Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][OH:24])=[C:21]([Cl:25])[N:20]=[C:19]2/[CH:26]=[CH:27]/[CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: CC/C=C/c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC/C=C/c1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 0.26 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloroimidazole-5-carboxaldehyde in 10 mL of methanol at 0° C. was added 0.24 g of sodium borohydride portionwise over 0.5 hours. The mixture was stirred for an additional 0.5 hours at 0° C. and then poured into a solution at 10% sodium hydroxide in water. The resulting mixture was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) provided 0.23 g of 1-[2'-carbomethoxybiphenyl-4-yl)methyl-2-(1-transbutenyl)-4-chloro-5-hydroxymethylimidazole. NMR (200 MHz, CDCl3) δ7.84 (d, 1H); 7.53 (t, 1H); 7.40 (t, 1H); 7.29 (m, 3H); 7.08 (d, 2H); 6.86 (d of t, 1H); 6.17 (d, 1H); 5.30 (s, 2H); 4.54 (br s, 2H); 3.63 (s, 3H); 2.23 (quint., 2H); 1.04 (t, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)=[O:5])C.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
A solution of the commercially available 2-amino-thiazole-4-carboxylic acid ethyl ester 2a (3.8 g, 22 mmol) and trityl chloride (6.8 g, 24.3 mmol) in 30 ml pyridine was stirred at room temperature for 16 hours. The precipitate was filtered off and the filtrate was concentrated to reduce the volume to 20 ml. To the crude 2-(trityl-amino)-thiazole-4-carboxylic acid ethyl ester in 20 ml pyridine was added a solution of sodium hydroxide (5.4 g) in 50 ml of 60% ethanol in water. The reaction mixture was stirred at room temperature over the weekend, and was then acidified with acetic acid to pH 5. The precipitate was collected and dried to give 2-(tritylamino)-thiazole-4-carboxylic acid as a white solid (6.1 g, 72% yield). LC/MS (m/z 385.08 (M−H)+); HPLC Rt: 3.732 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:10]([OH:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:57][CH2:58][C:59](O)=[O:60].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:33])[CH3:34])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[C@H:10]([O:37][C:59](=[O:60])[CH2:58][Cl:57])[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc([C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)cc2OCC3)n(C(C)C)n1
Reactant: O=C(O)CCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2ccc([C@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4OC(=O)CCl)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.9 %

Procedure:
Racemic-trans-3-Hydroxy-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.215 g, 0.42 mmol) was suspended in dry THF (10 mL) and triphenylphosphine (0.22 g, 0.85 mmol) and chloroacetic acid (82 mg, 0.85 mmol) were added. Diethyl azodicarboxylate (0.133 mL, 0.85 mmol) was added dropwise and the mixture was stirred at room temperature for 24 h. The mixture was concentrated and the resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM). The resultant impure material was dissolved in dry DCM (5 mL) and triphenylphosphine, chloroacetic acid and diethyl azodicarboxylate were added (quantities as above). The mixture was stirred at room temperature for 16 hr, then concentrated in vacuo, the crude product was triturated with ether and the liquor was concentrated. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give impure racemic-cis-3-(2-Chloro-acetoxy)-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.297 g), which was used in the subsequent step without further purification. LCMS RT=4.61, [M+H]+=585/587.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1.[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.Cl>O>[O:22]1[CH2:21][CH:20]1[CH2:18][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[N:12][S:13][C:14]=2[C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(O)c1snnc1-c1ccc(O)cc1
Reactant: BrCC1CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snnc1-c1ccc(OCC2CO2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 80 mg. of sodium hydroxide in 10 ml. of water is added 250 mg. of 4-(4-hydroxyphenyl)-5-carboxy-1,2,3-thiadiazole. The reaction mixture is stirred for 10 minutes and then treated dropwise with 0.4 ml. of epibromohydrin, maintaining the reaction mixture at room temperature under stirring for 48 additional hours. It is then acidified with 10% hydrochloric acid solution and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from chloroformmethanol affords the pure 4-[4(2,3-epoxypropoxy)phenyl]-5-carboxy-1,2,3-thiadiazole.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1CCCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: [H][H]
Solvent: C1CCCCC1
Product: CC(C)(C)C1CCC(O)CC1
Yield: 93.8 %

Procedure:
