Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)C(C)C)(C)C.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl>O1CCOCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CNCc1ccccc1
Temperature: 90 °C
Yield: 75 %

Procedure:
To a solution of ethyl bromoacetate (2.22 mL, 20.0 mmol) in 1,4-dioxane (40 mL) is added N,N-diisopropylethylamine (7.0 mL, 40.0 mol) and benzylamine (3.3 mL, 30.0 mmol), and the mixture is heated at 90° C. for 3 h. The reaction mixture is cooled to RT, dichloromethane is added, and the solution is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is residue purified by chromatography on silica gel; elution with EtOAc:MeOH:heptane (35:5:60) gives 2.9 g of the product 421. 1H NMR (CDCl3) δ 7.4-7.3 (m, 6 H), 4.19 (q, 2 H), 3.80 (s, 2 H), 3.40 (s, 2 H), 1.25 (t, 3 H); MS: m/z 194 (M++1).
Reaction SMILES: C([NH:3][C:4]([CH3:21])([CH:18]([CH3:20])[CH3:19])[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6])=O.[ClH:22]>CO.O>[ClH:22].[NH2:3][C:4]([CH3:21])([CH:18]([CH3:19])[CH3:20])[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(C)(NC=O)C(C)C)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)C(C)(N)C(C)C)cc1
Temperature: 80 °C

Procedure:
A suspension of 2-formamido-2,3-dimethyl-N-(p-tolylsulfonyl)butyramide (99.4 g, 0.318 mols) in 500 mL of methanol, 500 mL of water, and 500 mL of aqueous HCl 10% is heated at 80° C. until all the solid has dissolved (one hour). The reaction mixture is concentrated to 1/3 of the volume and the resulting precipitate is filtered off. After drying the title product is obtained as a white solid, having mp 161°-165° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:12])([CH3:14])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:35])[F:33])=[CH:29][CH:30]=3)=[O:22])[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=C(OCc1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 67.5 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (15 g, 68.93 mmol) and 4-trifluoromethoxybenzyl piperazine-1-carboxylate (25.17 g, 82.72 mmol) in DMF (75 ml) was stirred at 65-70° C. for 20 hours. The reaction mixture was allowed to return to room temperature and poured into water (475 ml), and extracted with ethyl acetate (150 ml). The aqueous layer was extracted with ethyl acetate (150 ml) again. The organic phases were combined, washed with water (400 ml) 3 times and a saturated saline solution (100 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to afford 4-trifluoromethoxybenzyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate (29.98 g, yield 83%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][CH3:17])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)nc1
Yield: 84 %

Procedure:
6-Chloronicotinic acid (1.6 g, 10.0 mmol) was dissolved in ethanol. Concentrated sulfuric acid (0.5 ml) was added to the solution, and the mixture was refluxed overnight. The reaction solution was concentrated under the reduced pressure. The residue was diluted with methylene chloride and was then washed with water, followed by drying over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (development system, n-hexane:ethyl acetate=5:1) to give ethyl 6-chloronicotinate 1.6 g (yield 84%) as a colorless oil.
Reaction SMILES: [CH:1]1([C@H:4]([N:7]2[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[C:8]2=[O:15])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:9]1[C:8](=[O:15])[N:7]([C@@H:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:21][CH2:20]2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-[(1R)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 154-156° C.; 1H NMR (300 MHz, CDCl3): δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.8 Hz, 1 H), 7.01 (s, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 4.05 (app. q, J=8.2 Hz, 1H), 3.14 (t, J=7.9 Hz, 2 H), 1.96-1.83 (m, 2 H), 1.07-1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81-0.75 (m, 1 H), 0.55-0.48 (m, 2 H), 0.35-0.28 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBrCl2 (M+H)+: 442.0089; Found m/z 442.0102.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.O[CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17].[Cl-].[Na+]>S(=O)(=O)(O)O>[Cl:17][CH2:16][C:15]([NH:14][CH2:13][C:7]1[CH:6]=[C:5]([C:8](=[O:11])[CH2:9][CH3:10])[CH:4]=[CH:3][C:2]=1[OH:1])=[O:18]
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCC(=O)c1ccc(O)c(CNC(=O)CCl)c1
Yield: 56.4 %

