Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCn1cc(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
Methyl 3-cyclohexyl-1H-indole-6-carboxylate (500 mg, 1.94 mmol) was added to a suspension of NaH (85.5 mg of 60% dispersion in mineral oil, 2.14 mmol) in DMF (5 mL), and the reaction mixture stirred at RT for 15 min. Methyl 5-bromovalerate (0.305 mL, 2.14 mmol) was then added and the reaction mixture stirred at RT overnight, after which the reaction was quenched with ice and extracted with ethyl acetate (2×50 mL). The extracts were then combined, washed with 1N HCl solution, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes to 25% ethyl acetate in hexanes as eluant to give the title compound as a colorless thick oil (0.41 g, 57% yield). MS m/z 372(MH+). 1H NMR (300 MHz, CDCl3) □ ppm 1.23 (m, 1 H) 1.35–1.48 (m, 5 H) 1.62 (m, 2 H) 1.69–1.89 (m, 6 H) 2.03 (m, 2 H) 2.29 (t, J=7.32 Hz, 2 H) 2.78 (m, 1 H) 3.62 (s, 3 H) 3.90 (s, 3 H) 4.11 (t, J=6.95 Hz, 2 H) 6.97 (s, 1 H) 7.60 (d, J=8.42 Hz, 1 H) 7.72 (d, J=9.51 Hz, 1 H) 8.00 (s, 1 H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[CH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][O:15]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:33]CCl>>[Cl-:33].[NH3+:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[CH2:13][C:14]1([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17][CH2:16][O:15]1
Reactant: COC(=O)C1(Cc2cccc(CNC(=O)OC(C)(C)C)c2)CCCO1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(Cc2cccc(C[NH3+])c2)CCCO1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.26 g of methyl 2-(3-{[(t-butoxycarbonyl)amino]methyl}benzyl)tetrahydro-2-furancarboxylate in 20 ml of dichloromethane was added 20 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, and the residue was dissolved in 30 ml of ethyl acetate. 2 ml of hydrogen chloride (4N solution in ethyl acetate) was added and the mixture was concentrated again, to give 0.84 g of the title compound as a brown oil.
Reaction SMILES: O.[SH2:2].[Na].Cl[C:5]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:8][O:7][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.O>[C:26]1([CH2:25][CH2:24][CH2:23][S:2][C:5]2[C:9]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:8][O:7][N:6]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: S
Reactant: BrCCCc1ccccc1
Reactant: Clc1nonc1-c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CCCSc2nonc2-c2cccnc2)cc1
Reaction time: 1 h

Procedure:
Sodium hydrogen sulfide monohydrate (0.74 g, 10.5 mmol) was added to a solution of 3 -(3-chloro-1,2,5-oxadiazol-4-yl) pyridine (1.27, 7.0 mmol) in DMF (30 ml) at room temperature and the reaction mixture was stirred for 1 h. Potassium carbonate (2.0 g, 14.5 mmol) and 1-bromo-3-phenylpropane (2.4 g, 12 mmol) were added and the reaction mixture was stirred for additionally 24 h. Water (50 ml) was added and extracted with ether. The combined ether phases were dried and evaporated. Purification by column chromatography (SiO2, eluent: ethyl acetate/methylene chloride (1:1)) gave the title compound.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].B[O-].C(=O)C.[CH3:12][C:13]1[CH:18]2C(C)(C)C(C2)[CH2:15][CH:14]=1.B([O-])[O-].N(CCO)CCO>CCOCC.C1COCC1>[CH3:4][CH:3]([CH2:2][C@@H:1]([OH:6])[CH2:18][C:13]([CH:14]=[CH2:15])=[CH2:12])[CH3:5]
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CC(C)CC=O
Agent: B[O-]
Agent: CC=O
