Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][NH:19][CH2:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:19]([CH2:20][CH3:21])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCNC
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CO
Product: CCN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg, 0.566 mmol) and excess N-methylethanamine (0.486 mL, 5.66 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford 2-chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (163 mg, 0.566 mmol, 100% yield). LC-MS (M+H)+=288.2.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][C@@H:7]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@@H:6]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:5]1)=[N+]=[N-].CCOC(C)=O>[Pd]>[Si:19]([O:18][C@@H:6]1[C@H:7]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH2:8][C@@H:4]([NH2:1])[CH2:5]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A suspension of [((1S,2S,4R)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl)methoxy](tert-butyl)dimethylsilane (2.13 g, 0.00552 mol) and 10% Pd/C (0.27 g, 0.00026 mol) in EtOAc (45.0 mL, 0.461 mol) was stirred under an atmosphere of hydrogen overnight. The reaction was purged with nitrogen and filtered the mixture through celite with EtOAc. The filtrate was concentrated to obtain 1.83 g (92.1%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:18]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 74 h

Procedure:
4-Cyanophenol (5.0 g) is dissolved in DMF (6 ml), and thereto are added ethyl 4-bromobutanate (7.94 ml) and potassium carbonate (6.4 g), and the mixture is stirred at room temperature for 74 hours. The reaction mixture is poured into water, and the colorless precipitates are collected by filtration and washed with water to give the title compound (9.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:25][O:26][C:27](=[O:28])[C:29]1[CH:34]=[CH:33][C:32]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.7 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (64 mg) in CH2Cl2 (1.5 ml) were added 4-methoxycarbonylphenyl-boronic acid (96 mg), copper-(II)-acetate (96 mg), molecular sieve and pyridine (70 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 18 hours. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 4:1=>0:1) to give the title compound (91 mg) as a colorless foam. MS (m/e, ISP neg. ion)=494.1 [M−H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=1>[Ni].CO.C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([NH2:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)Nc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Nc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 9 h
Yield: 82.4 %

Procedure:
A suspension of (5-bromo-2-nitro-phenyl)-tert-butyl-amine (Step 123.3) (6 g, 21.97 mmol) and Raney nickel (2 g) in MeOH/THF (1:1 v/v, 600 mL) is stirred for 9 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated. The residue purified by silica gel column chromatography (Hex/EtOAc, 97:3→3:1) to afford 4.4 g of the title compound as a black oil: ESI-MS: 243.0/245.0 [M+H]+; tR=2.75 min (System 1); TLC: Rf=0.89 (Hex/EtOAc, 1:1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+]>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2ccccn2)cc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
A mixture of 29.34 g (0.264 mol) of 4-fluoroaniline (1) and 29.98 g (0.264 mol) of 2-chloropyridine (2) was heated at 150° C. for 2 h. After having been cooled down to RT, it was distributed between 500 ml of 1N NaOH and 500 ml of ethyl acetate. The aqueous phase was extracted twice with in each case 300 ml of ethyl acetate and the combined organic phases were dried with magnesium sulfate. After the solvent had been evaporated, the residue was taken up in 500 ml of ethyl acetate and approx. 40 g of active charcoal were added. The mixture was stirred at RT for 10 minutes and filtered through kieselguhr. The active charcoal was rewashed 4 times with in each case 1 l of ethyl acetate. The solvent was removed in vacuo (i.v.) and the residue was precipitated from 120 ml of ethyl acetate. The solid was filtered off with suction and dried at 50° C. i.v. 41 g of 2-(p-fluoroanilino)pyridine (3) were obtained;
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH:5]1[C:10](OC)([O:11]C)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(O)(C(F)(F)F)=O>[F:1][CH2:2][CH2:3][O:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCF
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(OCCF)C1
Yield: 97.5 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-(2-fluoroethoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (123a) (6.5 g, 21.2 mmol), a water/TFA mixed solution (1/1, 20 mL) and di-tert-butyl dicarbonate (6.54 g, 30 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 5.4 g of the title compound as a light brown oily substance (98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:32]I.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:32])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(O)cc3)oc2C)cc1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC)cc3)oc2C)cc1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
A solution of 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.15 g, 0.352 mmol), methyl iodide (0.15 g, 1.06 mmol), tetrabutylammonium bromide (0.023 g, 0.0713) mmol) in CH2Cl2 (8 mL) was treated with a 50% weight solution of NaOH (0.1 mL), and stirred at room temperature. The reaction mixture was extracted with water and more CH2Cl2 and the organic layer dried (MgSO4). The solvent was removed in vacuo to give a crude oil which was purified by flash chromatography (2/1 hexanes/EtOAc) to afford 0.038 g (25%) 2-(4-{2-[2-(4-methoxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (500 MHz, CDCl3) δ 7.87-7.85 (m, 2), 6.90-6.88 (m, 2H), 6.78-6.71 (m, 4H), 4.21-4.06 (m, 4H), 3.80 (s, 3H), 2.88 (t, 2H, J=6.60 Hz), 2.29 (s, 3H), 1.47 (s, 6H), 1.23 (t, 3H, J=7.33 Hz); MS (ES+) Calc'd for C25H30NO6: Found m/e 440 (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:30][CH:29]=3)[CH:36]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OCC2CCN(C(=O)OC(C)(C)C)C2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 mmol, 302 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then 4-(4-benzyloxy-phenyl)-3-butyl-6-chloro-pyridazine (Example 1, 1.0 mmol, 352 mg) was added. The resulting mixture was stirred at 50° C. for 1 hour, poured into water and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give 3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(pyrrolidin-3-ylmethoxy)-pyridazine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Cl[CH2:19][C:20]1[CH:28]=[CH:27][C:23]2[O:24][CH2:25][O:26][C:22]=2[CH:21]=1>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([CH2:19][N:14]3[CH2:13][CH2:12][CH:11]([NH:10][C:9]4[C:4]5[CH:3]=[C:2]([Cl:1])[S:17][C:5]=5[N:6]=[CH:7][N:8]=4)[CH2:16][CH2:15]3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: Clc1cc2c(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)ncnc2s1

