Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](I)[CH3:2].[CH:4]12[NH:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH2:7][CH:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5]2>C(Cl)Cl>[CH2:1]([N:12]1[CH:4]2[CH2:11][CH2:10][CH2:9][CH:8]1[CH2:7][CH:6]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:5]2)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CC2CCCC(C1)N2
Reactant: CCI
Solvent: ClCCl
Product: CCN1C2CCCC1CC(NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 30 h
Yield: 44.4 %

Procedure:
Ethyl iodide (50 μL, 0.63 mmol) was added to a solution of the amine from Step B (100 mg, 0.42 mmol) in methylene chloride (2 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 h. The mixture was quenched with a saturated solution of sodium bicarbonate and extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford tert-butyl 9-ethyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamate (50 mg, 45%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 4.28 (br s, 1H), 3.99 (br s, 1H), 3.13-3.10 (m, 2H), 2.63 (q, J=7.0 Hz, 2H), 2.38-2.30 (m, 2H), 1.90-1.82 (m, 3H), 1.48-1.46 (m, 1H), 1.44 (s, 9H), 1.16-0.95 (m, 7H); MS (ESI+) m/z 269 (M+H).
Reaction SMILES: [O-:1][S:2]([O-:4])=[O:3].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1.Cl>CCO.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:2]([OH:4])(=[O:1])=[O:3])=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)O
Temperature: 70 °C
Yield: 56.9 %

Procedure:
A suspension of Na2SO3 (3.26 g, 25.9 mmol) in EtOH (32 ml) and water (40 ml) was added to a solution of 5-chloro-2-fluoro nitrobenzene (2.0 g, 11.4 mmol) in EtOH (24 ml) and the mixture was heated at 70° C. for 16 h. After cooling, the mixture was acidified to pH=2 with conc. HCl (2 ml) and the solvent was removed in vacuo. The residue was diluted with brine solution (12 ml) and the mixture was heated under reflux for 2 h. The solution was cooled in ice bath and the resulting precipitate was collected by filtration to give the title compound (1.54 g, 57%) which was used in the next step without further purification.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[O:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[CH:7][C:6]=1[CH3:29])C.[BH4-].[Na+].CO.Cl>O1CCCC1.C(OCC)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]([CH3:28])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[C:6]([CH3:29])[CH:7]=3)=[CH:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CO
Temperature: 60 °C
Yield: 98 %

Procedure:
414 mg of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) and 152 mg of sodium borohydride were suspended in 10 ml tetrahydrofurane. The mixture was heated to 60° C. and 0.85 ml of methanol was the added dropwise under vigorous stirring. The mixture was stirred at 60° C. until the gas evolution subsided. The mixture was then cooled and ice water followed by diethylether were added. Then a solution of hydrochloric acid (1N) was slowly added to acidify the solution. The organic phase was washed with water and dried. Evaporation of the solvent afforded {4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-methanol as a solidified foam in 98% yield. 1H-NMR (CDCl3, δ in ppm): 7.28-7.45 (m, 6H), 5.34 (s, 1H), 4.72 (s, 2H), 2.99 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][CH:12]3[N:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]4=[N:14][C:13]3=O)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[C:9]([CH2:11][CH:12]3[N:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]4=[N:14][C:13]3=[S:31])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cccc2scc(CC3C(=O)N=C4C=CC=CN43)c12
Solvent: Cc1ccccc1
Product: Cc1cccc2scc(CC3C(=S)N=C4C=CC=CN43)c12
Temperature: 170 °C

Procedure:
A suspension of 475 mg (1.6 mmol) of 3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-one and 525 mg (1.3 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide in 20 mL of toluene is heated at 170° C. for 90 minutes under microwave condition. The precipitated solid is collected to give the desired compound.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:12])[C:5]2[N:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:20][C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:22]=1[OH:31]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4](=[O:12])[C:5]3[N:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=[C:2]2[O:31][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([F:28])([F:29])[F:30])[C:21]=2[F:20])=[CH:14][CH:15]=1
Reactant: Oc1cccc(C(F)(F)F)c1F
Reactant: O=c1c2ncccc2nc(Cl)n1-c1ccc(F)cc1
Product: O=c1c2ncccc2nc(Oc2cccc(C(F)(F)F)c2F)n1-c1ccc(F)cc1
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-3-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (55 mg, 0.20 mmol) and 2-fluoro-3-trifluoromethylphenol (50 μl, 0.40 mmol) is heated to 140° C. for 18 hours. After cooling to RT, the crude mixture is purified by column chromatography (gradient from CH2Cl2 to 20% EtOAc/CH2Cl2) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.71 (1H, m), 7.83 (2H, m), 7.70 (4H, m), 7.45 (3H, m). MS (M+1): 420.07; RT=1.13 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[N:12][NH:13][CH:14]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:11]=[C:10]([CH3:9])[CH:14]=[N:13]2)=[CH:3][CH:4]=1
Reactant: Cc1cn[nH]c1
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cnn(-c2ccc(I)cc2)c1
Temperature: 130 °C
Yield: 49.5 %

