Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].S(Cl)(Cl)=O.[I-].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>O1CCCC1>[CH3:4][O:3][C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11](=[O:13])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH2:9][CH2:10]1)=[O:2]
Reactant: COc1ccccc1[Zn+]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Agent: [I-]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C(=O)c2ccccc2OC)CC1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
In an oven dried 1 neck round bottom flask with reflux condenser and stirbar, trans-4-carbomethoxycyclohexane-1-carboxylic acid (1.11 g; 5.4 mmol) was heated to reflux in the presence of 30 mL thionyl chloride. After 3 hours reflux, mixture cooled to 40° C. under nitrogen flow, and excess thionyl chloride was removed at reduced pressure. Residue was taken up in 5 mL of dry tetrahydrofuran and added to a 0° C. mixture of 2-methoxyphenylzinc iodide (11.0 mL; 5.4 mmol), tetrakis(triphenylphospine)palladium (0) (90 mg; 0.08 mmol) in 2.5 mL anhydrous tetrahydrofuran. Mixture was allowed to warm to room temperature over 16 hours. Reaction was quenched with 6 mL 1N HCl and ethyl acetate was taken in. Organics separated and aqueous re-extracted with 20 mL ethyl acetate. Combined organics were washed with sat. NaHCO3, water, brine and dried over MgSO4. Material was purified via flash silica plug (10:1) using 15% ethyl acetate in hexanes isocratic to give 900 mg of title compound. (64% yield)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14])[CH3:2].O.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14])[C:16](=[O:18])[CH3:17])[CH3:2]
Reactant: CCNc1cc(F)c([N+](=O)[O-])cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(C(C)=O)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 5.4 g (0.027 mole) of N-ethyl-2,5-difluoro-4-nitroaniline in 100 ml of acetic anhydride was added three drops of concentrated sulfuric acid. This mixture was stirred at room temperature for 30 minutes, and was poured into 200 ml of ice and water. The aqueous mixture was extracted with three portions of ethyl acetate. The extracts were combined and washed in succession with an aqueous, saturated sodium chloride solution and water. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield 6.1 g of N-ethyl-N-(2,5-difluoro-4-nitrophenyl)acetamide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][CH2:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12
Reactant: BrCc1cccnc1
Product: O=C(c1cn(Cc2cccnc2)c2cc(Cl)ccc12)N1CCC2(CC1)CNc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-1,2-dihydrospiro[indole-3,4′-piperidine] (prepared according to example 8) with commercially available 3-bromomethyl-pyridine gave the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:11](O)[CH2:12][OH:13]>>[CH3:10][C:2]1([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[O:13][CH2:12][CH2:11][O:1]1
Reactant: OCCO
Reactant: COC(=O)CCCC(C)=O
Product: COC(=O)CCCC1(C)OCCO1

Procedure:
Methyl 2-methyl-I,3-dioxolane-2-butanoate (25) was prepared from methyl 5-oxohexanoate and ethylene glycol in the manner described in Example 17 above on a 28 mmol scale to yield 4.94 g (94%) of product. The product was employed immediately in the manner described in Example 26 below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[N:32]([CH2:31][C:30]1[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:34][CH:33]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.1 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid (1.25 g) in methanol (20 ml) were added 4-methanesulfonylbenzylamine hydrochloride (1.6 g) and triethylamine (2.5 ml), and the mixture was stirred at 50° C. for 18 hrs. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, and dried. The solvent was evaporated under reduced pressure. 4N Hydrochloric acid ethyl acetate solution (10 ml) was added to the residue, and the mixture was stirred at room temperature for 18 hrs. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound (1.43 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[Na+]>FC(F)(F)C(O)=O>[OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)c1cccc(C)c1O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Methyl 2-hydroxy-3-methylbenzoate (Reference Compound No. 1-4-(1), 22.9 g, 0.138 mol) was dissolved in trifluoroacetic acid (190 mL), then an aqueous solution (90 mL) of sodium nitrate (12.9 g, 152 mmol) was added dropwise thereto over 1 hour at −10° C. After the reaction mixture was stirred at 0° C. for 1.5 hours, it was poured into ice-water (600 mL). The appeared solid was filtered and washed with methanol (100 mL) to give the titled reference compound (18.7 g) as a pale red solid. (Yield 64%)
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (863 mg) and 1-methyl-2-pyrrolidone (10 mL) was stirred at 120° C. for 1.5 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→5:95). The object fraction was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (933 mg) as a white powder.
