Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].ClCCl.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][C:8]([C:7]1[CH:6]=[C:5]([S:2]([NH:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:25]=2)(=[O:4])=[O:3])[CH:19]=[CH:18][CH:17]=1)=[O:9]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.1 %

Procedure:
To a mixture of 2.0 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate and 40 mL of dichloromethane were added 5.0 mL of pyridine, 1.0 g of methyl 6-aminonicotinate, and 761 mg of N,N-dimethylpyridin-4-amine, followed by stirring at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and then to the residue was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to obtain 1.8 g of methyl 6-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}nicotinate as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:23]([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[Cl:1][C:2]1[C:3]([CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Cl
Temperature: 110 °C
Reaction time: 72 h

Procedure:
5,6-dichloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 43.2, 500 mg, 1.424 mmol), trimethylboroxime (179 mg, 1.424 mmol), Pd(PPh3)4, (165 mg, 0.142 mmol), K2CO3 (295 mg, 2.136 mmol) and dioxane (4069 μL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 110° C. for 72 h. The RM was filtered through a pad of Celite®, which was washed with EtOAc. The combined filtrates were evaporated to dryness under reduced pressure and the residue was purified by flash chromatography (Silica gel column, 24 g, cyclohexane/EtOAc-EtOH (9:1)+0.1% NH4OH, gradient from 5% to 25% EtOAc-EtOH (9:1)+0.1% NH4OH) and recrystallized from cyclohexane/EtOAc to afford the title compound as a light yellow solid. UPLC-MS (Condition 1) tR=2.76 min, m/z=331.0 [M+H]+, m/z=329.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3H) 7.39 (d, J=9.05 Hz, 2H) 7.87 (d, J=9.05 Hz, 2H) 8.38 (d, J=1.71 Hz, 1H) 8.94 (d, J=1.96 Hz, 1H) 10.60 (s, 1H).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].[S].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.Cl>C(O)C.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]2[S:10][C:25]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[N:24][C:16]=2[CH:17]=1)([O-:23])=[O:22]
Reactant: [S-2]
Reactant: Cc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [S]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Sodium sulfide nonahydrate (875 mg, 3.78 mmol) and sulfur (120 mg, 3.78 mmol) were heated until molten. The water was driven off with nitrogen to give a solid. The obtained solid was added in portions to N-(2-chloro-5-nitrophenyl)-4-methylbenzamide (1 g, 3.44 mmol) in ethanol (20 mL) at 85° C. The solution was stirred at 85° C. for 3 h. After cooling, 2M aqueous HCl was added, and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 10:90 v/v to afford 400 mg (43%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=3[CH:5]=[N:6][CH:7]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: CCC(=O)NC1CCc2c(Br)cncc21
Reactant: Cc1cc(B(O)O)ccc1F
Product: CCC(=O)NC1CCc2c(-c3ccc(F)c(C)c3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)propionamide (intermediate A-4) was reacted with 4-fluoro-3-methylphenylboronic acid to give the title compound as grey solid in 86% yield. MS: 299.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH3:1][CH:2]([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: OB(O)c1cccnc1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCC(C)S(N)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCC(C)S(N)(=O)=O
Yield: 27.8 %

Procedure:
Methyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.47 g, 0.97 mmol) was coupled with pyridine-3-boronic acid (0.14 g, 1.2 mmol) according to the methods described in Part J of Example 1 and Part H of Example 370. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) and then recrystallized from methanol, isolated by filtration, and dried for 5 days under high vacuum at 100-140° C. to provide 0.13 g of methyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 191-192° C.
Reaction SMILES: [CH2:1]([C:8]([OH:18])([C:15]([OH:17])=[O:16])[CH2:9][C:10](=O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:26])C1C=CC=CC=1>CO.[C].[Pd]>[NH2:26][C@H:10]([CH2:9][C@@:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:18])[C:15]([OH:17])=[O:16])[C:11]([OH:13])=[O:12].[NH2:26][C@@H:10]([CH2:9][C@@:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:18])[C:15]([OH:17])=[O:16])[C:11]([OH:13])=[O:12]
Reactant: NCc1ccccc1
Reactant: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CO
Product: N[C@@H](C[C@](O)(Cc1ccccc1)C(=O)O)C(=O)O
Product: N[C@H](C[C@](O)(Cc1ccccc1)C(=O)O)C(=O)O