Procedure:
To 40 ml of concentrated sulfuric acid with stirring under ice-cooling is added a mixture of 10 g of 4'-hydroxypropiophenone and 10 g of N-hydroxymethylchloroacetic amide in a small portion. After addition, the reaction mixture is further stirred under ice-cooling for 130 minutes. The resulting mixture is poured into ice-cold water containing sodium chloride and the solution is extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried over sodium sulfate and then filtered. The filtrate is concentrated under reduced pressure and obtained white crystals are recrystallized from a mixture of hexane and ethanol to give 9.6 g of 3'-chloroacetamidomethyl-4'-hydroxypropiophenone as white crystals, melting at 143°-145° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[F:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1>CO>[F:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[O:13][C:2]([NH2:3])=[N:1][CH2:14]2)=[CH:8][CH:7]=1
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: NC1=NCC(COc2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.64 g, 10.0 mmol) in methanol (10 mL) was added dropwise 2-(4-fluoro-phenoxymethyl)-oxirane (1.68 g, 10 mmol) after which the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove methanol. Anhydrous diethyl ether (50 mL) was added after which the resulting white precipitate was removed by filtration through celite and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 0.77 g (37%) of 5-(4-fluorophenoxymethyl)-(4,5-dihydro-oxazol-2-yl)amine.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH:15]3[CH2:16][CH2:17][CH:11]2[CH2:12][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH:11]3[CH2:17][CH2:16][CH:15]2[CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
A 100-mL single-neck round-bottomed flask was purged with nitrogen and charged with 152a (2.5 g, 7.5 mmol), 10% palladium on carbon (50% wet, 250 mg) and methanol (40 mL). The mixture was evacuated, charged with hydrogen gas, and stirred at room temperature for 16 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 152b (1.51 g, 66%) as a colorless oil. MS-ESI: [M+H]+ 305.3
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[O:15][CH:16]1[CH2:19][N:18](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:17]1>C(Cl)Cl>[Br:11][C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][CH:35]=1)[O:15][CH:16]1[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:17]1
Reactant: O=C(Cl)Cl
Reactant: Brc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 0.5 h
Yield: 175.4 %

Procedure:
A solution of 22.7 g (0.23 mole) of phosgene in 200 ml of methylene chloride was treated with 29 g (0.23 mole) of potassium carbonate, stirred for 30 min, then 75.4 g (0.19 mole) of 3-(3-bromophenoxy)-1-diphenylmethylazetidine in 150 ml of methylene chloride was added dropwise. After stirring for 5 hr, the inorganic salts were removed by filtration and the filtrate was washed with water to destroy excess phosgene. Concentration (after drying) in vacuo yielded 96.85 g of oily residue. Trituration of the residue with isopropyl ether yielded 42 g of crude tan-gray product. A sample for analysis was recrystallized from isopropyl ether, m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([Si:5]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH2:1]([Si:5]([CH3:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Si](C)(C(=O)CC(C)C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCC[Si](C)(c1ccccc1)C(O)CC(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 45 (4.60 g, 17.7 mmol) in ethyl ether (150 mL) at 0° C. was added dropwise over 5 min lithium aluminum hydride (1 M in ethyl ether, 88.3 mmol). After stirring for 15 min at 0° C. under argon, the reaction mixture was diluted with ethyl ether (200 mL) and quenched with saturated Na2SO4 solution until evolution of hydrogen had ceased. The mixture was dried with solid Na2SO4 and filtered. The residue was extracted with ether (50 mL) and the organic extracts combined. Concentration provided a yellow oil of 46 as a mixture of diastereomers (3.6 g, 78%). This product was used in the next reaction without further purification: Rf=0.50 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.58-7.53 (m, 2H), 7.39-7.34 (m, 3H), 5.95-5.82 (m, 1H), 5.03-4.89 (m, 2H), 3.70 (dd, J=12.0, 2.3 Hz, 1H), 2.15-2.07 (m, 2H), 1.86-1.76 (m, IH), 1.59-1.49 (m, 2H), 1.23-1.12 (m, 1H), 1.03-0.84 (m, 7H), 0.33 and 0.34 (two singlets due to diastereomers, 3H); 13C NMR (75 MHz, CDCl3) δ 141.5, 135.8, 135.6, 134.7, 134.6, 129.6, 129.5, 128.2, 128.1, 113.2, 62.5, 62.1, 42.3, 42.2, 27.5, 24.2, 24.1, 23.6, 20.7, 20.8, 10.7, 10.5, −7.9, −8.0; IR (neat) 3571 (w), 3434 (m, br), 3069 (m), 2954 (s), 2913 (s), 2872 (m), 1638 (m), 1466 (m), 1427 (m), 1366 (w), 1251 (m), 1111 (s), 993 (m), 902 (m), 790 (s), 736 (s), 700 cm−1; MS (CI/CH4) m/e (rel. intensity) 263 (M++1, 2), 247 (13), 235 (10), 233 (12), 231 (13), 207 (13), 187 (11), 177 (20), 176 (15), 175 (69), (69), 151 (23), 137 (100), 131 (12), 115 (41). Anal. Calcd for C16H26OSi: C, 73.22; H, 9.98. Found: C, 72.85; H, 10.24.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: COc1cccc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 12.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (100 mg, 0.26 mmol) was reacted with 3-methoxy phenyl boronic acid (48 mg, 0.32 mmol) to give the title compound (15 mg, 10%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH:35][NH2:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:36][NH:35][CH:33]=[O:34])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 6.0 mmol) in THF (30 mL) was added 1,1′-carbonyldiimidazole (1.6 g, 7.2 mmol) at 0° C. The reaction mixture was stirred at rt for 1 h, then, formohydrazide (1.1 μg, 18.1 mmol) was added rapidly at rt. The reaction mixture was stirred at rt for 3 hrs and then diluted with EtOAc (100 mL). The combined organic layer was washed with saturated sodium chloride (10 mL), dried over Na2SO4, and concentrated to afford (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.6 g), which was used directly in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:20][CH2:21][CH2:22][OH:23]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:20][CH2:21][CH2:22][OH:23])=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: NCCO
Product: O=C(NCCO)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide was synthesized according to General Method 3, starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid 51 mg (0.83 mmol) of 2-amino-ethanol. LC/MS: [8.98 min, 480, 482]
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=O.BrBr.[NH2:16][C:17]1[S:18][CH2:19][CH2:20][N:21]=1>C(Cl)Cl.O>[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:16]=[C:17]3[N:21]([CH:1]=2)[CH2:20][CH2:19][S:18]3)=[CH:5][CH:6]=1)(=[O:12])[CH3:13]
Reactant: NC1=NCCS1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Agent: BrBr
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(-c2cn3c(n2)SCC3)cc1
Reaction time: 8 h

