Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:28][CH2:29][CH2:30][CH3:31])[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:9]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:8]=2[S:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C(Cl)Cl.C([O-])([O-])=[O:36].[K+].[K+].ClC1C=C(C=CC=1)C(OO)=O.[OH2:52]>>[O:52]=[S:7]1(=[O:36])[C:8]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:9]=2[N:10]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:5]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6]1
Reactant: O
Reactant: CCCCC1(CCCC)CSc2cc(OC)ccc2N(c2ccc([N+](=O)[O-])cc2)C1=O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClCCl
Product: CCCCC1(CCCC)CS(=O)(=O)c2cc(OC)ccc2N(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To 3,3-dibutyl-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 103; 2.57 g, 5.8 mmol) was added DCM (130 ml), water (130 ml) and K2CO3 (2.44 g, 17.6 mmol). The reaction mixture was cooled down to 0° C. and m-chloroperoxybenzoic acid (3.42 g, 13.9 mmol) was added in one portion. The reaction was allowed to complete overnight with the temperature slowly rising to room temperature. Then NaHCO3aq (sat) was added and the two layers were separated. The water layer was then extracted three times with DCM. The combined organic layers was dried, filtered and evaporated under reduced pressure. The product was purified by flash chromatography using DCM as eluent to give the title compound 2.4 g (87%). M/z 475.4.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:22]([CH:23]=O)=[CH:21][C:11]3[C:12]([C:15]4[N:19]([CH3:20])[N:18]=[CH:17][N:16]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:25])[CH2:5][C@@H:4]([CH3:26])[O:3]1.[NH:27]1[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]1=[O:35]>CO>[F:25][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][N:16]=3)[C:11]=2[CH:21]=[C:22]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:26])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:31]1([C:30](=[O:34])[NH:29][C:28](=[O:35])[NH:27][C:32]1=[O:33])[CH2:23]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-c4ncnn4C)noc3c2F)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: C[C@@H]1CN2c3c(cc4c(-c5ncnn5C)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 150 °C

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 537, 124 mg, 0.35 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (44.2 mg, 0.35 mmol) in methanol (3 ml) was heated at 150° C. for 1 hour in a microwave reactor. Solvent was removed and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% TFA). The solid was taken up in 9:1 CH2Cl2-MeOH and washed with NaHCO3 and brine. The aqueous layers were repeatedly extracted with additional 9:1 CH2Cl2-MeOH with each extract being washed with brine. The combined organic layers were dried (MgSO4) and concentrated and the residue was dissolved in THF. After removal of solvent, the solid residue was dried in vacuo at 50° C. overnight to afford desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][CH2:20][SH:21].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:20]([S:21][C:13](=[O:15])[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:16]([CH3:18])[CH3:17])[CH3:19]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution containing (R)-2-benzyloxycarbonylamino-3-methyl-butyric acid (5.0 g, 20.0 mmol) in anhydrous CH2Cl2 (20 mL) is added DMAP (258 mg, 2.0 mmol) followed by chilled EtSH (1.6 mL, 22.0 mmol). Dicyclohexylcarbodiimide (4.5 g, 22.0 mmol) is added in one portion and the reaction is complete after 30 min. The solid material is removed by vacuum filtration and the filtrate is concentrated. The crude product is purified by flash silica gel chromatography (hexane to 8:1 hexane/EtOAc) to provide (R)-2-benzyloxycarbonylamino-3-methyl-thiobutyric acid S-ethyl ester (5.21 g, 88%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ0.85 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.5 Hz, 3H), 2.27 (m, 1H), 2.88 (q, J=7.5 Hz, 2H), 4.35 (dd, J=9.5, 4.6 Hz, 1H), 5.13 (s, 2H), 5.25 (br d, J=9.5 Hz, 1H), 7.30-7.36 (m, 5H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[N:9][NH:10][C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C)P(=O)(N(C)C)N(C)C>[N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH:8]=[N:9][NH:10][C:11]2[N:12]=[N:13][C:14]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=NNc2ccc(Cl)nn2)cc1
Reactant: C1COCCN1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc(C=NNc2ccc(N3CCOCC3)nn2)cc1
Yield: 85.3 %

