Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.[Cl:34][C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=1[O:45][CH:46]([CH3:48])[CH3:47])/[C:38](=[N:40]/O)/[NH2:39]>CN(C=O)C>[Cl:34][C:35]1[CH:36]=[C:37]([C:38]2[N:40]=[C:13]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][C@@H:5]4[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:6]4)=[CH:17][CH:16]=3)[O:15][N:39]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: CC1(C)OC[C@@H](COc2ccc(C(=O)O)cc2)O1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OC[C@@H]4COC(C)(C)O4)cc3)n2)cc1Cl
Temperature: 140 °C
Yield: 69.9 %

Procedure:
To a slurry of (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid (0.303 g, 1.203 mmol) in DMF (1.367 ml) was added EDC (0.231 g, 1.203 mmol) followed by HOBT hydrate (0.163 g, 1.203 mmol). After about 1.5 h a solution of (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.250 g, 1.09 mmol) in DMF (1.367 ml) was added. The reaction mixture was heated to about 140° C. for about 2 hrs. After cooling to room temperature the reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide (R)-3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.339 g, 70%) as a colorless solid. LCMS (Table 1, Method c) Rt=3.36 min, m/z 445 (M+H)+.
Reaction SMILES: CCCC[CH2:5][C@H:6]([OH:24])/[CH:7]=C/[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C=C1.[CH2:25]([O:29]C(Cl)=O)[CH:26]([CH3:28])[CH3:27].C([N:35](CC)CC)C>>[OH:24][C:6]1[CH:7]=[CH:27][C:26]([C:25]([NH2:35])=[O:29])=[CH:28][CH:5]=1
Reactant: CCN(CC)CC
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: CC(C)COC(=O)Cl
Product: NC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Example 1 but using 0.506 g. of PGA1 0.250 ml. of triethylamine, 0.236 ml. of isobutylchloroformate, and 0.412 g. of p-hydroxybenzamide there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with chloroform-acetonitrile (6:4). The residue obtained by concentration of selected fractions, 0.260 g., an oil, as the title compound, having Rf 0.5 (TLC on silica gel in chloroform-acetonitrile (3:2)).
Reaction SMILES: [CH3:1][CH2:2][NH+:3]([CH2:6][CH2:7][N:8]1[N:20]=[C:19]2[C:10]3[C:11]([S:16][C:17]4[CH:24]=[C:23](Cl)[CH:22]=[CH:21][C:18]=42)=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]1=3)[CH2:4][CH3:5].CS([O-])(=O)=O.CCN(CCN1N=C2C3C(SC4C=C(Cl)C=CC=42)=C(CO)C=CC1=3)CC.FC(F)(F)C(O)=O>O>[CH3:5][CH2:4][N:3]([CH2:6][CH2:7][N:8]1[N:20]=[C:19]2[C:10]3[C:11]([S:16][C:17]4[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]1=3)[CH2:2][CH3:1]
Reactant: CC[NH+](CC)CCn1nc2c3c(c(C)ccc31)Sc1cc(Cl)ccc1-2
Agent: CCN(CC)CCn1nc2c3c(c(CO)ccc31)Sc1cc(Cl)ccc1-2
Agent: CS(=O)(=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the compounds according to Example Ia-3 and Ia-4 (cis-trans mixture) (300 mg), trifluoroacetic acid (10 ml) and water (10 ml) is stirred at room temperature for 24 hours and concentrated. The solid residue is washed with hot cyclohexane.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:23]=[C:22](N)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[N:6]1.N(OCCC(C)C)=O.CN(C)C=O>O1CCCC1>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[N:6]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2ccccc12
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1ccccc1Cn1nc(-c2ncc3ccccc3n2)c2cccnc21
Temperature: 95 °C
Reaction time: 5 h

Procedure:
200 mg (0.540 mmol) of the compound from example 5 were suspended in tetrahydrofuran (2.0 ml), then 145 μl (1.08 mmol) of isopentyl nitrite were added and the reaction mixture was heated to reflux for 30 min. Subsequently, dimethylformamide (1.0 ml) and 145 μl of isopentyl nitrite were added and the mixture was stirred at 95° C. for a further 5 h. The reaction mixture was subsequently separated directly by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product-containing mixed fractions were concentrated. The crude product was subsequently further purified by means of HPLC (eluent: water/methanol/1% trifluoroacetic acid 28:65:7). This gave 30 mg (15% of theory) of the title compound in solid form.
