Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][CH2:14][C:15](=[O:24])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C:10]1=[O:25])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][N:9]1[CH:12]([CH2:13][CH2:14][C:15](=[O:24])[CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:11][C:10]1=[O:25]
Reactant: CC(C)(C)OC(=O)CC(=O)CCC1CC(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC(=O)CCC1CC(=O)N1O

Procedure:
t-Butyl 5-(1-benzyloxy-2-oxo-4-azetidinyl)-3-oxopentanoate (90 mg, 0.26 mmol) was hydrogenated with 10% Pd/C in EtOAc for 1.5 h to yield t-butyl 5-(1-hydroxy-2-oxo-4-azetidinyl)-3-oxopentanoate (A). Compound A was directly taken on to the next step without undue delay. In an ice bath under argon atmosphere, compound A was dissolved in 1 mL of anhydrous CH3CN. The p-carboxybenzenesulfonyl azide (68.0 mg, 0.30 mmol, 110 mol %) was added as a solid followed by 1 mL of solvent as a wash and Et3N (125 microliter, 91 mg, 0.90 mmol, 330 mol %). The reaction was stirred at ice bath temperature and was gradually allowed to warm to ambient temperature over 1-2 h, and was stirred for a total of 27 h. The reaction eventually turned light brown and a white precipitate formed. The reaction mixture was diluted with 15 mL of CH2Cl2 and 35 mL of ether, and the solvent was evaporated after filtration to remove the solid. The resulting brown oil was passed through a short plug of silica as a solution in CH2Cl2 to yield 50 mg of a light brown oil after solvent removal. The oil was chromatographed by column (EtOAc and hexanes as eluting solvents) to yield two fractions as oils: compound B (13 mg, 16% overall yield) and compound C (13 mg, 17% overall yield). The diazo/azido/reduced product B was recrystallized in ether/hexanes to give orange-yellow needles on which X-ray crystallographic data were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[O:27][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(O)c1C
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cccc(C)c2C)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 88.5 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.16 g of 2,3-dimethylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(2,3-dimethylphenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (67)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]12[CH2:19][CH2:18][CH2:17][N:16]1[CH2:15][CH2:14][CH2:13]2>>[N:16]12[CH2:17][CH2:18][CH2:19][C:12]1([CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:13][CH2:14][CH2:15]2
Reactant: NCC12CCCN1CCC2
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCC12CCCN1CCC2

Procedure:
The procedures described in Example 1 were repeated except that 2-fluorobenzonitrile (671 mg, 5.54 mmol) and 5-aminomethyl-1-azabicyclo[3.3.0]octane (1.94 g, 13.9 mmol) were employed. In this case, the desired compound was obtained as a colorless liquid (1.26 g, 94.2%).
Reaction SMILES: C([Li])(CC)C.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH3:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1.CON(C)C(=O)CCC>C1CCCCC1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[CH2:22][C:25](=[O:26])[CH2:24][CH2:23][CH3:27])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1CCOC1
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1C
Agent: CCCC(=O)N(C)OC
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Product: CCCC(=O)Cc1c(NC(=O)OC(C)(C)C)cccc1OC
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A solution of 50 mL (65 mmol) of 1.3M sec-butyl lithium in cyclohexane was added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline (7.7 g, 32.5 mmol) in 100 mL. of THF keeping the temperature below -40° C. with a dry ice-ethanol bath. The bath was removed and the temperature allowed to rise to -10° C. and then the bath replaced. After the temperature had cooled to -60° C., 4.3 g (32.5 mmol) of N-methoxy-N-methylbutanamide in an equal volume of THF was added dropwise. The reaction mixture was stirred 1 hour, the cooling bath removed and stirred an additional 22 hours. It was then poured into a mixture of 200 mL of ether and 200 mL of 0.5N HCl. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated at reduced pressure to give 9.9 g of crude 1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-pentanone. This material was dissolved in 100 mL of methylene chloride and 20 mL of trifluoroacetic acid and stirred for a total of 23 hours. The mixture was washed with water, dried (MgSO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 2.19 g of 4-methoxy-2-propyl-1H-indole as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][CH2:41][C@@:40]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])([OH:44])[CH2:39]2)[C:34]([F:51])=[CH:33][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.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:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][C@H:38]4[CH2:43][CH2:42][CH2:41][C@@:40]([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])([OH:44])[CH2:39]4)[C:34]([F:51])=[CH:33][N:32]=3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CCOC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
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: CC#N
Product: CCOC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1

