Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:32]P([O-])([O-])=O)[CH:6]([O:7]P([O-])([O-])=O)[CH:5]([O:12]P([O-])([O-])=O)[CH:4]([O:17]P([O-])([O-])=O)[CH:3]([O:22]P([O-])([O-])=O)[CH:2]1[O:27]P([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].N1C=CC=CC=1>O>[CH:6]1([OH:7])[CH:5]([OH:12])[CH:4]([OH:17])[CH:3]([OH:22])[CH:2]([OH:27])[CH:1]1[OH:32]
Reactant: O=P([O-])([O-])OC1C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C1OP(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 65 °C

Procedure:
Crystalline sodium phytate C (4 g) was dissolved with sonication in water (20 ml) and converted to the free acid by passage through a column of Dowex 50×8-200 ion-exchange resign. The column eluate was adjusted to pH 8 with pyridine and evaporated to dryness. The residue was dissolved in water (30 ml) and pyridine (130 ml) containing N,N-dicyclohexylcarbodiimide (8 g) was added. The reaction mixture was heated to 65° C. for 18 h and evaporated to dryness. The residue was extracted with water (4×10 ml) filtered and the filtrate was evaporated to dryness to give the pentapyridinium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (3.355 g, 77% yield). 31P-NMR (D2O) δ: −8.83 & −13.53 (AB, J=22.3 Hz, 2P, ax-eq), −9.82 & −10.00 (AB, J=17.8 Hz, 2P, eq-eq), −10.18 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 8.65 (d, J=5.6 Hz, 10H), 8.48 (dd, J=7.9, 7.9 Hz, 5H), 7.94 (dd, J=7.0, 7.0 Hz, 10H), 5.00 (bd, J=10.5 Hz, 1H), 4.57 (ddd, J=9.6, 9.6, 5.5 Hz, 1H), 4.43-4.36 (m, 2H), 4.30-4.18 (m, 2H); 13C-NMR (D2O) δ: 147.0, 140.9, 127.3, 77.9 (t, J=6.8 Hz), 76.4-76.0 (m), 75.4-75.0 (m), 73.8 (t, J=6.8 Hz), 73.3 (bs), 72.8 (bs). The compound was then dissolved in water (30 ml) and passed through a column Dowex 50Wx8 Na+ form. The column eluate was concentrated to dryness to give Hexasodium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (2.25 g, 97%) and used for biological experiments in 98.5% purity without any further purification. The impurity is unreacted starting material (or tripyrophosphate hydrolyzed back to starting material). 31P-NMR (D2O) δ: −8.34 & −13.14 (AB, J=21.7 Hz, 2P, ax-eq), −9.53 & −9.70 (AB, J=17.8 Hz, 2P, eq-eq), −9.92 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 5.04 (bd, J=10.5 Hz, 1H), 4.65-4.59 (m, 1H), 4.51-4.36 (m, 2H), 4.32-4.18 (m, 2H); 13C-NMR (D2O) δ: 77.1-76.8 (m), 76.5-76.0 (m), 75.4-75.0 (m), 74.1-73.9 (m), 73.7-73.2 (m), 73.2-72.5 (m).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(S(C)(=O)=O)ccc2Cl)n1
Temperature: 150 °C
Yield: 26.1 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-chloro-5-(methylsulfonyl)benzoic acid (0.108 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (0.047 g, 0.463 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (26% yield) of pure product: MS (ES) m/z 522 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[C:15]([CH3:26])=[CH:16][C:17]([CH:24]=O)=[C:18]([CH:23]=3)[C:19](OC)=[O:20])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1.Cl.[NH2:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[OH:36].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:23]=[C:18]4[C:17]([CH2:24][N:29]([C@@H:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]5[OH:36])[C:19]4=[O:20])=[CH:16][C:15]=3[CH3:26])=[CH:9][CH:8]=2)[C:4]([CH3:27])=[N:3]1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-c3cn(C)nc3C)nc2)c(C)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1Cc1ccc(-c3cn(C)nc3C)nc1)C(=O)N([C@@H]1CCCC[C@H]1O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A solution of methyl 5-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-2-formyl-4-methylbenzoate (0.09 g), trans-2-aminocyclohexanol hydrochloride (0.04 g), triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.06 g) in THF (2.00 mL) was stirred at room temperature for 1.5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.00 mL) and THF (2.00 mL), sodium triacetoxyborohydride (0.11 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.05 g).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:31])[N:8]([C@H:13]([CH3:30])[C@:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])([OH:21])[CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].S(N)(N)(=O)=[O:33]>CO.C(Cl)(Cl)Cl>[NH2:2][C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:31])[N:8]([C@H:13]([CH3:30])[C@:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])([OH:21])[CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1)=[O:33]
Reactant: C[C@@H](n1cnc2cc(C#N)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: NS(N)(=O)=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@@H](n1cnc2cc(C(N)=O)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 8 h

