Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:35])[F:34])=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:34])[F:35])=[CH:27]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 71.9 %

Procedure:
Using an analogous procedure to that described in Example 44, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.3 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-hydroxy-2-trifluoromethylindole (75 mg, 0.37 mmol), (prepared as described for the starting material in Example 44), to give 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)4-(2-trifluoromethylindol-5-yloxy)quinazoline (105 mg, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[C:7]([Br:13])[CH:6]=2.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(Cl)Cl.CCOC(C)=O>[CH2:29]([O:28][C:26]([NH:1][C:2]1[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[C:7]([Br:13])[CH:6]=2)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1nc2cc(Br)c(F)cc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1nc2cc(Br)c(F)cc2cc1NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
DCM (10.0 mL) was added to a mixture of ethyl 3-amino-7-bromo-6-fluoroquinoline-2-carboxylate (882.5 mg, 2.818 mmol) and pyridine (592.1 mg, 7.485 mmol). The mixture was cooled to −10° C. A solution of benzyl chloroformate (650.6 mg, 3.623 mmol) in DCM (5.0 mL) was added slowly over a period of 5 min. The mixture was then allowed to warm to room temperature and was stirred for 2 h. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-30% EtOAc in hexanes) to give the sub-title compound as an off-white solid (854.9, 68%). LCMS calc. for C20H17BrFN2O4 (M+H)+: m/z=447.0. found 447.0.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2]
Reactant: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (3.00 g, 16.8 mmol, described in Intermediate 16) in DMF (100 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 740 mg, 18.5 mmol) and the resulting mixture was stirred for 30 min. Ethyl bromoacetate (1.87 mL, 16.8 mmol) in DMF (10 mL) was added dropwise over 10 min. The reaction mixture was stirred at 0° C. for 2 h, then quenched with H2O (200 mL). The mixture was extracted with EtOAc (5×200 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, followed by crystallization from hexane:EtOAc to give the title compound. MS: m/z=265 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:36])=[C:20]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:21]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].C(N(CC)CC)C.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>O1CCCC1.C(OCC)(=O)C>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:20]1[CH:21]=[C:16]([O:15][C:13]2[CH:12]=[CH:11][C:9]3[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:48]4[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]4)[S:7][C:8]=3[CH:14]=2)[CH:17]=[CH:18][C:19]=1[CH3:36])=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)CCl)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CN4CCN(C)CC4)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
N-[5-({2-[(Chloroacetyl)amino]-1,3-benzothiazol-6-yl}oxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (8.0 mL), triethylamine (155 μL, 1.13 mmol) and 1-methylpiperazine (100 μL, 0.902 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (50 mL×2) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (106 mg, 40%) as a colorless solid.
Reaction SMILES: C(=O)=O.[CH3:4][C:5]([CH3:7])=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[C:16]([C:22]2[NH:26][N:25]=[N:24][N:23]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1.[H-].[Na+].IC(C)C>CN(C)C=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[C:16]([C:22]2[N:23]=[N:24][N:25]([CH:5]([CH3:7])[CH3:4])[N:26]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)I
Solvent: CN(C)C=O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)C)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a chilled (-78° C., dry ice-acetone) solution of ethyl 3,3-bis (4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate (2.6 g, 7.3 mmoles) [prepared in Example 2] in 20 mL of dried N,N-dimethylformamide under argon was added NaH (0.44 g, 11.0 mmoles; 60% in mineral oil) followed by reagent grade 2-iodopropane (2.0 mL, 20.0 mmoles) in one single portion. The thick reaction mixture was stirred under argon at -78° C. for 30 minutes and the mixture was allowed to warm to room temperature slowly over a period of 16 hours. Analytical TLC eluted once with 50% ethyl acetate in hexanes showed only one spot at Rf =0.86. The white suspension was diluted with 40 mL of half saturated brine followed by 20 mL of ethyl acetate. The aqueous layer was washed with ethyl acetate (2×20 mL). The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. Analytical TLC eluted four times with 8% (v/v) ethyl acetate in hexanes showed two spots at Rf =0.38 (21) and Rf =0.49 (21a). The desired products were purified by silica gel column chromatography eluted with 8% EtOAc in hexanes. The fast moving product was collected to give 1.64 g (56.5%) of the title compound. MS (CI): m/e=399 for (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:40]=[C:5]2[N:6]([CH2:33][C:34](=O)[C:35]([F:38])([F:37])[F:36])[C:7](=[O:32])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][C:29](=[O:31])[O:28][N:27]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.Cl.[NH2:42][O:43][CH2:44][CH3:45].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH2:44]([O:43]/[N:42]=[C:34](/[C:35]([F:37])([F:36])[F:38])\[CH2:33][N:6]1[C:7](=[O:32])[C:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][C:29](=[O:31])[O:28][N:27]=3)=[CH:18][CH:19]=2)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=[C:2]([CH3:1])[N:40]=[C:5]12)[CH3:45]