Procedure:
0.13 g (0.52 mmol) of 4-benzyl-4-hydroxy-2-ketoglutaric acid and 0.11 ml (1.0 mmol) of benzylamine were dissolved in 5 ml of methanol, to which 0.1 g of 5% palladium carbon (50% hydrous product) was added, for reaction under hydrogen atmosphere at ambient temperature and atmospheric pressure. Two days later, the catalyst was filtered off, and the reaction solution was concentrated to dryness, to obtain 0.03 g (0.12 mmol) of (2S, 4S)/(2R, 4R)-2-amino-4-benzyl-4-hydroxyglutaric acid and 0.06 g (0.24 mmol) of (2R, 4S)/(2S, 4R)-2-amino-4-benzyl-4-hydroxyglutaric acid as a mixture.
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5]C(=O)C=[CH:2]1.S(=O)(=O)(O)O.[OH2:14].C([O:18][C:19](=[O:21])[CH3:20])(=O)C>>[CH3:2][C:1]([CH2:6][C:5]([CH2:20][C:19]([OH:18])=[O:21])=[O:14])=[O:8]
Reactant: O=C1C=CC(=O)C=C1
Reactant: O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 32 °C
Reaction time: 44 h

Procedure:
The benzoquinone (4) (2 g) was dissolved in acetic anhydride (5 ml) and concentrated sulfuric acid (0.5 ml) was added slowly. The mixture was stirred in the dark at a temperature of 32° C. and monitored by HPLC. After a period of time of 44 h, the reaction was worked up by pouring into iced water (50 ml) and extracting with dichloromethane (3×20 ml). The combined organics were washed with bicarbonate solution (3×50 ml), water (100 ml), dried (MgSO4), filtered and evaporated to yield triacetate (5) which solidified (1.78 g).
Reaction SMILES: CS[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]3[CH2:11][CH:12]([C:23]4[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=4[F:31])[CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][N:8]3[C:7]=2[CH:32]=1.O[O:34][S:35]([O-:37])=O.[K+].[CH3:39]O>C(OCC)(=O)C>[C:18]([O:17][C:16](=[O:22])[NH:15][C@H:13]1[CH2:14][N:8]2[C:9](=[N:10][C:6]3[CH:5]=[CH:4][C:3]([S:35]([CH3:39])(=[O:37])=[O:34])=[CH:32][C:7]=32)[CH2:11][C@@H:12]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1[F:31])([CH3:19])([CH3:20])[CH3:21]
Reactant: O=S([O-])OO
Reactant: CSc1ccc2nc3n(c2c1)CC(NC(=O)OC(C)(C)C)C(c1cc(F)c(F)cc1F)C3
Reactant: CO
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1Cn2c(nc3ccc(S(C)(=O)=O)cc32)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing 41 mg (0.088 mmol) of the product from Step B in 6.0 mL of methanol was added 160 mg (0.26 mmol) of oxone as a 2 mL aqueous solution. The reaction mixture was stirred at ambient temperature for 16 h, then diluted with 50 mL of ethyl acetate and washed sequentially with 0.5N aqueous sodium bicarbonate solution and saturated aqueous brine (50 mL each), dried over sodium sulfate, filtered and the solvent evaporated in vacuo to yield a crude solid. Purification by reverse phase HPLC (YMC Pro-C18 column, gradient elution, 5% to 80% acetonitrile/water with 0.1% TFA) afforded the pure title compound as a white foam. LC/MS 496.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c([N+](=O)[O-])cc2c1=O
Temperature: 95 °C
Yield: 54 %