Procedure:
A mixture of 1,4-diiodobenzene (4.00 g, 12.1 mmol), 4-methylpyrazole (0.972 g, 12.1 mmol), 8-hydroxyquinoline (0.176 g, 1.21 mmol) and K2CO3 (1.69 g, 12.2 mmol) in DMSO (12 mL) was degassed before being charged with CuI (0.310 g, 1.63 mmol). The mixture in a sealed tube was heated at 130° C. overnight. Water and EtOAc were added. The mixture was filtered. The organic layer was separated, then applied to a silica gel column, which was eluted with hexane, then with 5% EtOAc in hexane to give 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]([CH3:26])[CH3:25])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[H][H].[Pd]>[CH3:25][N:24]([CH3:26])[C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:16][N:15]=[C:14]2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:20]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc2ccnc(N3CCN(Cc4ccccc4)CC3)c2c1
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc2ccnc(N3CCNCC3)c2c1
Yield: 24.9 %

Procedure:
After dissolving 250 mg of 1-(4-benzylpiperazin-1-yl)-7-dimethylaminoisoquinoline as synthesized in above Step 2 in 20 ml of ethanol, 50 mg of 10% palladium-on carbon was added to the solution. This mixture was stirred for 16 hours at room temperature in hydrogen atmosphere. The insoluble matter was removed by filtration and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (methanol:chloroform=1:9) to provide 46 mg (25%) of 7-dimethylamino-1-piperazin-1-ylisoquinoline.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=1.[CH3:14]O>CCOC(C)=O>[CH3:14][O:12][C:11]([C:9]1[S:10][C:6]([CH3:5])=[CH:7][CH:8]=1)=[O:13]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)s1
Yield: 97 %

Procedure:
Add thionyl chloride (153 ml, 2.1 mol) dropwise over 20 min to a solution of 5-methylthiophene-2-carboxylic acid (100 g, 0.703 mol) in MeOH (1 L) at 0° C. and stir. After the addition is complete, heat the reaction mixture to reflux for 3.5 hours. Cool and concentrate in vacuo to give a thick oil. Dilute the oil with EtOAc (500 ml) and sequentially wash with water (300 ml) then brine (300 ml). Dry the organic layer over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give the title compound (106 g, 97%), which is used without further purification. ESI (m/z) 156(M+H).
Reaction SMILES: CN(C)[CH:3]=[C:4]([CH2:7][O:8][CH3:9])[CH:5]=[O:6].[OH-].[Na+].S(OC)([O:16][CH3:17])(=O)=O>CO.O>[CH3:17][O:16][CH:3]=[C:4]([CH2:7][O:8][CH3:9])[CH:5]=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: COCC(C=O)=CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC=C(C=O)COC
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of 3-(dimethylamino)-2-(methoxymethyl)-2-propenal, (E)- and (Z)- (53.06 g, 0.37 mol) and sodium hydroxide solution (29.7 g, 50, 0.37 mol) in methanol (60 mL) is refluxed for 20 minutes and concentrated in vacuo to obtain a white solid. A solution of the solid in water (250 mL) is treated dropwise with dimethyl sulfate (46.75 g, 0.37 mol), stirred at room temperature for one hour and extracted with methylene chloride. The organic extract is dried over anhydrous sodium sulfate, concentrated in vacuo and distilled to give the title product as a colorless liquid (19.66 g, bp 80° C./0.5 mm Hg, 41% yield).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:12]1[CH2:17][CH2:16][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)[O:5]C1C=CC=CC=1)#[N:2].C1COCC1.O.O.[OH-].[Li+].C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([NH:3][C:4]([N:12]1[CH2:13][CH2:14][C:15]([CH2:24][CH2:25][N:26]2[CH:31]3[CH2:32][CH2:33][CH:27]2[CH2:28][CH:29]([N:34]2[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=[C:35]2[CH3:43])[CH2:30]3)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:17]1)=[O:5])#[N:2]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=NC#N)Oc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)NC#N)CC1
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a precooled (0° C.) solution of phenyl N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboximidoate (27 mg, 0.047 mmol) in a mixed solvent of THF-H2O (2 mL, 3:1) was added lithium hydroxide monohydrate (7.7 mg, 0.18 mmol). After stirring for 3 hours on an ice-water bath, the reaction mixture was diluted with dichloromethane (20 mL) and buffered with saturated sodium bicarbonate solution (10 mL). The aqueous phase was extracted with dichloromethane (3×10 mL). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash chromatography on silical gel, eluting with a gradient of 10-30% methanol in ethyl acetate to afford N-cyano-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidine-1-carboxamide as a white solid (20 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.1 Hz, 1H), 7.33-7.29 (m, 5H), 7.17-7.14 (m, 1H), 7.11-7.04 (m, 2H), 4.53-4.48 (m, 1H), 4.09 (br, 1H), 3.55-3.51 (m, 2H), 3.21 (br, 2H), 3.06-3.03 (m, 2H), 2.45 (s, 3H), 2.37-2.29 (m, 2H), 1.87-1.64 (m, 10H), 1.59-1.55 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 165.0, 152.3, 146.7, 143.7, 134.0, 128.9, 127.3, 126.2, 125.0, 121.8, 121.4, 119.4, 111.6, 57.2, 55.6, 49.3, 48.0, 46.3, 36.3, 35.9, 30.0, 21.8, 14.9. HRMS m/z (M+H)+ calcd: 497.3029, obsd: 497.3026.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH:15]([CH2:17][C:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=O.[C:32]1([CH3:45])[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:34][CH:33]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[C:32]1([CH3:45])[CH:33]=[CH:34][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([CH2:15][CH2:17][C:18]3([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:41][CH2:40]2)=[CH:36][CH:37]=1
Reactant: O=CCC1(CCN2CCOCC2)CCCCC1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(NC2CCN(CCC3(CCN4CCOCC4)CCCCC3)CC2)cc1
Reaction time: 3 h
Yield: 46 %

