Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[OH-].[Na+]>C(Cl)Cl>[F:7][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=[N+]([O-])c1ccc(CCN2CCN(CC(O)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCN2CCN(CC(F)c3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DAST (6.6 μL, 0.050 mmol) was added to 1-(4-nitrophenyl)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethanol (10 mg, 0.025 mmol) in DCM (1 mL) and the resulting mixture was stirred at RT for 72 h. Then 1 N NaOH was added and the mixture was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The crude product was purified by mass directed preparative HPLC to yield 1-[2-fluoro-2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.[Si]([O:46][CH2:47][CH:48]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:48][CH2:47][OH:46])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CCO)CC1
Reaction time: 1 h

Procedure:
To 150 mg (0.28 mmol) of amine 7-2 in MeOH was added 145 mg (0.83 mmol) of (t-butyldimethylsilyloxy) acetaldehyde and several drops of HOAc. After stirring for 1 h, 35 mg (0.55 mmol) of NaCNBH3 was added and the reaction was stirred overnight in a sealed flask. The mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over MgSO4, and concentrated by rotary evaporation. The residue was dissolved in dry EtOAc, saturated with HCl(g) and stirred for 1 h. The reaction was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by reverse phase HPLC, but was not of sufficient purity, so it was then purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 11-1 as a white solid. Data 11-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.6 (m, 2H), 3.0 (m, 2H), 2.9 (s, 3H), 2.5 (m, 2H), 2.2 (m, 2H), 1.8 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H31F2N3O3: 472.2406. Found: 472.2386.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](=[O:37])[O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:16]2
Reactant: O=C(Cl)NN1CCc2ccccc2C1
Reactant: Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NN1CCc2ccccc2C1)Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-5-ol (1.50 g), triethylamine (1.47 g), and chloroform (15 ml), 1,2,3,4-tetrahydroisoquinolin-2-ylcarbamyl chloride (1.55 g) in chloroform (10 ml) was added dropwise with stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred under reflux for 3 hrs, at ambient temperature overnight and poured into dilute sodium bicarbonate solution. The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was recrystallized from ethanol-toluene to give 800 mg (31%) of product, mp 162-163° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N+:23]([C:26]1[N:27]=[C:28]2[N:33]([CH:34]=1)[CH2:32][CH2:31][C@H:30]([CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:39][CH:38]=1)[O:29]2)([O-:25])=[O:24].[F:49][C:50]([F:62])([F:61])[C:51]1[CH:52]=[C:53]([OH:60])[C:54](=[CH:58][CH:59]=1)[C:55](O)=[O:56]>O.CN(C=O)C>[OH:60][C:53]1[CH:52]=[C:51]([C:50]([F:49])([F:61])[F:62])[CH:59]=[CH:58][C:54]=1[C:55]([N:46]1[CH2:47][CH2:48][N:43]([C:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][C@@H:30]3[O:29][C:28]4=[N:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:34][N:33]4[CH2:32][CH2:31]3)=[CH:38][CH:39]=2)[CH2:44][CH2:45]1)=[O:56]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCNCC3)cc1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(C(F)(F)F)cc1O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 11 h
Yield: 68.9 %