Procedure:
A mixture of 9.3 g (0.03 mol) of 7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid and 12.9 g (0.15 mol) of piperazine is warmed at 120° C. in 60 ml of dimethylsulphoxide for 15 minutes. After a short time, a precipitate separates out from the hot solution. The mixture is concentrated under a high vacuum, the residue is stirred with 30 ml of water and the mixture is heated again at 95° C. for 30 minutes. The mixture is brought to pH 8 with 2N hydrochloric acid, and the precipitate is filtered off with suction and washed with water and methanol. 5.8 g (54% of theory) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 296°-298° C. are isolated.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22](C=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH3:36][O:37][CH2:38][CH2:39][NH:40][CH3:41].[C:42](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:41][N:40]([CH3:42])[CH2:39][CH2:38][O:37][CH3:36])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: CNCCOC
Reactant: CC(=O)O
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: COCCN(C)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 59.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (856 mg, 1.71 mmol) was dissolved in acetonitrile (17.0 mL), and the solution was treated with (2-methoxyethyl)methylamine (2.76 mL, 25.7 mmol), acetic acid (1.47 mL, 25.7 mmol) and sodium triacetoxyborohydride (1.81 g, 8.56 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-[N-(2-methoxyethyl)methylaminomethyl]indol-2-yl]isoindolinone (586 mg, 60%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][NH:6][S:5]1(=[O:10])=[O:9].Br[C:12]1[N:17]=[C:16]([CH3:18])[C:15]([Br:19])=[CH:14][N:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CN(C=O)C.O>[Br:19][C:15]1[C:16]([CH3:18])=[N:17][C:12]([N:6]2[CH2:7][CH2:8][N:4]([CH3:3])[S:5]2(=[O:10])=[O:9])=[N:13][CH:14]=1
Reactant: CN1CCNS1(=O)=O
Reactant: Cc1nc(Br)ncc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(C)S2(=O)=O)ncc1Br
Temperature: 80 °C

Procedure:
Sodium hydride (0.128 g, 60% disp. in oil) was added to a stirred solution of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (0.433 g) in THF (10 ml). DMF (10 ml) was added and the mixture heated at 80° C. for 5 min then a solution of the product from step (i) (0.8 g) in DMF (5 ml) was added. The mixture was heated at 60° C. for 10 min, poured into water (100 ml), acidified with citric acid and extracted with ethylacetate. The organics were evaporated under reduced pressure and the residue purified by chromatography on silica eluting with diethylether, yield 0.58 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:31]([NH2:33])=[O:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:14]2[CH2:13][CH2:12][C:11]3[C:10]([C:31]([NH2:33])=[O:32])=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:34]#[N:35])=[CH:3][CH:4]=4)[C:16]=3[C:15]=2[CH:17]=1)=[O:30]
Reactant: CN(C)C=O
Reactant: NC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 100 °C

Procedure:
1-(4-Bromophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (5.2g) and Zn(CN)2 (0.9g) were dissolved in 100 ml DMF under N2. Then Pd(Ph3P)4 (1.38 g) was added. The reaction mixture was heated up to 100° C. under N2 for 12 hours. After the reaction is completed by HPLC, the solvent was evaporated, and the residue was suspended in ethyl acetate and water. After filtration, and washing with water and ethyl acetate, the filtrate of the organic layer was separated and dried with Na2SO4. After filtration and evaporation of solvent, the residue was triturated with ether. Solid obtained was filtered and washed with ether, then dried under vacuum. The desired compound (3.4 g) was obtained and characterized by 1H NMR, LC-MS (468, M+1), and CHN analysis. IKK-2 resin IC50≦1 μM.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)#[CH:12]>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccc2ccccc2c1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(Cn2nncc2-c2ccc3ccccc3c2)cc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), 2-ethynylnaphthalene (0.503 g, 3.31 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 4 hours; yield, 0.80 g (93%). EI-MS: m/z 285 [M+].
Reaction SMILES: [C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CS(O)(=O)=[O:25].OO>C(OCC)(=O)C>[C:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][OH:25])=[O:21])(=[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)NCCCCCC(=O)O
Reactant: CS(=O)(=O)O
Agent: OO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCC(=O)NCCCCCC(=O)OO
Temperature: -15 °C