Procedure:
The mixture of 5.55 g (20 mmoles) of 4-nitrobenzylidene-(6-chloro-3-pyridazinyl)-hydrazine [prepared by the process described in Step a:], 7.66 g (88 mmoles) of morpholine and 5.5 ml of hexamethylphosphoric cid triamide is heated at 150° C. for 24 hours. After cooling, the mixture is triturated with 56 ml of water, the precipitate is filtered, washed with cold ethanol and dried to give 5.6 g (85%) of the named compound; m.p. 245° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Li]CCCC.CN([CH:19]=[O:20])C.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([CH:19]=[O:20])[CH:6]=[CH:5][N:4]=1
Reactant: CN(C)C=O
Reactant: COc1cccnc1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nccc(C=O)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of 2,3-dimethoxypyridine (1.0 g, 7.19 mmol) in dry THF (30 mL), cooled to −78° C., was added 2.5 M nBuLi in hexanes (6.33 mL, 15.8 mmol). The mixture was allowed to warm to 0° C. and stirred for 1 hour, before cooling to −78° C. A solution of DMF (2.4 mL, 31.5 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to 0° C. and saturated aqueous ammonium chloride solution was added. The resultant biphasic mixture separated and extracted twice with diethyl ether. The combined organic phase was washed with water, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 20% ethyl acetate in cyclohexane) to afford the title compound (0.79 g, 65%) as a white solid. LCMS (Method B): RT-=2.71 min, [M+H]+=168.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:44])(=[N:29]C(C3CCCN3C(OC(C)(C)C)=O)=O)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.S(=O)(=O)(O)O>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:44])(=[NH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)N=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CS(=N)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-(1-tert-butoxycarbonyl-pyrrolidin-2-carbonyl)sulfoximide (1.2 g, 0.00182 mol, nonpolar isomer) in methanol (4 mL) was added conc. sulfuric acid (0.7 g, 0.00728 mol) at 5-10° C. The reaction mixture was stirred at 25-30° C. for 4 hr and then diluted with water. Product obtained was extracted in chloroform at 8-9 pH. Organic layer was dried and concentrated to give 640 mg of titled product in 63% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([NH2:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([C:33](O)=[O:34])[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:22])[CH:9]([NH:21][C:33]([CH:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24](=[O:23])[CH2:25]2)=[O:34])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C1CC(C(=O)O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C1CC(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of (1RS,2RS)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine (150 mg, 0.42 mmol) in acetonitrile (10 ml) were added 3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (73 mg, 0.42 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) and 1-hydroxy-1H-benzotriazole (63.6 mg, 0.42 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from ethyl acetate-hexane to give a highly polar isomer (61 mg, 31%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:4]1.[H-].[Na+].I[CH3:23]>CN(C=O)C>[CH3:23][O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH2:4]1
Reactant: CI
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC[C@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Racemic trans 2-(3-hydroxymethyl-cyclohexyl)-isoindole-1,3-dione (0.37 g, 1.427 mmol) was dissolved in DMF (7 mL) and cooled to 0° C. At that temperature, NaH (60%, 0.136 g, 3.424 mmol) was added, followed by iodomethane (0.54 mL, 8.676 mmol) about 10 minutes later. After another 10 minutes the ice bath was removed, and the reaction mixture was heated to 38° C. After 3 hours, another 6 equivalents of iodomethane were added and the reaction mixture was stirred at 38° C. overnight before being cooled, quenched by addition of saturated aqueous NH4Cl, and extracted times with Et2O. The organic layers were combined, dried (Na2SO4), filtered, and evaporated. The remaining orange oil was purified by SiO2 chromatography (24 g SiO2, hexanes/EtOAc 0 to 10% EtOAc) to give 0.21 g of racemic trans 2-(3-methoxymethyl-cyclohexyl)-isoindole-1,3-dione as white crystalline solid (54% yield).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11](OCC)=O.Cl.[C:20]1(=[N:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>O1CCCC1.CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:11]2[C:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[NH:29][N:30]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: NN=C1CCc2ccccc21
Reactant: CCOC(=O)c1cccc(OC)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1

Procedure:
In a similar manner to Example 1, indan-1-one hydrazone (3.55 g) was dissolved in tetrahydrofuran (80 ml) at 0° C. under nitrogen with stirring. n-Butyllithium (28.8 ml of a 2.5M solution in hexane) was added to the solution and the mixture was stirred at 0° C. for 0.5 h. Ethyl 3-methoxybenzoate (2.16 g) was added, followed by 3M hydrochloric acid (80 ml) and the mixture was worked up as described in Example 1 to give 3-(3-methoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 172-174° C.
Reaction SMILES: C(O[O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1CC)(=O)C.[H-].C([Al+]C[CH:22]([CH3:24])C)C(C)C.C[OH:26].O>C1(C)C=CC=CC=1>[F:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:24][CH:22]=[O:26])=[CH:11][CH:10]=1
Reactant: CO
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCc1cc(F)ccc1OOC(C)=O
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=CCOc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a stirred solution of 1.98 g (10 mmoles) of ethyl-p-fluorophenoxy acetate (Example 155) in 15 ml of dry toluene, cooled to -78° C., under argon, is added, dropwise over 30 minutes, 8 ml of a 1.4 M solution of diisobutylaluminum hydride in toluene (11 mmoles). The mixture is stirred for 2 hours at -78° C., 1 ml of methanol is added, followed by 5 ml of water, dropwise. The gel formed is filtered through Celite and washed with 100 ml of ether, portionwise. The organic phase is separated, washed twice with 25 ml of a saturated brine solution, dried with magnesium sulfate, filtered, and evaporated. The oil obtained is distilled at 71°-73° C. (0.1 mm) to give 600 mg (45%) of the subject product as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][C:15]3[CH2:19][C:18](=[O:20])[NH:17][N:16]=3)OCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClB(Cl)Cl>C(#N)C>[C:1]1([C:7]2[N:16]3[N:17]=[C:18]([OH:20])[CH:19]=[C:15]3[CH2:14][CH2:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(CCCC2(c3ccccc3)OCCO2)=NN1
Agent: ClB(Cl)Cl
Solvent: CC#N
Product: Oc1cc2n(n1)C(c1ccccc1)=CCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.9 %