A mixture composed of 100 g (0.649 mole) of 4-tert-butyl-cyclohexanone, 1.35 g of the catalyst prepared as indicated in Example 1 and 150 g of cyclohexane were put into an autoclave under nitrogen and then hydrogen was introduced until the pressure settled at about 106Pa. The mixture was then heated to 70° and the reaction was followed by gas chromatography. The reaction was stopped by cooling and the autoclave was flushed with nitrogen. After filtering, the catalyst was recovered under argon flow, washed with cyclohexane and recycled for the following hydrogenation operations. The clear filtrate was evaporated to give a residue that, once distilled, provided 95.15 g of an isomeric mixture containing 87.7% of cis isomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Li])CCC.Cl[C:38]([O:40][CH3:41])=[O:39]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:38]([O:40][CH3:41])=[O:39])=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: C[Si](C)(C)C#Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)C#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g, 0.33 mol) in dry diethyl ether (400 mL) was cooled to 0° C. under a nitrogen atmosphere. To this solution was added, dropwise over 45 minutes, a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 330 mL, 0.33 mol) via a dropping funnel maintaining the internal temperature below 2° C. The mixture was allowed to warm to room temperature over about 1 hour. Diethyl ether (300 mL) was added to the mixture and the organic solution was washed with water, saturated brine and then dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was cooled to about −78° C. n-Butyl lithium (1.6M in hexanes, 450 mL, 0.72 mol) was added dropwise via a dropping funnel over about 1 hour while the temperature was maintained below −66° C. After complete addition the mixture was stirred at −78° C. for about 1 hour and then a precooled solution of methyl chloroformate (110 mL, 1.4 mol) in dry diethyl ether (200 mL) was added in a continuous stream as fast as possible. The mixture was allowed to cool to −78° C. and the allowed to warm to room temperature over 1.5 h. The organic reaction mixture was washed with water and saturated brine and then dried over anhydrous magnesium sulfate. The solvents are remove under reduced pressure and the residue dried under reduced pressure to give the title compound as a brown solid, 36.5 g (61%). 1H NMR (CDCl3) δ 7.58 (dd, 2H, J=9, 5.4 Hz), 7.07 (t, 2H, J=8.5 Hz), 3.84 (s, 3H). MS (+ve ion electrospray) 178 (30), (M+).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][N:7]=1
Reactant: CSc1ccc(C(O)c2ccc(F)nc2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccc(Cc2ccc(F)nc2)cc1
Reaction time: 0.08 h
Yield: 89 %

Procedure:
A solution of (6-fluoropyridin-3-yl)(4-(methylthio)phenyl)methanol (1.716 g, 6.88 mmol) in DCM (3.0 mL) was treated with trifluoroacetic acid (2.56 mL, 34.4 mmol) resulting in a green solution. The mixture was stirred for 5 min, and then triethylsilane (3.30 mL, 20.65 mmol) was added dropwise. The green color dissipated rapidly to give a straw colored solution, and a brief exotherm was observed (DCM started refluxing). The mixture was stirred for 30 min, and then extracted into DCM from saturated aqueous NaHCO3. The DCM extracts were dried (MgSO4) and purified by flash chromatography (5% to 7.5% EtOAc/hexane) to give 2-fluoro-5-(4-(methylthio)benzyl)pyridine (89% over 2 steps) as a colorless oil. 1H NMR (400 MHz, d6-DMSO) δ 8.15 (s, 1H); 7.81 (t, J=8.22 Hz, 1H); 7.20 (s, 4H); 7.10 (d, J=8.41 Hz, 1H); 3.94 (s, 2H); 2.44 (s, 3H). 19F NMR (376 MHz, d6-DMSO) δ −72.37 (s, 1F). m/z (ESI, +ve ion) 234.0 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH3:14]>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:2][CH3:1])(=[O:12])=[O:11])=[CH:6][C:5]=1[CH3:14]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Methylamine (2.0 M in tetrahydrofuran, 46.37 mL, 92.75 mmol) was added to a stirred solution of 4-bromo-3-methyl-benzenesulfonyl chloride (5.0 g, 19 mmol) in tetrahydrofuran at 0° C., and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), washed with 2.0 N aqueous HCl (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 4-bromo-3-methyl-N-methyl-benzenesulfonamide (4.2 g, 85.7%) as a white solid. MS cald. for C8H10BrNO2S [M+] 264.1, obsd. 263.9.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:37]=[CH:36][C:20]2[N:21]([CH2:25][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:37]=[CH:36][C:20]3[N:21]([CH2:25][C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=4)[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1ccc(CN2CCOc3cc(N)ccc32)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3Cc2ccc(C(=O)OC)cc2)nc1Cl
Yield: 70.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.21 g, 1.2 mmol), thionyl chloride (2 mL), methyl 4-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (101b) (0.28 g, 0.97 mmol) and pyridine (5 mL). The resulting solid was washed with dichloromethane/hexane=1/1 to obtain 0.31 g of the title compound as a light yellow solid (70%).
