Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][C:18]=1[CH2:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+].S1(CCCC1)(=O)=O>[I-].[K+].O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:28][CH2:27][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][C:17]=3[Cl:16])[NH:23][C:22](=[O:26])[CH2:21]4)[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)c(Cl)cc2N1
Yield: 74.9 %

Procedure:
In a 50 ml 3 necked round bottom flask there were placed 1 gram (4.56 mmol) of 3-piperazinylbenzo[d]isothiazole; 1.25 grams (5.43 mmol) of 6-chloro-5-(2-chloroethyl)indolin-2-one; 50 mg of potassium iodide; 0.82 gram (5.94 mmol) of potassium carbonate and 3 ml of sulfolane. The contents of the flask were heated to 95° C. to 100° C. The reaction was monitored by HPLC. After completion of the reaction, 50 ml of DM water was added to the reaction mixture and stirred. The product was filtered off and washed with water and dried to obtain 1.41 grams (75%) of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydro-2H-indol-2-one. The crude product was purified by IPA and/or THF. The product matched the spectra of a standard NMR and showed the correct retention time by HPLC with 98.0% assay. The melting point of the compound was found to be 218° C.-220° C., and was found to conform with the melting point of 218°-220° C. as disclosed in U.S. Pat. No. 5,206,366.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:16]([NH2:18])=[N:15][S:14](=[O:20])(=[O:19])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl.CC(O)=O>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:16]([NH2:18])=[N:15][S:14](=[O:19])(=[O:20])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:29]
Reactant: CSCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CS(=O)CCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-(4-(methylthio)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (Example 233) (79 mg, 0.25 mmol) in DCM/CH3CO2H (20:1, 20 mL) was added MCPBA (1.0 equiv.) at room temperature. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with 15% MeOH in dichloromethane to give the title compound (74 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.74-1.77 (m, 2H), 1.88-1.95 (m, 2H), 2.50 (s, 3H), 2.68-2.73 (m, 1H), 2.77-2.83 (m, 1H), 4.19 (t, 2H), 6.58-6.60 (d, J=8.4 Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 8.33 (s, 1H), 10.92 (s, 1H). MS 332 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=2)[N:12]=[C:11]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(OCc2ccccc2)n(Cc2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of methyl 4-{[5-(benzyloxy)-3-tert-butyl-1H-pyrazol-1-yl]methyl}benzoate (2.14 g, 5.65 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (0.27 g, 5.7 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Ethanol (10 mL) and saturated aqueous ammonium chloride solution (1.0 mL) were added to the reaction mixture, and the precipitated solid was filtered off. The filtrate was concentrated and the residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title compound (1.97 g, yield 99%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[NH:12])SC.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C(O)=O>C(O)C.C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[NH:12]
Reactant: CSC(=N)Nc1ccccc1F
Reactant: C1CCNC1
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: N=C(Nc1ccccc1F)N1CCCC1

Procedure:
To stirred solution of 2.0 g (0.006 mol) of N-(2-fluorophenyl)-S-methylisothiourea in 50 ml of ethanol was added 2.0 g (0.028 mol) of pyrrolidine and the reaction refluxed for eight hours. The solvent was then evaporated and to the residue was added 100 ml of water and 20 ml of 2 N sodium hydroxide. The aqueous phase was then extracted with ethyl acetate (3×100 ml) and the organic phase dried over magnesium sulphate. Evaporation of the solvent gave a crude residue. This crude residue was then dissolved in 25 ml of hot isopropanol and oxalic acid was added in excess. Upon cooling a white solid crystallized and was collected by filtration and dried at 60° C. for 24 hours to give the oxalate salt of N-(2-fluorophenyl)-1-pyrrolidinecarboximidamide, M.P. 172-173° C.