CC=2C(Cl)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:30](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:33])=[CH:17][CH:18]=2)[C:9](=[O:11])[CH:10]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Yield: 64 %

Procedure:
2-(2-Hydroxyethyl)-5-(4-aminobenzyl)-1,5-benzothiazepine-4-one as prepared in Example 21 (0.105 g, 0.31 mM) was treated using the procedure described in Example 22, with o-toluoyl chloride (0.04 ml, 0.33 mM) substituted for 2-phenylbenzoyl chloride, to yield the title product as a white solid (0.086 g, 64%) m/z (MH+) 447
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[OH:23][C@@H:24]([CH2:28][NH2:29])[C:25]([OH:27])=[O:26].CO>C[O-].[Na+]>[OH:23][C@@H:24]([CH2:28][NH:29][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])[C:25]([OH:27])=[O:26]
Reactant: NC[C@H](O)C(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC[C@H](O)C(=O)O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 93.5 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (90 mg, 0.31 mmol) and 2-(S)-hydroxy-3-amino-propionic acid (Sigma-Aldrich) (96 mg, 0.92 mmol) in 0.5 N NaOMe in MeOH solution (1.22 mL, 0.61 mmol) was microwaved at 120° C. for 1 h and concentrated. Residue was dissolved in water (70 mL) and acidified by 1 N HCl solution to pH=3-4. It was extracted with EtOAc, Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (105 mg, 0.29 mmol) in 92% yield. LC-MS ESI−: 366.99 (M−1)−.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C([Mg]Br)C.[CH3:18][C:19]1([CH3:27])[C:21]([CH3:23])([CH3:22])[CH:20]1[C:24](Cl)=[O:25]>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[C:4]([C:24]([CH:20]1[C:21]([CH3:23])([CH3:22])[C:19]1([CH3:27])[CH3:18])=[O:25])=[CH:5][NH:6]2
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Fc1c(F)c(F)c2[nH]ccc2c1F
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3c(F)c(F)c(F)c(F)c23)C1(C)C
Yield: 11.5 %

Procedure:
A mixture of 4,5,6,7-tetrafluoroindole (Matrix Scientific, 1.0 g. 5.3 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.4 mL, 6.4 mmol), zinc chloride (1.0 M solution in Et2O, 6.4 mL, 6.4 mmol) and the product of Example 1A (7.9 mmol) in 40 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.19 g, 0.61 mmol, 12% yield). MS (DCI/NH3) m/z 314 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9]C)=[O:8])[S:4][N:3]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[S:4][N:3]=1
Reactant: COC(=O)c1cc(O)ns1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(O)ns1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of methyl 3-hydroxyisothiazole-5-carboxylate (300 mg, 1.73 mmol) in MeOH (2 mL) is added 1N NaOH (6 mL, 6 mmol). After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-hydroxyisothiazole-5-carboxylic acid (250 mg).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:9]([NH:14][CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:39])[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CC#N.O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:9]([N:14]([C:31]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH3:15])=[N:10][N+:11]([O-:13])=[O:12])=[CH:5][N:6]=1
Reactant: CNC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C(=O)Oc1ccccc1)C(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)Oc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 1-(2-chloro-5-thiazolylmethyl)-1- phenoxycarbonyl-3-methyl-2-nitroguanidine (Compound No. 6), CH3CN (15 ml) and pyridine (0.55 ml) was cooled to 3°-C. followed by addition of phenyl chlorocarbonate (1.7 ml) in CH3CN (3 ml) below 8° C. over 2 minutes under stirring. After stirring at the same temperature for 1 hour and 25 minutes and then at room temperature for 1 hour, pyridine (0.55 ml) and phenyl chlorocarbonate (1.7 ml) was added to the mixture followed by stirring at room temperature for 1 hour and 15 minutes and at 40° C. for 2 hours. Additional phenyl chlorocarbonate (1.7 ml) was added to the mixture which was stirred for 20 minutes. To the reaction mixture was added CHCl3 (30 ml) and then a mixture of conc. hydrochloric acid (2 ml) and water (8 ml). The reaction mixture was partitioned and the aqueous layer was extracted with CHCl3 (20 ml×3). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (3:2) to afford 0.7 g of 1-(2-chloro-5-thiazolylmethyl)-I,3-diphenoxycarbonyl-3-methyl-2-nitroguanidine (Compound No. 2) as an oil.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]([C:9]1[CH:10]=[C:11]([C:20]2[C:21]([OH:34])=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)[C:12]([OH:19])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]1([Cl:4])[O:34][C:21]2[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:25][C:20]=2[C:11]2[CH:10]=[C:9]([C:5]([CH3:6])([CH3:7])[CH3:8])[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]=2[O:19]1
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
45.21 grams of phosphorous trichloride in 50 ml of toluene was added dropwise over 85 minutes to a solution of 123.0 grams of 4,4',6,6'-tetra-tert.-butyl-2,2'-biphenol and 60.6 grams of triethylamine in about 600 ml of toluene and stirred at room temperature overnight (about 20 hours). The reaction product was filtered free of triethylamine hydrochloride, the desired product being isolated by removal of the solvent at reduced pressure to yield a solid m.p. 168°-174°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1.Cl[CH2:21][CH2:22][C:23]([N:25]=[C:26]=[S:27])=[O:24]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:26]3[S:27][CH2:21][CH2:22][C:23](=[O:24])[N:25]=3)[CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:6]=2[CH:19]=1
Reactant: O=C(CCCl)N=C=S
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCCN2
Solvent: C1CCOC1
Product: O=C1CCSC(N2CCN=C(c3ccccc3Cl)c3cc(Cl)ccc32)=N1
Temperature: 25 °C