Procedure:
After adding sodium triacetoxyborohydride (579 mg, 2.73 mmol) to a solution of 4-[2-[1-(formylmethyl)cyclohexyl]ethyl]morpholine (625 mg, ca. 1.82 mmol), 4-(p-toluidino)piperidine (519 mg, 2.73 mmol) and acetic acid (0.21 mL, 3.64 mmol) in 1,2-dichloroethane (10 mL), the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with chloroform. The organic layer was washed with saturated brine and dried (anhydrous sodium sulfate), and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (30 g Merck Art 9385, chloroform:methanol=1:0-10:1) to obtain the title compound as a colorless oil (346 mg) (48% yield).
Reaction SMILES: C[O:2][C:3]1C=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])C.[NH:12]1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[OH:2][C:3]1[C:4]([CH:9]=[O:11])=[CH:5][CH:6]=[CH:7][N:12]=1
Reactant: COc1ccccc1C(C)=O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=Cc1cccnc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 134.8 %

Procedure:
To a stirred solution of 1-(2-methoxy-phenyl)-ethanone (69 μL, 0.50 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (200 mg, 0.50 mmol) and AcOH (0.10 mL, 1.4 mmol) in THF (5 mL) was added NaBH(OAc)3 and the mixture was stirred at room temperature for 48 hours. Purification of the crude light yellow foam to (267 mg) by column chromatography on silica gel (100:1:1-CH2Cl2:MeOH:NH4OH) followed by radial chromatography on silica gel (100:1:1-CH2Cl2:MeOH:NH4OH) afforded the desired product (83 mg, 27%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]O.ClC1C=C(N)C=CC=1OCC1C=CC=CN=1>>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[CH:12]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: OCc1cccc(F)c1
Agent: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Yield: 88.8 %

Procedure:
Compound 3A (1.65 g, 78%) was prepared from 4-amino-2-chloro-phenol (1.06 g, 7.38 mmol), 3-fluorobenzyl alcohol (2.4 g, 16.8 mmol) by a route analogous to that used for the preparation of 1C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33](O)=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 8 h
Yield: 7.2 %