Procedure:
To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.31 g, 0.72 mmol) in acetonitrile (6.0 mL) was added ethyl 2-((1R,3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-hydroxy-cyclohexyl)ethanoate, 60a, (0.20 g, 0.60 mmol) and degassed under N2. Na2CO3 (0.90 mL of 2 M, 1.81 mmol) was added followed by Pd(PPh3)4 (0.10 g, 0.09 mmol). The reaction was sealed and microwaved at 120° C. for 30 min. The material was concentrated under reduced pressure then diluted in EtOAc and aqueous saturated NaHCO3, then extracted with additional EtOAc (3×), dried (Na2SO4) and concentrated in vacuo. The material was diluted in DCM and silica gel chromatography (Hexanes:EtOAc) gave 217 mg of product 60c. LC MS+: 602.49 at 4.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.OB(O)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1>C1(C)C=CC=CC=1.CO.C(=O)([O-])[O-].[Na+].[Na+].O.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>[CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccc2ccccc2c1
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: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2ccc3ccccc3c2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 2-bromonaphthalene (5.0 g) and tetrakis(triphenylphosphine)palladium(0) (0.56 g) in toluene (50 ml) was added a solution of dihydroxy(3-nitrophenyl)borane (4.44 g) in methanol and 2M sodium carbonate solution in water (12 ml). The resulting mixture was stirred at 80° C. for 4 hours and extracted with ethyl acetate. After evaporation of the solvent, the crude residue was crystallized from hexane to give 3-(2-naphthyl)-1-nitrobenzene (5.4 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:4][C:3]=1[CH3:10]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 362.9 %

Procedure:
A mixture of 4-bromo-3,5-dimethylphenol (4.6 g, 22.88 mmol), 3,4 dihydro-2H-pyran (2.69 mL, 29.7 mmol) in 8.0 mL of CH2Cl2, and camphorsulfonic acid (106 mg, 4.56 mmol) was stirred at room temperature for 21 h. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 20 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-pyran (23.68 g, 92%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N:11]=O)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O

Procedure:
2,6-di tert.butyl-4-aminophenol was prepared by hydrogenating a mixture of 23.5 grams of 2,6-di tert.butyl-4-nitrosophenol, 2 grams of 5% Palladium on carbon, and 200 milliliters of absolute ethanol in a Parr Pressure Reaction Apparatus. The reduction was accomplished in 1 hour at a maximum hydrogen pressure of 50 psi and a maximum temperature of 50° C. The resulting solution of 2,6-di tert.butyl-4-aminophenol was removed from the Pressure Apparatus and filtered to remove the catalyst.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1B(O)O.C([O-])(O)=O.[Na+].Br[C:26]1[CH:31]=[CH:30][N:29]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:28](=[O:36])[C:27]=1[C:37]#[N:38]>O1CCOCC1.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>[CH:33]1([CH2:32][N:29]2[CH:30]=[CH:31][C:26]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[C:10]=4[CH3:16])=[CH:7][C:2]=3[F:1])=[C:27]([C:37]#[N:38])[C:28]2=[O:36])[CH2:34][CH2:35]1
Reactant: Cc1nccc(Oc2ccc(B(O)O)c(F)c2)c1C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
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: C1COCCO1
Product: Cc1nccc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)c(F)c2)c1C
Yield: 15.5 %

Procedure:
To a solution of intermediate 22 (0.34 g 1.321 mmol) in 1,4-dioxane (5.5 ml) and a saturated solution of NaHCO3 (5.5 ml) was added intermediate 5 (0.28 g, 1.123 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.15 mg, 0.132 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/AcOEt 1:1 as eluent). The desired fractions were collected and evaporated in vacuo to give a residue that was triturated with Et2O to yield compound 10 (0.068 g, 16%)
Reaction SMILES: [SH-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[N+:11](=[N:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1Cl)[O-].[N+](C1C=CC=CC=1)(=NC1C=CC=CC=1)[O-]>CO>[Cl:10][C:7]1[CH:8]=[CH:9][CH:4]=[C:5]([NH:11][NH:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=2)[CH:6]=1
Reactant: [O-][N+](=Nc1cc(Cl)ccc1Cl)c1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [O-][N+](=Nc1ccccc1)c1ccccc1
Agent: [SH-]
Solvent: CO
Product: Clc1cccc(NNc2cccc(Cl)c2)c1
Temperature: 70 °C
Yield: 76 %