Reaction SMILES: C[C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH2:11][CH:12]=O)[N:5]=[C:4]([CH3:14])[CH:3]=1.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:19]=2[O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.CN(C=O)C>[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([N:25]3[CH2:30][CH2:29][N:28]([CH2:12][CH2:11][S:10][C:6]4[N:5]=[C:4]([CH3:14])[CH:3]=[CH:2][C:7]=4[C:8]#[N:9])[CH2:27][CH2:26]3)[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: Cc1cc(C)c(C#N)c(SCC=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccc(C#N)c(SCCN2CCN(c3cccc4c3OCCO4)CC2)n1
Reaction time: 2 h

Procedure:
4,6-Dimethyl-2-(2-oxo-ethylsulfanyl)nicotinonitrile (2.9 g) was dissolved in 1,2-dichloroethane (150 mL), a solution of 4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazine (2.6 g) in DMF (150 mL) was added, followed by addition of sodium triacetoxyborohydride (14.9 g) and stirring for 2 h. The mixture was poured on water and Na2CO3 added until pH reached 7-8. The mixture was extracted with ethyl acetate, the combined organic phases dried and evaporated to give an oil which was subjected to purification by column chromatography (silica gel; ethyl acetate and heptane) giving an oil which precipitated as the oxalate salt (0.36 g) from acetone. LC/MS (m/z) 397 (MH+), RT=1.91, purity: 97%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:27][N:26]([C:28](=[O:39])[CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:25][CH2:24][C:22]=2[N:23]=1>ClCCl>[NH2:31][CH2:30][CH2:29][C:28]([N:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:18]([NH:17][CH:9]3[CH2:8][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)[N:19]=[CH:20][C:21]=2[CH2:27]1)=[O:39]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of tert-butyl {3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}carbamate (0.19 g; 1.0 equiv; 0.44 mmoles) in dichloromethane (1 mL) and stir for 16 hours. Concentrate the mixture and then partition the residue between dichloromethane and 1N sodium hydroxide. Separate the layers and further extract the aqueous layer with dichloromethane. Wash the combined organic extracts with brine, dry over sodium sulfate, filter, and concentrate to afford the desired 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (0.145 g; 98%): MS (m/z): 338(M+1).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)[CH2:5][C:4](=[O:17])[CH:3]=1.O.[C:19](O)(=[O:22])[CH2:20][CH3:21]>C(OC(=O)CC)(=O)CC.FC(S(O)(=O)=O)(F)F>[OH:17][C:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)[CH2:7][C:2](=[O:1])[C:3]=1[C:19](=[O:22])[CH2:20][CH3:21]
Reactant: O=C1C=C(O)CC(c2ccc3c(c2)CCC3)C1
Reactant: CCC(=O)O
Agent: CCC(=O)OC(=O)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
3-Hydroxy-5-(5-indanyl)cyclohex-2-en-1-one (4.0 g; 18 mmole) was dissolved in a mixture of propionic acid (4 ml) and propionic anhydride (4 ml) at 130° C. under nitrogen. To the resulting clear solution was added 8 drops of trifluoromethyl sulphonic acid and the mixture was allowed to stir at 130° C. under nitrogen for a further 11/2 hours. The mixture was poured into water (500 ml) and stirred until all the anhydride had reacted (approx 30 min). The resulting solid was filtered off, pressed dry at the pump and then dissolved in dichloromethane and purified by column chromatography over silica gel (eluant dichloromethane) to give 3-hydroxy-5-(5-indanyl)-2-propionylcyclohex-2-en-1-one (1.88 g; 37%), mp 98° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].[F-:23].[K+].[K+].[Br-].Cl[C:28]([F:34])([F:33])C(OC)=O>O.[Cu]I.CN(C=O)C>[C:1]([C:5]1[CH:10]=[C:9]([C:28]([F:34])([F:23])[F:33])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(F)(F)Cl
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1OCc1ccccc1
Reactant: [F-]
Agent: [Cu]I
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(C(F)(F)F)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
A mixture of 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (913 mg, 2.5 mmol), KF (291 mg, 5 mmol), KBr (595 mg, 5 mmol), CuI (570 mg, 3 mmol), methyl chlorodifluoroacetate (1.6 mL, 15 mmol) and DMF (5 mL) was stirred at 125° C. in a sealed tube overnight, cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by column chromatography (0-5% EtOAc—Hexane) to yield 1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (591 mg, 67%). 1H NMR (400 MHz, CDCl3) 7.66 (s, 1H), 7.37 (m, 5H), 7.19 (s, 1H), 5.21 (s, 2H), 1.32 (s, 9H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH2:32]1[O:40][C:39]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][C:34]=2[O:33]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:33]1[C:34]2[CH:35]=[CH:36][C:37]([N:18]3[C:19]4[C:15](=[CH:14][C:13]([C:11]([N:8]5[CH2:7][CH2:6][N:5]([CH:1]6[CH2:2][CH2:3][CH2:4]6)[CH2:10][CH2:9]5)=[O:12])=[CH:21][CH:20]=4)[CH:16]=[C:17]3[C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:38][C:39]=2[O:40][CH2:32]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc2c(c1)OCO2)N1CCN(C2CCC2)CC1
