Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:29])[CH:23]([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:17])([F:18])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:29])([F:30])[CH:23]([F:28])[C:24]([F:25])([F:26])[F:27])[C:3]=1[Cl:31]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 30 mL of acetonitrile, and 0.9g of N-chlorosuccinimide was added under cooling with ice. After stirring for 30minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 3.12 g of 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[N+:22]([O-])=O.Cl.O>CO.[Fe]>[NH2:22][C:3]1[C:4]([C:20]#[N:21])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: COc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(N)c(N)c(C#N)n2)cc1C(F)(F)F
Yield: 49.5 %

Procedure:
4-Amino-6-(4-methoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile (65 mg, 0.19 mmol) was suspended in methanol (1.5 ml) and concentrated HCl (0.5 ml) was added dropwise (exotherm). The suspension was stirred while iron powder (37 mg, 0.67 mmol) was added in portions (exotherm), and the mixture was heated to reflux for 1 hour. Mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml). Organics were dried and evaporated then flash chromatographed over silica (4 g Combiflash cartridge, 7:3 heptane/ethyl acetate) to afford 29 mg of 3,4-diamino-6-(4-methoxy-3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile as a light brown solid. 1H NMR (DMSO) δ 8.08-8.01 (m, 2H) 7.05-7.00 (m, 2H), 3.94 (s, 3H). MS m/z 309.7 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:26])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:26][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([CH3:1])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:24])[CH3:25])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COCOc1ccc(Cc2c(C)cc(C(=O)OC)cc2C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccc(Cc2c(C)cc(C(=O)O)cc2C)cc1C(C)C
Temperature: 50 °C
Yield: 98.3 %

Procedure:
To a stirring solution of methyl 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoate (0.750 g, 2.11 mmol) in MeOH (20.0 mL) at 0° C. was added 1 M NaOH (12.64 mL, 12.64 mmol). The reaction mixture was heated at 50° C. for 16 h, cooled to 0° C. and acidified with 2 N HCl. The mixture was extracted with ethyl acetate (20 mL) and washed with H2O (10 mL×2). The solvent was removed under reduced pressure to afford 3,5-dimethyl-4-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoic acid as white solid (0.71 g, 98%): 1H NMR (300 MHz, DMSO-d6): δ 12.76 (s, 1 H), 7.65 (s, 2 H), 6.98 (m, 1 H), 6.91 (m, 1 H), 6.60 (m, 1 H), 5.17 (s, 2 H), 4.00 (s, 2 H), 3.37 (s, 3 H), 3.23 (m, 1 H), 2.27 (s, 6 H), 1.14 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-ethyl acetate (4:1); Rf=0.00.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[CH3:24][N:25]([CH3:26])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc(C(=C2CCCC2)c2ccc(Cl)nc2)cc1
Solvent: CCO
Product: CN(C)c1ccc(C(=C2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 180 °C

Procedure:
4.5 g of 2-chloro-5-[(cyclopentylidene)(4-methylsulfonylphenyl)-methyl]pyridine, prepared in Example 6, and 50 ml of a 33% solution of dimethyl-amine in ethanol are placed in a 125 ml autoclave. The mixture is heated at 180° C. under pressure for 7 hours. After cooling, the solvent is evaporated off under vacuum and the residue is taken up with water and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated under vacuum. The resulting oil crystallizes from an ethyl ether/isopropyl ether mixture to give 2.8 g of 2-(dimethylamino)-5-[(cyclopentylidene)(4-methylsulfonylphenyl)methyl]pyridine in the form of crystals melting at 122°-123° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(NS(C)(=O)=O)cc3)c2CC1
Reaction time: 0.08 h

