Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[F-].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: BrCc1ccncc1
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(O)cc2)c(C)c1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccncc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(2,4-dimethylphenyl)-4-hydroxy-N-isobutylbenzenesulfonamide (33 mg, 0.099 mmol), and potassium fluoride, 40% by weight on alumina (40% KF.Al2O3 43.1 mg, 0.297 mmol) in acetonitrile (0.2 mL) were stirred for 5 mins, before addition of 4-(bromomethyl)pyridine (0.099 mmol) in acetonitrile (0.2 mL). The reaction mixture was capped and stirred at RT for 18 hours. Additional 40% KF.Al2O3 (43 mg) and more alkylating reagent (0.1 mmol) were added to the tube, which was capped and stirred for a further 18 hours. The reaction had additional potassium fluoride, 40% by weight on alumina (43 mg) and alkylating reagent (0.1 mmol), and then recapped and stirred for 2 days. The sample was filtered through cotton wool, and DMSO added to bring the total volume to 1 mL. The solutions were purified by mass directed autoprep on Sunfire C18 column using acetonitrile water with a formic acid modifier. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]([CH3:48])[C:44]([F:47])([F:46])[F:45])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O=P(Cl)(Cl)Cl.C(O)CO.C(=O)=O>N1C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[C:10]([C:29]([N:42]([CH2:41][CH2:40][O:39][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:34])[CH3:33])[CH:43]([CH3:48])[C:44]([F:46])([F:45])[F:47])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(NCCO[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: O=C=O
Solvent: c1ccncc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
To a solution of 5-(benzyloxy)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (28-02) (150 mg, 342 μmol, Eq: 1.00) and N-(2-(tert-butyldimethylsilyloxy)ethyl)-1,1,1-trifluoropropan-2-amine (41) (102 mg, 376 μmol, Eq: 1.1) in pyridine (1.5 ml) was added POCl3 (157 mg, 95.6 μl, 1.03 mmol, Eq: 3.00) at −10° C. (ethylene glycol-dry-ice bath), then the reaction mixture was stirred at 0° C. for 2 hr. Ice cooled-water was slowly added to the reaction mixture at 0° C., which was extracted with ethyl acetate. The organic layer was washed with aqueous saturated NaHCO3 solution, dried (MgSO4), concentrated, and chromatographed (silica gel, gradient 5 to 50% ethyl acetate-hexane) to obtain 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-((1-(4-chlorophenyl)cyclopentyl)methyl)-6-hydroxy-N-(1,1,1-trifluoropropan-2-yl)pyrimidine-4-carboxamide (42) (oil, 138 mg, 199 μmol, 58.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=C(C)C=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:35])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1cccc(C)c1
Product: O=C1NC(=S)NC12CC(c1cccc(F)c1F)Oc1ccc(Br)cc12
Temperature: 150 °C
Yield: 73.7 %

Procedure:
A suspension of 6-bromo-2-(2,3-difluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (212 mg, 0.52 mmol) and Lawesson's Reagent (201 mg, 0.52 mmol) in dry m-xylene (4.5 mL) was heated at 150° C. in a 10 mL CEM microwave test tube for 25 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2,3-difluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (163 mg, 74%). 1H-NMR (CDCl3): 2.33 (t, 3H), 2.54 (d, 1H), 5.36 (s, 1H), 6.17 (d, 1H), 6.91 (d, 1H), 7.17 (m, 3H), 7.30 (m, 2H), 7.46 (s, 1H).
Reaction SMILES: I(O)(O)(O)(O)(O)=[O:2].[OH:8][C@@H:9]1[C@H:25]2[C@@H:16]([CH2:17][CH2:18][C:19]3[C@:24]2([CH3:26])[CH2:23][CH2:22][C:21](=[O:27])[CH:20]=3)[C@H:15]2[C@@:11]([CH3:33])([C@@:12]([OH:32])([C:28](=[O:31])CO)[CH2:13][CH2:14]2)[CH2:10]1>O.C1COCC1.[OH-].[Na+]>[OH:8][C@@H:9]1[C@H:25]2[C@@H:16]([CH2:17][CH2:18][C:19]3[C@:24]2([CH3:26])[CH2:23][CH2:22][C:21](=[O:27])[CH:20]=3)[C@H:15]2[C@@:11]([CH3:33])([C@@:12]([OH:32])([C:28]([OH:2])=[O:31])[CH2:13][CH2:14]2)[CH2:10]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: [O-][I+](O)(O)(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A solution of orthoperiodic acid (21.4 g, 94 mmol) in water (80 ml) was added to a solution of (8S,9S,10R,11S,13S,14S,17R)-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (Hydrocortisone, 17.0 g, 46.9 mmol) in THF (350 ml), and the reaction mixture was stirred at room temperature in an open flask for 2 hours. Then the mixture was poured onto ice. After the ice had molten, the mixture was extracted with ethyl acetate (3 times 150 ml). Evaporation of the solvent gave a white solid, which was dissolved in aqueous NaOH (1 M, 150 ml). The solution was washed with ethyl acetate, and acidified with conc. aqueous HCl. The precipitate formed was collected by filtration, and dried on the sinter overnight to afford the target compound as an off-white powder (15.51 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:18]([C:22]1[N:26]2[CH2:27][CH2:28][CH:29]([C:31](OCC)=O)[CH2:30][C:25]2=[N:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:18]([C:22]1[N:26]2[CH2:27][CH2:28][CH:29]([C:31]3[O:9][N:8]=[C:6]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=4)[N:7]=3)[CH2:30][C:25]2=[N:24][N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1CCn2c(nnc2C(C)(C)C)C1
Reactant: Cc1ccc(C(N)=NO)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CCn4c(nnc4C(C)(C)C)C3)n2)cc1
Yield: 49 %