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[CH:9]=[C:10]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:11]=[C:12]([N:14]2[CH:18]=[N:17][N:16]=[N:15]2)[CH:13]=1)=[O:7]>O.C1COCC1>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[CH:11]=[C:12]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)[CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-n3cnnn3)c2)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of LiOH.H2O (1.86 g, 44.2 mmol) in H2O (40 mL) was added dropwise to a suspension of 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester (10 g, 34 mmol) in THF (25 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned clear. Solvent was removed under vacuum and the aqueous solution was acidified by addition of 10% HCl to pH=3. The resulting precipitate was collected and dried to afford 4′-Methyl-5-tetrazol-1-yl-biphenyl-3-carboxylic acid as white solid (8.85 g, 93%). MS (M+H)=281.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[OH:36])[CH:31]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:31][C:30]4[CH:33]=[CH:34][C:35]([OH:36])=[C:28]([Cl:27])[CH:29]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)c(Cl)c3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 3-chloro-4-hydroxybenzaldehyde to provide 22 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:28])[N:12]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:11]1[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:28])[N:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL). The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greeted than 10). The aqueous layer was extracted with additional dichloromethane (100 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL). After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.65 (m, 1H); 7.62-7.49 (m, 4H), 7.32-7.22 (m, 2H), 7.13-7.06 (m, 1H), 3.42 (dd, J=7.5, 5.2 Hz, 1H), 1.87-1.70 (m, 1H), 1.58-1.43 (m, 1H), 0.80 (t, J=7.4 Hz, 3H). ESI-MS m/z 298.2 (MH+). The reaction described above and compound III are shown below.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.CC#N>O>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:27]([CH3:26])[CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:5][CH2:4]1
Reactant: CNCc1ccc(F)cc1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Solvent: CC#N
Solvent: O
Product: CNc1cc(N(C)Cc2ccc(F)cc2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (60 mg, 0.158 mmol), N-methyl-N-(4-fluorobenzyl)amine (24 μL, 0.18 mmol) and MeCN (1 mL) is irradiated in a microwave oven for 45 min at 160° C., and after cooling diluted with water. The mixture is extracted with EtOAc, the combined organic phases are dried with Na2SO4, filtered and concentrated and directly used in the next step. Yield: 80 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[C:15]([Br:17])[S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sccc2C(C)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCc2sc(Br)cc2C(C)C1
Reaction time: 0.25 h

Procedure:
The product of step d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1 CHCl3 /HOAc. N-Bromo-succinimide (62 mg, 0.35 mmol) was added and the reaction was stirred for 15 minutes. Concentration and purification by silica gel chromatography gave the subtitle compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH:9](CC)[CH2:10][O:11][C:12]3[CH:19]=[C:18]([F:20])[C:17]([Br:21])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.O1CCCC1.[Li+].[OH-].Cl>O>[Br:21][C:17]1[C:18]([F:20])=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1nc2c(s1)C(CC)COc1cc(F)c(Br)cc1-2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed ethyl 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (350 g, 940.33 mmol, 1.00 equiv), tetrahydrofuran (1.3 L), water (2.6 L), and LiOH (62 g, 2.59 mol, 2.73 equiv). The resulting solution was stirred at room temperature for 3 h, cooled to <10° C. and adjusted to pH=2-3 with hydrochloric acid. The precipitates were collected by filtration, washed with 4×1 L of water and dried to afford 260 g (80%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid as a brown solid.
Reaction SMILES: ClC[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[C:13]([CH:18]4[O:22][CH2:21][CH2:20][O:19]4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9](=[O:23])[N:8]2[CH2:7][C:6]1[CH:24]=[CH:25][C:3]([S:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][CH:5]=1
Reactant: O=C1CCc2c(C3OCCO3)cccc2N1Cc1ccc(CCl)cc1
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Product: O=C1CCc2c(C3OCCO3)cccc2N1Cc1ccc(Sc2ccccc2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
1-(4-Chloromethylbenzyl)-5-(1,3-dioxolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (1.0 g, 2.79 mmol), thiophenol (0.37 ml, 3.63 mmol) and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) (0.84 ml, 5.59 mmol) were added to THF (30 ml), followed by heating under reflux for 7 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 1.13 g (yield: 94%) of 5-(1,3-dioxolan-2-yl)-1-(4-phenylsulfanylbenzyl)-3,4-dihydro-1H-quinolin-2-one as a white solid.
