Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]1[CH2:22][C:23]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-:28].[Na+].[OH2:30]>>[CH2:1]([N:8]1[C:12]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]1[CH2:22][C:23]([OH:30])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(C(=O)c2ccc(Cl)cc2)n1Cc1ccccc1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1Cc1ccccc1

Procedure:
A suspension of 3.0 g. (0.009 mole) of 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2 -acetonitrile in 20 ml. of ethanol and 18 ml. (0.018 mole) of 1N sodium hydroxide is refluxed for 6 hours. The mixture is diluted with water, and the ethanol evaporated in vacuo. The solution is washed with chloroform and ether and acidified with 3N hydrochloric acid. The precipitated solid is collected and dried in vacuo to give 1-benzyl-5-(p-chlorobenzoyl)-pyrrole-2-acetic acid as white crystals, M.P. 162-163° C. Analysis: Calcd. for C20H15ClNO3 : C, 67.70; H, 4.65; N, 3.96%. Found: C, 67.79; H, 4.65; N, 3.97%.
Reaction SMILES: [C:1]([C:6]1[C:7]([Cl:19])=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[CH3:21]NC.C=O>C(O)(=O)C.CN(C)C=O>[Cl:19][C:7]1[C:6]([C:1](=[O:5])[C:2](=[CH2:21])[CH2:3][CH3:4])=[CH:17][C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=2[C:8]=1[Cl:18]
Reactant: CCCC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 0 °C
Yield: 71.4 %

Procedure:
A stirred mixture of 5-butyryl-6,7-dichloro-2,3-dihydro-2-benzofurancarboxylic acid (12.0 g, 0.04 mole), dimethylamine hydrochloride (4.3 g, 0.052 mole), para-formaldehyde (1.9 g, 0.063 mole) and acetic acid (4 drops) was heated on a steam bath for 21/2 hours. Dimethylformamide (35 ml) was added and heating was continued for 11/2 hours. The reaction mixture was poured into ice water, extracted with ether, washed with water and dried over magnesium sulfate. The ether was evaporated in vacuo and the residue triturated with butyl chloride (100 ml) to give 9.0 g of 6,7-dichloro-2,3-dihydro-5-(2-methylenebutyryl)-2-benzofurancarboxylic acid which melted at 148° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([F:18])[C:11]([F:19])=[C:10]([F:20])[C:9]=1[F:21].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:7][C:8]1[C:9]([F:21])=[C:10]([F:20])[C:11]([F:19])=[C:12]([F:18])[C:13]=1[S:14]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
To a solution of 1,3-butane diol (0.9 g, 10 mmol) and TEA (0.61 g, 6 mmol) in CH2Cl2 (4 mL) at 0° C. was added pentafluorobenzenesulfonyl chloride (0.53 g, 2 mmol) dissolved in CH2Cl2 (4 mL). The solution was stirred for 6 h over which time the solution slowly warmed to rt. Saturated aqueous NaHCO3 (25 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (50 mL) and washed with 0.5 M HCl (3×20 mL), saturated aqueous NaHCO3 (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (0.26 g, 40%). 1H NMR (400 MHz CDCl3) δ 4.62 (m, 2H), 4.13 (m, 1H), 2.11 (m, 1H), 1.94 (m, 1H), 1.40 (d, 3H, J=6.2 Hz). Anal. Calcd. For C10H9F5O4S: C, 37.51; H, 2.83. Found: C, 37.70; H, 2.93.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]([NH:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:23]([O:38][CH3:39])[CH:22]=1)[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]([NH:18][C:19](=[O:40])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])=[O:29])=[C:23]([O:38][CH3:39])[CH:22]=1)[CH3:17])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(N)c1
Yield: 82.3 %