Reaction SMILES: [CH2:1]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:18]N1C(=O)CCC1=O>CN(C=O)C>[Br:18][C:15]1[S:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:17][CH:16]=1
Reactant: CCCCCCCCCCCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc(Br)s1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
2-Dodecylthiophene (100 g, 396 mmol, 1 eq) prepared above was placed in a three-necked flask equipped with a dropping funnel and a reflux tube. The atmosphere in the flask was replaced by Ar, 400 ml of dehydrated N,N-dimethylfolmamid (hereinafter referred to as “DMF”) was added thereto, and the mixture was stirred. The reaction solution was cooled to 0° C., and N-bromosuccinimide (84.5 g, 475 mmol, 1.2 eq) dissolved in 120 ml of dehydrated DMF in a separate vessel was added dropwise to the reaction solution. After the completion of the dropwise addition, the mixture was stirred for one hr, was brought to room temperature, and was stirred for 6 hr. The solvent was removed by evaporation, and the residue was extracted with diethyl ether, followed by washing with water until pH=7. The extract was dehydrated over Na2SO4, and the solvent was removed by evaporation, and the residue was purified by chromatography on silica gel to give an objective substance 2-bromo-5-dodecylthiophene (about 118 g yield about 90%) as a light yellow liquid. An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (CDCl3, TMS/ppm): 0.88 (t, 3H, J=6.83 Hz), 1.26 (m, 18H), 1.62 (m, 2H), 2.73 (t, 2H, J=7.32 Hz), 6,53 (d, 2H, J=4.39 Hz), 6.84 (d, 2H, J=3.90 Hz).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]=[O:22])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([OH:22])[CH3:1])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CC1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Methylmagnesium bromide (1 M solution in THF, 0.526 ml, 0.526 mmol) was added dropwise to 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (114 mg, 0.439 mmol) in THF (2.2 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(2-hydroxy-propyl)-cyclohexanecarboxylic acid benzyl ester (80.7 mg, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH2:22][O:23]CC2C=CC=CC=2)[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:6]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH2:22][OH:23])[CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:7][C:6]=1[NH:31][C:32](=[O:48])[CH2:33][CH:34]1[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:41][C:40]2[C:35]1=[CH:36][CH:37]=[CH:38][CH:39]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(C=C(CCCC2CCCCC2)COCc2ccccc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(CC(CO)CCCC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of 1.54 g (2.30 mmol) of N-[2-t-butyl-5-(5-cyclohexyl-2-benzyloxymethyl-1-pentenyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 208) in 15 ml of ethanol was vigorously stirred in a stream of hydrogen in the presence of 1.54 g of 10% w/w palladium-on-charcoal at room temperature for 4 hours and 20 minutes and then at 40° C. for 2 hours. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by distillation under reduced pressure. The concentrate was purified by column chromatography through 75 g of silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent. Fractions containing the desired compound together with a small amount of impurities were combined and concentrated by distillation under reduced pressure. The concentrate was again purified by column chromatography under the same conditions as above, to give 1.19 g (yield 90%) of the title compound as a foam-like material.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]2[CH:19]([CH2:20]2)[C:18]1=[O:24].O>ClCCl>[F:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:22](=[O:23])[CH:21]2[CH:19]([CH2:20]2)[C:18]1=[O:24]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1C2CC2C(=O)N1CCCCCCO
Solvent: ClCCl
Solvent: O
Product: O=C1C2CC2C(=O)N1CCCCCCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethylaminosulfurtrifluoride (76mg) was added dropwise to a stirred solution of 3-(6-hydroxyhex-1-yl)-3-azabicyclo[3.1.0]hexane-2,4-dione (from step (b), 100mg) in dichloromethane (2.0 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature and water (3 ml) was then added. The reaction mixture was extracted with ether (2×10 ml) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica (5 g) using 40% ethyl acetate/hexane as eluant to give the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH2:19]>CC(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:19][CH2:18][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:14][CH2:13]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCNCC1
Reactant: C=CS(C)(=O)=O
Solvent: CC(C)O
Product: COc1ccc([N+](=O)[O-])cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