Procedure:
A mixture of the product of Example 11B (40.3 mg, 0.18 mmol), triethylamine (0.037 mL, 0.26 mmol), 2-(3,5-difluorophenyl)acetic acid (36.4 mg, 0.21 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (61.8 mg, 0.19 mmol) in DMF (0.75 mL) was stirred overnight, diluted with EtOAc, washed with 1 N NaOH and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (3% EtOAc/CH2Cl2) to give the title compound as a white solid (4.8 mg, 0.013 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.44 (d, 1H), 8.23-7.90 (m, 3H), 7.26-7.00 (m, 3H), 3.80 (s, 2H); MS (DCI) M/Z 401.2 (M+NH4)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[N:6]1([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNCC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of acryloyl chloride (4.576 g, 50.558 mmol) in 50 ml of CH2Cl2 was added dropwise and very carefully piperidine (4.305 g, 50.558 mmol). The reaction flask was vented during the exothermic addition. After the addition was completed, the white slurry was stirred at 0° C. for 40 min and at RT for 1 h. The reaction was diluted with 70 ml CH2Cl2 and washed first with about 60 ml 2N HCl and then with about 60 ml of a mix of 2N NaOH and brine. The organic layer was dried over Na2SO4. The solution was evaporated by heating in a H2O bath at 60° C. without vacuum. Once most solvent had been evaporated off, it was furthered dried to a clear oil under high vacuum at RT for 30 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=O)[CH3:2].[N:12]1[NH:13][C:14](=[O:18])[CH:15]=CC=1>>[O:18]=[C:14]1[NH:13][N:12]=[C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])[CH:2]=[CH:15]1
Reactant: O=c1cccn[nH]1
Reactant: CC(=O)c1cccc(C#N)c1
Product: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
7.3 g of 3-acetylbenzonitrile are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: Cl[C:2]1[N:11]2[C:12](=[S:21])[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>C(O)(=O)C.[Zn]>[C:15]1([N:13]2[C:12](=[S:21])[N:11]3[CH2:2][NH:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=4[C:10]3=[N:14]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: S=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Agent: [Zn]
Solvent: CC(=O)O
Product: S=c1n(-c2ccccc2)nc2n1CNc1ccccc1-2

Procedure:
A mixture of 5-chloro-2-phenyl-1,2,4-triazolo[4,3-c]-quinazolin-3-thione (200 mg, 0.64 mmol) and zinc dust (10 mg, 150 mmol) in acetic acid (5 ml) was heated to reflux temperature. The reaction was filtered, neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was washed with ethanol and filtered to afford 2-phenyl-5,6dihydro-1,2,4-triazolo[4,3-c]quinazolin-3-thione (compound 29), m.p. 222-223° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.Cl>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]2[CH2:21][CH2:22][N:23]([C:2]3[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=3)[CH2:24][CH2:25]2)[CH:14]=1
Reactant: Cc1cc(C)nc(N2CCNCC2)c1
Reactant: Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: Cc1cc(C)nc(N2CCN(c3ccc([N+](=O)[O-])c(C)c3)CC2)c1
Yield: 44.4 %

Procedure:
A solution of 5-chloro-2-nitro-toluene (895 mg, 5.23 mmol) in diglyme (2.5 mL) was added to a stirred suspension of 1-(4,6-dimethyl-pyridin-2-yl)-piperazine (500 mg, 2.62 mmol) and potassium carbonate (900 mg, 6.54 mmol) in diglyme (5 mL) and heated at reflux overnight. The mixture was cooled, the inorganic salts filtered off and washed with ethyl acetate. The filtrate was concentrated to dryness under high vacuum to obtain a residue which was dissolved in 6N hydrochloric acid (10 mL) and washed with toluene. The aqueous layer was basified to pH 8 with ammonium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, bicarbonate solution, and brine dried over sodium sulfate, filtered and concentrated to dryness to give the crude compound. Purification by column chromatography over silica gel (60-120 mesh) using 15% ethyl acetate in hexane as a eluent afforded 1-(4,6-dimethyl-pyridin-2-yl)-4-(3-methyl-4-nitro-phenyl)-piperazine (380 mg, 45%).
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:26][C@@H:25]([F:28])[C@@H:24]3[C@H:20]2[CH2:21][NH:22][CH2:23]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:35]1([CH2:40][CH:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:50][C:51](O)=[O:52])[CH3:42])[CH2:39][CH2:38][CH2:37][CH2:36]1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[N:35]1([CH2:40][CH:41]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[CH2:50][C:51]([N:22]2[CH2:21][C@@H:20]3[C@@H:24]([C@H:25]([F:28])[CH2:26][CH2:27][C:19]3([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:23]2)=[O:52])[CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: CC(CN1CCCC1)Oc1ccccc1CC(=O)O
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(CN1CCCC1)Oc1ccccc1CC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 20 °C
Reaction time: 20 h
Yield: 41.7 %

Procedure:
0.04 g of hydroxybenzotriazole hydrate is added to a solution, cooled to +5° C., of 1 g of (3aR, 7R,7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride and 0.924 g of 2-{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetic acid in 40 cm3 of dry dichloromethane, followed by 0.79 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.51 cm3 of diisopropylethylamine. After stirring for 2.5 hours at +5° C. and for 20 hours at 20° C., the reaction mixture is washed twice with 50 cm3 of water, dried over magnesium sulphate and then concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 31 cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions of 25 cm3. Fractions 11 to 31 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 cm3 of dichloromethane, the solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. This wash with a basic solution is repeated again. 0.68 g of (3aR, 7R,7aR)-2-{{[3-(1-pyrrolidinyl)-2-propoxy]phenyl}acetyl}-4,4-diphenyl-7-fluoroperhydroisoindole is obtained in the form of a white solid.