Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-:25].[NH4+]>O1CCCC1>[ClH:25].[CH2:17]([O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCc1ccccc1
Reactant: [Cl-]
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: c1ccc(COC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (5.0 g) in tetrahydrofuran (50 mL) was added sodium hydride (1.0 g, a 66% dispersion in liquid paraffin) and the mixture was stirred at room temperature for 10 minutes. Then, 3.6 mL of benzyl bromide was added and the mixture was refluxed for 1 hour. This reaction mixture was poured into aqueous ammonium chloride solution and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate, followed by addition of 15 mL of 4 N-HCl solution in ethyl acetate, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected to provide 4.4 g of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:27]=O.[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:27][C:21]4[C:20]5[C:24](=[CH:25][CH:26]=[C:18]([C:17]([F:30])([F:29])[F:16])[CH:19]=5)[NH:23][CH:22]=4)[C:37]([C:33]4[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=4)=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Reactant: Cn1ccnc1C=O
Reactant: O=Cc1c[nH]c2ccc(C(F)(F)F)cc12
Product: Cn1ccnc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1c[nH]c2ccc(C(F)(F)F)cc12

Procedure:
This compound was made following the procedure described above, starting with 1-(cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-(trifluoromethyl)-1H-indole-3-carbaldehyde, followed by 1-methyl-1H-imidazole-2-carbaldehyde. 498.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(O[CH:38]1[CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39]1)(=O)=O.Cl.O1CCOCC1>CN(C=O)C.O>[NH:40]1[CH2:41][CH:38]([N:22]2[CH:21]=[CH:20][C:19]([C:7]3[N:6]([CH2:5][C:4]4[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[CH:12][C:13]5[N:14]([C:15]([CH3:18])=[N:16][N:17]=5)[C:9]=4[CH:8]=3)=[N:23]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nnc2ccc3c(cc(-c4ccn(C5CNC5)n4)n3Cc3cccc(Cl)c3)n12
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
6-(3-Chlorobenzyl)-1-methyl-7-(1H-pyrazol-5-yl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (25 mg, 0.069 mmol, from Example 103, Step 5) in DMF (1.5 mL) was treated with Cs2CO3 (34 mg, 0.10 mmol, Aldrich) and tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (26 mg, 0.10 mmol, prepared as in WO 2012004703). The mixture was heated at 70° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water and extracted with three portions of EtOAc. The combined extracts were washed twice with brine, then were dried over sodium sulfate, filtered, and concentrated. The residue, dissolved in acetonitrile (1.0 mL) was treated with 4.0 M HCl in dioxane (0.40 mL, 1.6 mmol). After 20 minutes, the solvent and excess HCl were removed in vacuo. The residue was re-dissolved in methanol and pH was made basic by the addition of a few drops of NH4OH solution. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded clean product (13.2 mg, 46%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(CCl)c1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1(Cc2cc(C)ccn2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (-78° C.) solution of ethyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (5.1 g, 19.8 mmol; Example 30, Step A) in anhydrous THF (50 mL), a solution of solution of sodium bis(trimethylsilyl)amide (20 mL, 1M, 20 mmol) was added over a period of 15 min. The resultant mixture was stirred at -78° C. for 1 h., and 2-chloromethyl-4-methylpyridine (3.5 g, 24.7 mmol) was added. The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was diluted with dichloromethane was washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25-40% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.2 g (6.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acid methyl ester using 1.33 g (31.6 mmoL) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.7 g of crude product are obtained which is used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:33][C:34](=[O:36])[CH3:35])C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([C:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:33]/[C:34](=[O:36])[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C=O)c(OCc2ccccc2)c1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCCCC(C)(C)c1ccc(/C=C/C(C)=O)c(OCc2ccccc2)c1
Reaction time: 24 h
Yield: 73.8 %