Procedure:
85 Parts of an aqueous solution of technical sodium hydrosulfide containing 35 percent NaHS and 9 percent Na2S 2 O3 were added to a mixture comprising 65.4 parts of 2,2'-dichlor-5,5'-dichloroazoxybenzene in 196 parts of methanol at room temperature within 90 minutes. The reaction mixture was then refluxed at 70° C to75° C for a period of 5 hours. The pH had been kept between 9 and 9.4. After this period the starting azoxybenzene was shown to be all consumed and the reaction mixture was cooled down to 0° C to 5° C, and the resulting precipitate filtered off and washed with water until alkali-free. After drying below 70° C 48 parts of 2,2'-dichloro,-5,5'-dichlorohydrazobenzene of a melting point of 116° C were obtained, this representing yield of 76 percent of the theory.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C)[CH:8]=[C:7]([C:12](C)(C)[CH3:13])C=1O)(C)(C)[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH3:2][CH:1]=[CH:5][CH2:10][CH2:9][CH2:8][CH2:7][CH2:12][CH3:13]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC=CCCCCCC
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a toluene solution (84.0 ml) of 2,6-di-tert-butyl-4-methylphenol (9.78 g, 44.5 mmol), diisobutylaluminum hydride (1.5M toluene solution, 18.5 ml, 27.8 mmol) was dropwise added over a period of 30 minutes under an argon atmosphere at 0° C. Then, the mixture was stirred at the same temperature for 90 minutes. Then, at -78° C., a toluene solution (30.0 ml) of 3-(3-oxa-4-tert-butoxycarbonylbutyl)-7-exo-(2-chloro-4,4-dimethyl-3-oxo-1-nonen-6-ynyl)-8-endo-hydroxy-cis-bicyclo[4.3.0]non-2-ene (1.37 g, 2.78 mmol) was dropwise added to the reaction solution over a period of 10 minutes. Then the temperature was raised from -78° C. to -60° C. over a period of two hours. To the reaction solution, a saturated sodium chloride aqueous solution was added, and the mixture was stirred for a while. Then, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue thereby obtained was purified by silica gel column chromatography (ethyl ether : n-hexane =1 : 1-2) to obtain 3-(3-oxa-4-tert-butoxycarbonylbutyl)-7-exo-(2-chloro-4,4-dimethyl-3α-hydroxy-1-nonen-6-ynyl)-8-endo-hydroxy-cis-bicyco[4.3.0]non-2-ene (1.18 g, 86.0%) as a highly porous component and 3-(3-oxa-4-tert-butoxycarbonylbutyl)-7-exo-(2-chloro-4,4-dimethyl-3β-hydroxy-1-nonen-6-ynyl)-8-endo-hydroxy-cis-bicyclo[4.3.0]non-2-ene (0.16 g, 11.6%) as a low polar component, each as a slightly yellow oily substance. The spectrum data of the α-epimer are shown below. The spectrum data of the β-epimer were substantially the same as α-epimer.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:20])[N:10]=[C:11]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:3]=12.ClC1N=C[N:25]=C2N(C)N=C(C3OC([N+]([O-])=O)=CC=3)C=12>>[NH2:25][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([CH3:20])[N:10]=[C:11]([C:12]3[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:3]=12
Reactant: Cc1nc(Cl)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Product: Cc1nc(N)c2c(-c3ccc([N+](=O)[O-])o3)nn(C)c2n1

Procedure:
The procedure described in Example 3b was repeated using 4-chloro-1,6-dimethyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine as starting material instead of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, the reaction conditions being the same. The crystalline product was collected, washed with water and dried. Recrystallisation from dimethyl formamide gave 4-amino-1,6-dimethyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point > 300° C. identical with the product obtained in Example 2.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:22]([O:24]C)=O)=[N:12][C:13]([C:20]#[N:21])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=O)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCOCC>C1(C)C=CC=CC=1>[C:20]([C:13]1[N:12]=[C:11]([C:22]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:28]=2[O:27][CH3:26])=[O:24])[C:10]([OH:9])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)#[N:21]
Reactant: COC(=O)c1nc(C#N)c2cccnc2c1OC(=O)c1ccccc1
Reactant: COc1cccc(CN)c1OC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1cccc(CNC(=O)c2nc(C#N)c3cccnc3c2O)c1OC