Procedure:
Add 4-methylbenzamidoxime (1.44 g, 9.3 mmol) to a 1M solution of potassium tert-butoxide (8.6 mL, 8.6 mmol) diluted with tetrahydrofuran (120 mL). Add ethyl 3-t-butyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (2.0 g, 7.2 mmol) and stir overnight at room temperature. Dissolve the reaction in a 1:1 mixture of half saturated aqueous sodium bicarbonate and ethyl acetate. Separate the phases and extract the aqueous phase with ethyl acetate. Wash the combined organic layers with aqueous saturated sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by silica gel flash chromatography eluting with 25-100% ethyl acetate:hexane followed by 5% methanol:ethyl acetate. Recrystallize from dichloromethane and hexane to afford the title compound as a white solid (1.19 g). 1H NMR (CDCl3) δ 1.46 (s, 9H), 2.4 (s, 4H), 2.59 (m, 1H), 3.4 (m, 1H), 3.54-3.69 (m, 2H), 4.11 (m, 1H), 4.38 (m, 1H), 7.22-7.33 (m, 2H), 7.9-7.98 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH:16]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:30][C:26]1[CH:25]=[C:24]([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH2:15][O:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2ccccc2)c2cccc(C)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
(R)-N-(2-(3-(3-Methylphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester (3.5 g, 8.6 mmol) was dissolved in 96% ethanol (10 ml) and a 12 N sodium hydroxide solution (2.2 ml) was added. The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and dichloromethane (100 ml) and water (10 ml) were added. A concentrated hydrochloric acid solution (3.4 ml) was added with cooling on an ice-bath. The phases were separated and from the organic phase the solvent was evaporated in vacuo. Water (100 ml) was added to the residue and the aqueous solution was washed with small portions of ethyl acetate. The aqueous phase was reduced to approx. 10 ml in vacuo. Dichloromethane (250 ml) and water (40 ml) were added and pH of the solution was adjusted to 8.5 with a 4 N sodium hydroxide solution. The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give 2.4 g (74%) of the title compound.
Reaction SMILES: Cl[CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:11].S([O-])([O-])(=O)=[O:13].[NH4+].[NH4+]>O>[CH3:10][C:8]1([CH3:9])[CH2:7][CH2:6][CH2:5][NH:4][CH:2]1[C:3]([OH:11])=[O:13]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC1(C)CCCNC(=O)C1Cl
Agent: [NH4+]
Solvent: O
Product: CC1(C)CCCNC1C(=O)O
Temperature: 150 °C
Yield: 79.5 %

Procedure:
A suspension of 7.0 g (0.04 moles) of 3-chloro-4,4-dimethyl-2-oxoperhydroazepine and 13.84 g (0.043 moles) of Ba(OH)2.8H2O in 150 ml of water, was heated in a Parr apparatus at 150° C. for 4 hours. Then, 5.79 g (0.043 moles) of ammonium sulphate were added. The precipitate was filtered off, and the solution was evaporated in vacuo to dryness. The residue was treated with hot 2-propanol nd filtered, to yield 5 g of the title compound. M.P. >305° C.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.Br[C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O.C(O)C.[Cu]>[Cl:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1
Reactant: Cc1ccc(O)cn1
Reactant: Clc1cccc(Br)c1
Agent: [Cu]
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2cccc(Cl)c2)cn1