The compound was synthesized by heating a solution of 1-[2-(methyloxy)-5-nitrophenyl]piperazine (0.5 g, 2.11 mmol) and methyl vinyl sulfone (0.336 g, 3.16 mmol) in iPrOH (25 mL) to reflux overnight. Reaction was cooled to rt and dried directly onto silica gel. Purified by silica gel chromatography 0-20% MeOH/NH4OH in EtOAc to obtain 0.5 g (69% yield) of the desired compound as a solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.6 (m, 4H) 2.7 (t, J=6.8 Hz, 2H) 3.0 (m, 8H) 3.9 (s, 3H) 7.1 (d, J=9.0 Hz, 1H) 7.6 (d, J=2.7 Hz, 1H) 7.9 (dd, J=9.1, 2.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])=[CH:25][C:21]=1[C:22](O)=[O:23].C1COCC1>CN(C=O)C>[F:17][C:11]1[CH:12]=[CH:13][C:14]([NH:16][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([CH2:29][NH:30][C:31]([C:33]([CH3:34])([CH3:36])[CH3:35])=[O:32])[CH:27]=[CH:28][C:20]=2[Cl:19])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:18]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1ccc(F)c(C(=O)Nc2ccc(Br)cc2)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(F)c(C(=O)Nc3ccc(Br)cc3)c2)c1

Procedure:
PPA (0.142 mL 50% solution in DMF) was added dropwise to a mixture of N-(4-bromophenyl)-2-fluoro-5-amino-benzoic acid amide (57 mg, 0.19 mmol), 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid (50 mg, 0.19 mmol), 64 μL TEA and 10 mL THF. The reaction was refluxed overnight, additional PPA (0.14 mL) was added and it was refluxed for additional 4.5 h. The crude reaction mixture was concentrated i.vac., EtOAc was added and the organic phase was washed with 2 M aq. HCl, satd. NaHCO3, dried with Na2SO4 and purified via HPLC (Method A) to furnish the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[C:34]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:45]2[CH2:46][CH2:47][CH:42]([C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:43][CH2:44]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC(C(=O)c3ccccc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) in acetonitrile (5 ml) was added diisopropylethylamine (0.45 mmol, 74 μL) and 4-benzoylpiperidine hydrogen chloride (0.15 mmol). The reaction mixture was stirred at room temperature for 16 hours whereupon the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (59 mg) which was characterized by its mass spectrum: MS m/z (%): 462 ([M+H]+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[S:49][CH:50]=[C:51]([CH2:53]O)[N:52]=2)[CH2:44][CH2:43]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH2:53][C:51]2[N:52]=[C:48]([N:45]3[CH2:46][CH2:47][O:42][CH2:43][CH2:44]3)[S:49][CH:50]=2)[C:6]2[CH:7]=[C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)[O:9][C:5]=2[CH:4]=1
Reactant: OCc1csc(N2CCOCC2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OCc2csc(N3CCOCC3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 0.10 g, 0.315 mmol), triphenylphosphine (0.124 g, 0.473 mmol) and (2-morpholinothiazol-4-yl)methanol (Example 5B, 0.086 g, 0.429 mmol) were added in a 25 mL round-bottom flask and purged under vacuum and nitrogen. Tetrahydrofuran (8 mL) was then added and the mixture was treated with DIAD (0.083 g, 0.410 mmol) in tetrahydrofuran (10 mL). The mixture was stirred at 22° C. for 1 hour and diluted with ethyl acetate. This was washed with sat. NaHCO3 (1×) and brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel column chromatography (2.5×10 cm, 40% ethyl acetate in CH2Cl2) and the residue obtained after concentration was crystallized in ethyl acetate to give the title material as crystals (0.083 g, 53%) and as an amorphous impure solid from the mother liquor (0.169 g). LC (Method F): 2.466 min. HRMS (ESI) calcd for C22H22N5O5S2 [M+H]+ m/z 500.1057, found 500.1075. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.82 (s, 1H) 7.07 (s, 1H) 6.67 (d, J=2 Hz, 1H) 6.62 (s, 1H) 6.40 (d, J=1.5 Hz, 1H) 5.10 (s, 2H) 4.19 (s, 3H) 3.82 (s, 3H) 3.81 (m, 4H) 3.46 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[OH:23].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[C:11]([C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:23][C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[Cl:15])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CC(C)(C)c1ccc(C(=O)O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)O)c(Oc2ccc(F)cc2Cl)c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
In a pressure-vessel, a stirring mixture of 2-bromo-4-tert-butylbenzoic acid (1.00 g, 3.89 mmol) and 2-chloro-4-fluorophenol (860 mg, 620 μL, 5.87 mmol) in toluene (20 mL) was added Cs2CO3 (2.53 g, 7.78 mmol) followed by copper(I) triflate benzene complex (98 mg, 0.19 mmol). The sealed vessel was heated to 120° C. for 16 h. After cooling to room temperature, the reaction mixture was partitioned between 50 mL EtOAc and 50 mL H2O. The aqueous layer was acidified using 2.0 N HCl(aq) and re-extracted with EtOAc. The combined organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-3% MeOH/CH2Cl2 to give the product, 4-tert-butyl-2-(2-chloro-4-fluorophenoxy)benzoic acid as a white solid (907 mg, 2.81 mmol) in 72% yield. LC/MS: m/z 323.2 (M+H) at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13](Cl)=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25]>O1CCOCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=3)=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: O=C(NCC1CCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NCC1CCCC1)c1cnc(Nc2ccc(F)c(Cl)c2)nc1C(F)(F)F
Yield: 66.2 %

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide (116 mg Example 183a), 3-chloro-4-fluoroaniline (ex-Aldrich, 275 mg), and 1,4-dioxan (1.2 ml) were stirred at 100° C. under nitrogen for 6 h. The cooled reaction mixture was evaporated in vacuo, treated with ethyl acetate (5 ml), washed with aqueous 2M hydrochloric acid (2×3 ml), followed by brine, and dried (Na2SO4). The solution was evaporated in vacuo to give the title compound (104 mg).