Procedure:
A solution of 2-benzyloxy-4-(1,1-dimethylheptyl)benzaldehyde (65.2 g, 0.193 mole) and of 1-triphenylphosphoranylidene-2-propanone (62.0 g, 0.195 mole) in dichloromethane (195 ml) was heated at reflux for 20 hous. Another portion of 15.5 g yield (15.5 g, 0.047 mole) was added and heating at reflux continued for 24 hours. The reaction mixture was cooled, evaporated and diluted with ether. The resulting precipitate of triphenylphosphine oxide was removed by filtration. The crude oil was purified via column chromatography on 1.5 kg of silica gel eluted with 20% etherhexane to yield 53.9 g (74%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13]SC3C([N+]([O-])=O)=CC=CN=3)[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Br[CH2:66][C:67]([C:69]1[CH:70]=[C:71]2[C:75](=[CH:76][CH:77]=1)[CH2:74][CH2:73][CH2:72]2)=[O:68]>CC(C)=O.O>[CH2:74]1[C:75]2[C:71](=[CH:70][C:69]([C:67](=[O:68])[CH2:66][S:13][C@H:10]3[C:11](=[O:12])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C@@H:9]3[C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:37][CH:38]=3)=[CH:77][CH:76]=2)[CH2:72][CH2:73]1
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)CCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCC4)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-{(2R,3R)-1-(4-fluorophenyl)-3-[(3-nitropyridin-2-yl)dithio]-4-oxoazetidin-2-yl}phenoxy)acetate (0.100 g, 0.179 mmol) in acetone (2 ml) and water (0.5 ml) was added triphenylphosphine (0.047 g, 0.179 mmol). After 30 minutes, the mixture was concentrated. To the residue was added dichloromethane (3 ml) followed by the addition of triethylamine (0.073 g, 0.717 mmol) and 2-bromo-1-(2,3-dihydro-1H-inden-5-yl)ethanone (0.107 g, 0.448 mmol). After 30 minutes, full conversion of the thiol had been achieved. The mixture was concentrated and to the residue was added formic acid (2 g) and trifluoroacetic acid (0.2 g). The mixture was allowed to stir at room temperature for 3 h. The crude product was purified through preparative HPLC using an eluent of 10-50% CH3CN in 0.1M NH4OAc buffer. Freeze drying of pure fractions afforded the desired compound. 1H NMR [(CD3)2SO), 400 MHz] δ1.96-2.04 (m, 2H), 2.83-2.89 (m, 4H), 4.23-4.34 (m, 5H), 5.09 (d, 1H), 6.76-7.74 (m, 11H).
Reaction SMILES: NC1C=CC(C#N)=CC=1[N+]([O-])=O.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH2:22])[CH:16]=1)#[N:14].[Cl:23][C:24]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:25]=1[CH:26]=O>>[Cl:23][C:24]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][C:25]=1[C:26]1[NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][C:17]=2[N:22]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: N#Cc1ccc(N)c(N)c1
Agent: N#Cc1ccc(N)c([N+](=O)[O-])c1
Product: N#Cc1ccc2[nH]c(-c3cc([N+](=O)[O-])ccc3Cl)nc2c1

Procedure:
4-Amino-3-nitrobenzonitrile was reduced to 4-cyano-1,2-phenylenediamine as for compound 19. This was reacted with 2-chloro-5-nitrobenzaldehyde as described in route 1 step 4 to give 2-(2-chloro-5-nitro-phenyl)-1H-benzoimidazole-5-carbonitrile.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1>>[C:9]1([C:6]2[N:7]=[CH:8][C:3]([CH2:2][C:19]3[CH:20]=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Reactant: OB(O)c1cncnc1
Product: c1ccc(-c2ccc(Cc3cncnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (219 mg, 0.88 mmol) and pyrimidine-5-boronic acid (164 mg, 1.32 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. White solid. Yield: 43 mg, 20%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.02 (s, 2H), 7.39-7.44 (m, 1H), 7.44-7.56 (m, 3H), 7.70 (dd, J=8.2, 0.9 Hz, 1H), 7.95-8.00 (m, 2H), 8.58-8.67 (m, 3H), 9.13 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=33.4, 120.5, 126.8, 128.8, 129.1, 132.2, 133.3, 136.9, 138.7, 149.7, 156.4, 156.9, 157.3; (ESI): m/z=247.83 [M+H]+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:30])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([I:29])[CH:23]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:31][C:32]1([CH3:39])[CH2:37]C(=O)[O:35][C:33]1=[O:34].IC1C=CC(NC(C2C=CC(N3CCN(C(=O)CC(C)(C)C(O)=O)CC3)=NC=2)=O)=CC=1C>>[I:29][C:24]1[CH:23]=[C:22]([NH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:5])[CH2:31][C:32]([CH3:39])([CH3:37])[C:33]([OH:35])=[O:34])[CH2:9][CH2:10]3)=[N:15][CH:16]=2)=[O:30])[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1I
Reactant: CC1(C)CC(=O)OC1=O
Agent: Cc1cc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C(=O)O)CC3)nc2)cc1I