Procedure:
To a solution of methyl 8-(benzoyloxy)-5-cyano-1,6-naphthyridine-7-carboxylate (264 mg, 0.792 mmol) in anhydrous toluene (12 ml) was added 2,3-dimethoxybenzyl amine (132 mg, 0.79 mmol) and the solution was stirred at reflux under argon overnight. The solvent was removed under reduced pressure to give a brown syrup which was subsequently taken up into ether (10 ml). After stirring for 4 hours the solids were collected by vacuum filtration and dried overnight on an aberhalden to give an off white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)nc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OCCO)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(5-nitro-pyridin-2-yloxy)-ethanol (1.0 g, 5.4 mmol) in MeOH (30 mL) was added 10 wt % Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): m/z 155 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: O=C(O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 28 %

Procedure:
The title compound was prepared in 28% yield from 4-(trifluoromethyl)-benzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (br s, 1H), 8.04 (s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.81 (d, 2H, J=8.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.54 (d, 2H, J=8.0 Hz), 4.69 (s, 2H). [M+H] calc'd for C14H11F3N2O2, 297; found 297.
Reaction SMILES: [OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O-:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CO>[OH:1][C:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COc1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCCc5cc(C(=O)[O-])ccc54)s3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCCc5cc(C(=O)O)ccc54)s3)n2)c1

Procedure:
To a solution of methyl (R or S)-5-hydroxy-5-(5-(6-((4-methoxypyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (fast or slow enantiomer from step 2, 101 mg, 0.2 mmol) in MeOH (6 mL) was added a solution of sodium hydroxide (2 mL, 0.3 M, 0.6 mmol) and the mixture was heated to reflux for 1 hour. Methanol was removed under reduced pressure and the residue was diluted with 10 mL of water. The pH was adjusted to 6 with 1 M HCl, during which time a precipitate developed. The white precipitate was collected by filtration and washed with water and dried to afford (R or S)-5-hydroxy-5-(5-(6-((4-methoxypyridin-2-yl)amino)-4-methylpyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[H-].[Na+].Br[CH2:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([Cl:33])=[CH:28][CH:29]=[N:30]2)=[CH:25][CH:24]=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27]([Cl:33])=[CH:28][CH:29]=[N:30]3)=[CH:25][CH:24]=2)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc2cc(CBr)ccc12
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2c(Cl)ccnc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
4-(Benzyloxycarbonyl)-piperazin-2-one (1.1 g, 4.6 mmol) is dissolved in THF (50 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.18 g, mmol) and 60% sodium hydride (0.24 g, 6.0 mmol). The reaction mixture is stirred at 0° C. for 30 minutes then treated dropwise with a solution of 7-bromomethyl-4-chloroquinoline (1.2 g, 4.6 mmol), Example 14, in THF (50 mL). The resulting solution is stirred at 0° C. for 2 h then quenched with ammonium chloride solution and concentrated. Dilution with ethyl acetate is followed by a water wash; the organic layer is dried (sodium sulfate) and concentrated. The residue is chromatographed (4% methanol/methylene chloride) to yield solid 4-(benzyloxycarbonyl)-1-(4-chloroquinolin-7-ylmethyl)-piperazin-2-one (1.2 g, 2.9 mmol). A portion of this material (0.75 g, 1.8 mmol) is dissolved in acetonitrile (20 mL) and treated with iodo trimethylsilane (0.78 mL, 5.4 mmol) at room temperature for 3 hours. The reaction is quenched with methanol and concentrated to dryness. Methanol addition and concentration is repeated four times. The final residue is taken up is 2M aqueous HCl; the solution is washed with ether and concentrated. The residue is recrystallized from isopropanol and ether to yield the title compound (0.63 g, 2.3 mmol) MS m/z: M+=275; 1HNMR (CD3OD, 300 MHz) δ9.1 (d, 1H), 8.5 (d, 1H), 8.2-8.3 (m, 2H), 8.0 (d, 1H), 5.2 (s, 2H), 4.1 (s, 2H), 3.7-3.8 (m, 2H), 3.6-3.7 (m, 2H).