Procedure:
To a solution of 0.022 g of 1-(4-amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99) in DMF (1 mL) was added 1 equivalent of triethylamine. After 5 min, 1 equivalent of methanesulfonyl chloride was added and the mixture was stirred overnight. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was purified by preparative TLC (50% EtOAc/hexanes) to give 1-(4-methanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. This mono-mesylate was then dissolved in 9:1 CH2Cl2/MeOH (2 mL) and treated with 3 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The resulting oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.004 g of the title compound as a white solid. MS (ESI): exact mass calculated for C21H24N4O2S, 396.16. found, m/z 397.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.42 (t, J=7.7 Hz, 2H), 7.37-7.34 (m, 1H), 7.22-7.20 (m, 2H), 7.13-7.10 (m, 2H), 5.34 (s, 2H), 2.97-2.93 (m, 4H), 2.92 (s, 3H), 2.90-2.87 (m, 2H), 2.82-2.78 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:5]1[CH2:6][C@@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([O:9][CH3:10])=[O:8])=[O:24]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1Br
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
Into a flame-dried 100 ml three-necked round-bottomed flask containing 30 ml of distilled THF was placed 3.00 g (16.575 mmol) of (cis)-4-hydroxy-L-proline, methyl ester; the vessel was immersed in an ice/water bath and the suspension was allowed to stir under argon for 5 minutes. At this time, 6.35 ml (36.465 mmol) of diisopropylethylamine was added slowly via syringe; the mixture was allowed to stir for 10 minutes, whereupon 3.64 g (16.576 mmol) of 2-bromobenzoyl chloride was added dropwise via syringe over the course of 10 minutes. The mixture was allowed to stir at 0° for 2 hours then gradually brought to room temperature overnight. The mixture was concentrated under vacuum to a minimal volume, transferred to a separatory funnel, and diluted with 100 ml of ethyl acetate, then washed with 1N HCl (2×30 ml), saturated sodium bicarbonate (2×30 ml), and brine (30 ml). The organic solution was dried over sodium sulfate, filtered, and concentrated under vacuum. Recrystallization from hot ethyl acetate yielded 3.034 g (55.6%) of the title compound, m.p. 145.5°-146.8° C.; a second recrystallization of the mother liquor yielded 1.726 g to bring the net yield to 4.760 g (87.3%).
Reaction SMILES: II.[CH3:3][O:4][C:5]1[C:13]2[O:12][CH:11]([CH2:14][CH:15]=[CH2:16])[C:10](=O)[C:9]=2[CH:8]=[CH:7][CH:6]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(O)(=O)C>C1COCC1.[Zn]>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][CH:15]=[CH2:16])=[C:10]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CBr
Reactant: C=CCC1Oc2c(OC)cccc2C1=O
Agent: II
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCc1oc2c(OC)cccc2c1CC(=O)OC
Temperature: 0 °C
Yield: 67 %

Procedure:
THF (10 ml) was added to zinc powder (5.92 g) and then a catalytic amount of iodine was added. While vigorously stirring the resulting solution, a small amount of a solution of 7-methoxy-3-oxo-2-(2-propenyl)-2,3-dihydrobenzofuran (6.16 g) and methyl bromoacetate (8.9 ml) in THF (90 ml) was added at room temperature. After confirming generation of heat, the reaction solution was cooled to 0° C. and the remainder of the solution was added dropwise for 15 minutes. The reaction solution was stirred at 0° C. for 3 hours, cooled to room temperature and was stirred for another 2.5 hours. Acetic acid (5.5 ml) was added to the reaction solution and the resultant was filtered through Celite. After removing the solvent under reduced pressure, the residue was dissolved in toluene (100 ml) and p-toluenesulfonic acid (536 mg) was added thereto, followed by stirring the resulting mixture at room temperature for 2 hours. The reaction solution was poured into water (150 ml) and the resultant was extracted twice with ethyl acetate (50 ml). After combining the organic layers, the resultant was washed with saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and dried over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using a silica gel to obtain the desired compound (5.23 g, yield: 67%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].[C:23]1(C)C=CC(S(OCC)(=O)=O)=C[CH:24]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(O)c1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A solution of 5-hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine (500 mg, 1.78 mmol, from step 120f) in dimethylformamide (15 mL) was treated with ground KOH (170 mg, 1.7 mmol) and stirred for 30 minutes at room temperature. To this mixture was rapidly added ethyl p-toluenesulfonate (430 mg, 2.14 mmol), and the resultant was stirred at 80° C. overnight. The mixture was concentrated to remove the dimethylformamide, and the residue was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (MgSO4), filtered and concentrated under vacuum to give 1.0 g of unpurified product. This material was purified by chromatography (silica gel: hexane/EtOAc, 1:1) to give 537 mg (98%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ: 1.40 (s, 9H), 1.42 (t, J=6 Hz, 3H), 2.30 (m, 2H), 3.92 (t, J=9 Hz, 2H), 4.05 (q, J=6 Hz, 2H), 4.30 (m, 1H), 4.54 (m, 1H), 6.80 (m, 1H), 7.95 (m, 2H). MS (CI/NH3) m/e: 309 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:10]2)[C:2]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2Br)CC1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2-c2ccncc2)CC1
Temperature: 100 °C
Reaction time: 20 h
Yield: 35.1 %