Procedure:
1-Hydroxybenzotriazole (0.19 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 g) were added to a DMF solution (5 ml) of (R)-2-nitro-7-(4-piperazin-1-ylphenoxymethyl)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (0.40 g) and 4-(trifluoromethyl)salicylic acid (0.25 g), and the mixture was stirred at room temperature for 11 hours. Water was added to the reaction mixture. After stirring the mixture for a while, the precipitate was collected by filtration. The resulting crude product was purified by silica gel column chromatography (methylene chloride:methanol=90:10) and recrystallized from ethanol-acetone to afford the title compound as a white powder (0.42 g).
Reaction SMILES: [F:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4].[Li]C(C)(C)C.CN([CH:22]=[O:23])C>C(OCC)C>[F:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:22]=[O:23])=[CH:9][CH:8]=1)=[C:3]([F:5])[F:4]
Reactant: CN(C)C=O
Reactant: FC(F)=C(F)Oc1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=Cc1ccc(OC(F)=C(F)F)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Compound 32 intermediates: To a solution of 4-(trifluorovinyloxy)-bromobenzene (9.25 g, 36.6 mmol) in dry diethyl ether (60 mL) at −78° C. was added t-BuLi (23.7 mL, 1.7 M in pentane) dropwise. One hour later, DMF (4.3 mL, 1.5 eq) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Then the reaction mixture was allowed to warm up to room temperature for about 45 min, and quenched by adding water (10 mL). The ethereal layer was collected and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with water twice (50 mL×2), and dried over sodium sulfate. After filtration and evaporation of the solvent, the product was dried in vacuum overnight to give 4-(trifluorovinyloxy)benzaldehyde as yellow oil, which can be used in next step without further purification. 1H NMR (CDCl3): δ 10.18 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C.O>[C:10]1(/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Oc1ccc(/C=C/c2ccccc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(/C=C/c2ccccc2)cc1
Yield: 40.2 %

Procedure:
Prepared according to the method described in Example 24b) from trans-4-hydroxystilbene (2.6 g), (±)-α-(chloromethyl)-3-pyridinepropanol (2.5 g) and sodium hydroxide (0.54 g) in ethanol (50 ml) and water (10 ml) at reflux for 2 hours to give the title compound as a solid (1.84 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([N:24]2[CH2:25][CH2:26][N:27]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:23]2=[O:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)cc3Cl)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)cc3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A 0° C. mixture of 3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150 g, 0.499 mmol) and TEA (0.1 mL, 0.716 mmol) in DCM (5 mL) was treated with a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treated with water, stirred for 10 min, the layers separated and the organic layer dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (176 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 10.57 (s, 1 H), 8.34 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 7.96 (s, 1 H), 7.92 (d, J=2.6 Hz, 1 H), 7.46 (dd, J=8.8, 2.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1 H), 7.19 (d, J=2.4 Hz, 1 H), 6.55 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.76 (m, 8 H), 3.46 (t, J=8.2 Hz, 2 H), 3.37 (t, J=11.7 Hz, 2 H), 1.76-1.66 (m, 2 H), 1.59 (d, J=12.4 Hz, 2H); MS (ESI) m/z: 497.2 (M+H+).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20](Br)[CH:21]=[CH2:22]>C1COCC1>[C:8]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH:21]=[CH2:20])#[N:9]
Reactant: C=CCBr
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (−78° C.) of benzyl cyanide (5.00 g, 42.7 mmol) in anhydrous THF was added LiHMDS (1M in THF, 46.9 mL, 46.9 mmol) dropwise. After 0.5 hour, allyl bromide (5.16 g, 42.6 mmol) was added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature, and the solvent was removed under vacuum. The residual material was purified using silica gel column chromatography eluting with 100% hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.44 (m, 5H), 5.81 (m, 1H), 5.12 (m, 2H), 4.35 (t, J=6.9 Hz, 1H), 2.61 (m, 2H) ppm. ES MS M+1=158.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[C:12](#[N:16])[CH2:13][CH2:14][CH3:15].Cl.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:11][C:12](=[NH:16])[CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCCC#N
Reactant: CCOC(=O)c1cccn1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCC(=N)Nn1cccc1C(=O)OCC
Temperature: 75 °C
Yield: 74.1 %