Reaction SMILES: Cl.NC1C=CC2N=C(S[C@@H](CC(N)C)CC)SC=2C=1.NC1C=CC2N=C(S)SC=2C=1.C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1N1C=NC2C1=NC(Cl)=NC=2Cl)(=O)C.C([O:63][C@@H:64]1[C@H:68]([O:69]C(=O)C)[C@@H:67]([CH2:73][O:74]C(=O)C)[O:66][C@H:65]1[N:78]1[C:101]2[N:100]=[C:99]([Cl:102])[N:98]=[C:82]([NH:83][C@H:84]([CH3:97])[CH2:85][S:86][C:87]3[S:88][C:89]4[CH:95]=[C:94]([NH2:96])[CH:93]=[CH:92][C:90]=4[N:91]=3)[C:81]=2[N:80]=[CH:79]1)(=O)C>N>[NH2:96][C:94]1[CH:93]=[CH:92][C:90]2[N:91]=[C:87]([S:86][CH2:85][C@H:84]([NH:83][C:82]3[C:81]4[N:80]=[CH:79][N:78]([C:101]=4[N:100]=[C:99]([Cl:102])[N:98]=3)[C@@H:65]3[O:66][C@H:67]([CH2:73][OH:74])[C@@H:68]([OH:69])[C@H:64]3[OH:63])[CH3:97])[S:88][C:89]=2[CH:95]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5ccc(N)cc5s4)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC[C@H](CC(C)N)Sc1nc2ccc(N)cc2s1
Agent: Cl
Product: C[C@H](CSc1nc2ccc(N)cc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 63 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 6-amino-2-[(R)-2-aminopropyl-1-propylthio]benzothiazole hydrochloride [prepared by a Mitsunobu reaction as described in Example 1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (13.1 g, 75 mmol) and 6-amino-2-mercaptobenzothiazole (13.7 g, 75 mmol) followed by acidic hydrolysis]) (2.51 g, 7.2 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.68 g, 6.0 mmol), followed by deacylation of the purified 2',3',5'-tri-O-acetyl-N-[(R)-1-(6-amino-2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine in methanolic ammonia (200 ml) (previously saturated at -10° C.) to provide the title N-[(R)-1-(6-amino2-benzothiazolyl)thio-2-propyl]-2chloroadenosine (1.97 g, 63%) as a foam (following column chromatography), 1H NMR (DMSO-d6) δ 1.36 (3H, d, --CHCH3), 3,50-3.71 (4H, m, H-5'a and H-5'b and --CH2 --), 3.95 (1H, d, H-4'), 4.14 (1H, d, H-3'), 4.53 (1H, q, H-2'), 4.63 (1H, m, --CH), 5.08 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 6.71, 6.99, 7.53 (3H, 3d, Ar-H), 8.41 (1H, s, H-8), 8.52 (1H, d, N--H). HPLC retention time 10.29 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:13][CH:14]([CH2:18][CH2:19][Br:20])[C:15](Cl)=[O:16]>C(OCC)C.O>[Br:13][CH:14]([CH2:18][CH2:19][Br:20])[C:15]([NH:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=1)=[O:16]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(NCc1ccc(C(F)(F)F)cc1)C(Br)CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of (4-(trifluoromethyl)phenyl)methanamine (3 g, 17 mmol) in diethyl ether (60 mL) under nitrogen at 0° C. was added 2,4-dibromobutanoyl chloride (2.3 mL, 17 mmol) and the reaction mixture was stirred for 1 h at rt. The mixture was then diluted with water and extracted with 200 mL of ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure to afford 2,4-dibromo-N-(4-(trifluoromethyl)benzyl)-butanamide (6.5 g, 87%). LCMS (method F) RT 2.01 min, m/z 434.8, 483.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39-2.47 (m, 2H) 3.50-3.67 (m, 2H) 4.41 (dd, J=13.05, 6.02 Hz, 2H) 4.59-4.64 (m, 1H) 7.49 (d, J=7.53 Hz, 2H) 7.71 (d, J=8.03 Hz, 2H) 9.06 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]#[N:16])=[CH:10][CH:9]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)#[N:16]
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
5-Cyano-1H-indole-2-carboxylic acid ethyl ester (1.71 g, 8.0 mmol) was added to a solution of ethanol (10 mL) and potassium hydroxide (2 g) and the resulting mixture heated at reflux for 1 hour. Water was added to dissolve the precipitate, and 6N HCl was added to bring the pH to 1. A precipitate formed. The mixture was cooled in an ice bath, filtered, and the resulting colorless solid washed with cold water and dried (1.51 g). A portion (1.4 g) was suspended in hot acetic acid (40 mL) and cooled giving a solid which was filtered, washed with cold ethyl acetate and dried: Yield 980 mg 70%; HPLC (60/40) 3.09 minutes (97%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C)[CH:3]=1.[CH3:16][Si:17]([CH2:20][CH3:21])([CH3:19])[CH3:18]>>[CH2:9]([O:8][C:4]1[CH:3]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC[Si](C)(C)C