Procedure:
The title compound was prepared (69 mg, 47%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.37 mmol) and 5-(chloromethyl)benzo[d][1,3]dioxole (63 mg, 0.37 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (s, 1H), 6.95 (s, 1H), 6.75-7.05 (m, 2H), 5.95 (s, 2H), 5.85 (d, 1H), 4.25 (m, 1H), 3.65 (s, 2H), 3.10 (m, 2H), 2.40 (m, 2H), 2.15 (m, 2H), 1.90 (m, 2H). MS (ESI) m/z: Calculated: 402.90; Observed: 403.2 (M++1).
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[N:22]([CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(COS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN=[N+]=[N-])C2
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
A mesyl compound (Example 3, 1 g) and sodium azide were added to dimethylformamide (20 ml), and the mixture was stirred at 100° C. for 50 minutes. After completion of the reaction, pressure was reduced to concentrate the mixture. The concentrate was diluted with a solvent mixture of chloroform and methanol (5:1), washed with water, and dried. When the solvent was evaporated, 759 mg of the title compound was obtained (91.6%). This substance was recrystallized from a solvent mixture of chloroform-n-hexane, obtaining yellow powdery crystals having a melting point of 192°-194° C.(dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=O)[NH:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[S:37][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)NNC(=O)c2ccncc2)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)(C)OC(=O)N1CCC(OCc2nnc(-c3ccncc3)s2)CC1

Procedure:
4-{2-Oxo-2-[N′-(pyridine-4-carbonyl)hydrazino]ethoxy}piperidine-1-carboxylic acid tert-butyl ester (Preparation 16) was treated with Lawesson's reagent in a similar manner to that described in Example 138, affording the title compound: RT=3.47 min, m/z (ES+)=377.1 [M+H]+.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]3[CH2:20][CH:11]3[CH2:12][O:13]2)=[CH:8][CH:7]=1)=O>CO.S(=O)(=O)(O)O>[NH2:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]3[CH2:20][CH:11]3[CH2:12][O:13]2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC1CC21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(N)ccc2c1OCC1CC21
Reaction time: 24 h
Yield: 53.6 %

Procedure:
Methyl (1aRS,7bSR)-5-(2,2-dimethylpropionylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 43, 0.310 g) was suspended in methanol (7.5 mL) and concentrated sulphuric acid (4 drops) was added. The reaction mixture was heated to reflux, under an atmosphere of nitrogen, for 36 hours. A further 2 drops of concentrated sulphuric acid was added and heating was continued for a further 24 hours. After cooling, the mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 5-20% to give methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.120 g) as an off-white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1)=[O:5].CC(C)=O.[N:24]([O-:26])=[O:25].[Na+].CCCCCC>O>[N+:24]([CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1)=[O:5])([O-:26])=[O:25]
Reactant: CCCCCCCCc1ccc(C(=O)CCCl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCc1ccc(C(=O)CC[N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
3-Chloro-1-(4-octylphenyl)propan-1-one (110 g) and acetone (1 L) are charged into a round bottom flask equipped with a condenser and guard tube and stirred. Sodium nitrite (271 g) is added and the mixture is slowly heated to 80° C. and maintained at that temperature for about 21 hours. The mass is cooled to 58° C., sodium nitrite (10 g) is added, and the mass is maintained at 78° C. for about 6 hours. The solvent is evaporated under reduced pressure. The compound obtained is diluted with water (250 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer is dried over anhydrous sodium sulphate (50 g) and concentrated under reduced pressure to give solid. Hexane (500 mL) is added and the mixture is cooled to −10° C. and stirred for 20 minutes. The formed solid is separated by filtration and washed with cold hexane (2×100 mL) to obtain the title compound as an off-white solid. Yield: 75 g.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][CH2:7][C:8]([O:10]CC)=O.Cl.[O-:17][C:18]#[N:19].[Na+]>>[I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH2:7][C:8](=[O:10])[NH:19][C:18]1=[O:17]
Reactant: CCOC(=O)CNCc1cccc(I)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Product: O=C1CN(Cc2cccc(I)c2)C(=O)N1
Yield: 96.7 %