Procedure:
To a solution of 1-amino-1H-pyrrole-2-carboxylic acid ethyl ester (10.8 g, 70.1 mmol) in 250 mL of dioxane in a sealed tube at room temperature was added butyronitrile (61 mL, 700 mmol) followed by 4 N HCl in dioxane (70 mL, 280 mmol). The tube was flushed with Ar, sealed, and heated at 75° C. for 14 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo and then diluted with 240 mL of dioxane. Triethylamine (78 mL, 560 mmol) was added and the reaction was heated at 75° C. for 6 h. After cooling to room temperature, the reaction was concentrated in vacuo to give the crude product. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:1) gave the title compound as a light brown solid (11.6 g, 74%): 1H NMR (CDCl3) δ 6.80 (q, 1H, J=1.96 Hz), 6.59 (t, 1H, J=2.16 Hz), 6.03 (q, 1H, J=2.6 Hz), 4.54 (brs, 2H), 4.11 (q, 2H, J=7.12 Hz), 2.27 (t, 2H, J=7.96 Hz), 1.66 (hex, 2H, J=7.72 Hz), 1.19 (t, 3H, J=7.12 Hz), 0.95 (t, 3H, J=7.32 Hz); 13C NMR (CDCl3) δ 166.7, 160.2, 124.8, 119.8, 116.0, 107.2, 60.0, 35.6, 20.6, 14.9, 14.1; MS (ESI+) 224.10 (M++H).
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.C([Mg]Cl)(C)C.C(OCC)(=O)C.[C:17]([OH:22])(=[O:21])[CH:18]([CH3:20])[CH3:19]>O>[C:17]([OH:22])(=[O:21])[C:18]1[CH:20]=[CH:5][CH:1]=[CH:2][CH:19]=1
Reactant: CC(C)C(=O)O
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To compound (B-2) (14.16 g, 61.0 mmol) in a second dry round bottom flask under N2 is added 70 mL of dry THF. The mixture is cooled to about −10° C. To the cold mixture is slowly added isopropyl magnesium chloride (63.3 ml, 2 M, 127 mmol). The resulting mixture is then stirred at −10° C. for about 20 min. Then, this mixture is slowly cannulated drop wise into the flask containing the (B-1) reaction while maintaining the temperature at −20° C. After addition is complete, the reaction is slowly warmed to RT and stirred at RT for about 1.6 hours. The reaction mixture is then cooled to −10° C. and quickly cannulated to another flask containing 15 mL of ethyl acetate and 10 mL of isobutyric acid at −10° C. under N2. After stirring for about 5 minutes, 10 mL of water is rapidly added. The cooling bath is removed, and the reaction mixture is stirred for 10 minutes at RT. The mixture is transferred to a separation funnel, and water (200 mL) is added. The water layer is extracted with EtOAc (3×400 mL). The aqueous layer is then acidified with HCl (2M) to pH 3, and is extracted with EtOAc (3×500 mL), dried over sodium sulfate and concentrated in vacuo. The resulting material is purified by silica gel column chromatography using 0-10% MeOH in DCM to afford benzoic acid (B-3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.28 mmol) in 50 mL of THF (distilled from Na-benzophenone) is cooled to 0+ C. and sodium borohydride (1.9 g, 51.4 mmol) is added portionwise. The reaction is stirred at 0° C. for 2 h, then warmed to RT, and after 2 h, quenched with water (5 mL). The solvent is evaporated and the aqueous residue is acidified by addition of aqueous 6N HCl. The product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-fluorobenzenesulfinic acid: NMR (DMSO-d6) 7.12 (app t, 2H, J=8.3), 7.5 (dd, 2H, J=8.3, 6); ESI-MS 159 [M−1]−.
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[O:20][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([Si:22]([CH2:25][CH3:26])([CH2:27][CH3:28])[CH2:23][CH3:24])[O:20][CH:21]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC[Si](CC)(CC)c1cc(CN)co1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)NCc1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Dodecanoyl chloride (109 mg, 0.49 mmol) was added to a solution of 4-aminomethyl-2-triethylsilylfuran (Compound 29, 70 mg, 0.33 mmol) and triethylamine (69 microliter, 0.49 mmol) in tetrahydrofuran (3 ml) at room temperature. After stirring at room temperature overnight (ca. 15 hours), most of the solvent was evaporated and the residue was purified by chromatography on preparative silica thin layer plates (developed with 50% ethyl ether/hexane) to give the title amide as a colorless oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][NH2:13].[S:14](N)([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][NH:13][S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NS(N)(=O)=O
Reactant: NCCC1COc2ccccc2O1
Solvent: C1COCCO1
Product: NS(=O)(=O)NCCC1COc2ccccc2O1