Procedure:
To a mixture of tert-butyl (1-(5-bromo-2-chloropyrimidin-4-yl)piperidin-4-yl)methylcarbamate (229 mg, 0.564 mmol), pyridine-4-boronic acid (76 mg, 0.618 mmol) and Pd(Ph3P)2Cl2 (40 mg, 0.056 mmol) in dioxane (3 mL), aq. Na2CO3 (180 mg, 1.69 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give tert-butyl (1-(2-chloro-5-(pyridin-4-yl)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (80 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[Si:14]([CH:2]([OH:1])[C@@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CC[C@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g, 135 mmol) in anhydrous DMF (70 mL) was added tert-butyldiphenylsilyl chloride (18.14 g, 66 mmol, 17.2 mL), and the solution was stirred at room temperature under nitrogen atmosphere for 1 h. After removal of the solvent by evaporation, the residue was dissolved in CHCl3, washed with water and brine, dried (Na2SO4), filtered, and concentrated. After crystallization from hexane, the oily residue gave the title compound 4 as a white crystalline solid (20.8 g, 98%). M.P. 76° C.; 1H NMR (CDCl3) δ 7.68-7.65 (m, 4H, arom.), 7.47-7.39 (m, 6H, arom.), 4.63-4.61 (m, 1H, H-5), 3.90-3.87 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.70-3.67 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.69-2.65 (m, 1H, H-3), 2.56-2.52 (m, 1H, H-3), 2.32-2.23 (m, 2H, H-4), 1.06 (s, 9H, t-Bu).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]1[CH2:13][CH2:12][CH2:11][C:9]=1[N:10]=2.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:15]=1)[C:7](=[O:14])[C:8]1[CH2:13][CH2:12][C:11](=[CH:21][C:20]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=3)[C:9]=1[N:10]=2
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=c1c2c(nc3ccc(Cl)cn13)CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C=C2CCc3c2nc2ccc(Cl)cn2c3=O)cc(OC)c1OC
Yield: 60.9 %