Procedure:
Step AAH (6): To a soln of 3-(3-(2-phenyl-1,3-dioxolan-2-yl)propyl)-1H-pyrazol-5(4H)-one (1.1 g, 4.01 mmol) in acetonitrile (15 mL) was added trichloroborane (1.0 M in CH2Cl2, 10.02 mL, 10.02 mmol) at −10° C. under nitrogen. The mixture was allowed to warm to rt, and stirred at rt for 6 h. The reaction was quenched with 50 mL of aqueous 0.1 N HCl (50 mL). The mixture was extracted with dichloromethane (3×80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified using silica gel column chromatography (60% EtOAc/hexanes) to afford 7-phenyl-4,5-dihydropyrazolo[1,5-a]pyridin-2-ol (510 mg, 60% yield) as a solid. LC-MS (M+H)+ 213.06. 1H NMR (500 MHz, methanol-d4) δ ppm 7.42-7.53 (m, 2 H) 7.29-7.40 (m, 3 H) 5.55 (s, 1 H) 5.50 (t, J=4.88 Hz, 1 H) 2.86 (t, J=7.63 Hz, 2 H) 2.35-2.45 (m, 2 H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([N:8]1[C:16](=[O:17])[NH:15][C:14]2[C:13]([CH3:18])=[N:12][C:11]3=[C:19]([C:23]4[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[CH3:31])[C:20]([CH3:22])=[N:21][N:10]3[C:9]1=2)[CH2:6][CH3:7])[CH3:4].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[CH2:32]([N:15]1[C:14]2[C:13]([CH3:18])=[N:12][C:11]3=[C:19]([C:23]4[C:24]([CH3:31])=[CH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])[C:20]([CH3:22])=[N:21][N:10]3[C:9]=2[N:8]([CH:5]([CH2:6][CH3:7])[CH2:3][CH3:4])[C:16]1=[O:17])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CCC(CC)n1c(=O)[nH]c2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)n1c(=O)n(Cc2ccccc2)c2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium hydride (28 mg, 0.71 mmol) was added to a solution of 1-(1-ethylpropyl)-6-mesityl-4,7-dimethyl-2,3-dihydro-1H-pyrazolo[5,1-b]purin-2-one (230 mg, 0.59 mmol) in N,N-dimethylformamide (5 mL) at room temperature. After 30 minutes, benzyl bromide (0.079 mL, 0.65 mmol) was added, followed by stirring at 70° C. for one hour. Water was added under ice-cooling, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15-20% ethylacetate/hexane), to give the title compound (259 mg) as brown crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.[N:29]([CH2:32][C:33]1[N:42]=[C:41](Cl)[C:40]2[CH2:39][C:38]([CH3:45])([CH3:44])[CH2:37][CH2:36][C:35]=2[N:34]=1)=[N+]=[N-].[N-]=[N+]=[N-]>>[CH3:44][C:38]1([CH3:45])[CH2:37][CH2:36][C:35]2[N:34]=[C:33]([CH2:32][NH2:29])[N:42]=[C:41]([N:16]3[CH2:15][C:14]4[CH:20]=[C:10]([C:8]5[CH:9]=[C:4]6[NH:3][C:2]([CH3:1])=[N:21][C:5]6=[N:6][CH:7]=5)[CH:11]=[CH:12][C:13]=4[O:19][CH2:18][CH2:17]3)[C:40]=2[CH2:39]1
Reactant: CC1(C)CCc2nc(CN=[N+]=[N-])nc(Cl)c2C1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Agent: [N-]=[N+]=[N-]
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3nc(CN)nc5c3CC(C)(C)CC5)CCO4)cc2[nH]1

