Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:28]1[C:29]([CH3:46])=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([C:37]([CH3:45])([CH3:44])[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O>[C:21]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:28]3[C:29]([CH3:46])=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([C:37]([CH3:44])([CH3:45])[C:38]([O:40][CH:41]([CH3:42])[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH2:13][CH2:12]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
To 10 ml of N,N-dimethylformamide, 0.16 g of a 60% dispersion of sodium hydride in mineral oil and 1.30 g of 4-(diphenylmethoxy)-1-piperidinepropanol were added, followed by stirring at room temperature under reduced pressure for 1 hour. While the reaction mixture was cooled with ice water, 1.31 g of isopropyl 2-(6-chloro-7-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was added, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, ice water was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:5). The desired fraction was collected to yield 582 mg of isopropyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propoxy)-7-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 4 ml of ethanol; 2 ml of a 1 N aqueous solution of sodium hydroxide was added and reaction mixture was heated under reflux for 7 hours. After cooling, reaction mixture was concentrated under reduced pressure followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized by the addition of a small amount of water and ethyl ether, collected by filtration, washed with ethyl ether and dried to yield 0.413 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.Br[C:24]1[N:28]2[N:29]=[CH:30][C:31]([C:33]([F:36])([F:35])[F:34])=[N:32][C:27]2=[N:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:24]2[N:28]3[N:29]=[CH:30][C:31]([C:33]([F:34])([F:35])[F:36])=[N:32][C:27]3=[N:26][CH:25]=2)=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1-c1cccnc1
Yield: 44.2 %

Procedure:
3-[2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine (151 mg, 0.51 mmol) was coupled to 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.09 g, 0.34 mmol) as described in Example 37, step e, using 2 M Na2CO3 (0.51 ml) and tetrakis(triphenylphosphine)palladium(0) (0.019 g) in 1,2-dimethoxyethane (2 ml). The crude residue was purified by flash chromatography (silica gel, 2.5% MeOH/CH2Cl2) and triturated with Et2O to yield the title compound (54 mg, 45%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.47 (2H, m), 7.94-7.97 (1H, m), 8.08-8.12 (1H, m), 8.24 (1H, dd, J 7.0, 2.3 Hz), 8.62 (1H, s), 8.69 (1H, dd, J 4.8, 1.6 Hz), 8.82 (1H, s), 8.88 (1H, s); MS (ES+) m/z 359, 360.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][N:13]=1.[CH2:18]([O:20][C:21](=O)[O:22]CC)[CH3:19]>>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:21]([O:20][CH2:18][CH3:19])=[O:22])=[N:13][CH:14]=1
Reactant: Cc1ccncn1
Reactant: CCOC(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)Cc1ccncn1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 78.1 %

Procedure:
To a flask containing LiHMDS (32 mL, 31.89 mmol, 1.0 M in THF) at −70° C., was slowly added 4-methylpyrimidine (1.0 g, 10.63 mmol). After 5 min of stirring at −70° C., diethylcarbonate (1.93 mL, 15.95 mmol) was added, the reaction was slowly warmed to room temperature and stirred for 4 days. The reaction mixture was quenched by addition of 1 N HCl, neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow oil (1.38 g, 78%). MS 167 (MH+).
Reaction SMILES: C([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[N:9]=1)(=O)C.[ClH:32]>CO>[ClH:32].[ClH:32].[ClH:32].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][CH2:18]2)[N:9]=1
Reactant: CC(=O)Nc1nc(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1

Procedure:
A mixture of 2-acetamido-4-[3-(4-benzhydrylpiperazin-1-yl)propyl]thiazole (1.2 g), methanol (25 ml) and conc. hydrochloric acid (6 ml) was refluxed under heating for 5 hours. After concentration of the reaction mixture, the resultant crystals were recrystallized from a mixture of methanol and diethyl ether to obtain white crystals (1.05 g) of 2-amino-4-[3-(4-benzhydrylpiperazin-1-yl)propyl]thiazole trihydrochloride, mp 205°-215° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15]C.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:15]
Reactant: COc1ccc2c(nnn2CC2CC2)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-Bromo-1-(cyclopropylmethyl)-5-methoxy-1H-benzotriazole (8.0 g, 28 mmol) was dissolved in dichloromethane (200 mL), cooled to 0° C. and treated with boron tribromide (57 mL, 1 M dichloromethane solution, 57 mmol, 2 equiv). The ice bath was removed and the mixture was warmed to ambient temperature and stirred for 4 hours. The mixture was treated slowly with water (exotherm), the pH of the solution was adjusted to pH>10 with 1 N aqueous sodium hydroxide and stirred for an additional 30 minutes. The pH of the mixture was then adjusted to pH 6-7 with ammonium chloride (aqueous saturated) and extracted exhaustively with dichloromethane containing 5% methanol. The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: C1(OC2C=CC=CC=2[N+:14]([O-:16])=[O:15])C=CC=CC=1.O(C1C=CC=CC=1N)C1C=CC=CC=1.[O:31]([C:38]1[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=1[NH:40][C:41](=[O:43])[CH3:42])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[N+]([O-])(O)=O>C(O)(=O)C>[N+:14]([C:46]1[CH:45]=[CH:44][C:39]([NH:40][C:41](=[O:43])[CH3:42])=[C:38]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:47]=1)([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccccc1Oc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccccc1
Agent: Nc1ccccc1Oc1ccccc1
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1Oc1ccccc1
Yield: 60 %