Agent: [O-]B[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=C)C[C@H](O)CC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Isovaleraldehyde (2.15 g, 2.68 mL, 25 mmol) in ether (6 mL) was added dropwise to a rapidly stirred solution of B- isoprenyldiisopinocampheylborane, lIpc2BIpn, maintained at -78° C. Stirring was continued for 1 h, when the 11B NMR spectrum of an aliquot showed a peak at δ 52 ppm corresponding to a borinate indicating completion of the reaction. The reaction mixture was warmed to 0° C. and acetaldehyde (2.1 mL, 37.5 mmol) was added when one equiv of α-pinene was eliminated. 11B NMR showed a peak at δ 32 ppm corresponding to a boronate. THF was substituted with EE and 1.1 equiv. of diethanolamine (2.6 mL), 27.5 mmol) was added and stirred for 2 h. The precipitated boron components were filtered and the filtrate was concentrated and distilled (92°-94° C./19 mm Hg) to yield 2.5 g (65%) of (-)-ipsenol. [α]D =-17.67° (c 1, MeOH) which corresponds to 96% ee. The spectral properties were identical to the racemic mixture of Example 6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18]O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[N:11]([C:12]([S:16][CH3:17])=[N:13][CH:14]=[CH:15]3)[N:18]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(CC(=NO)c2ccc(F)cc2)n1
Agent: Cl[Fe]Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Product: CSc1nccc2cc(-c3ccc(F)cc3)nn12
Temperature: 20 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a 0° C. solution of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime (4.0 g, 14 mmol) in ethylene glycol dimethyl ether (40 mL) was added trifluoroacetic anhydride (3.0 g, 14 mmol) dropwise. The reaction was allowed to warm to 20° C., then re-cooled to 0° C. Triethylamine (2.9 g, 29 mmol) was added dropwise so that the internal reaction temperature did not exceed 10° C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. Iron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heated to 80° C. for 2 hours. An additional portion of iron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heated at 80° C. for 2 hours. An additional portion of iron (II) chloride (18 mg, 0.14 mmol) was added and the mixture heated at 80° C. for 4 hours. The reaction was allowed to cool to room temperature and stirred overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×20 mL) and the organic layers combined. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica chromatography eluting with 1% acetone in dichloromethane to yield 2.54 g (68%) of 2-(4fluorophenyl)-7-(methylsulfanyl)-pyrazolo[1,5-c]pyrimidine. 1H NMR (CDCl3): δ 8.04 (dd, 2H),7.80 (d, 1H), 7.20 (m, 3H), 6.79 (s, 1H), 2.76 (s, 3H). MS m/z 260 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][OH:13])=[N:7][CH:8]=1.[H-].[Na+].[Br:16][C:17]1[C:18](Cl)=[N:19][C:20]([CH3:23])=[N:21][CH:22]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:16][C:17]1[C:18]([O:13][CH2:12][C@H:10]2[CH2:11][C@@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=2)=[N:19][C:20]([CH3:23])=[N:21][CH:22]=1
Reactant: COc1ccc([C@H]2C[C@@H]2CO)nc1
Reactant: Cc1ncc(Br)c(Cl)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methanol (S,S-DD3, ent2) (1.1 g, 6.1 mmol) in THF (25 mL) was added sodium hydride (300 mg, 7.4 mmol). The reaction mixture stirred at ambient temperature for 30 minutes. Next, a solution of 5-bromo-4-chloro-2-methylpyrimidine (MM2) (1.5 g, 7.4 mmol) in THF (5 mL) was added and the reaction mixture was stirred at ambient temperature for two hours. Aqueous sodium bicarbonate (20 mL) was carefully added and the mixture was extracted with EtOAc (2×50 mL). The combined organics were dried over MgSO4, filtered and concentrated to afford the title compound as a yellow oil, which was sufficiently pure to use in the subsequent step without further purification. 1H NMR (500 MHz, DMSO): δ 8.60 (s, 1 H), 8.12 (d, J=3.0 Hz, 1 H), 7.30-7.22 (m, 2 H), 4.42 (d, J=7.1 Hz, 2 H), 3.78 (s, 3 H), 2.50 (s, 3 H), 2.19 (dt, J=8.6, 4.6 Hz, 1 H), 1.75 (s, 1 H), 1.14 (dt, J=8.8, 4.7 Hz, 1 H), 1.04 (dt, J=8.9, 4.7 Hz, 1 H); LRMS m/z (M+H) 350.3 found, 350.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4C(C)=CC=C4C)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.NO.Cl.C(N(CC)CC)C>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:14]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:23])[C:17]=3[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(-n3c(C)ccc3C)cccc21