Procedure:
A solution of (1R,2R)-7-cyano-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (obtained in example 2, 500 mg, 1.2 mmol) in MeOH (5 mL) and CHCl3 (5 mL) was cooled to 0° C. and HCl gas was bubbled until saturation (1.5 h). The mixture was allowed to stand at 0° C. overnight and was then concentrated and the residue was slowly added to aqueous K2CO3 solution (2.5 g). The yellowish precipitate formed was filtered, dried, taken up in methanol and allowed to react with sulfamide (350 mg, 3.6 mmol) at reflux for 3 h. The reaction mixture was then concentrated and partitioned between water and CHCl3. The organic layer was separated, dried over Na2SO4, filtered, concentrated and the resulting residue, whose thin layer chromatography showed the presence of three different compounds, was flash chromatographed. The first compound to elute was identified as the methyl imidate. The second compound to elute was the amide (title compound), the physical parameters of which are as follows: mp 235°-236° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.63 (s, 1H, N=CH--N), 8.42 (d, J=8.2, 1H, arom), 8.13 (d, J=1.5, 1H, arom), 7.98 (dd, J=8.2, J=1.5, 1H, arom), 7.77 (s, 1H, triazole), 7.74 (s, 1H, triazole), 7.48 (dt, Jd =6.4, Jt =8.8, 1H, arom), 6.9-6.8 (m, 2H, arom), 6.3 (broad s, 2H, NH2), 5.92 (dq, Jd =1.2, Jq =7.3, 1H, MeCH), 5.56 (d, J=1.3, 1H, OH), 5.16 (d, J=14.1, 1H, CH(H)), 4.03 (d, J=14.1, 1H, CH(H)), 1.32 (d, J=7.3, 3H, CHMe); GC/MS 224 (Tr--CH2COHAr, C10H8F2N3O), 216 (N-ethylheterocycle-1, C11H11N3O2).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](O)=[O:8].B(F)(F)F.CCOCC.Cl>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:7][OH:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CO)cc1F
Temperature: 25 °C
Yield: 92 %

Procedure:
To an ice-cooled suspension of NaBH4 (204 mg, 5.4 mmol, 2 eq.) in THF (10 mL) was added dropwise 3-fluoro 4-nitro benzoic acid (500 mg, 2.7 mmol, 1 eq.) in THF (10 mL) over 30 minutes. BF3-Et2O (7.3 mmol, 2.7 eq.) was then added dropwise over 30 minutes. The solution was stirred at room temperature over night. 1N HCl was added dropwise to quench NaBH4 excess. The solvent was removed in vacuo, the residue dissolved in DCM, washed with water, brine. The organic layer was then dried over MgSO4 and the solvent removed in vacuo to give 425 mg of 3-fluoro 4-nitro benzyl alcohol (92% yield). The compound was used in the following step with no further purification.
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2]>O>[CH3:5][CH2:4][C:3]([CH2:8][O:9][CH2:8][C:3]([CH2:6][OH:7])([CH2:1][OH:2])[CH2:4][CH3:5])([CH2:6][OH:7])[CH2:1][OH:2]
Reactant: CCC(CO)(CO)CO
Solvent: O
Product: CCC(CO)(CO)COCC(CC)(CO)CO

Procedure:
DE 10 2010 033 844 A1 likewise concerns a process for obtaining ditrimethylolpropane from the secondary streams of trimethylolpropane preparation. This involves dissolving the high-boiling fractions and residues obtained in water and catalytically hydrogenating the aqueous solution in the presence of an acidic compound to split formaldehyde-containing acetals. After removal of solids, the aqueous hydrogenated material is then contacted both with basic and with acidic ion exchangers. A trimethylolpropane-enriched product stream is distilled out of the aqueous eluate, and ditrimethylolpropane remains as the distillation residue. In order that ditrimethylolpropane is obtained in sufficient quality in the distillation residue, in the process according to DE 10 2010 033 844 A1, the treatment of the aqueous hydrogenated material both with basic and with acidic ion exchangers is absolutely necessary.
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH:21][C:22]([NH2:24])=[S:23]>>[CH:14]12[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH:15]2[NH:21][C:22]1[S:23][CH:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[C:3](=[O:5])[N:24]=1
Reactant: NC(=S)NC1CC2CCC1C2
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: O=C1N=C(NC2CC3CCC2C3)SC1Cc1ccc(O)cc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid and N-bicyclo[2.2.1]hept-2-ylthiourea according to Method E and C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:19][NH:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[CH:14]1([CH2:19][N:20]([CH2:21][CH3:22])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCNCC1CCCC1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (3.00 g, 15.6 mmol) in toluene (60 mL) was added N-(cyclopentylmethyl)-N-ethylamine (2.70 g, 21.2 mmol) synthesized by the method described in International Patent Publication WO2006/073973 and potassium carbonate (6.50 g, 47.0 mmol), and the mixture was refluxed by heating for 68 hours. The reaction mixture was cooled to room temperature, then added with water, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)benzaldehyde (3.34 g, 71%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].C([O-])([O-])=O.[K+].[K+].Br[CH:22]([CH3:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[CH:22]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])([CH3:24])[CH3:23]
Reactant: COCc1cc(C(=O)OC)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)OC)ccc1OC(C)C
Temperature: 90 °C
Yield: 98.4 %