Reaction SMILES: C([O-])(=O)C.[Na+].C([O:9][C:10]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH:20]([NH:22][OH:23])[CH3:21])=[CH:12][C:11]=1[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>O.O1CCOCC1>[CH3:25][C:24]([C:11]1[CH:12]=[C:13]([CH:20]([N:22]([OH:23])[C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH3:21])[CH:14]=[C:15]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]=1[OH:9])([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)Oc1c(C(C)(C)C)cc(C(C)NO)cc1C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(=O)N(O)C(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.82 g (0.01 mole) of sodium acetate in H2O (7 mL) is added to a solution of 1.07 g (0.0033 mole) of 2,6-bis(1,1-dimethylethyl)-4-[ 1-(hydroxyamino)ethyl]phenol acetate (Example 2) in dioxane (35 mL). Isobutyryl chloride (0.488 g, 0.00458 mole) is added dropwise and the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated to half volume, diluted with H2O, and extracted with Et2O. The Et2O extracts are washed with saturated NaHCO3, brine, dried over Na2SO4, and evaporated to dryness. The residue is recrystallized from n-hexane to give white crystals, 0.62 g (56%), m.p. 147°-148.5° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[N:18][CH:19]=1)=[O:13]>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[N:3]([NH:11][C:12]([C:14]2[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=2)=[O:13])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NN1c2ccccc2CC1C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1c(C)cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A mixture of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2-methyl-2,3-dihydro-indol-1-yl)-amide (246 mg, 0.68 mmol) and MnO2 (296 mg, 3.4 mmol) in DCM (10 mL) is stirred at rt for 1.5 h. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is triturated with ether to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (2-methyl-indol-1-yl)-amide (158, 65%). MS: 361 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.39 (s, 3H), 2.83 (s, 3H), 6.36 (s, H), 7.10-7.29 (m, 3H), 7.44-7.62 (m, H), 8.17 (s, H), 8.25 (d, H), 8.35 (d, H), 8.97 (s, H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C-:19]#[N:20].[Na+].O>CN(C=O)C.O>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:19]#[N:20])=[C:2]([Br:1])[CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-[3-bromo-4-(bromomethyl)phenyl]-1,3-benzoxazole (156 mg, 0.42 mmol), and sodium cyanide (41 mg, 0.84 mmol) in DMF:H2O (3:1, 16 mL) was stirred at rt for 18 h. Water (50 mL) was added to the reaction mixture and it was extracted with EtOAc (3×). The organics were combined, washed with brine (2×), dried over Na2SO4, and evaporated to dryness to give an orange oil. The crude oil was purified by flash chromatography eluting with a gradient of EtOAc:hexane (0 to 30 min: 0 to 20% EtOAc) to afford the desired [4-(1,3-benzoxazol-2-yl)-2-bromophenyl]acetonitrile as a yellow solid (M.p. 190–191° C.). 1H NMR (CDCl3, 300 MHz) δ 8.50 (s, 1H), 8.22 (dd, 1H), 7.78 (m, 1H), 7.70 (d, 1H), 7.60 (m, 1H), 7.39 (m, 2H), 3.91 (s, 2H). MS (ESI) 313 (M)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17]CC2C=CC=CC=2)[C:6]1=[O:25])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of acetic acid (1R,2R)-benzyloxycyclohexyl-2,5-dioxo-pyrrolidin-3-(R)-yl ester (3a (1.1 g, 3.18 mmol) in MeOH was added 10% Pd—C (110 mg), and the reaction vessel was flushed twice with H2. The reaction mixture was agitated at ambient temperature under H2 (charged balloon). After 4 hours, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to give acetic acid 1R,2R-hydroxycyclohexyl-2,5-dioxopyrrolidin-3-(R)-yl ester (4a) as a white hygroscopic foam (0.82 g, 99% yield); MS (ES+) 256.1 [M+H]+, 278.0 [M+Na]+, 533.1 [2M+Na]+; 1H-NMR (400 MHz, CDCl3) δ 1.11-1.34 (m, 3H), 1.64-1.75 (m, 3H), 2.02-2.09 (m, 2H), 2.12 (s, 3H, CH3), 2.22 (br s, 1H), 2.63 (dd, 1H, J=18.0 Hz, 4.8 Hz), 3.11 (dd,1H, J=8.8 Hz, J=18 Hz), 3.82 (ddd,1H, J=4.16 Hz, J=10.6 Hz, J=12.8 Hz), 4.16 (ddd, J=4.4 Hz, J=10.4 Hz, J=14.8 Hz), 5.34 (dd, 1H, J=8.8 Hz, J=4.8 Hz); 13C-NMR (100 MHz, CDCl3) δ 20.52, 24.16, 24.98, 27.77, 35.03, 35.40, 58.44, 67.43, 68.40, 170.11, 173.89, 174.08.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:42])[CH:19]([C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)[CH:27]=[C:28](O)[CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:42])[CH:19]([C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=2)[CH:27]=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