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(COC)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C

Procedure:
To the mixture of 1-(2-(4-chlorophenyl)-1-methoxybutan-2-yl)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1H-indole (70 mg) in ethanol/H2O (3 mL/1 mL) was added NH2OH—HCl (178 mg) and triethylamine (87 mg) and the reaction mixture was refluxed for 18 h in an oil bath, cooled to room temperature, concentrated, and extracted with ethyl acetate (30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified using a silica gel column (20-40% ethyl acetate in hexane) to afford the title compound as a brown solid. LC/MS m/z=329.1 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:28][O:29][NH3+:30].[Cl-].C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1>[CH3:28][O:29][NH:30][C:3](=[O:5])[CH:2]([CH3:1])[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:12]=2)[CH:7]=1
Reactant: CC(C(=O)O)c1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Reactant: CO[NH3+]
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONC(=O)C(C)c1ccc2cc(OCc3ccc4ccccc4n3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the acid of Example 1 (2.32 g, 6.5 mmol), 0-methylhydroxylamine hydrochloride (0.54 g, 6.5 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (1.25 g, 6.5 mmol) in tetrahydrofuran (100 ml) is added triethylamine (2.0 ml, 2 equiv). After overnight stirring at room temperature, the solvent is removed and methylene chloride is added. This is followed by sequential washings with 0.05N hydrochloric acid and water (2x). After drying over magnesium sulfate, the solvent is removed to afford a crude solid which is recrystallized from ethyl acetate to afford a white crystalline solid, 0.6 g(24%), m.p. 162°-164° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)[C:15]([C:16](=O)[CH:17]=[CH:18]N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH:30]1([NH:35][C:36]([NH2:38])=[NH:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:38]=[C:36]([NH:35][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:37]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C=CC(=O)c1c(-c2ccncc2)nn2c(NC3CCCC3)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc(NC2CCCC2)n2nc(-c3ccncc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (0.3 g, 0.94 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was heated at reflux for 3 days. The mixture was allowed to cool to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated. The resulting residue was purified by flash chromatography (7:3 ethyl acetate-acetone) to give 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.23 g, 65%) as a colored syrup which was used in the next step without further purification. To a solution of 1-[7-(cyclopentylamino)-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (0.10 g, 0.27 mmol) in tetrahydrofuran (10 mL) was added cyclopentyl guanidine hydrochloride (0.06 g, 0.38 mmol) followed by potassium tert-butoxide (0.085 g, 0.76 mmol). The resulting mixture was heated at reflux for 12 hours. Upon cooling to room temperature, water was added. The mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (1:9 methanol-dichloromethane) to give the title compound (89 mg, 75%) as a white solid. 1H NMR (CDCl3): δ 8.64 (d, 2H), 8.04 (d, 1H), 7.58 (m, 3H), 7.28 (t, 1H), 6.32 (d, 1H), 6.02 (d, 1H), 5.95 (d, 1H), 5.03 (d, 1H), 4.22 (m, 1H), 3.97 (m, 1H), 1.2–2.2 (m, 16H); MS m/z 440 (M+1).