Procedure:
The crude 2-(2,3 dihydrobenzo[1,4]dioxin-2-yl)ethylamine in dioxane (100 mL) was combined with sulfamide (3.0 g, 31 mmol) and heated to reflux for 2 h. The solution was cooled and evaporated in vacuo to yield an orange solid, which was purified by column chromatography (DCM:MeOH—10:1) to yield a white solid. The solid was re-crystallized from DCM to yield the title compound as a solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].[CH2:20]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]I)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C.O1CCCC1>[C:1]([NH:4][C:5]([CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(CCI)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1

Procedure:
To a solution of diethyl acetamidomalonate (277 g) and sodium ethylate (86.6 g) in anhydrous ethanol (850 ml) is added a solution of 2-(4-octylphenyl)ethyl iodide (7) (146 g) in anhydrous tetrahydrofuran (533 ml), and the mixture is refluxed under heating for 6 hr. The reaction mixture is concentrated and partitioned between water and hexane, and the hexane layer is washed three times with water. The obtained hexane layer is dried over anhydrous magnesium sulfate and concentrated. The residue is recrystallized from hexane to give the title compound (8) as colorless crystals. The resulting Compound (8) has the same physico-chemical characteristics as indicated in Example 7.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[N:34]=[CH:35][N:36]([CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])[CH:37]=2)[CH:28]=1>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:36]5[CH:37]=[C:33]([C:29]6[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=6)[N:34]=[CH:35]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: NCCCCn1cnc(-c2cccnc2)c1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCCCn4cnc(-c5cccnc5)c4)cc3)cc2s1)C1CC1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (50 mg, 127.4 μmol) and 4-(4-pyrid-3-ylimidazol-1-yl)butylamine (110.2 mg, 0.51 mmol) in 0.5 ml of NMP is heated at 150° C. by microwave for 8 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 36 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclo-propanecarbonylamino)benzothiazol-6-yl ester (beige-colored solid).
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])=[CH:9][CH:8]=1)=[O:5].[OH:21]S(O)(=O)=O>>[O:20]=[C:16]1[N:15]([CH2:14][CH2:13][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[NH:6][C:4](=[O:5])[C:3]3=[O:21])[CH2:19][CH2:18][O:17]1
Reactant: O=C(C=NO)Nc1ccc(CCN2CCOC2=O)cc1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2ccc(CCN3CCOC3=O)cc2C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Concentrated H2SO4 (20 ml) is heated to 50° C. The compound obtained in Step D (25.24 mmoles) is added slowly in solid form, maintaining the temperature between 60 and 70° C. The reaction mixture is then stirred for one hour at 80° C. The mixture is brought to ambient temperature and then poured onto 200 g of crushed ice. After 30 minutes, the red solid formed is filtered off and washed intensively with ice-cold water; it is then dried in vacuo in the presence of P2O5 and at 40° C. overnight to yield the title product, which is used directly in the next Step.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11]CCCC.[CH2:28]([O:35][CH2:36][CH2:37]CN1C2C(=CC=CC=2)C(O)(C2C(O)=CC3OCOC=3C=2)C1=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][CH:36]([CH3:37])[CH2:11][N:6]1[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH:4]([C:17]2[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:5]1=[O:16])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1N(CCCOCc2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CC(CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21)OCc1ccccc1

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 1-[3-(benzyloxy)propyl]-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (92%): 1H NMR (300 MHz, CDCl3) δ7.42-6.95 (m, 9H), 6.56 (s, 1H), 6.24 (s, 1H), 5.86 (ABq, 1H), 5.81 (ABq, 1H), 4.99 (s, 1H), 4.42 (s, 2H), 3.91-3.76 (m, 2H), 3.46 (t, 2H), 2.03-1.93 (m, 2H); MS (ES+) m/z 418.3 (M+1).