Procedure:
Ethyl N-(3-iodobenzyl)glycinate (0.567 g) was treated with 1M HCl (3.9 ml) and sodium cyanate (0.345 g) and then refluxed for 30 min. Concentrated HCl (4.5 ml) was added and the reaction mixture refluxed again for 30 min. The reaction mixture was evaporated under reduced pressure and then triturated with EtOAc (3×20 ml). The combined extracts were dried (Na2SO4) and evaporated under reduced pressure to give the title compound (0.543 g). LCMS RT 2.63 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:15](=[O:28])[CH:16]=[CH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CN(C)C=O.O1CCOCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)=[CH:16][C:15](=[O:28])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CNc1ccc(O)cc1)C(=O)C=Cc1ccc2ccccc2c1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2ccc(O)cc2)c(-c2ccc3ccccc3c2)cc1=O
Temperature: 80 °C
Yield: 44.4 %

Procedure:
In 12 ml of N,N-dimethylformamide was dissolved 1.7 g of methyl 2-(4-hydroxyphenylaminomethylene)-5-(2-naphthyl)-3-oxo-4-pentenoate, and they were reacted at 140° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/methanol (19:1 by volume) mixture). The purified oily substance was dissolved in 15 ml of dioxane and the resulting solution was heated to 80° C. To this solution was added dropwise at 80° C. a solution formed by dissolving 1.1 g of 2,3,5,6-tetrachloro-p-benzoquinone in 15 ml of dioxane. After this addition was completed, the solvent was removed by distillation under reduced pressure, and to the residue was added 20 ml of a chloroform/methanol (5:1 by volume) mixed solvent. The crystals thus formed were collected by filtration, washed with 5 ml of the same mixed solvent as mentioned above, and then dried to obtain 0.75 g of methyl 1-(4-hydroxyphenyl)-6-(2-naphthyl)-4-oxo-1,4-dihydronicotinate having a melting point of 280° C. or more.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([C:20]2[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=2)C=CC=CC=1>>[C:20]1([CH3:14])[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[O:28])=[CH:22][CH:21]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Product: Cc1ccc(NC(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 4-phenylphenyl isocyanate. 1H NMR (400 MHz, CDCl3): 7.31-7.12 (m, 7H), 7.07 (d, J=8.0 Hz, 2H), 6.32 (s, 1H), 4.06-4.00 (m, 2H), 2.79 (td, J=13, 2.5 Hz, 2H), 2.56 (d, J=6.8 Hz, 2H), 2.28 (s, 3H), 1.79-0.165 (m, 3H), 1.30-1.18 (m, 2H).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]([O:18]CC)=O)=[C:4]12.[CH:21]1([C:24](=[N:26]O)[NH2:25])[CH2:23][CH2:22]1.C(Cl)Cl>C(O)C>[CH:21]1([C:24]2[N:26]=[C:16]([C:15]3[N:14]=[CH:13][N:5]4[C:6]5[CH:12]=[CH:11][S:10][C:7]=5[C:8](=[O:9])[N:3]([CH3:2])[C:4]=34)[O:18][N:25]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ncn2c3ccsc3c(=O)n(C)c12
Reactant: NC(=NO)C1CC1
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(=O)c2sccc2n2cnc(-c3nc(C4CC4)no3)c12
Temperature: 25 °C

Procedure:
Sodium (50 mg) was dissolved in dry ethanol (20 ml). Ethyl 4,5-dihydro-4-methyl-5-oxo-imidazo[1,5-a]thieno[2,3-e]-pyrimidine-3-carboxylate (0,55 g, 2 mmole), cyclopropanecarboxamide oxime (0,5 g, 5 mmole), and 5 g crushed mol. sieves 4 Å were added. The mixture was refluxed for 6 hours, then cooled to room temperature, where methylene chloride was added (30 ml). The mol. sieves were filtered off and the filtrate was reduced to 5 ml by evaporation in vacuo. Addition of water (25 ml) afforded a crystalline precipitate of the title compound which was collected by filtration. M.p. 215°-21° C. (Compound 8).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:24][C:25]#[N:26])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].S(C)C.CO>C1COCC1>[NH2:26][CH2:25][CH2:24][O:23][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2ccc(F)c(Cl)c2)C1
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2ccc(F)c(Cl)c2)C1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-chloro-4-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (2.28 g, 6 mmol) was dissolved in anhydrous THF (50 mL), and the solution was heated to reflux under nitrogen. A solution of 10 M of BH3.Me2S (1.8 mL, 18 mmol) in THF was added dropwise and stirring was continued under reflux overnight. The resulting solution was cooled to 0° C., CH3OH was added dropwise to quench the reaction. Evaporation of the solvent led to crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-4-fluorophenyl)methyl)piperidine-1-carboxylate (2 g, yield 87%), which was used in the next step without further purification.