Procedure:
A stirred solution of methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (310 mg, 0.56 mmol) in MeOH—THF (10 mL, 1:1, v/v) was hydrogenated over 5% Pd—C (50 mg, 16 wt %) overnight. The mixture was filtered to remove the catalyst and the filtrate was evaporated to give methyl (S)-3-amino-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate (240 mg) as a gum.
Reaction SMILES: [C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[C:1]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:28][CH2:27][C:26]1[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:31])[F:32])=[CH:30][CH:29]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCC#Cc1cccc(C=O)c1
Product: CCCCCCCCCCC#Cc1cccc(CNCc2ccc(C(F)(F)F)cc2)c1
Yield: 37 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 3-dodec-1-ynylbenzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound (37%). M+(LC/MS(ESI)): 430.5. HPLC (Condition A), Rt: 4.82 min (HPLC purity 94.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>C(O)C>[OH:10][C:9]1[C:4]2[C:5](=[CH:11][CH:12]=[C:2]([CH3:1])[CH:3]=2)[C:6](=[O:8])[C:19]=1[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: Cc1ccncc1
Solvent: CCO
Product: Cc1ccc2c(c1)C(O)=C(c1ccncc1)C2=O
Temperature: 165 °C

Procedure:
A mixture of 47.5 g (293 mmol) 4-methyl-phthalic anhydride and 28.6 ml (293 mmol) 4-picoline is heated to 165° C. for 18 h. The resulting material is stirred in 190 ml of boiling ethanol, filtered and washed with ethanol and diethyl ether, yielding the title compound: An. calc. (C15H11NO2) C, 75.94%; H, 4.67%; N, 5.90%; O, 13.49%; An. meas. C, 75.60%; H, 4.64%; N, 6.02%; O, 13.60%; 1H NMR (DMSO-d6) δ 8.70 (d, 2H), 8.14 (d, 2H), 7.34 (m, 2H), 7.29 (s, 1H), 2.38 (s, 3H); FAB MS (M+H)+=238.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][N:29]=3)[C@@H:24]([NH:31]C(OC(C)(C)C)=O)[C@H:23]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[F:46])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.FC(F)(F)C(O)=O.CO>C(Cl)Cl>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C@H:20]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][N:29]=3)[C@@H:24]([NH2:31])[C@H:23]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=3[F:46])[CH2:22][CH2:21]2)=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: N[C@@H]1c2nccnc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
In a 50 mL round-bottomed flask was dissolved (5R,8S,9S)-9-(tert-butoxycarbonylamino)-8-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (38.1 mg, 0.060 mmol) in methylene chloride (1 mL) to give a colorless solution. trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at rt for 1 h. LCMS showed complete conversion. Volatiles were removed in vacuo, and the residue was partitioned between ethyl acetate/0.5N sodium hydroxide/saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried and concentrated to give a tan oil. flash column chromatography up to 10% methanol (2M ammonia) in methylene chloride afforded the desired product (22 mg, 69%) as a white solid: MS (ESI)[M+H+]=536.2; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 2H), 8.11 (d, J=4.9 Hz, 1H), 7.42 (s, J=16.5 Hz, 1H), 7.17-6.95 (m, 4H), 6.24-5.97 (m, 2H), 4.69-4.34 (m, 4H), 3.31-2.81 (m, 3H), 2.37 (dd, J=23.5, 13.6 Hz, 4H), 2.17-1.67 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −137.10-−137.50 (m), −142.45 (d, J=20.6 Hz).
Reaction SMILES: [S:1]([C:5]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:4])(=[O:3])=[O:2].C([O:20][C:21](=[O:23])[CH3:22])(=O)C>>[C:21]([C:22]1[CH:11]=[CH:10][C:6]([C:7]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:5]=2[S:1]([OH:4])(=[O:3])=[O:2])=[O:8])=[C:5]([S:1]([OH:4])(=[O:3])=[O:2])[CH:13]=1)([OH:20])=[O:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(C(=O)O)c(S(=O)(=O)O)c1
Product: O=C(O)c1ccc(C(=O)OC(=O)c2ccc(C(=O)O)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A dry 500 ml 3-neck flask was equipped with a condenser, stirrer and thermometer under a nitrogen atmosphere. The vessel was charged with 2-sulfoterephthalic acid (100 g, 447 mmol).and acetic anhydride (127 ml). The solution was stirred at 100° C. for 4 hours and then cooled to room temperature (the reaction mixture became homogeneous at 90° C.). A precipitate which had begun to form at 76° C. was then collected by filtration at room temperature (25° C.) under a N2 atmosphere. It was washed with methylene chloride (5×200 ml) and dried in dessicator under high vacuum for 24 hours. The dry white product melted at 210°-213° C. (Lit 208°-210° C.); 66.8 g (65%).
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[CH3:25][OH:26]>>[CH2:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:26][CH3:25])=[CH:21][CH:22]=2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOc1nc(N)c2ncn(Cc3ccc(Cl)nc3)c2n1
Reactant: CO
Agent: [Na]
Product: CCCCOc1nc(N)c2ncn(Cc3ccc(OC)nc3)c2n1
Yield: 50 %