Reactant: CCON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(F)(F)F)c2nc(C)nn12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N\OCC)C(F)(F)F)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
A mixture of 2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl-4-(3,3,3-trifluoro-2-oxopropyl) [1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.14 g), 2-(aminooxy)ethane hydrochloride (0.37 g) and pyridine (5 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.041 g, 28%).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([O:13]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3]2.[Br:25][C:26]1[CH:35]=[CH:34][C:29]2[CH:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=1.C(=O)([O-])[O-].Cl>CN(C=O)C.C(#N)C>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([CH2:10][C:11]([NH:33][C:31]1[S:32][C:28]3[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:29]=3[CH:30]=1)=[O:13])[CH2:3]2
Reactant: Nc1cc2ccc(Br)cc2s1
Reactant: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
89.2 mg (0.24 mmol) of pentafluorophenyl (1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 ml of DMF, mixed with 71.2 mg (0.31 mmol) of 6-bromo-1-benzothiophene-2-amine and stirred at room temperature overnight. 1 g of MP-carbonate (polymer-bound carbonate, capacity: 2.5-3.5 mmol/g; from Argonaut Technologies, USA) is added. After 3 h, the polystyrene resin is filtered off and washed with THF. The combined filtrates are concentrated in vacuo, and the crude product is purified by preparative HPLC. The hydrochloride is prepared by mixing the product with a mixture of 1 M hydrochloric acid and acetonitrile and again concentrating. Drying under high vacuum results in 14 mg (14% of theory) of the title compound.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:29])([F:28])[F:30])[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.265 g, 0.99 mmol), tetrakis(triphenylphosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (220 mg, 43%). MS (ISP) 576.3 [(M+H)+]; mp 252° C.
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][N:5]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[N:5]=[CH:6][CH:7]=[CH:8][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: N#Cc1cccnc1-c1cccs1
Temperature: 90 °C
Yield: 100.7 %

Procedure:
To an oven-dried, N2-purged, 50-mL, round-bottomed flask containing a magnetic stir bar were added cesium fluoride (1.34 g, 8.80 mmol), bis(tri-t-butylphosphine)palladium (66.0 mg, 0.13 mmol), and 2-chloro-3-cyanopyridine (559 mg, 4.00 mmol). The flask was sealed with a septum and purged with dry N2 atmosphere. Anhydrous dioxane (4 mL) was added via syringe. Neat 2-(tri-n-butylstannyl)thiophene (2.38 g, 2.02 mL, 6.38 mmol) was added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) was added and the mixture was filtered through a pad of silica. The filtrate was concentrated by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 25% ethyl acetate, 75% hexanes=product Rf˜0.4) to give ˜750 mg of the title compound as a beige solid that was used without further purification for the next step. MS (ESI−) m/z 186.7 (M+H)+; 1H NMR (CDCl3) δ 7.19 (dd, J=5.1, 4.0 Hz, 1H), 7.23-7.27 (m, 1H), 7.56 (dd, J=5.1, 1.0 Hz, 1H), 8.00 (dd, J=8.1, 2.0 Hz, 1H), 8.27 (d, J=4.1 Hz, 1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:15])[CH:3]=1.[Br:16][C:17]1[CH:22]=[C:21]([Br:23])[CH:20]=[C:19]([Br:24])[N:18]=1.C(N(CC)CC)C.CN1CCCC1=O>O>[Br:23][C:21]1[CH:22]=[C:17]([Br:16])[N:18]=[C:19]([S:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:15])[CH:3]=2)[CH:20]=1.[Br:16][C:17]1[CH:22]=[C:21]([S:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:15])[CH:3]=2)[CH:20]=[C:19]([Br:24])[N:18]=1
Reactant: Brc1cc(Br)nc(Br)c1
Reactant: CCOC(=O)COc1ccc(S)cc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Br)n2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(Br)nc(Br)c2)cc1C
Temperature: 80 °C

Procedure:
A mixture of ethyl (4-mercapto-2-methylphenoxy)acetate (1.0 g, 4.4 mmol), 2,4,6-tribromopyridine (1.26 g, 4.0 mmol; prepared as described in Chem. Ber. 1989, 122, 489), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.163 g, 0.20 mmol), triethylamine (1.23 mL, 8.8 mmol) and N-methylpyrrolidinone (12 mL) was heated under nitrogen at 80° C. for 3 h. The reaction mixture was then poured into water (60 mL) and extracted with ethyl acetate (3×70 mL). The combined organic layers were dried with anhydrous magnesium sulfate and evaporated in vacuo. Column chromatography of the crude product (silica gel Fluka 60, hexanes/ethyl acetate 98:2-80:20) afforded ethyl [4-(4,6-dibromopyridin-2-ylsulfanyl)-2-methylphenoxy]acetate as the minor product and ethyl [4-(2,6-dibromopyridin-4-ylsulfanyl)-2-methylphenoxy]acetate as the major product.