Procedure:
3 g of a potassium salt of 5-hydroxy-2-methylpyridine, 3.83 g of m-bromochlorobenzene and 200 mg of a copper powder were suspended in 8 ml of dimethylformamide, followed by allowing the mixture to react in a nitrogen gas stream at 130° C. for 13 hours while stirring. The reaction mixture was diluted with 40 ml of ethanol and filtered. The filtrate was immediately concentrated, and 80 ml of chloroform was added to the residue. The mixture was washed with a 0.01 N aqueous sodium hydroxide solution. The chloroform layer was washed with water, dried with anhydrous sodium sulfate and dried to solidify to obtain 2.96 g of oily 5-(m-chlorophenoxy)-2-methylpyridine.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[N:49]=[CH:48][N:47]=[C:46]2[C:42]=1[N:43]=[CH:44][N:45]2[CH2:50][C:51](O)=[O:52])=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:51](=[O:52])[CH2:50][N:45]2[CH:44]=[N:43][C:42]3[C:46]2=[N:47][CH:48]=[N:49][C:41]=3[NH:40][C:38]([O:37][CH2:27][C:28]2[CH:36]=[CH:35][C:34]3[O:33][CH2:32][O:31][C:30]=3[CH:29]=2)=[O:39])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(piperonyloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.64 (s, 1H), 8.58 (s, 0.6H), 8.57 (s, 0.4H), 8.34 (m, 1H), 8.31 (s, 0.4H), 8.28 (s, 0.6H), 8.27 (m, 1H), 7.72 (m, 2H), 7.04 (s, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 6.01 (s, 2H), 5.39 (s, 1.2H), 5.28 (s, 0.8H), 5.09 (s, 2H), 4.57 (s, 0.8H), 4.29 (m, 2.4H), 4.09 (t, 2H), 3.88 (t, 0.8H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=C)[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C[N+]1([O-])CC[O:33]CC1.S(=O)(O)[O-].[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.C(O)(C)(C)C.O.C1COCC1.[Cl-].[Na+].O.O=[Os](=O)(=O)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][CH:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=[O:33])[CH3:16])=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2]
Reactant: C=CCC(CN(C)C(=O)c1cc(C#N)cc2ccccc12)c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: CN(CC(CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
3-Cyano-N-[2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-1-naphthamide (1.5 g, 4.03 mmol) was dissolved in a mixture of acetone (30 mL), tert-butanol (15 mL) and water (7.5 mL) and stirred at room temperature during addition of OsO4 (0.40 mL of 2.5% in tert-butanol, 0.04 mmol). 4-Methylmorpholine N-oxide (2.08 g, 17.8 mmol) was added and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium bisulfite (15 mL) was added and the mixture stirred for 5 min and then concentrated. The residue was diluted with water (100 mL) and then extracted thrice with CH2Cl2. The combined organic solutions were washed with brine and the solvent removed by evaporation. The residue was dissolved in a mixture of THF (21 mL) and water (7 mL) whereupon sodium periodate (0.95 g, 4.43 mmol) was added. The solution was stirred at room temperature overnight and then diluted with water (150 mL) and brine (75 mL). The mixture was extracted thrice with ethyl acetate and the combined organic solutions were washed with water and then with brine. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (ethyl acetate-heptane, 7:3). There was obtained 1.43 g (95%) of 3-cyano-N-[2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-1-naphthamide as a colourless oil. 1H NMR (400 MHz, CDCl3): 2.4-4.4 (cm, 8H), 6.8-8.0 (cm, 9H), 8.2 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:8]=12.CC1(C)[C@]23C4(ON4S(=O)(=[O:34])C2)C[C@H]1CC3.[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[C:12]([OH:34])=[CH:11][N:10]=[C:9]2[N:13]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[CH:17]([CH3:18])[CH3:19])[CH:14]=[CH:15][C:8]=12
Reactant: CC1(C)[C@@H]2CC[C@@]13CS(=O)(=O)N1OC13C2
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(O)cnc21
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
sec-Butyl lithium (8.06 mL, 11.3 mmol, 1.4 M in cyclohexane) was added dropwise to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 5.13 mmol, prepared as described in L′Heureux, et al., Org. Lett., 5(26) p. 5023 (2003)) in THF (100 mL) at −78° C. The reaction was stirred for 30 minutes. (1R)-(−)-(10-camphorsulfonyl)oxaziridine (2.94 g, 12.8 mmol) in THF (10 mL) was added rapidly, and the reaction was stirred at −78° C. for 30 minutes. A solution of saturated ammonium chloride (50 mL) was added, and the reaction mixture was allowed to reach room temperature. After one hour, the aqueous phase was extracted with AcOEt, dried over MgSO4 and concentrated to a solid, which was triturated in ether. The solid (most of the camphor side product) was filtered off, and the filtrate concentrated and purified by chromatography (25M, toluene/AcOEt 95/5) to yield a paste. The paste was triturated with hexanes, and the filtrate was concentrated to dryness to yield 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (820 mg, 51.8% yield) as an oil, which solidified upon standing.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)#[N:10].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>>[Br:8][C:7]1[C:2]([C:11]2([C:9]#[N:10])[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncccc2Br)CC1