Procedure:
Sodium (415 mg, 18.0 mmol) was added and completely dissolved in methanol (18 ml). Thereafter, 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine (300 mg, 0.90 mmol) was added thereto, and the resultant was heated under reflux for 24 hours. The reaction solution was concentrated under reduced pressure, water (30 ml) was added to the residue, and the resultant was neutralized with concentrated hydrochloric acid under ice cooling. The precipitated solid was collected by filtration, and crude crystal was purified by silica gel column chromatography (methylene chloride:methanol=50:1) to obtain 148 mg of the title compound (yield: 50%).
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([O:21][CH2:20][CH2:19][C:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1CCC1
Reactant: BrCCOCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOCc2ccccc2)CCC1
Temperature: 0 °C
Yield: 71.3 %

Procedure:
A solution of 3.0 g (23 mmol) of ethyl cyclobutanecarboxylate in 10 mL of tetrahydrofuran was added to a −78° C. solution of 25.74 mmol of lithium diisopropylamide in 45 ml tetrahydrofuran. The reaction was warmed to 0° C. over 15 min and then cooled to −78° C., followed by the addition of 3.64 mL (25.74 mmol) of benzyl 2-bromoethyl ether in 10 mL of tetrahydrofuran. The reaction was gradually warmed to room temperature over 16 h and then quenched with 20 mL of saturated ammonium chloride. The reaction was concentrated and ethyl acetate was added. The organic layer was isolated, dried with magnesium sulfate, and concentrated under vacuum to afford an oil, which was purified by silica gel chromatography eluting with ethyl acetate:hexane (2:8) to afford 4.3 g (70%) of ethyl 1-[2-(benzyloxy)ethyl]cyclobutanecarboxylate as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.31-7.22 (m, 5H), 4.01 (q, J=7 Hz, 2H), 4.40 (s, 2H), 2.40 (t, J=7 Hz, 2H), 1.92-1.84 (m, 6H), 1.14 (t, J=7 Hz, 3H). GC-MS m/z 263 (M+H).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24](O)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:28]1([NH:27][CH:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:26])[N:16]2[CH2:15][CH2:14][CH2:13][N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: O=C1c2ccccc2C(Nc2ccccc2)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 9 h
Yield: 93.8 %

Procedure:
Para-toluenesulphonic acid (50 mg) is added to an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (5 g) and aniline (1.7 g) in xylene (100 cc) at a temperature close to 20° C. in a Dean Stark apparatus. Agitation is continued for 9 hours at a temperature close to 135° C. After cooling to a temperature close to 20° C., the solution is washed with aqueous sodium bicarbonate solution (2×50 cc) then with distilled water (2×30 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 80° C. The residue obtained is dissolved in methylene chloride (10 cc) and poured onto silica (100 g) contained in a column of 2 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume) (1300 cc) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). The precipitate formed is recrystallized from boiling acetonitrile (30 cc). 5.7 g of 3-phenylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone are obtained, melting at 119° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(Br)n1
Product: Brc1cccc(CN2CCOCC2)n1
Yield: 61.4 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.415 g, 2.23 mmol) and morpholine (0.195 g, 2.23 mmol). The crude product was purified (SiO2: 0-3% 2 M NH3 in MeOH/DCM) to give the title compound (0.352 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:32].[C:33](Cl)(=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1.[CH3:46][C:47]([NH2:51])([CH3:50])[CH2:48][NH2:49].C(N(CC)CC)C>O1CCCC1>[NH2:51][C:47]([CH3:50])([CH3:46])[CH2:48][NH:49][C:33]([NH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([OH:29])([C:21]([F:22])([F:23])[F:24])[C:25]([F:28])([F:26])[F:27])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:32])=[O:34]
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: CC(C)(N)CN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(N)CNC(=O)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
A solution of 2-(4-((4-(4-amino-3-fluorobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.861 mmol, 0.4 g) and 4-nitrophenyl carbonochloridate (0.861 mmol, 0.174 g) in tetrahydrofuran (5 mL) was stirred at room temperature for 30 minutes. 2-Methylpropane-1,2-diamine (1.723 mmol, 0.152 g) was added, followed by triethylamine (2.58 mmol, 0.360 mL, 0.261 g) and the reaction stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to afford the title compound (45.3 mg). MS (ESI) m/z 579.2 [M+H]+
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1)C.[BH4-].[Li+]>O1CCCC1.CO.C(OCC)(=O)C.Cl>[OH:3][CH2:4][CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)(=[O:22])=[O:23])=[N:8][CH2:7]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4nccs4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(CCO)S3)[nH]c12)S(=O)(=O)c1nccs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 13.7 %