Procedure:
4-{4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-2,2-dimethyl-4-oxo-butyric acid was prepared from 4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester and 2,2-dimethysuccinic anhydride following a procedure similar to the one described in the synthesis of 4-{4-[5-(4-iodo-3-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-dimethyl-4-oxo-butyric acid above. HRMS m/z calcd for C23H27N4O4I [M+H]+: 551.1150. Found: 551.1152.
Reaction SMILES: [H-].[K+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH:6]=[CH:5][CH:4]=1.[Cl-:22].[Cr+3:23].[Cl-:24].[Cl-]>C1COCC1>[Cl:22][Cr:23]([Cl:24])[C:14]1[CH:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[N:3]=[CH:4][CH:5]=[CH:6]3)[C:21]2[C:16]([CH:15]=1)=[CH:17][CH:18]=[CH:19][CH:20]=2
Reactant: C1=CC(c2cccc3cccnc23)c2ccccc21
Reactant: [Cr+3]
Reactant: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cl[Cr](Cl)C1=Cc2ccccc2C1c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
0.05 g of potassium hydride (1.23 mmol) were suspended in 20 ml of THF and 0.3 g of 1-(8-quinolyl)indene (1.23 mol) were slowly added. The resultant violet suspension was stirred for three hours at room temperature and then added dropwise to a mixture of 0.46 g of chromium(III) chloride 3THF (1.23 mmol) in 50 ml of THF. Once this addition was complete the mixture was stirred for a further 16 hours. The solvent was removed in vacuo and the resultant solid extracted several times with hot toluene on a G4 frit. Once the solvent had been distilled off from the combined extracts the product was obtained as a green powder. This was washed several times with hexane and dried under HV, giving 0.22 g of dichloro[1-(8-quinolyl)indenyl]chromium(III) (50%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[C:20]1(C)[C:21]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.N1C=CC=C[CH:32]=1>>[S:26]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([C:21]1[CH:20]=[CH:25][C:24]([CH3:32])=[CH:23][CH:22]=1)(=[O:27])=[O:28]
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCO
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-hydroxyethoxyl)ethoxy)ethoxy)propanoate (10 g, 35.97 mmol, 1.00 equiv) in pyridine (40 mL). This was followed by the addition of toluenesulfonyl chloride (6.8 g, 35.79 mmol, 1.00 equiv), in portions at 0° C. The resulting solution was stirred for 4 h at 0° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of dichloromethane. The resulting mixture was washed with 3×20 mL of 3% hydrochloric acid (aq) and 20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum to give 14 g (90%) of tert-butyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21]Br)=[O:4].[CH:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([CH3:25])[CH3:24]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]=1[CH2:21][N:29]1[CH2:30][CH2:31][N:26]([CH:23]([CH3:25])[CH3:24])[CH2:27][CH2:28]1)=[O:4]
Reactant: COC(=O)c1c(CBr)c(-c2ccccc2)nc2ccccc12
Reactant: CC(C)N1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)c1c(CN2CCN(C(C)C)CC2)c(-c2ccccc2)nc2ccccc12
Temperature: 10 °C
Reaction time: 8 h