Procedure:
4-Acetamidoacetophenone (44 g, 0.25 mole) was suspended in 500 ml methylene chloride and treated with bromine (44 g, 0.275 mole). The reaction mixture was stirred overnight, then evaporated in vacuo. The residue was suspended in 200 ml of absolute EtOH and treated with 2-amino-4,5-dihydrothiazole (60 g, 0.59 mole). The reaction was stirred for 2 days, then taken up in water and extracted with methylene chloride. The organic phase was washed with water and then brine, and then dried over sodium sulfate. Flash column chromatography (silica, eluting with methylene chloride/methanol, 98/2) gave 6-(4-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C(OCC)C.[CH:20]1([Mg]Cl)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OCC)(=O)C>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[OH:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: CC1(C)COc2c(C=O)cc(Br)cc21
Reactant: Cl[Mg]C1CCCCC1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(C)COc2c(C(O)C3CCCCC3)cc(Br)cc21

Procedure:
Following General Procedure K and using 5-bromo-3,3-dimethyl-2,3-dihydrobenzofuran-7-carbaldehyde (Intermediate 30, 0.765 g, 3 mmol), 10 mL of anhydrous diethyl ether, and a 2M solution of cyclohexyl magnesium chloride solution in ether (3 mL, 6 mmol) followed by flash column chromatography using 10% ethyl acetate in hexane, the title compound was obtained (0.62 g, 61%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.O[C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[F:15][C:14]([F:17])([F:16])[CH2:13][O:12][C:21]1[N:22]=[CH:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[N:25][CH:26]=1
Reactant: COC(=O)c1cnc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.4 %

Procedure:
Cesium carbonate (2.96 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.57 g) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (700 mg) in DMF (20 mL), and the mixture was stirred at room temperature for 20 hours. Aqueous ammonium chloride and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (197 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:18]([CH2:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:19](=O)[CH2:20][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31]([OH:34])([CH3:33])[CH3:32])=[CH:26][N:25]=2)=O)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:48].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH:1]1([S:4]([C:7]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3[CH:18]([C:19]2[NH:48][C:22]([C:24]3[N:25]=[CH:26][C:27]([CH:30]([OH:35])[C:31]([CH3:33])([OH:34])[CH3:32])=[CH:28][CH:29]=3)=[CH:21][CH:20]=2)[CH2:37][CH:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COc1ccc2c(cnn2C(CC2CCOCC2)C(=O)CCC(=O)c2ccc(C(O)C(C)(C)O)cn2)c1S(=O)(=O)C1CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(cnn2C(CC2CCOCC2)c2ccc(-c3ccc(C(O)C(C)(C)O)cn3)[nH]2)c1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.7 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)-5-methoxy-1H-indazol-1-yl]-1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.37 g), ammonium acetate (0.23 g), acetic acid (0.34 mL) and ethanol (10 mL) was stirred at room temperature for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted from hexane-ethyl acetate (1:1-0:1, volume ratio) to give the title compound (60 mg, yield 17%) as a colorless amorphous solid. MS: 595 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[F:27][C:26]([F:28])([F:29])[C:23]1[CH:22]=[CH:21][C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH3:12])=[CH:19][CH:18]=2)=[CH:25][CH:24]=1
Reactant: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cc1

Procedure:
To a solution of 4-(1-hydroxy-propyl)-benzoic acid methyl ester (300 mg, 1.55 mmol) in toluene (10 mL) is added 1, 1′-(azodicarbonyl)dipiperidine (ADDP, 585 mg, 2.32 mmol) at 0° C., followed by the addition of tributylphosphine (0.58 mL, 2.32 mmol) and 4′-trifluoromethyl-biphenyl-4-ol (442 mg, 1.86 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 hours at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-trifluoromethyl-biphenyl-4-yloxy)-propyl]-benzoic acid (570 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: CC1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCC(C)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described in paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 4-methylpiperidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-methylpiperidin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.66 (m, 2H), 0.92 (d, 3H), 1.13 (m, 2H), 1.68 (m, 3H), 2.30 (s, 3H), 2.83 (m, 1H), 2.99 (t, 2H), 4.07 (d, 2H), 7.03 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.01 (d, 1H), 8.39 (s, 1H), 9.95 (s, 1H); Mass Spectrum: M+H+ 437.