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.O>O1CCCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:8][CH2:9]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: COC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1

Procedure:
A solution of 2.95 g of p-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]benzonitrile in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 15 minutes. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated, whereby 2.6 g (93%) of 4-[trans-4-(p-cyanophenyl)cyclohexyl]butyraldehyde were obtained as a slightly yellowish oil; Rf-value (toluene/ethyl acetate vol. 95:5) 0.23.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:8]([C:10]2[C:11]3[NH:18][CH:17]=[C:16]([C:19](O)=[O:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.[NH2:57][CH:58]1[CH2:63][CH2:62][N:61]([C:64](=[O:68])[C@@H:65]([OH:67])[CH3:66])[CH2:60][CH2:59]1>ClCCl>[OH:67][C@@H:65]([CH3:66])[C:64]([N:61]1[CH2:62][CH2:63][CH:58]([NH:57][C:19]([C:16]2[C:12]3[N:13]=[CH:14][N:15]=[C:10]([C:8]4[CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[O:22][CH2:23][CH:24]4[CH2:25][CH2:26]4)[C:11]=3[NH:18][CH:17]=2)=[O:20])[CH2:59][CH2:60]1)=[O:68]
Reactant: C[C@H](O)C(=O)N1CCC(N)CC1
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5-acetyl-2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid from example A81 (43 mg; 0.12 mmol) in dichloromethane (2 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 mmol), triethylamine (0.24 mmol) and 1-hydroxybenzotriazole (0.12 mmol). The suspension is stirred for 20 min at ambient temperature and then (S)-1-(4-amino-piperidin-1-yl)-2-hydroxy-propan-1-one hydrochloride from example A190 (0.16 mmol) is added. The reaction mixture is stirred overnight at ambient temperature. The volatiles are evaporated and the crude is distributed between ethyl acetate and aqueous phosphate buffer (1M, pH=7). The organic phase is separated, washed with aqueous phosphate buffer and evaporated to dryness. The obtained crude product is purified by preparative HPLC yielding 38 mg of the title compound as white solid.
Reaction SMILES: [CH:1]1(NCCC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]1([C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1>>[CH:1]1([CH2:19][CH2:20][CH2:21][NH:22][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: CCCNC1CCCCC1
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCC4CCCCC4)CC3)cc2o1

Procedure:
Condensation of cyclohexyl-1-propylamine (0.9 g, 6.4 mmol) and ketone 5 (1.5 g, 6.4 mmol), following the procedure described in Example 1, gave 6-{trans-4-[(3-cyclohexylpropyl)amino]cyclohexyl}-3H-benzoxazol-2-one (352 mg, 15%), as a white solid: 1H NMR (500 MHz, DMSO-d6): δ 7.12 (br s, 1H), 6.97-6.93 (m, 2H), 3.70-3.10 (br s, 2H), 2.53 (t, J=7 Hz, 2H), 2.48-2.39 (m, 2H), 1.95 (br d, J=12 Hz, 2H), 1.77 (br d, J=12 Hz, 2H), 1.70-1.59 (m, 5H), 1.50-1.38 (m, 4H), 1.23-1.08 (m, 8H), 0.90-0.81 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:9]([C@@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:18]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@H]1CC[C@@H](Nc2cc(Cl)ncn2)CC1

Procedure:
58.6 g (0.39 mol) of 4,6-dichloropyrimidine were placed in 400 ml of toluene, and a mixture of 61.0 g (0.39 mol) of cis-4-tert-butylcyclohexylamine and 50.0 g (0.50 mol) of triethylamine in 100 ml of toluene was added dropwise at from 70° to 80° C. The mixture was subsequently stirred at reflux for 4 hours. After cooling, it was extracted by stirring with water, the organic phase was dried and concentrated, to give a colorless oil which crystallized after trituration with petroleum ether. Filtration with suction left 70.5 g (67.0% of theory) of colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5](SC)=[C:6]([F:8])[CH:7]=1.O[O:13][S:14]([O-:16])=O.[K+].[CH3:18]O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:14]([CH3:18])(=[O:16])=[O:13])=[C:4]([F:11])[CH:3]=1