Trifluoromethanesulphonic anhydride (93 μL, 0.57 mmol) was added dropwise to a stirred solution of 2-(4′-chloro-5-hydroxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) (150 mg, 0.38 mmol) and pyridine (88 μL, 1.1 mmol) in DCM (3 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h, then 1M hydrochloric acid was added. The organic layer was filtered through a polytetrafluoroethylene (PTFE) frit and concentrated in vacuo to give the title compound (205 mg, 100%) as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]([C:12]([OH:14])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH3:18].S(=O)(=O)(O)O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:15]=[C:11]([C:12]([O:14][CH2:17][CH3:18])=[O:13])[C:10]([OH:16])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccccc2)ccc1O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)ccc1O
Yield: 55 %

Procedure:
To 18.58 g of 5-phenylsalicylic acid, 350 ml of ethanol, 100 ml of toluene and 42 ml of concentrated sulfuric acid were added. The mixture was heated under reflux for 14 hours. After it was confirmed with TLC that the starting materials were almost disappeared, the reaction liquid was poured into a mixed medium of diluted hydrochloric acid-ethyl acetate. The mixture was extracted, and the organic phase was collected and washed with saturated sodium chloride aqueous solution. After dried with magnesium sulfate, the liquid was concentrated to form a crude product. The product was recrystallized from ethanol to obtain 11.53 g of ethyl 5-phenylsalicylate in the form of colorless crystallites. The yield was 55%. The product was confirmed with NMR and mass spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[N:18]=[C:5]2[C:6](=[O:17])[CH2:7][CH:8]3[C:13]([CH:12]=[N:11][C:10]([CH3:15])([CH3:14])[C:9]3=[O:16])=[C:4]2[N:3]=1.Cl.[CH2:20]([N:22]([CH2:25][CH2:26][Cl:27])[CH2:23][CH3:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[ClH:27].[CH3:1][C:2]1[N:18]=[C:5]2[C:6](=[O:17])[CH:7]([CH2:21][CH2:20][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:8]3[C:13]([CH:12]=[N:11][C:10]([CH3:14])([CH3:15])[C:9]3=[O:16])=[C:4]2[N:3]=1
Reactant: CC1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCC1C(=O)C2=NC(C)=NC2=C2C=NC(C)(C)C(=O)C21

Procedure:
4.2 gm of 2,7,7-trimethyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were dissolved in 100 ml of dimethylformamide, and the solution was admixed with 3.4 gm of diethylamino ethyl chloride hydrochloride and 4.1 gm of potassium carbonate. The mixture was refluxed for 8 hours, the solvent was distilled off in vacuo, the residue was admixed with water and extracted with chloroform. The chloroform phase was evaporated and the residue was purified on a silicagel column (eluant: chloroform/acetone 19:1). The dihydrochloride was precipitated from acetone/methanol with ethereal hydrochloric acid and recrystallized from acetone/methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: Cc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-carboxylate and 4-methylbenzyl bromide in substantially the same manner, as described in Step 1 of Example 25. The product was obtained as a semi-solid contained 0.8 mole equivalent DMF. Mass spectrum (ESI, [M+H]+) m/z 372. 1H NMR (400 MHz, DMSO-d6) δ 7.93 (d, 1H, J=7.94 Hz), 7.55 (d, 1H, J=9.01 Hz), 7.40 (dd, 1H, J=8.85 and 1.98 Hz), 7.32 (s, 1H), 7.04 (d, 2H, J=7.96 Hz), 6.90 (d, 2H, J=7.94 Hz), 5.79 (s, 2H), 4.28 (q, 2H), 2.20 (s, 3H), and 1.28 ppm (t, 3H).