Procedure:
Methyl 4-hydroxy-3-(methoxymethyl)benzoate (9.50 g; 48.42 mmol; 1 eq.) was dissolved in DMF (142.50 mL). Then K2CO3 (26.77 g; 193.68 mmol; 4 eq.) and 2-bromopropane (18.18 mL; 193.68 mmol; 4 eq.) were added to the reaction mixture. It was heated to 90° C. for 3 hours. The reaction mixture was cooled to RT and diluted with EtOAc. It was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a yellow oil (11.35 g, 98%). 1H NMR (DMSO-d6, 300 MHz) δ 7.95-7.84 (m, 2H), 7.13-7.11 (d, J=8.63 Hz, 1H), 4.81-4.69 (sept, J=6.07 Hz, 1H), 4.39 (s, 2H), 3.81 (s, 3H), 3.36 (s, 3H), 1.31-1.29 (d, J=6.01 Hz, 6H). LC/MS (Method B): 239.2 (M+H)+. HPLC (Method A) Rt 4.25 min (Purity: 95.8%).
Reaction SMILES: CN(C)C=O.[CH3:6][C@@:7]1([CH2:10][N:11]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[N:13]=[C:12]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:9][O:8]1.[N:31]1([C:37]([O:39][CH2:40][CH:41]=[CH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.O>C(OCC)(=O)C>[N+:16]([C:14]1[N:13]=[C:12]([S:19]([C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[N:11]([CH2:10][C@:7]([OH:8])([CH3:6])[CH2:9][N:34]2[CH2:33][CH2:32][N:31]([C:37]([O:39][CH2:40][CH:41]=[CH:42][C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:51])([F:52])[F:50])=[CH:45][CH:44]=3)=[O:38])[CH2:36][CH2:35]2)[CH:15]=1)([O-:18])=[O:17]
Reactant: O=C(OCC=Cc1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 67.4 %

Procedure:
N,N-Dimethylformamide (0.18 ml) solution of (R)-1-(2-methyl-2-oxiranylmethyl)-4-nitro-2-(4-nitrobenzenesulfonyl)imidazole (36 mg) and 3-(4-trifluoromethylphenyl)-2-propenyl piperazin-1-carboxylate (34 mg) was stirred at 60° C. for 1 day. To the reaction mixture was added water and ethyl acetate, the organic layer was taken by separation. The ethyl acetate layer was washed with water and an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfonate. The residue obtained by removal of the solvent by distillation was purified by use of a thin layer chromatography (eluent: dichloromethane/methanol=30/1), there was obtained 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-{3-[4-nitro-2-(4-nitrobenzenesulfonyl)imidazol-1-yl]-2-hydroxy-2-methylpropyl]piperazin-1-carboxylate (45 mg, yield: 67%) as pale yellow amorphous product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[C:5]#[N:6].B>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:6])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(Br)cc(C#N)c1
Agent: B
Solvent: C1CCOC1
Product: COc1cc(Br)cc(CN)c1
Temperature: 70 °C
Yield: 19.2 %

Procedure:
3-Bromo-5-methoxybenzonitrile (13.1 g, 61.8 mmol) was dissolved in dry tetrahydrofuran (100 mL) in a flame-dried flask and cooled in an ice bath. A solution of borane in tetrahydrofuran (100 mL, 0.10 mol, 1.0 M) was slowly added over a period of 30 minutes. After the addition was complete, the mixture was heated at 70° C. overnight and quenched slowly with ice water and Na2CO3 (saturated aqueous solution). After removal of THF, the residue was extracted with large amounts of EtOAc three times. The combined organic layers were washed with water, dried, and concentrated to give the crude product, which was purified by silica gel column chromatography to give the desired product as a white powder (2.57 g, 19%). LCMS for C8H10BrNO (M+H)+: m/z=216.9, 218.9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:27]=[CH:26][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:27]=[CH:26][C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:12][S:13](=[O:15])(=[O:14])[C:9]=3[CH:8]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=S1(=O)N=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCCCBr)cc21
Reactant: C1CCNCC1
Product: O=S1(=O)N=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCCCN3CCCCC3)cc21

Procedure:
According to the method in example 10, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole 1,1-dioxide and Piperidine were converted to yield 6-(4-Piperidin-1-yl-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole 1,1-dioxide, MS: 467 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:15]([C:16]2[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]1)(=[O:10])=[O:9].C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH:12]=[C:13]([CH2:24][NH:25][CH3:26])[CH:14]=[C:15]1[C:16]1[C:17]([C:22]#[N:23])=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:10])=[O:9]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2Cl)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 157 %

Procedure:
To a solution of tert-butyl {[1-[(2-chlorophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (211 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol-water to give the title compound as a white solid (yield 144 mg, 78%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6]1)=[O:4].Cl>C1COCC1.[Li+].[OH-]>[O:10]=[C:8]1[N:7]([CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:9]1
Reactant: COC(=O)C1CC(=O)N(CCCn2cccc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CC(=O)N(CCCn2cccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled solution (0° C.) of 5-oxo-1-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-carboxylic acid methyl ester in THF, 0.2M LiOH is added and RM is stirred for 3 hours gradually warming to room temperature. Reaction mixture is acidified with 1N HCl and product extracted into ethyl acetate. The organic phase is washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to yield 5-oxo-1-(3-pyrrol-1-yl-propyl)-pyrrolidine-3-carboxylic acid.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:33][CH2:34][NH2:35])[CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O.[BH4-].[Na+].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>CO>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]([CH2:33][CH2:34][NH:35][CH2:48][C:44]2[NH:45][CH:46]=[CH:47][N:43]=2)[CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:20]=1
Reactant: NCCN(Cc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1)C1CCCc2cccnc21
Reactant: O=Cc1ncc[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCc2ccc(CN(CCNCc3ncc[nH]3)C3CCCc4cccnc43)cc2)nc1
Reaction time: 17 h
Yield: 40.1 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (333 mg, 0.57 mmol) in dry MeOH (5 mL) was added 2-imidazolecarboxaldehyde (110 mg, 1.14 mmol) and the mixture was stirred for 17 hours. To this solution was added sodium borohydride (110 mg, 2.91 mmol) in one portion and the mixture was stirred for 40 min. The reaction mixture was concentrated in vacuo and partitioned between CH2Cl2 (25 mL) and saturated aqueous sodium bicarbonate (25 mL). The aqueous layer was washed with CH2Cl2 (2×20 mL) and the combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The crude amine was dissolved in THF (10 mL) and protected with di-t-butyldicarbonate (1.0 g, 4.59 mmol). Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 96:4 followed by 9:1) gave the desired product (110 mg, 22%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2].[C:28](Cl)(=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=2)[C:8]=1[Br:26])[CH3:2]
Reactant: CCCCC(=O)Cl
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. solution of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (3.0 g, 6.8 mmol) in chloroform (90 mL) was added valeryl chloride (0.97 mL, 8.2 mmol) and tin (IV) chloride (1.2 mL, 10 mmol). This reaction mixture was allowed to stir at ambient temperature for three hours. It was then refluxed for a total of 17.5 hours. During refluxing was added valeryl chloride (1.94 mL, 16.4 mmol) in two portions and tin (IV) chloride (2.4 mL, 20 mmol) in two portions. The reaction mixture was allowed to cool to ambient temperature. It was then poured into ice water and diluted with additional chloroform. The organic phase was washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered, and solvent evaporated. The residue was then purified several times by flash chromatography using (1) 20%–50% methylene chloride in hexane and 100% methylene chloride, (2) 100% hexane, 1–10% ethyl acetate in hexane and (3) 100% hexane and 5–40% 1,2-dichloroethane in hexane and 100% methylene chloride. Further purification was done by IPLC using 90% acetonitrile (0.1% formic acid) in water as the mobile system. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at 60° C. for 30 minutes yielded [1-bromo-6-(3-pentanoyl-benzo[b]thiophen-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester as a clear, light brown gum (0.0979 g, 2.72%); 1H NMR (400 MHz, DMSO-d6): δ8.23 (d, 1H, J=8.81 Hz), 8.06–8.14 (m, 3H), 7.94–7.96 (m, 1H), 7.72 (dd, 1H, J=8.81 Hz and 1.79 Hz), 7.44–7.52 (m, 3H), 5.11 (s, 2H), 4.19 (q, 2H, J=7.11 Hz), 2.37 (t, 2H, J=7.30 Hz), 1.18–1.20 (m, 2H), 1.38–1.45 (m, 2H), 0.9–1.05 (m, 3H), 0.56 ppm (t, 3H, J=7.37 Hz).