Procedure:
o-Nitrophenyl phenyl ether was reduced catalytically to o-phenoxyaniline, m. 43°-5°, which was acetylated to 2'-phenoxyacetanilide, m. 82°-4°. Yields from both reactions were essentially quantitative. The 2'-phenoxy-acetanilide was dissolved in acetic acid and treated at 60°-80° with red fuming nitric acid to produce a 60-70% yield of 4'-nitro-2'-phenoxy-acetanilide, m. 176°-183°. This was deacetylated by refluxing with methanolic hydrochloric acid to 4-nitro-2-phenoxyaniline, m. 116°-8°. The yield was 99% of theoretical.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([OH:18])=[O:17])[CH2:14]1)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH:13]1[CH2:21][CH2:20][CH2:19][C@H:15]([C:16]([OH:18])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)O)C1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)nipecotic acid (1145 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 16 hours. Triethylamine (708 mg, 7 mmol) was added thereto, and then solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (238 mg, yield of 37%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH:14]=[CH:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:11]=[CH:10]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(OCc1ccccc1)N1C=CC(c2cccc(Cl)c2Cl)C=C1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(c2cccc(Cl)c2Cl)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 95.7 %

Procedure:
To a solution of intermediate 45 (7.0 g, 19.5 mmol) in toluene (150 mL) was added RhCl (PPh3)3 (2.1 g, 2.0 mmol) as a slurry in toluene (50 mL). The reaction was subjected to an atmosphere of H2 at 40 psi and heated to 70° C. After 6 h, the reaction was filtered through silica gel and the silica gel was washed with 1:9 EtOAc/toluene. The filtrate was dissolved in toluene, concentrated in vacuo, and purified by flash chromatography on silica gel column (elution with PE/EtOAc=50:1) to give benzyl 4-(2,3-dichlorophenyl)piperidine-1-carboxylate (intermediate 46) (6.8 g, 96%) as an oil. HPLC: 99%, RT 30843 min. MS (ESI) m/z 386.1 [M+NA]+.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Sm+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[CH3:26][NH:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30].[CH3:39][C:40]1[O:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>O1CCCC1>[CH2:31]([C@@H:29]1[NH:30][C@H:44]([C:43]2[O:46][C:40]([CH3:39])=[CH:41][CH:42]=2)[N:27]([CH3:26])[C:28]1=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sm+3]
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Temperature: 25 °C
Reaction time: 29 h
Yield: 46 %

Procedure:
In an inert atmosphere glovebox, samarium (III) trifluoromethanesulfonate (1.20 g, 2.0 mmol) was added to a flame-dried 250 mL 3-neck round bottom flask fitted with a glass stopper, a septum, and a vacuum hose adapter followed by powdered 4 Å molecular sieves (4.0 g). Following removal from the glove-box, the reaction was placed under nitrogen and (S)-phenylalanine methyl amide (8.91 g, 50 mmol) was added as a solution in 80 mL of tetrahydrofuran immediately followed by freshly distilled (77° C., 14 mmHg, Vigreaux collumn) clear, colorless 5-methylfurfural (3.98 mL, 40 mmol). After stirring for 29 hours at room temperature, the reaction mixture was filtered through a plug of silica with dichloromethane, concentrated and purified by silica gel chromatography (1:1 ethyl acetate:hexanes) to afford the title compound as a clear, colorless oil in 46% yield (4.93 g, 18.2 mmol) and the faster eluting (2R, 5S) isomer as a pale yellow oil in 38% yield (4.10 g, 15.2 mmol). IR (film) 3482, 3325, 2922, 2862, 1695, 1563, 1495, 1477, 1453, 1402, 1326, 1267, 1218, 1098, 1021, 1006, 956.8, 938.9, 791.1, 734.4, 701.5 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 5H, PhH), 6.11 (m, 1H, CHCHCCH3), 5.89 (m, 1H, CHCHCCH3 ), 5.19 (s, 1H, NCHN), 3.79 (dd, J=7.2, 4.5 Hz, 1H, CHCONMe), 3.26 (dd, J=14.4, 4.5 Hz, 1H, one of CH2Ph), 3.09 (dd, J=14.1, 7.5 Hz, 1H, one of CH2Ph), 2.64 (s, 3H, NCH3), 2.21 (s, 3H, ArCH3), 2.10 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 173.9, 153.5, 148.5, 137.3, 129.6, 128.9, 127.0, 111.2, 106.6, 71.3, 60.5, 37.8, 27.4, 14.0; HRMS (CI) exact mass calc'd for (C16H18N2O2) requires m/z 270.1368, found m/z 270.1368. [α]D=−156.5 (g=1.0, CHCl3). The enantiopurity of the catalyst was confirmed (>99% ee) by HPLC analysis (AD column, 5% isopropanol in hexanes, 1 mL/min, 254 nm); (2S, 5S) isomer tr=22.9 min, (2S, 5R) isomer tr=25.7 min. The relative stereochemistry of catalyst 5 was confirmed by NOE studies.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:6]([C:8]([O:10]CC)=O)[N:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][CH3:27].Cl.O>C(O)CO>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:6]([C:8](=[O:10])[NH:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH2:26][CH3:27])[N:7]=1
Reactant: CCOC(=O)c1nc(NC)sc1-c1ccncc1
Reactant: CCN1CCCC1CN
Agent: Cl
Solvent: OCCO
Solvent: O
Product: CCN1CCCC1CNC(=O)c1nc(NC)sc1-c1ccncc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 43.5 %