Reactant: CCCCCCCOc1cccc(Br)c1
Product: CCCCCCOc1cccc(C#C[Si](C)(C)C)c1
Yield: 52.4 %

Procedure:
According to the method described in Example S117a, 1-bromo-3-(heptyloxy)benzene (1 g, 4 mmol) was reacted with trimethylsilylethane (0.43 g, 4.4 mmol) to give the title compound as a yellow oil (575 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.19 (t, 1H, J=7.6 Hz), 7.05 (d, 1H, J=7.2 Hz), 6.99 (s, 1H), 6.87 (d, 1H, J=7.0 Hz), 3.94 (t, 2H, J=6.8 Hz), 1.79-1.75 (m, 2H), 1.47-1.30 (m, 6H), 0.91 (t, 3H, J=6.8 Hz), 0.26 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)=[O:15])[CH2:10][CH2:9]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>C1COCC1.O>[CH3:44][S:45]([NH:48][C:27]([C:26]1[CH:30]=[CH:31][C:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:14]([N:11]3[CH2:10][CH2:9][C:8](=[CH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:13][CH2:12]3)=[O:15])=[CH:18][CH:19]=2)=[CH:24][CH:25]=1)=[O:28])(=[O:47])=[O:46]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc(-c2ccc(NC(=O)N3CCC(=Cc4ccccn4)CC3)cn2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
The compound (80 mg, 193 μmol) obtained in Example 28 was dissolved in THF (5 mL), and CDI (47 mg, 290 μmol) was added thereto, followed by stirring at 60° C. for 2 hours. Thereafter, methanesulfonamide (28 mg, 290 μmol) was added to the mixture, followed by stirring for 10 minutes, and diazabicycloundecene (hereinafter referred to as DBU) (51 μL, 347 μmol) was added thereto, followed by stirring at room temperature for 16 hours. Water was added to the resulting mixture, and after extraction with methanol:chloroform (1:6), the extract was washed with a saturated ammonium chloride aqueous solution and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:6), thereby giving the title compound (30 mg, 32%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:34]([C:38]1[CH:39]=[CH:40][C:41]([CH2:42][N:18]([CH2:17][C:16]2[CH:32]=[CH:33][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=3)=[CH:14][CH:15]=2)[C:19]2[CH:31]=[CH:30][C:22]3[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=3[CH:20]=2)=[CH:44][CH:45]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(C)(C)C)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.6 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (150 mg, 0.34 mmol) in anhydrous DCE (3 mL) were added 4-tert-butylbenzaldehyde (Aldrich, 85 μL, 0.51 mmol) and sodium triacetoxyborohydride (110 mg, 0.51 mmol). The reaction mixture was stirred at rt for 72 hrs. The solvent was removed under reduced pressure. The residue was taken up with an aqueous solution of NaOH (2 mL, 1N) and extracted with Et2O (6 ml). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (pentane/DCM (2/3)) gave 71 mg (31%) of the title compound as a yellow oil. HPLC, Rt: 6.4 min (purity: 86.3%). 1H NMR (CDCl3) δ: 7.85-6.90 (m, 15H), 4.62 (brs, 4H), 2.62 (t, J=7.6 Hz, 2H), 1.70 (s, 6H), 1.61 (m, 2H), 1.33 (m, 2H), 1.30 (s, 9H), 0.93 (t, J=7.2 Hz, 3H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:32](O)[CH2:33][OH:34].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2([O:34][CH2:33][CH2:32][O:26]2)[CH:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCCO
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CN(Cc2ccccc2)CCC12OCCO2
Temperature: 25 °C
Yield: 66 %

Procedure:
p-Toluenesulfonic acid monohydrate (1.5 g) was added to a solution (600 ml) of ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate (CAS Registry No. 1454-53-1, 44.7 g) and ethylene glycol (100 ml) in toluene and the resultant mixture was heated under reflux overnight. After cooling the mixture to room temperature, ice water (500 ml) and a saturated aqueous solution (300 ml) of sodium bicarbonate were added thereto followed by extraction with ethyl acetate (400 ml) for three times. The organic phase was washed successively with water (200 ml) twice and brine (300 ml) and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (30.4 g) as a yellow oil (yield: 66%).