Yield: 24 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3,4-methylenedioxybenzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (24%).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:50])[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:50])[CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C1CCOCC1
Product: CCN(Cc1ccc(OCCN(C)C2CCOCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 23.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-(tetrahydropyran-4-yl)acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.8 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].N1C2C(=CC=CN=2)C=C1.[Cl-:23].[Cl-].[Cl-].[Al+3]>S(Cl)(Cl)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([Cl:23])=[O:6]
Reactant: [Cl-]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: c1cnc2[nH]ccc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-fluoro-5-nitrobenzoic acid (2.90 g, 10.8 mmol) was dissolved in thionyl chloride (20.0 mL) and the reaction was heated to reflux overnight. The reaction was cooled and was concentrated to provide a white solid which was dried under vacuum overnight. Compound 2 (512 mg, 4.33 mmol) was dissolved in methylene chloride (10.0 mL), under an atmosphere of argon and aluminum trichloride (2.85 g, 21.4 mmol) was added. The reaction was stirred at room temperature for 1 hour. The 3-fluoro-5-nitrobenzoyl chloride formed above was dissolved in methylene chloride (10.0 mL) and was added to the reaction. The reaction was stirred at room temperature overnight. The reaction was quenched with methanol and concentrated under reduced pressure. The resulting solid was extracted with ethyl acetate and saturated sodium bicarbonate. The organic portion was dried with anhydrous magnesium sulfate, adsorbed onto silica and purified by silica gel flash chromatography with 40%-50% ethyl acetate:hexanes. The appropriate fractions were combined and concentrated to provide compound 295 as a white solid characterized by MS and 1H-NMR (139 mg, LRMS (ESI) [M+H+]+=286.1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[CH2:5]P(=O)(OC)OC.[H-].[Na+].[OH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.CCOCC>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:4]=1[CH:5]=[CH:32][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][OH:20])=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(OCCCCCCO)cc1
Reactant: COc1ccc(OC)c(CP(=O)(OC)OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(OC)c(C=Cc2ccc(OCCCCCCO)cc2)c1
Temperature: 6 °C
Reaction time: 1.5 h

Procedure:
A mixture of dimethyl 2,5-dimethoxybenzylphosphonate (2.92 g, 11.2 mmol) and sodium hydride (60% in oil, 1.08 g, 27.0 mmol) in dry DMF (92 ml) was cooled with in an ice-bath under argon. To this was added dropwise a solution of 4-(6-hydroxyhexyloxy)benzaldehyde (13) (2.50 g, 11.3 mmol) in dry DMF (55 ml). The reaction mixture was stirred at 6° C. for 1.5 h and then at room temperature for 4 h. Ether (300 ml) and water (250 ml) were added and the mixture shaken well. The organic layer was separated and washed with water (4×250 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica (dichloromethane/methanol; 19:1 yield (14) (1.89 g, 47%) as an oil; δH (CDCl3) 1.46 (4 H, m, CH2), 1.60 (2 H, m, CH2), 1.79 (2 H, m, CH2), 3.65 (2 H, t, J =6.6 Hz, OCH2), 3.81 (3 H, s, OCH3), 3.83 (3 H, s OCH3), 3.96 (2 H, t, J=6.5 Hz, OCH2), 6.76 (1 H, dd, JH3', JH4 '=8.9 Hz, JH6',H4' =3.0 Hz, H4'), 6.82 (1 H, d, JH4',H3' =8.9 Hz, H3'), 6.87 and 7.45 (4 H, AA'BB', PhH), 7.03 (1 H, d, J=16.5 Hz, vinylic H), 7.13 (1 H, d, JH4',H6' =3.0 HZ, H6') and 7.31 H, d, J=16.5 Hz, vinylic H); δc (CDCl3) 25.5, 25.6, 29.2, 32.6, 55.7, 56.2, 62.8, 67.8, 111.3, 112.2, 113.1, 114.5, 120.7, 127.6, 127.7, 128.7, 130.4, 151.2, 153.7 and 158.7.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.Cl.[CH:10]12[O:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:11][CH:10]3[O:17][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[CH:5]=[CH:4][N:3]=1.[Cl:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:11][CH:10]3[O:17][CH:14]([CH2:15][CH2:16]3)[CH2:13]2)[N:7]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ccnc(N2CC3CCC(C2)O3)n1
Product: Clc1nccc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %
Yield: 4 %

Procedure:
A 745 mg (5 mmol) portion 2,4-dichloropyrimidine (1) was dissolved in 20 mL EtOH at 0 C. 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (2, 748 mg, 5 mmol) was added followed by the addition of NEt3 (2.1 mL, 15 mmol). The mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated, dissolved in EtOAc and washed with saturated NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated. The mixture was purified by silica gel chromatography (20-70% EtOAc in hexanes) to give 1,003 mg (4.4 mmol, 89%) of 3-(2-chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3) along with 50 mg (0.22 mmol, 4%) of 3-(4-chloro-pyrimidin-2-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (4).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:21][C:3]1[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)cccc1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for example 1, (3-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 2) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as dark brown amorphous solid. MS: 417.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=1)=[O:28])=[N+:22]=[N-:23]>>[CH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[C:27]([NH:26][CH2:25][CH2:24][N:21]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]2[N:6]=[C:2]([NH2:1])[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=2)[N:23]=[N:22]1)=[O:28]
Reactant: [N-]=[N+]=NCCNC(=O)c1ccc2ccccc2c1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3ccc4ccccc4c3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.095 g, 0.344 mmol) was reacted with N-(2-azidoethyl)-2-naphthamide (0.083 g, 0.344 mmol) following the general click procedure to give tert-butyl 4-(5-(1-(2-(2-naphthamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-2-amino-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H), δ 8.01 (s, 1H), δ 7.72 (m, 4H), δ 7.39 (m, 2H), δ 7.26 (s, 1H), δ 6.33 (s, 1H), S 6.04 (s, 2H), δ 4.51 (s, 2H), δ 3.88 (s, 2H), δ 2.48 (t, 2H), δ 2.12 (s, 2H), δ 1.47 (m, 13H), δ 1.17 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.5, 150.4, 149.5, 148.3, 138.6, 134.9, 132.7, 131.4, 129.2, 128.5, 128.1, 127.9, 126.8, 124.0, 122.3, 106.5, 84.9, 49.4, 40.4, 29.9, 29.2, 28.9, 28.6, 28.2, 27.9, 28.6, 27.9, 27.8, 25.6 ppm; HRMS (ESI) calcd for C28H35N7O3(M+) 517.2801. found 517.2792, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-2-naphthamide hydrochloride (0.140 g, 90% yield). 1H NMR (300 MHz, CD3OD) δ ppm; 13C NMR (75 MHz, CD3OD) δ ppm; HRMS (ESI) calcd for C23H27N7O (M+) 417.2277. found 417.2274.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH:10]([CH3:30])[CH:11]([C:17]1[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:22]=1)[C:12](OCC)=[O:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH:11]([C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)[CH:10]([CH3:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(c1nc(N2CCOCC2)cc(=O)[nH]1)C(C)C
Reactant: Nc1ccc(F)cc1
Product: CC(C)C(C(=O)Nc1ccc(F)cc1)c1nc(N2CCOCC2)cc(=O)[nH]1

Procedure:
The product is prepared according to the procedure described in example 70, using 0.023 ml of 4-fluoroaniline and 36 mg of ethyl 3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanoate in place of the ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate. After purification by silica column chromatography, eluent: 940303 CH2Cl2/CH3CN/MeOH, 15 mg of N-(4-fluorophenyl)-3-methyl-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]butanamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](=O)(O)[O-:11].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[C:10]=[O:11]
Reactant: Cc1ccc(CN)cc1
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(CN=C=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of p-methyl benzylamine (25 g, 0.21 mol) in CH2Cl2 (200 mL) and aqueous saturated solution of sodium bicarbonate (200 mL) was cooled to 0° C. and then treated dropwise with a 20% solution of phosgene in toluene (100 mL). The reaction was stirred at room temperature for 20 minutes and then the organic layer removed and the aqueous layer back-extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to give 20.6 g 1-isocyanatomethyl-4-methyl-benzene that was utilized directly in the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7](OC)=O.C(C[C:20]([O:22]C)=[O:21])#N.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[C:20]([CH2:7][C:6]1[CH:5]=[C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:3][C:2]=1[NH:1][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N
Reactant: COC(=O)CC#N
Reactant: O=C(Cl)c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=C(O)Cc1cc(-c2ccccc2)sc1NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Methyl 2-amino-5-phenyl-thiophene-3-carboxylate (1.3 g, 0.0055 mole) in hexamethyl phosphoramide (prepared by the method of Chemische Berichte, 99, 94 (1966) but using methyl cyanoacetate in place of ethyl cyanoacetate) (20 ml.) was stirred and treated with benzoyl chloride (1.56 g, 1.28 ml, 0.011 mole). The solution was stirred for 2 hours, poured into water (750 ml), stored overnight and the title compound filtered off (1.31 g) m.p. 190° C.