Procedure:
A 250 mL beaker was charged with 35.0 g (0.112 mol) of N-lauroyl-6-aminocaproic acid and 70 mL of 98% methanesulfonic acid. The resulting solution was cooled in an ice bath and, with stirring, 21.2 g of 90% hydrogen peroxide (19.0 g, 0.559 mol of hydrogen peroxide) was added dropwise at a rate so that the temperature of the reaction mixture did not rise above 20° C. (required 15 min.). The resulting solution was stirred at room temperature for 3 hrs., cooled to -15° C., and poured over ice. Ethyl acetate (150 mL) was added, the mixture was warmed to 60° C. in a water bath, and the water layer separated. An additional 100 mL of water was added, the solution again warmed to 60° C. and the water layer separated and discarded. The ethyl acetate solution was cooled to -15° C., and the crystals which formed were removed by filtration and washed with 2×50 mL portions of -15° C. ethyl acetate. The yield of N-lauroyl-6-aminoperoxycaproic acid was 33.1 g; analysis for available oxygen (AvO) indicated 4.31% (theoretical yield=36.9 g having an AvO of 4.86%), mp 70°-75° C.
Reaction SMILES: OC1C(C2(CO)C3C(=CC=CC=3)N(CC[CH2:22][N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])C2=O)=CC2OCOC=2C=1.C1([CH2:40][CH2:41][N:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]([C:53]3[C:61]([OH:62])=[CH:60][C:56]4[O:57][CH2:58][O:59][C:55]=4[CH:54]=3)([CH2:51]O)[C:43]2=[O:63])CC1>>[O:63]=[C:43]1[C:44]2([C:53]3=[CH:54][C:55]4[O:59][CH2:58][O:57][C:56]=4[CH:60]=[C:61]3[O:62][CH2:51]2)[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:42]1[CH2:41][CH2:40][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 45 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 45% yield: 1H NMR (300 MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.28-7.26 (m, 1H), 7.15 (d, 1H), 7.05-7.00 (m, 1H), 6.86 (d, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.85-5.83 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.94-3.68- (m, 4H), 2.15-2.10- (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 168.2, 155.9, 148.8, 142.4, 141.9, 134.0, 132.5, 132.0, 128.9, 124.1, 123.4, 123.3, 119.4, 108.4, 103.2, 101.5, 93.6, 80.4, 58.2, 38.0, 35.6, 26.8; MS (ES+) m/z 469.3 (M+1), 491.3 (M+23).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15](O)[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:15]1[N:14]2[N:18]=[CH:19][CH:20]=[C:13]2[N:12]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:16]=1
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol (11.7 mmol) is charged to 250 mL roundbottom flask. To this flask is added 4 mL N,N-dimethylaniline, followed by 40 mL POCl3. This suspension was sonicated to break up the starting material and stirred at room temperature for 18 hours. After 18 hours, a solution formed. The solution was reduced in vacuo and cooled to 0° C. in ice bath. The reaction is then quenched with sat. NaHCO3(aq) and extracted with DCM (×3). The combined organics are dried with Na2SO4 and the solvent was removed in vacuo. The resulting oil was purified via silica gel column on 20% to 100% ethyl acetate in hexanes gradient to yield 7-chloro-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidine (2.65 grams, 77% across 2 steps) as white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 78.6 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-n-butyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+].NC(C1C=CC=CC=1)C1(N(C)C)CCCC1>C(OCCCC)CCC.C1COCC1.CO>[NH2:10][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1([N:3]([CH2:1][CH3:2])[CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: [Li]c1ccccc1
Reactant: CCN(CC)C1(C#N)CCCC1
Agent: CN(C)C1(C(N)c2ccccc2)CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCOCCCC
Product: CCN(CC)C1(C(N)c2ccccc2)CCCC1
Yield: 47 %

Procedure:
The title compound (0.45 g, 47%) was prepared from 1-(diethylamino)cyclopentane carbonitrile D11 (0.65 g, 3.9 mmol), and phenyllithium in dibutylether (2.4 ml of a 1.8M solution; 4.3 mmol) in THF (4 ml), followed by reaction with sodium borohydride (0.445 g, 11.7 mmol) in methanol (4 ml) in a similar manner to that described in D2. 1H NMR (CDCl3) δ: 0.42 (1H, m), 1.10 (6H, m), 1.35 (3H, m), 1.55 (1H, m), 1.66 (2H, m), 1.80-2.08 (3H, m), 2.53-2.70 (4H, m), 4.22 (1H, s), 7.20-7.31 (3H, m), 7.47 (2H, m).