Procedure:
7-chloro-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one (4 g), prepared according to Example 1, was reacted with 3,4,5-trimethoxy-benzaldehyde (8,87 g) in methanol (160 ml) in the presence of sodium methoxide (1.65 g) at reflux temperature for 140 hours. After cooling the precipitate was filtered, washed with water until neutral and crystallized from CH2Cl2 /methanol to give 4.4 g of 7-chloro-3-(3,4,5-trimethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one, m.p. 222°-223° C., NMR (CDCl3) δ ppm: 3.13 (br s) (4H, cyclopentane protons), 3.95 (br s) (9H, --OCH3), 6.82 (s) (2H, phenyl protons), 7.42 (br s) (1H, =CH--), 7.58 (d) (2H, C-5 and C-6 protons), 9.02 (t) (1H, C-8 proton).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:44])[C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C@H:25]([CH2:45][C:46]2[CH:51]=[CH:50][C:49](O)=[C:48]([O:53][CH3:54])[CH:47]=2)[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([C:40]([F:41])([F:42])[F:43])[CH:33]=1)[C:29]([N:26]1[CH2:27][CH2:28][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][C@H:25]1[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[C:48]([O:53][CH3:54])[CH:47]=1)=[O:44]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoromethane sulfonic acid anhydride (5.25 ml) was added dropwise over 30 minutes to an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-hydroxy-3-methoxybenzyl)piperazine (14.3 g) and 4-(dimethylamino)pyridine (0.47 g) and 2,6-lutidine (3.6 ml) in dichloromethane (150 ml) below 10° C. After being stirred at the same temperature for 2 hours, the reaction mixture was poured into water. The pH of the whole mixture was adjusted to 7 with diluted hydrochloric acid and the organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of toluene and ethyl acetate (100:1–5:1) to give the objective trifluoromethanesulfonic acid 4-[[(2R)-1-[3,5-bis(trifluoro-methyl)benzoyl]-4-benzylpiperazin-2-yl]methyl]-2-methoxyphenyl ester as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1.C[Al](C)C>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2cccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 5-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid ethyl ester (Step 174.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 2 h at 80° C. Title compound: ESI-MS: 534.1 [M+H]+; tR=3.56 min (System 1); TLC: Rf=0.14 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]=[CH2:13]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:12][CH2:13][C:9](=[O:11])[CH2:8]2)=[CH:6][CH:7]=1
Reactant: C=C
Reactant: O=C(O)Cc1cccc(Br)c1
Product: O=C1CCc2ccc(Br)cc2C1

Procedure:
Scheme 3 illustrates a route to 7-substituted tetralin derivatives 10 and 11. 3-Bromophenylacetic acid is converted to the corresponding acid chloride and this is subjected to Friedel-Crafts reaction with ethene, affording the 7-bromo-2-tetralone 9. This intermediate may be elaborated using the procedures described in Scheme 1 to provide the acid (10) and aniline (11).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C@H:9]1[C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=O)(C)(C)C.[ClH:18]>>[ClH:18].[CH3:13][N:12]([CH3:14])[C:10](=[O:11])[C@@H:9]1[CH2:15][CH2:16][CH2:17][NH:8]1
Reactant: CN(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Product: CN(C)C(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the subtitle product of step i) (5.0 g) was added hydrochloric acid (20 ml, 4M). The mixture was stirred at room temperature for 3 h before the solvent was evaporated to afford the subtitle compound as a colourless solid. Yield: 3.50 g
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[CH:13]([OH:14])[CH:7]([CH2:8][N:9]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH2:15]([N:9]1[CH2:10][CH:11]2[CH:13]([O:14][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:7]([CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:12]2)[CH2:8]1)[CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCCCN1CC2CN(CCCC)CC(C1)C2O
Product: CCCCN1CC2CN(CCCC)CC(C1)C2OC(=O)c1ccc(Cl)cc1
Yield: 57.5 %

Procedure:
10.18 g of 3,7-di-n-butyl-3,7-diazabicyclo[3.3.1]nonane-9-ol are reacted with 7.7 g of 4-chloro-benzoyl chloride as described in Example 8 to obtain 3,7-di-n-butyl-9-(4'-chlorobenzoyloxy)-3,7-diazabicyclo[3.3.1]nonane, which is converted into its fumarate. The salt, melting at 180°-181° C., is obtained with a yield of 57.5%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:20]#[N:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.S(=O)(=O)(O)[OH:24].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]([NH2:21])=[O:24])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC(=O)C1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
(a′) 1-benzyl-4-cyano-4-phenylpiperidine, prepared in situ via neutralization of its hydrochloride, is treated with 94-96% sulfuric acid and acetic acid in toluene at 80-100° C. and the 1-benzyl-4-phenyl-4-piperidinecarboxamide thus obtained is treated with bromine in the presence of sodium methoxide; and then