Procedure:
5 Parts of 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine and 12 parts of 3-chloropropionylisothiocyanate is dissolved in 100 parts by volume of tetrahydrofuran and the resultant solution refluxed for about 18 hours. The reaction mixture is then cooled to ambient temperature and filtered. The solvent is removed from the filtrate and the residue crystallized from a mixture of methylene chloride and hexane to afford 7-chloro-5-(o-chlorophenyl)-2,3-dihydro-1-(5,6-dihydro-4-oxo-4H-1,3-thiazin-2-yl)-1H-1,4-benzodiazepine. This compound is represented by the following formula ##STR31##
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([CH3:40])([CH3:39])[CH2:12][C:13]1[N:14]=[C:15]([CH:24](O)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[N:16]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:17]=1>C(Cl)Cl>[CH3:10][C:11]([CH3:40])([CH3:39])[CH2:12][C:13]1[N:14]=[C:15]([CH:24]([F:7])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)[N:16]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:17]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)Cc1ccc(-c2ccccn2)cc1
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(F)Cc1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylaminosulfur trifluoride (0.1 mL, 0.8 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-[1-hydroxy-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (for synthesis see Example 1) (71 mg, 0.16 mmol) in methylene chloride (5 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-[1-fluoro-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.CN(C)CCN(C)C.[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C>O1CCCC1>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([B:27]([OH:32])[OH:28])=[CH:8][C:7]=2[CH:11]=1
Reactant: FC(F)(F)c1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cc(C(F)(F)F)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
To a solution of 5-(trifluoromethyl)-1-benzofuran (5.0 g, 26.86 mmol) in dry tetrahydrofuran (120 mL) were added tetramethylethylenediamine (3.74 g, 32.2 mmol). The solution was kept below −60° C. under nitrogen, while n-BuLi (12.8 mL, 32.2 mmol, 2.5 M solution in hexane) was added dropwise. The solution was warmed to −10° C. over 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of triisopropyl borate (10.0 g, 53.19 mmol). After warming to room temperature the mixture was quenched with hydrochloric acid (70 mL, 2N) and stirred for 1 h. The alkaline aqueous layer was brought to pH 5 and extracted with ethyl acetate (3×80 mL). All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give [5-(trifluoromethyl)-1-benzofuran-2-yl]boronic acid (2.0 g, crude) as light yellow oil; which was used for the next step without further purification.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[C:9]([F:17])[CH:8]=1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1>[F:17][C:9]1[CH:8]=[C:7]([B:18]([OH:23])[OH:19])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCOc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1ccc(B(O)O)cc1F
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
A solution n-butyllithium (2.5 M in hexanes, 4.4 ml) was added dropwise over 5 minutes to a stirring solution of 1-bromo-3-fluoro-4-propoxybenzene (2.3 g) in tetrahydrofuran (10 ml) at -70° C. The solution was stirred at -70° C. for 15 minutes and then transferred by cannula to a solution of triisopropyl borate (4.14 g) in tetrahydrofuran (10 ml) at -78° C. Once addition was complete the mixture was stirred at room temperature for 30 minutes. A solution of dilute hydrochloric acid (2 M, 30 ml) was added and the mixture extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the sub-title compound as a white solid (1.19 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[CH:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(COC(C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COC(C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 38.4 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (14) (0.50 g, 1.2 mmol) dissolved in 5 mL of anhydrous dichloromethane (DCM) was reacted with 0.14 mL (0.2 g, 1.5 mmol) of oxalyl chloride. After completion of the reaction, a solution of 0.34 mL of benzyl alcohol (0.25 mL, 0.26 g, 2.4 mmol) and 0.26 mL of pyridine (0.15 g, 1.9 mmol) in dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.23 g (38% yield) of the title compound (32a) as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (31a).