Procedure:
A mixture of ethyl 2-methylamino-5-(4-pyridyl)-4-thiazolecarboxylate (2.63 g), 2-aminomethyl-1-ethylpyrrolidine (2.6 g) in a mixture of ethyleneglycol (10 ml) and conc. HCl (0.5 ml) was stirred at 80° C. for 6 hours. The reaction mixture was poured into water and the resultant solution was extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on alumina eluting with a mixture of diisopropylether and ethylacetate (1:1) and the fractions containing the desired compound were combined and evaporated in vacuo to give 2-methylamino-5-(4-pyridyl)-4-[(1-ethyl-2-pyrrolidinyl)methylcarbamoyl]thiazole (1.5 g). mp 76°-8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].CC([O-])=O.[Na+].[I:17]Cl.O>C(O)(=O)C>[I:17][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: ClI
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(I)cc([N+](=O)[O-])c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a mixture of 2-methyl-6-nitroaniline (106.5 g, 0.7 mol) and NaOAc (63.2 g, 0.77 mol) in acetic acid (525 mL) was added a solution of ICl (125 g, 0.77 mol) in acetic acid (350 mL). The mixture was heated at 80° C. for 50 min and poured into H2O (2100 mL). After stayed at the room temperature for 16 h, the mixture was filtered to furnish yellow solid that was washed with H2O (3×350 mL). Drying under reduced pressure at 40° C. for 48 h afforded the title compound (191 g, 98%). 1H NMR (CDCl3) δ 2.22 (s, 3H), 6.20 (br s, 2H NH), 7.53 (s, 1H), 8.34 (s, 1H). ESI-MS m/z 279 (MH+).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24]C(=O)C)[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].C[O-].[Na+].[C:31]1([CH3:41])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38].C(OC(=O)C)(=O)C>CO.N1C=CC=CC=1.C(Cl)Cl>[C:1]([NH:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:41])(=[O:39])=[O:38])[O:11][C@@H:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: C=CCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccccc2C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 44 %