Procedure:
7.8 g of crude 3-bromomethyl-2-phenyl-quinoline-4-carboxylic acid methyl ester (compound of Description 2) were dissolved, under nitrogen atmosphere, in 130 ml of dry THF. The solution was cooled to 10° C. and 2.8 g (21.6 mmol) of 1-isopropylpiperazine, dissolved in 20 ml of THF, were added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. Salts were filtered off and the filtrate was evaporated in vacuo to dryness, taken up with 2 N HCl and washed with EtOAc; the aqueous layer was basified with 10% NaOH and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo to dryness to obtain a crude material which was purified by flash column chromatography on 230-400 mesh silica gel, utilising a mixture of Et2O/iPr2O 70:30 containing 0.3% ammonium hydroxide (28%). 3.8 g of the title compound were recovered as a yellow solid.
Reaction SMILES: C(O[C@@H:5]1[O:20][C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:11]([O:12][CH3:13])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C([SH:28])C.B(F)(F)F.CCO[CH2:36][CH3:37].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:36]([C@:5]1([O:20][C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:11]([O:12][CH3:13])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])[SH:28])[CH3:37]
Reactant: CO[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)O[C@@H](COC(C)=O)[C@H]1OC(C)=O
Reactant: CCOCC
Reactant: CCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@@]1(S)O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC)[C@H]1OC(C)=O
Reaction time: 1 h

Procedure:
1,2,4,6-Tetra-O-acetyl-3-O-methyl-α-L-idopyranose (prepared as described for its per-benzoyl analogue by replacing benzoyl chloride with acetic anhydride; Jaurand et al. Bio. Med. Chem. Lett, 1992, 2, 897-900) (48.4 g) is dissolved in toluene (175 ml). Ethanethiol (20 ml) and boron trifluoride etherate (1M in toluene, 134 ml) are added under a nitrogen atmosphere. After stirring for 1 hour, aqueous sodium hydrogen carbonate (400 ml) and the mixture is added and the mixture is stirred for 1 hour. The mixture is then poured into ethyl acetate. The organic phase is washed twice with water and concentrated. Purification by chromatography on a column of silica gel gives 29.6 g of compound 52.
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[CH2:14])=[CH:5][CH:4]=1.CO[C:17]([C:19]#CC(OC)=O)=O.CCCCCC.CCOC(C)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH:11]1[C:12]2[CH:3]=[CH:4][C:5]3[C:6](=[CH:13][CH:14]=[CH:17][CH:19]=3)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C=Cc1ccc(OC)c2ccccc12
Reactant: COC(=O)C#CC(=O)OC
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)ccc1ccccc12
Yield: 61.2 %

Procedure:
1-methoxy-4-vinyl naphthalene 18.42 g (0.1 mol) and acetylene dicarboxylic acid dimethyl ester 28.42 g (0.2 mol) were dissolved in nitrobenzene, 200 ml, and they were reacted for 7 hours at the temperature of 130° C. After cooling, nitrobenzene was escaped in vapor under a reduced pressure condition, silica gel column chromatography (developing solvent n-hexane: an acetic acid ethyl=9:1) process was performed to residual elements, crude material, 23.08 g, was obtained. Further, objective phenanthrene compounds, 19.85 g (yield 61.2%) was obtained by recrystallizing from n-butanol. A melting point was 150.2 to 151.0° C. An infrared absorption spectrum of this phenanthrene compound is shown in FIG. 4.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:21][N:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[OH:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[C:23]([C:24]([F:25])([F:26])[F:27])=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:21][N:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 94.6 %

Procedure:
(R/S)-Ethyl 2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetate (Int-VIII, 380 mg, 0.83 mmol) was dissolved in THF (5.00 mL) and MeOH (5 mL). Then, 1N LiOH (0.83 mL, 0.83 mmol) was added. It was stirred for 20 min and additional 1N LiOH (0.83 mL, 0.83 mmol) was added. After stirring for 15 min, the solution was neutralized by 1N HCl to pH=5. The reaction mixture was concentrated and then EtOAc was added. The EtOAc was washed with brine. The organic layer was dried, filtered and concentrated to give (R/S)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 376 mg, 0.785 mmol, 95% yield): LCMS=432.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.02-8.20 (2 H, m), 7.49-7.79 (7 H, m), 5.27 (1 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[C:29]([C:30](Cl)=[O:31])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=1[F:36]>O1CCCC1>[F:23][C:24]1[C:25]([F:36])=[C:26]([F:35])[C:27]([F:34])=[C:28]([F:33])[C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:31]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)c(F)c(F)c(F)c3F)c2)CC1
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) was allowed to stand for 10 min. Pentafluorobenzoyl chloride (33 μL, 0.229 mmol) was added to the reaction mixture. The reaction mixture was mixed for 2 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 51 mg (>100%) of the title compound.