Reaction SMILES: [C:1](=[O:58])([O:6][CH:7]([C@:9]12[O:16][C@:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)([O:14][CH2:15]1)[C@H:12]([O:34]CC1C=CC=CC=1)[C@@H:11]([O:42]CC1C=CC=CC=1)[CH:10]2[O:50]CC1C=CC=CC=1)[CH3:8])[O:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[C:1](=[O:58])([O:2][CH:3]([CH3:5])[CH3:4])[O:6][CH:7]([C@:9]12[O:16][C@:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)([O:14][CH2:15]1)[C@H:12]([OH:34])[C@@H:11]([OH:42])[CH:10]2[OH:50])[CH3:8]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
To a solution of isopropyl 1-[(1R,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethyl carbonate 13a (244 mg, 0.3 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.16 mL, 1.5 mmol) and 10% Pd/C (36 mg, 0.03 mmol) in turn at room temperature. The mixture was stirred at room temperature under H2 for 4 hours and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=4/1 to give the title compound 13 as a white solid (120 mg, 75.0%, HPLC: 92.3%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 537.3[M+H]+; and 1H NMR (600 MHz, DMSO-d6) δ(ppm): 7.40 (m, 2H), 7.29 (m, 1H), 7.11 (d, 2H), 6.84 (m, 2H), 5.58 (brs, 1H), 5.04 (brs, 2H), 4.93 (m, 1H), 4.73 (m, 1H), 4.50-3.98 (m, 5H), 3.54 (m, 2H), 3.44 (m, 2H), 1.31 (m, 6H), 1.23-1.20 (m, 6H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[O:15][N:14]=[C:13]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:12]=12.C([O:24][C:25](=O)[C:26](=[O:33])[CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:20]([C:17]4[CH:18]=[CH:19][C:12]5=[N:11][O:15][N:14]=[C:13]5[CH:16]=4)[C:27]([C:28](=[O:32])[CH2:29][CH2:30][CH3:31])=[C:26]([OH:33])[C:25]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCCC(=O)CC(=O)C(=O)OCC
Reactant: O=Cc1ccc2nonc2c1
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: CCCC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc2nonc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1,2,5]oxadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-heptanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH:9]1([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([O:26][CH2:27][O:28][CH3:29])[CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:17]([CH2:18][CH2:19][N:20]1[CH2:21][CH2:22][CH:23]([O:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:25]1)[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COCOC1CCN(CCNC2CCCCCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOC1CCN(CCN(C2CCCCCCC2)S(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.49 ml of 3-chloropropanesulfonyl chloride was dropwise added, at 0° C., to a solution of 1.19 g of 1-(2-cyclooctylaminoethyl)-4-methoxymethoxypiperidine and 0.67 ml of triethylamine in 10 ml of dichloromethane. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (eluant: 2% methanol/dichloromethane) to obtain 1.2 g of 1-{2-[N-(3-chloropropylsulfonyl)-N-cyclooctylamino]-ethyl}-4-methoxymethoxypiperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[Cl:28][C:29]1[CH:30]=[C:31]([CH3:41])[C:32]2[NH:37]C(=O)[O:35][C:34](=O)[C:33]=2[CH:40]=1.N1C=CC=CC=1>ClCCl.C(N(CC)C=O)C.C(#N)C>[Cl:28][C:29]1[CH:30]=[C:31]([CH3:41])[C:32]2[N:37]=[C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:11]=3)[O:15][C:34](=[O:35])[C:33]=2[CH:40]=1
Reactant: O=C(O)c1cc(OCC(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Agent: CCN(C=O)CC
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(OCC(F)(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 1-(3-chloro-2-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazole-5-carboxylic acid (i.e. product of Step C) (7.9 g, 24 mmol) stirred in dichloromethane (100 mL) was added N,N-diethylformamide (4 drops). Oxalyl chloride (4.45 g, 35 mmol) was added dropwise over a period of 45 minutes. The resulting solution was stirred at room temperature for 4 hours and then concentrated under vacuum. The isolated acid chloride was dissolved in dry acetonitrile (10 mL) and added to a suspension of 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (i.e. product of Step D) (4.9 g, 23 mmol) stirred in dry acetonitrile (14 mL). Pyridine (10 mL) was added, and the solution heated at reflux 6 hours. After cooling using an ice bath, a precipitate of white solid (9.15 g) was collected. The 1H NMR spectrum of the collected precipitate showed peaks consistent with the title compound and residual 6-chloro-8-methyl-2H-3,1-benzoxazine-2,4(1H)-dione starting material. A small portion of the collected precipitate was recrystallized from acetonitrile to yield the pure title product melting at 178–180° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)[N:13]=1>O.CO>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[N:2][OH:3])[N:13]=1
Reactant: NO
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
3.5 g of hydroxylamine hydrochloride were added to 100 ml of a 1:1 mixed solution of water and methanol containing 3.5 g of potassium carbonate at 0° C. The solution was stirred at 0° C. for 10 minutes. At 0° C., 13.0 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour and then warmed at 60° C. for 1 hour. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=5:1) to obtain 7.7 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime.