Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:47])[C@H:7]([N:23]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]2[O:44][CH2:45][O:46][C:40]=2[CH:39]=1)[S:24]([C:27]1[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[CH3:36])(=[O:26])=[O:25])[CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:45]1[O:44][C:41]2[CH:42]=[CH:43][C:38]([CH2:37][N:23]([S:24]([C:27]3[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=3[CH3:36])(=[O:25])=[O:26])[C@H:7]([CH2:8][NH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]3[CH:19]=[CH:20][CH:21]=[CH:22]3)=[O:11])[C:6]([OH:47])=[O:5])=[CH:39][C:40]=2[O:46]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)O)c(C)c1
Reaction time: 1.5 h
Yield: 113.8 %

Procedure:
A solution of tert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionate (915 mg, 1.3 mmol) in 20% trifluoracetic acid-methylene chloride (15 ml) was stirred for 1 hour. Extra trifluoroacetic acid (0.5 ml) was added and stirring continued for 1.5 hours. The material was then condensed on the rotary evaporator and the residue was taken up in toluene (40 ml) and again condensed. This procedure was repeated twice (2×40 ml toluene, to remove traces of trifluoracetic acid) to provide 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionic acid as a golden tan solid (896 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][CH2:30][OH:31])[C:14]3=[O:32])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:31][CH2:30][CH2:29][CH2:28][C@H:15]1[CH2:16][C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:34][CH:33]=3)=[CH:12][CH:11]=2)[C:14]1=[O:32])(=[O:38])=[O:37]
Reactant: O=C1[C@@H](CCCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one (34 mg, 0.070 mmol) in DCM (3 mL) at 0° C. is added MsCl (50 μL) and TEA (100 μL). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give 3-{(3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-2-oxopyrrolidin-3-yl}propyl methanesulfonate (39.1 mg, 99%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:8][C:9]([S:10]([CH3:12])=O)=[C:5]2[C:4](=[O:20])[CH2:3]1.[OH-].[Na+].SC[CH2:26][OH:27]>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[CH2:19][C:6]2=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[S:8][C:9]([S:10][CH2:12][CH2:26][OH:27])=[C:5]2[C:4](=[O:20])[CH2:3]1
Reactant: OCCS
Reactant: CS(=O)c1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2c(SCCO)sc(-c3ccccn3)c2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
6,6-Dimethyl-3-methanesulphinyl-1-(pyrid-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (160 mg, 0.5 mmol) was suspended in ethanol (5 mL) and 4M sodium hydroxide solution (138 μL, 0.55 mmol) was added. 2-Mercaptoethanol (43 mg, 0.55 mmol) was added and the suspension was stirred at 20° C. for 2 h. After this time, further 2-mercaptoethanol (10 mg, 0.12 mmol) and 4M sodium hydroxide solution (35 μL, 0.12 mmol) was added and the mixture stirred for a further 2 h. The mixture was then diluted with ethyl acetate and 1M HCL (1 mL) was added. The ethyl acetate layer was washed with water, dried (Na2SO4), then evaporated to dryness. The residue was purified by chromatographed on silica gel, eluting with ethyl acetate, to yield the title compound as a pale yellow solid (58 mg, 36%). mp 175-177° C. Found: C, 61.18; H, 5.62; N, 3.97%. C17H19NO2S2 requires: C, 61.26; H, 5.70; N, 4.20%. 1HNMR (360 MHz, CDCl3)δ 1.08 (6H, s), 2.45 (2H, s), 2.93 (2H, s), 3.33 (2H, t, J=7.2 Hz), 3.98-4.02 (2H, m), 7.16-7.20 (1H, m), 7.46-7.49 (1H, m), 7.72-7.76 (1H, m), 8.64-8.66 (1H, m). MS (ES+) 334 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32](O)(=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:13][C@@H:14]([C:29](=[O:31])[NH2:30])[CH2:15][CH2:16][C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:18])=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CCC(=O)N[C@@H](CCCCN)C(=O)O)C(N)=O
Product: CCCCCC(=O)NCCCC[C@H](NC(=O)CC[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(N)=O)C(=O)O

Procedure:
In the same manner as described in Example 1-(2), 1.10 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)lysine and 0.69 g of an N-hydroxy-5-norbornene-2,3-dicarboxyimide active ester of hexanoic acid were reacted to obtain 1.17 g of Nα -(t-butyloxycarbonyl-alanyl-D-isoglutaminyl)-Nε -hexanoyl-lysine; melting point: 116° to 118° C. (decomp.); [α]D25 -12.1° (c 1.1, methanol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:33])=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15]([Cl:33])=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)O)c(=O)n1-c1ccc(C#N)cc1
Reactant: O=S(Cl)Cl
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.6 g of 1-(4-cyanophenyl)-4-hydroxycarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one and 16 ml of thionyl chloride was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was crystallized in a liquid mixture of n-hexane-toluene to give 1.65 g of the desired compound as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][CH:40]4[CH2:41][CH2:42][S:37][CH2:38][CH2:39]4)=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCSCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(O)cc3c2C)C2CCCCC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC4CCSCC4)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.3 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.50 g) synthesized in Example A155(1) was dissolved in tetrahydrofuran (10 mL), and tetrahydrothiopyran-4-ol (142 mg), tributylphosphine (0.45 mL) and 1,1′-(azodicarbonyl)dipiperidine (0.45 g) were added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 hr, then hexane (10 mL) was added to the mixture, and the precipitate was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (0.14 g, 23%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]2=[N:12][N:11]=1)=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][CH:16]=3)([O:6]CC)=[O:5])[CH3:2]>C(O)C.[OH-].[Na+]>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]2=[N:12][N:11]=1)=[CH:19][C:18]([C:24]([F:26])([F:27])[F:25])=[CH:17][CH:16]=3)([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(O)Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n12
Yield: 64.4 %

Procedure:
A solution of 1-[(diethoxyphosphoryl)methyl]-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (750 mg, 1.85 mmol) in 20 ml of ethanol and 20 ml of 10% sodium hydroxide was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in water and applied to an ion-exchange column (Amberlite IR-120, H+ -form) prewashed with 4M hydrochloric acid followed by deionized water. Elution with deionized water gave an acidic eluate, which was concentrated in vacuo to give 448 mg (65%) of the title compound, m.p. 276°-280° C. (from water); 1H-NMR (DMSO-d6): δ 1.16 (t, 3H), 3.98 (quint, 2H), 4.08 (d, 2H), 7.64 (d, 1H), 7.68 (s, 1H), 8.42 (d, 1H), 12.28 (s, 1H), MS: m/e 377 (MH+).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[CH2:7]([SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>>[CH3:1][C:2]([OH:6])(/[CH:4]=[CH:5]/[Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH3:10])[CH3:3]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(C)(C)O
Product: CCCC[Sn](/C=C/C(C)(C)O)(CCCC)CCCC
Temperature: 80 °C

Procedure:
A mixture of 2-methylbut-3-yn-2-ol (2.00 g), tributyltinhydride (10.5 g) and αα′-azobisisobutyronitrile (190 mg) was heated (neat) to 80° C. under stirring. After 4 h the reaction mixture was cooled to room temperature. The crude product was purified by chromatography eluting with petroleum ether/Et2O 7:1 to afford the title compound as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:17]\[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[C:4]([Cl:10])[CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C\c1ccc(Br)cc1Cl
Temperature: 37 °C
Reaction time: 78 h

Procedure:
A suspension of 4-bromo-2-chlorobenzaldehyde (1150 mg, 5240 μmol), (r)-(+)-2-methyl-2-propanesulfinamide (1588 mg, 13100 μmol), copper(ii) sulfate (696.4 μl, 15720 μmol) in DCM (10 mL) was stirred at 37° C. for 78 h. Reaction filtered through Celite, and solid washed repeatedly with DCM. Filtrate concentrated then purified on silica (80 g) eluting product with 0>30% of EtOAc/Hex. MS (ESI pos. ion) m/z: 322/324 (MH+). Calc'd exact mass for C11H13BrClNOS: 321/323.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27]>[OH-].[OH-].[Pd+2].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1F

Procedure:
The title compound was prepared from (E)-ethyl 3-(2-fluoro-4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (CB13) using palladium hydroxide on carbon and ethanol as solvent; isolated as a tan solid (0.871 g, 67%, 85% pure): 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.92-7.82 (m, 2H), 7.79 (d, J=9.0 Hz, 2H), 7.43-7.36 (m, 2H), 7.32 (t, J=7.8 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 2.67 (dd, J=8.2, 7.2 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ (376 MHz, CDCl3) δ −58.03, −117.98; ESIMS m/z 423 ([M]+).
Reaction SMILES: [C:1]1([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl[C:15]1[N:24]=[C:23]([NH2:25])[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=1>>[NH2:25][C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[CH:21]=2)[N:16]=[C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)=[O:7])[CH2:13][CH2:12]2)[N:24]=1
Reactant: O=C(C1=CCCC1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Product: COc1cc2nc(N3CCN(C(=O)C4=CCCC4)CC3)nc(N)c2cc1OC

Procedure:
N-(1-cyclopenten-1-ylcarbonyl)piperazine (1.8 g., 0.01 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.4 g., 0.01 mole) are reacted according to the procedure of Example 127(a). The isolated product crystallized from methanol affords analytically pure 4-amino-2-[4-(1-cyclopenten-1-ylcarbonyl)piperazinyl]-6,7-dimethoxyquinazoline, m.p. 256.5°-258.0° C. (corr.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([CH3:32])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])=[CH:15][CH:14]=1>ClCCl>[CH3:8][CH:9]([CH3:32])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:20][C:21]([OH:23])=[O:22])=[CH:17][CH:18]=1
Reactant: CC(C)CCOc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCOc1ccc(N(CC(=O)O)S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 16.8 %

Procedure:
Trifluoroacetic acid (2.5 mL) was added in one portion to a stirred solution of 1,1-dimethylethyl N-{4-[(3-methylbutyl)oxy]phenyl}-N-(methylsulfonyl)glycinate (intermediate 7, 140 mg, 0.378 mmol) in dichloromethane (5 mL) at room temperature under an atmosphere of nitrogen. The resulting mixture was stirred for 3 h then the volatiles evaporated. A portion of the crude orange product was purified by reverse phase mass directed preparative HPLC to give the title compound as a white solid (20 mg). LC/MS: 3.22 min; z/e 333, calcd (M+18) 333. 1H NMR (400 MHz; MeOD): 0.95 (6H), 1.75 (2H), 1.85 (1H), 3.05 (3H), 4.05 (2H), 4.35 (2H), 6.90 (2H), 7.40 (2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:8])=[O:7].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19]Cl)[CH3:16]>>[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][N:8]=[S:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])[CH3:16]
Reactant: CCN(CC)CCCl
Reactant: N=S(=O)(c1ccccc1)c1ccco1
Product: CCN(CC)CCN=S(=O)(c1ccccc1)c1ccco1
Yield: 48 %

Procedure:
In a manner analogous to that described in Example 1, Stage 3, from S-(2-furyl)-S-phenyl-sulphoximide and 2-diethylaminoethyl chloride, there is obtained N-(2-diethylaminoethyl-S-(2-furyl)-S-phenyl-sulphoximide in a yield of 48% of theory. The corresponding fumarate, after recrystallisation from ethyl acetate/isopropanol, melts at 133° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH:17]=[O:18])[CH:14]=[N:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[C:1]([N:5]1[C:9]([NH:10][C:11]2[N:16]=[C:15]([CH2:17][OH:18])[CH:14]=[N:13][CH:12]=2)=[CH:8][CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nccc1Nc1cncc(C=O)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)n1nccc1Nc1cncc(CO)n1
Reaction time: 1 h

Procedure:
To a solution of 14.99 g of 6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyrazin-2-carbaldehyde in 235 ml of ethanol was added 2.31 g of sodium borohydride under cooling with ice, followed by stirring the reaction mixture for 1 hour. After slowly adding 61 ml of 1M hydrochloric acid to the reaction mixture under cooling with ice, ethanol was concentrated in vacuo. The obtained residue was diluted with water, and extracted with chloroform. The resulting chloroform solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=20/1) to give the title compound as a brown solid.
Reaction SMILES: [OH:1][CH:2]1[O:10][C@H](CO)[C@@H:7](O)[C@H:5](O)[C@H:3]1[NH2:4].[C:13]([O-:16])([OH:15])=O.[Na+]>[Fe]>[NH2:4][C@H:3]([C:2]([OH:10])=[O:1])[CH2:5][CH2:7][C:13](=[O:16])[OH:15]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C([O-])O
Agent: [Fe]
Agent: [Na+]
Product: N[C@@H](CCC(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
MION-47 and amino-CLIO (25-35 nm) were prepared as described elsewhere. D-Glucose, D-(+)-Glucosamine hydrochloride, succinic anhydride, Concanavalin A (ConA) and Sephadex G-25 were from Sigma Aldrich Co. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and sulfo-N-hydroxysuccinimide (sulfo-NHS) were from Pierce (Rockford, Ill.). To synthesize a glucose-functionalized nanoparticle (Glu-CLIO), NH2-CLIO was first converted to a carboxylic group functionalized nanoparticle, followed by coupling of 2-amino-glucose using a water-soluble carbodiimide. To obtain a carboxylic functionalized CLIO, 2.0 mg succinic anhydride was added into 200 uL NH2-CLIO (10 mg Fe/mL, 42 NH2 per 2064 Fe) with 300 uL (0.1 M) NaHCO3 buffer, pH 8.5. The mixture was incubated at room temperature for two hours and succinic acid removed using a Sephadex G-25 column eluted with MES buffer (0.5 M NaCl, 0.05 M MES), pH 6.0. To conjugate 2-amino-glucose to carboxy functionalized CLIO (CLIO-COOH), 2 mg EDC and 2 mg sulfo-NHS were added into 500 uL CLIO-COOH (mg Fe/mL) in MES buffer, pH 6.0. The mixture was allowed to react for two hours at room temperature and purified by Sephadex G-25 column eluted with PBS buffer at pH 7.4. Subsequently 2 mg Glucosamine was added into above solution and the mixture reacted for one hour at room temperature. Unreacted glucosamine was removed with Sephadex G-25 in PBS.
Reaction SMILES: F[C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.N[C:15]1C=CC=C(C)C=1C(O)=O>>[CH3:15][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Product: Cc1cccc2[nH]c(=O)oc(=O)c12

Procedure:
Prepared analogously to Compound 27E replacing 2-amino-6-fluorobenzoic acid with 2-amino-6-methylbenzoic acid. 1H NMR (DMSO-d6, 500 MHz) δ 2.32 (s, 3H), 7.09 (m, 1H), 7.21-7.25 (m, 1H), 7.51-7.61 (m, 1H), 11.65 (br.s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:13]Br>C(OCC)C.O.[Cl-].[Al+3].[Cl-].[Cl-]>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH2:2][Br:13])=[CH:5][CH:6]=1)(=[O:12])[CH3:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CC(=O)c1ccc(C(=O)CBr)cc1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a stirred solution of 1,4-diacetylbenzene (5.3 g, 32.7 mmol), aluminum chloride (0.05 g, 0.38 mmol) in diethylether (50 ml) was added bromine (5.3 g, 32.7 mmol) dropwise over 20 minutes. The mixture was stirred for 30 minutes, and diluted with water. The whole was concentrated to remove diethylether, and the aqueous suspension was filtered to give 7.0 g of white solid. The compound was used for next reaction without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>ClCCl>[CH3:17][CH:16]([CH3:18])[C:15]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:19]
Reactant: NCCCC(=O)O
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane (700 ml) were added 54 ml (407 mMol) triethylamine and the reaction mixture was stirred at room temperature for 10 minutes. To this mixture was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in dichloromethane (300 ml) dropwise and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 1N sodium hydroxide and stirred for 30 minutes. This solution was then poured into diethyl ether, diluted with water and the phases separated. The aqueous phase was acidified with hydrochloric acid and then extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give an oil. Bulb to bulb distillation (0.05 mm Hg, pot temperature=235° C.) gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:43])[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[NH:23][C:24]2([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[C:32]3[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:34])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:43])=[C:17]([NH:23][C:24]2([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[C:32]3[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:34])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(Br)cc2NC2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1ccc(Br)cc1NC1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of rac-4-{4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-benzoylamino}-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.044 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred for 3 h, concentrated. The residue was dissolved in DCM, the resulting solution was washed with Na2CO3 solution, dried with Na2SO4, concentrated to give 22 mg rac-4-Bromo-2-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-ylamino]-N-piperidin-4-yl-benzamide. MS: [M+H]+=587