Procedure:
2,3-Dibromopyridine (5 g, 21 mmol) and tert-butyl 4-cyanopiperidine-1-carboxylate (3.0 g, 14 mmol) were reacted in the presence of potassium hexamethyldisilazide (17.1 mmol) using the method described in example 8-1 to afford the desired product: tert-butyl 4-(3-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 8.53 (1 H, dd, J 1.5, 4.6 Hz), 7.97 (1 H, dd, J=1.5, 8.0 Hz), 7.18 (1 H, dd, J=4.4, 8.0 Hz), 4.23 (2 H, br s), 3.29 (2 H, br s), 2.48 (2 H, br s), 2.15 (2 H, br s), 1.47 (9 H, s).
Reaction SMILES: Cl[CH:2]([O:12][CH2:13][CH:14]([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[C:3]([N:9]([F:11])[F:10])([N:6]([F:8])[F:7])[CH2:4][F:5].[N-:21]=[N+:22]=[N-:23].[Na+].CC(C)=O>O>[N:21]([CH:2]([O:12][CH2:13][CH:14]([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[C:3]([N:9]([F:11])[F:10])([N:6]([F:8])[F:7])[CH2:4][F:5])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])C(COC(Cl)C(CF)(N(F)F)N(F)F)[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(OCC([N+](=O)[O-])[N+](=O)[O-])C(CF)(N(F)F)N(F)F

Procedure:
A mixture of 1.7 g of 1-chloro-2,2-bis(difluoramino)-3-fluorodinitroethoxypropane, 0.7 g of sodium azide, 10 ml of acetone, and 5 ml of water was refluxed for 72 hours. The mixture was extracted with methylene chloride, washed with water, and concentrated to give 1.3 g of light yellow liquid. I.R. showed an absorption for azide at 4.7μ.
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([OH:10])=O)[CH3:7])=[O:4].[NH2:24][C@H:25]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH3:26]>>[N:1]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][CH2:11][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:24][C@H:25]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH3:26])=[O:10])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Reactant: CCNC(=O)[C@H](C)N
Product: CCNC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
The condensation of Z-Pro-Ala with Ala-NH-Et by the procedure in Example 7 yields Z-Pro-Ala-Ala-NH-Et; m.p. 219°-220° C. from 2-propanol--AcOEt); (α)D20 =-36.2°; c=0.2 (dimethylformamide). This intermediate is successively converted, as described in Example 2, into (1) BOC-Asp(Obzl)-Pro-Ala-Ala-NH-Et, m.p. 133°-136° C. (AcOEt--petroleum ether), (α)D20 =-61.1°, c=0.2 (MeOH); (2) Asp(OBzl)-Pro-Ala-Ala-NH-Et.HCl, m.p. 189°-193° C. (MeOH--Et2O), and (3) Ac-Asp(OBzl(-Pro-Ala-Ala-NH-Et, m.p. 191°-193° C. (AcOEt--petroleum ether), (α)D20 =-68.5°, c=0.2 (MeOH). Hydrogenolysis of the latter product by the procedure in Example 1 yields the title compound, Nα -Acetylaspartyl-prolyl-alanyl-alanine ethylamide; m.p. 153°-155° C. (melting begins at 143° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:32])([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCCC1>[OH:32][C:11]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCNCC1
Yield: 23.5 %

Procedure:
A solution of 4.5 gm (10.4 mMol) 1-tert-butoxycarbonyl-4-hydroxy-4-(6-benzyloxynaphth-2-yl)piperidine, 5 mL 5N hydrochloric acid in 20 mL ethyl acetate and 20 mL tetrahydrofuran was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between ethyl acetate and 2N sodium hydroxide. The phases were separated and the aqueous phase extracted well with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 10% methanol in dichloromethane. Fractions containing product were combined and concentrated under reduced pressure to provide 0.814 gm (24%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[CH:23]=1.[H-].[Na+]>CN(C)C=O>[Br:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: CN1CCN(C(=O)c2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of (6-Chloro-pyridin-3-yl)-(4-methyl-piperazin-1-yl)-methanone (2.00 g, 7.46 mmol) in 10 mL dimethylformamide was added 3-Amino-5-bromo-1-methyl-1H-pyridin-2-one (1.80 g, 8.95 mmol) and sodium hydride (537 mg, 22.4 mmol). After stirring for 18 hours, this was quenched with water. This was extracted with ethylacetate. The ethylacetate layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazine-1-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one (900 mg, 1.94 mmol). MS (ESI) 406.0 (M+H)+.