Procedure:
A solution of allyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-mannopyranoside, prepared as described above, (6.46 g, 16.7 mmol) and methanolic NaOMe (2 mL; 1M solution) in MeOH (100 mL) was stirred for two hours at room temperature, and neutralized by addition of Dowex 50W-X8 [H+ ]. After the resin was filtered off, the filtrate was concentrated followed by coevaporation with pyridine. A solution of tolylsulfonyl chloride (3.50 g, 18.3 mmol) in pyridine (20 mL) and CH2Cl2 (30 mL) was added dropwise to a cooled solution of the residue in pyridine (30 mL) and CH2Cl2 (50 mL) at 0°-5° C. over 30 minutes, and the mixture was stirred for 10 hours at room temperature then cooled. Acetic anhydride (30 mL) was added to the mixture, and the mixture was stirred for five hours room temperature. The mixture was concentrated, and the residue was chromatographed on silica gel, with toluene EtOAc (1:2), to give allyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-6-O-tolylsulfonyl-α-D-mannopyranoside (3.68 g, 44%);
Reaction SMILES: [C:1]([N:4](C)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22]3[C:21]4[CH:23]=[C:24]([NH:27][C:28](=[O:36])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:35])[CH:25]=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]([C:37]([NH2:39])=[O:38])=[N:15]2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=O)C>[OH-].[Na+].CCO>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:20]2[CH2:19][CH2:18][C:17]3[C:16]([C:37]([NH2:39])=[O:38])=[N:15][N:14]([C:11]4[CH:10]=[CH:9][C:8]([S:5]([NH:4][CH3:1])(=[O:6])=[O:7])=[CH:13][CH:12]=4)[C:22]=3[C:21]=2[CH:23]=1)=[O:36]
Reactant: CC(=O)N(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solid of 1-(4-{[acetyl(methyl)amino]sulfonyl}phenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide was dissolved in 0.5 N solution of NaOH in EtOH (3 mL) and stirred at room temperature for 2 h. A suspension was formed. It was filtered and washed to give the desired compound (29 mg, 53%.) IKK-2 resin IC50≦1 μM.
Reaction SMILES: [C:1](=[O:8])([O-])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Si:9]([O:16][C@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:18]1[NH:22][CH:21]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=2)[CH2:20][CH2:19]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([CH2:23][C@@H:21]2[CH2:20][CH2:19][C@H:18]([C@H:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:22]2[C:1]([O:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:8])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](c1ccccc1)[C@H]1CCC(Cc2ccc(N)nc2)N1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)nc2)CC[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of 121 mg (0.30 mmol) of 5-({(5R)-5-[(R)-([tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]pyrrolidin-2-yl}methyl)pyridin-2-amine in 5 mL of anhydrous THF (from Step B above) was added tert-butyl carbonate (66 mg, 0.30 mmol), followed by TEA (42 μL, 0.30 mmol) and the resulting solution stirred at room temperature under nitrogen atmosphere overnight. The reaction mixture was put directly on a preparative plate (1500 μM) and eluted with 60% ethyl acetate in hexane to afford the title compound (40.3 mg, 27%). LC-MS: C28H43N3O3Si calculated 497.23 found m/z (ES) 498.2 (MH)+ and 398.2 (M-Boc)+.
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:20])([CH3:19])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:21](O)[CH2:22][OH:23].COC(OC)OC>C([O-])(O)=O.[Na+]>[C:3]([SiH2:7][O:8][C:9]([CH3:20])([CH3:19])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2([CH3:17])[O:23][CH2:22][CH2:21][O:18]2)[CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: OCCO
Reactant: CC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)ccn1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccnc(C2(C)OCCO2)c1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-2-yl]-ethanone (1.78 g, 6.71 mmol) in ethylene glycol (7.14 mL, 127.95 mmol) was treated with trimethylorthoformate (1.50 mL, 13.67 mmol) followed by LiBF4 (128 mg, 1.34 mmol). The reaction mixture was heated at 95° C. overnight. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 1:1 hept-EA) gave the title compound as a yellow oil. TLC:rf (1:1 hept-EA)=0.50. LC-MS-conditions 02: tR=0.91 min, [M+H]+=310.40.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:12]([C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[C:43]([I:44])=[CH:42][NH:41][C:40](=[O:45])[N:39]=1.CO.CN(C)CCN(C)C>CC([O-])=O.CC([O-])=O.[Cu+2].O>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:14]1[CH:15]=[CH:16][C:17]([N:41]2[CH:42]=[C:43]([I:44])[C:38]([NH2:37])=[N:39][C:40]2=[O:45])=[CH:18][CH:19]=1)[CH3:13])[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Nc1nc(=O)[nH]cc1I
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: O
Product: CC(c1ccc(-n2cc(I)c(N)nc2=O)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
Cu(OAc)2 (6.02 g, 33.13 mmol, 1.1 eq.) was added to a mixture of [3-(tert-butoxycarbonyl-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-amino)-propyl]-carbamic acid tert-butyl ester (15.18 g, 30.12 mmol, 1 eq.), 4-amino-5-iodo-1H-pyrimidin-2-one (7.85 g, 33.13 mmol, 1.1 eq.), MeOH (400 mL) and H2O (100 mL), followed by N,N,N′,N′-tetramethyl-ethane-1,2-diamine (7.69 g, 66.26 mmol, 2.2 eq.). The Mixture was stirred at RT under air for 48 h (weekend) before concentrated to a volume ca. 130 mL. The residue was diluted with CH2Cl2 (200 mL). The CH2Cl2 extract was washed with brine and concentrated. The crude product was purified by flash chromatography (CH2Cl2:MeOH:NH4OH/35:1:0.01) to afford [3-({1-[4-(4-amino-5-iodo-2-oxo-2H-pyrimidin-1-yl)-phenyl]-ethyl}-tert-butoxycarbonyl-amino)-propyl]-carbamic acid tert-butyl ester (16.06 g, 87%).