Procedure:
Ethyl(2-{7-[methyl(1,3-thiazol-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (200 mg) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and the mixture was cooled to 0° C. Lithium borohydride (20 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The organic layer was dried over sodium sulfate, and filtrated, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (25 mg, yield 14%) as a pale-Yellow solid. MS:423(MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([O:22][CH2:21][C@@H:13]1[C@@H:14]2[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:12]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Yield: 100 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (1.000 g, 0.003060 mol), pyridine (495.1 μL, 0.006121 mol), 4-dimethylaminopyridine (0.0748 g, 0.000612 mol) and acetic anhydride (577.5 μL, 0.006121 mol) were stirred in methylene chloride (20 mL) at room temperature for 1 h. The solution was diluted with Methylene chloride, extracted with HCl 1N, dried over NA2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/DCM 0% to 25%) to obtain the product (1.129 g, 84%) as an oil.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24].C(#N)C>O>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(-c4ccccc4)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.4 g (1.678 mmol) of 1-biphenyl-4-yl-piperazine, 0.682 g (1.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.223 ml (1.6 mmol) of triethylaminein 20 ml acetonitrile is stirred for 14 hours at 60° C. and then diluted with water. It is extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=40:1).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH2:6]([Si:9]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16](CO)=[CH:15][CH:14]=1)[CH:7]=[CH2:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:24]([Si:9]([CH2:6][CH:7]=[CH2:8])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:1][Br:5])=[CH:19][CH:20]=1)[CH:25]=[CH2:26]
Reactant: BrC(Br)(Br)Br
Reactant: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CBr)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
5 ml of methylene chloride and CBr4 (4.97 g, 15.0 mmol) were slowly added to 4-{3-(triallylsilyl)propyl}benzyl alcohol (5) (3.0 g, 10.0 mmol) and triphenylphosphine (PPh3) (3.93 g, 15.0 mmol) under a nitrogen atmosphere, and the mixture was stirred for 1 hour. Cooled distilled water was added to the reaction mixture. The aqueous layer was extracted with methylene chloride, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure to give a crude product. The crude product was purified by separating by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=20/1) to give 4-{3-(triallylsilyl)propyl}benzyl bromide (6) (yield amount: 2.80 g, yield: 77%), as shown in the following chemical reaction formula.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:30][CH2:31][CH2:32][F:33])(=O)=O.[H-].[Na+]>O1CCCC1.O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:30][CH2:31][CH2:32][F:33])[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCCCF)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCF)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (400 mg, 1.2 mmol) and 3-fluoropropyl trifluoromethanesulfonate (433 mg, 2.1 mmol) in tetrahydrofuran (10 mL) was added sodium hydride as 60% dispersion in mineral oil (146 mg, 3.6 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with water (20 mL) and methylene chloride (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 40 g, ISCO, 1-20% methanol in methylene chloride) to afford the title compound as a colorless oil, which was used in the next step without any further purification (475 mg, 100%).