Procedure:
Prepared as an acetate salt by the method of example 6 using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and 2-(azidomethyl)-4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (reagent preparation 45) in step 3 followed by reduction of the azide to the amine (LaRock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations 1989, VCH Publishers, Inc., New York). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.54 (dd, 1H), 7.04 (d, 1H), 4.68 (s, 2H), 4.34-4.28 (m, 2H), 3.92-3.87 (m, 2H), 3.63-3.59 (m, 2H), 2.69 (t, 2H), 2.54 (s, 3H), 2.46 (s, 2H), 1.86 (s, 5H), 1.59 (t, 2H), 0.86 (s, 6H); MS (EI) for C27H31N7O: 470 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.O>CS(C)=O>[N:10]1([C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:14]=[N:13][CH:12]=[N:11]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1cnccc1Cl
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cnccc1-n1cncn1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 82.3 %

Procedure:
A mixture of known 4-chloro-nicotinonitrile (3.325 g, 24 mmol) (Tetrahedron Lett. 46:135-137, 2005), 1H-[1,2,4]triazole (1.99 g, 28.8 mmol), and CsCO3 (9.30 g, 28.5 mmol) in DMSO (5.0 mL) was stirred at 55° C. for 1.5 h. The resulting thin light brown slurry was shaken with water (50 mL) and extracted with DCM (1×50 mL, 2×25 mL). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum at 90° C. to afford the title compound as a beige solid (3.38 g, 82%).
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([N:12]2[CH2:17]COC[CH2:13]2)=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[CH3:17][N:12]([CH3:13])[C:10]([CH:6]1[C:5]2[N:45]=[C:43]([NH:42][C:32]3[CH:33]=[CH:34][C:35]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)=[C:30]([O:29][CH3:28])[CH:31]=3)[N:44]=[CH:3][C:4]=2[CH2:9][CH2:8][CH2:7]1)=[O:11]
Reactant: CN(C)C=C1CCCC(C(=O)N2CCOCC2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(C(=O)N(C)C)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-(morpholine-4-carbonyl)-cyclohexanone (25 mg, 0.11 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (31 mg, 0.084 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (23 mg, 67%). MS ISP (m/e): 407.4 (100) [(M+H)+]. mp 150-152° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH:14]([C:18]([OH:20])=[O:19])C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Cl-].[Na+].[CH3:24]N(C=O)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][CH2:14][C:18]([O:20][CH3:24])=[O:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(CC(C(=O)O)C(=O)O)C1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC1=CCN(C(=O)OC(C)(C)C)C1
Temperature: 150 °C
Yield: 92 %

Procedure:
To a solution of 4.52 g (14.4 mmol) 2-(1-tert.-butoxycarbonyl-2,5-dihydro-1H-pyrrol-3-yl-methyl)-malonic acid idimethylester n 140 ml DMF were added 1.94 g (108 mmol) water and 1.26 g( 21.6 mmol) sodium chloride. The mixture was degassed and heated to 150° C. for 30 h under an atmosphere of argon. After this period of time no starting material could be detected by TLC. The mixture was cooled to room temperature, diluted with 200 ml ether and washed three times with water, then with brine. The organic layer was dried over MgSO4 and evaporated. Purification by bulb-to-bulb distillation gave 3.38 g (92%) of 3-(2-methoxycarbonyl-ethyl)-2,5-dihydropyrrole-1-carboxylic acid tert. butylester as a colorless oil, b.p. 130° C. (0.2 mbar).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:13])=[CH:8][CH:7]=2)[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Product: CN(C)c1ccc(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)cc1
Yield: 7.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(dimethylamino)phenyl)acetic acid and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 35, (2S,4R)-4-benzyl-1-(2-(4-(dimethylamino)phenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (2.5 mg, 7.6%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.56 (m, 2H), 7.23 (t, 2H), 7.12 (m, 5H), 6.98 (m, 6H), 6.64 (m, 2H), 4.46 (m, 1H), 3.49 (s, 2H), 3.24 (m, 1H), 2.84 (s, 6H), 2.60 (m, 3H), 1.87 (m, 2H). MS (EI) for C34H34FN3O3: 552.6 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[N:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:14]([CH3:17])([O-:16])=[O:15]>>[CH2:5]([NH:4][C:3]([S:2][CH3:1])=[CH:17][N+:14]([O-:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CSC(=NCc1ccccc1)SC
Product: CSC(=C[N+](=O)[O-])NCc1ccccc1

Procedure:
A mixture of nitromethane (4 ml), zeolite, RE 70 Na-Y (500 mg) and benzyl carbonimidodithioic acid dimethyl ester (XI, 500 mg) was refluxed for 110 hr. It was filtered and filtrate concentrated and treated with pet. ether. The solid that separated out was filtered and characterized as compound XII.