Reactant: CSc1c(F)cc(Br)cc1F
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Product: CS(=O)(=O)c1c(F)cc(Br)cc1F
Reaction time: 12 h
Yield: 40 %

Procedure:
Combine 5-bromo-1,3-difluoro-2-methylsulfanyl-benzene (1.1 g, 4.6 mmol), oxone (11 g, 18.4 mmol) and methanol (20 mL). Stir for 12 hours. Filter the suspension and evaporate the filtrate. Dissolve the residue in dichloromethane (100 mL) and add water (100 mL). Separate the organic layer and wash with brine (50 mL). Dry with MgSO4, filter and concentrate in vacuo. Chromatograph the residue on a column eluting the material with diethyl ether in hexane (0 to 5%) to give 497 mg of the title compound (40%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:12]=[N:13][N:14]=[C:4]2[C:3]=1[N+:15]([O-:17])=[O:16].ClCCl.C(N(CC)CC)C.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][NH2:40])[CH:29]=1>C(O)C>[N+:15]([C:3]1[C:4]2[N:5]([N:12]=[N:13][N:14]=2)[C:6]2[C:11]([C:2]=1[NH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][CH2:34][C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1c(Cl)c2ccccc2n2nnnc12
Reactant: NCCOCCCc1cccnc1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
5-Chloro-4-nitrotetrazolo[1,5-a]quinoline (28.86 g, 0.11 mol), dichloromethane (600 ml), and triethylamine (21.14 ml, 0.11 mol) were combined and the resulting solution was chilled to 0° C. 2-(3-Pyridin-3-ylpropoxy)ethylamine (22.9 g, 0.13 mol) was added dropwise. The reaction was allowed to slowly warm to room temperature, then stirred at room temperature for 1 hour and finally at reflux for 2 hours. The reaction was cooled to room temperature and then quenched with water (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (3×50 ml). The combined organic fractions were washed with brine (100 ml), dried (Na2SO4), filtered and concentrated to yield a yellow solid. The solid was slurried in ethanol (150 ml) and filtered to provide 34.3 g of 4-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinolin-5-amine.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[C:5]2[C:10]([CH3:11])=[N:9][O:8][C:6]=2[N:7]=1.[OH-].[Na+].CN(C=O)C.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][S:1][C:2]3[N:3]([CH3:13])[C:4](=[O:12])[C:5]4[C:10]([CH3:11])=[N:9][O:8][C:6]=4[N:7]=3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cc1noc2nc(S)n(C)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1noc2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4)cc3)n(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of 6-mercapto-3,5-dimethylisoxazolo-[5,4-d]pyrimidin-4(5H)-one (800 mg) and sodium hydroxide (165 mg) in 50% ethanol (10 ml)-DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.25 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to provide the title compound as colorless solid (470 mg). 1H-NMR (CDCl3) 8: 2.57(3H,s), 3.55(3H,s), 4.59(2H,s), 7.46(2H,d,J=8.6Hz), 7.58(2H,d,J=8.4Hz), 7.74(2H,d,J=8.4Hz), 7.76(2H,d,J=8.6Hz).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]=12.[Cl:20]N1C(=O)CCC1=O>CN(C)C=O>[Cl:20][C:3]1[N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2ncc(Cl)n2c1
Yield: 29.3 %

Procedure:
In 10 ml of N,N-dimethylformamide, 0.3 g of 1,2-dihydro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2-oxo-3-pyridinecarbonitrile was stirred together with 0.19 g of N-chlorosuccinimide at 60° to 80° C. for 2 hours. After cooling, the solvent was removed by distillation under reduced pressure and water was added to the residue to take the solid by filtration. The solid was recrystallized from large quantities of methanol to obtain 0.1 g of 5-(3-chloroimidazo[1,2-a]pyridin-6-yl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile.