Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:11])[CH2:10][CH2:9]2)=[C:4]([F:12])[CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[F:12][C:4]1[CH:3]=[C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][C:5]=1[C:8]1([OH:11])[CH2:9][CH2:10]1
Reactant: Nc1ccc(C2(O)CC2)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(C2(O)CC2)c(F)c1)Oc1ccccc1
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a stirred solution of 1-(4-amino-2-fluorophenyl)cyclopropanol (0.7 mg, 4.19 mmol, 1.0 eq) in acetone (10 mL) was added pyridine (0.33 mL, 4.19 mmol, 1.0 eq) and phenyl chloroformate (0.5 mL, 4.19 mmol, 1.0 eq) and stirred at 0° C. to RT for 1 h. The solvent was evaporated, the residue diluted with water (10 mL×2), extracted with EtOAc (25 mL), brine (10 mL) and dried over Na2SO4 and evaporated under vacuum; the resulting residue was purified by CC using EtOAc/PE (1:4 as eluent to get phenyl 3-fluoro-4-(1-hydroxycyclopropyl)phenylcarbamate (0.9 g, 75%, off white solid; TLC system: EtOAc/PE (1:1), Rf: 0.6).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28]C(=O)C(C)(C)C)[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([OH:46])[C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[OH:46][CH:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][OH:28])[C:12]3=[N:13][CH:14]=2)[CH:37]=1)[C:43]([OH:45])=[O:44]
Reactant: O=C(O)C(O)c1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1nn(CO)c2ncc(-c3cccc(C(O)C(=O)O)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (4.5 g, 9.7 mmol), (±)-(3-bromo-phenyl)-hydroxy-acetic acid (2.7 g, 11.6 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (355 mg, 0.5 mmol) in THF/Acetonitrile/saturated NaHCO3 (20 ml/20 ml/50 ml) was stirred at 100° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. The crude was purified by reverse phase HPLC afforded hydroxy-{3-[1-hydroxymethyl-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (1.7 g, 35% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.86 (s, 3H), 5.05 (s, 1H), 5.14 (s, 2H), 7.10 (m, 1H), 7.21 (d, 1H), 7.40-7.50 (m, 3H), 7.67 (d, 1H), 7.79 (s, 1H).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21].[P:22]([O-:28])([O:26][CH3:27])([O:24][CH3:25])=[O:23].[K+].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(#N)C>[CH3:25][O:24][P:22](=[O:23])([O:26][CH3:27])[O:28][CH2:2][N:3]1[C:7](=[O:8])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:21]
Reactant: COP(=O)([O-])OC
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COP(=O)(OC)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 0 °C
Yield: 41.1 %

Procedure:
Thirty grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 17.1 g of potassium dimethyl phosphate, 0.6 g of potassium carbonate, and 0.15 g of potassium iodide were slurried into 75 mL of acetonitrile. The reaction mixture was heated at reflux for 3 hours. The solution was filtered to remove potassium chloride precipitate and concentrated to thick oil. Isopropyl alcohol was added to the oil and cooled to 0° C. The product was filtered and dried under vacuum. Sixteen grams of the title compound was obtained (40.9% yield); mp 123.1-124.3° C. Proton nuclear magnetic resonance spectroscopy (1H NMR) deuterated dimethyl sulfoxide (DMSO-d6): 3.6 ppm (d, 6H), 5.3 (d, 2H), 7.3-7.5 (m, 10H), 10.0 (s, 1H); doublets from long range phosphorous coupling.
Reaction SMILES: [CH3:1][C:2]1([C:15](OCC)=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].[BH4-]>C1COCC1.C(O)C.O>[OH:16][CH2:15][C:2]1([CH3:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a mixture of 1-tert-butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (0.10 g, 0.37 mmol) in THF (10 mL) and ethanol (20 mL) was added LiBH4 (0.032 g, 1.5 mmol). The mixture was stirred for about 8 h at rt. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The EtOAc extracts were combined, dried over anhydrous Na2SO4, and concentrated in vacuo to give tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate (0.067 g, 80%): LC/MS (Table 2, Method i) Rt=0.29 min; MS m/z: 130 (M-Boc+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:12])([NH2:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S([C:17]1[CH:25]=[CH:24][CH:23]=C[C:18]=1[C:19]([OH:21])=[O:20])(O)(=O)=O.C1(P(=O)[OH:33])C=CC=CC=1.[OH2:35]>>[NH2:1][C:2]([NH2:11])([NH2:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:25][CH2:24][C:23]([OH:33])=[O:35]
Reactant: O=[PH](O)c1ccccc1
Reactant: O=C(O)c1ccccc1S(=O)(=O)O
Reactant: O
Agent: CCCCCCCCC(N)(N)N
Product: O=C(O)CCCCC(=O)O

Procedure:
Into a 230 g capacity, stirred autoclave was added 147.7 g nylon 66 dry salt, 8.8 g of a 50% aqueous solution of triaminononane (TAN)/6 salt, 2.85 g sulfobenzoic acid, 1 drop of a 5% solution of phenyl phosphinic acid and 46 mL DI water. (TAN/6 salt is the salt formed from TAN and adipic acid.) The autoclave was sealed, purged with nitrogen and pressurized to 250 psi with nitrogen. The reaction mixture was heated to 243° C. over a period of about 32 minutes while the water was distilled off. Pressure was then reduced to atmospheric in about 30 minutes. The temperature was increased to 276° C. and the reaction mass was held at that temperature for about 30 minutes. The resulting polymer was melt spun directly from the autoclave through a 6 hole spinneret. The resulting yarn had a denier of 161, a relative viscosity (RV) of 34.7 and a melting point of 251° C. The yarn exhibited boiling water shrinkage of 9.6%, and upon analysis was found to have 24.4 amine ends and 172.7 acid ends.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[CH2:18]=O>C(O)=O>[CH3:18][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: c1ccc2c(c1)CCC2CCC1CCCCN1
Reactant: C=O
Solvent: O=CO
Product: CN1CCCCC1CCC1CCc2ccccc21

Procedure:
45 g. of 1-[2-(2-piperidyl)ethyl]indane prepared as described above is mixed with 100 ml. of 37% formalin and 200 ml. of 98% formic acid is added while swirling and the solution is then heated overnight on a steam bath. The reaction mixture is worked up by concentrating in vacuo, dissolving in water, filtering, basification and extraction with ether. The ether extracts are dried over potassium hydroxide and after removal of the ether, the product is distilled collecting 42.6 g. (88%), N-methyl-1-[2-(2-piperidyl)ethyl]indane, boiling point 128°-130° C/0.2 mm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])=[CH:14][C:13]=1[CH3:36].I[CH2:39][CH3:40]>CS(C)=O.CCOCC>[CH3:7][O:8][C:9](=[O:37])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:39][CH3:40])[CH2:19][C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:35])=[CH:14][C:13]=1[CH3:36]
Reactant: CCI
Reactant: COC(=O)COc1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCN(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)c1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58.9 %

Procedure:
A suspension of potassium carbonate (76 mg, 0.55 mmol), and (2-methyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester (225 mg, 0.50 mmol, example 18.2) in DMSO (3 ml) was treated with iodoethane (0.04 ml, 0.53 mmol) in DMSO (0.5 ml) and stirred for 19 h at RT. Again iodoethane (0.34 ml, 4.20 mmol) in 2 portions over 7 h was added. The reaction mixture was taken up in ether and washed with KHSO4-solution (10%). The organic phase was washed with NaCl (10%), dried (Na2SO4) and evaporated. Purification by flash chromatography (SiO2, n-heptane/AcOEt=9/1) gave 141 mg of pure (4-{ethyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2-methyl-phenoxy)-acetic acid methyl ester, MS: 479.5 (MH)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:7][C@H:6]1[CH2:24][OH:25])(=[O:4])=[O:3].[H][H]>CO>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][OH:25])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1C[C@@H](P(=O)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: [H][H]
Solvent: CO
Product: CS(=O)(=O)N1C[C@@H](P(=O)(C2CCCCC2)C2CCCCC2)C[C@H]1CO
Yield: 59856.5 %

Procedure:
An autoclave was charged with 1.70 g (4.5 m-xol) of (2S,4S)-N-methanesulfonyl-4-diphenylphosphinyl-2-hydroxymethylpyrrolidine [VII], 850 mg of 5% Ph/Al2O3 and 20 ml of methanol, and the mixture was stirred for 2 days at 150° C. under 150 atm. pressure of hydrogen. The reaction mixture was subjected to microfiltration and the filtrate was concentrated and subjected to column chromatography on silica gel (solvent: ethanol) to be separated from a fraction insoluble in the organic solvent. The eluent was concentrated until dryness under reduced pressure whereby 1050 g (yield: 84%) of crystals were obtained.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C@@H:16]([CH3:25])[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:13][C:11]1[N:10]=[C:9]([NH:15][CH:16]([CH3:25])[C:17]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[O:18])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: C[C@H](N)C(=O)NCC(F)(F)F
Reactant: Clc1cc(-c2ccccc2)nc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(-c2ccccc2)nc(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 80 °C
Yield: 30.4 %

Procedure:
As shown in FIG. 3—step i, a mixture of phenylboronic acid (1.22 g), 2,4,6-trichloropyrimidine (compound 1011), tetrakis(triphenylphosphine) palladium(0) and 2N sodium carbonate (15 mL) in DME (25 mL) was heated at 80° C. overnight. After cooling to rt, addition of water (30 mL), extraction with dichloromethane (3×20 mL), drying and evaporation, purification by column chromatography (SiO2, 10-20% ethyl acetate in hexane) afforded the desired product, 6-phenyl-2,4-dichloropyrimidine (compound 1012) (0.544 g). As shown in FIG. 3—step ii, compound 1012 (0.34 g) was mixed with (S)-2-amino-N-(2,2,2-trifluoroethyl)propanamide (0.3 g) and diisopropylethylamine (0.63 mL) in isopropanol (5 mL) and the reaction mixture heated at 80° C. overnight. Evaporation gave a residue, which after aqueous workup and purification (SiO2, 20% ethyl acetate/hexane) produced 2-(2-chloro-6-phenyl-pyrimidin-4-ylamino)-N-(2,2,2-trifluoro-ethyl)propionamide (compound 1013) (0.165 g). As shown in FIG. 3—step iii, compound 1013 (29 mg), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-7-(toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 1005), PdCl2dppf2 (7 mg), and potassium phosphate (32 mg) were heated in 1,4-dioxane (2 mL) at 80° C. overnight. To the reaction was added aqueous lithium hydroxide solution (2 mL). After heating at 60° C. for 1 h, water (20 mL) was added. Extraction with dichloromethane (3×), drying, evaporation and purification (SiO2, 50-100% ethyl acetate/hexane) gave 3.7 mg of 2-[6-phenyl-2-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrimidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-propionamide (compound 18).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH:17]=[O:18])[CH:7]=1.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH:17]=[O:18])[CH:7]=1
Reactant: COc1ccc(Br)cc1-c1nc2ccccn2c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=Cc1c(-c2cc(Br)ccc2O)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (0.1 g, 3 mmol) was dissolved in dichloromethane (0.5 mL) at −78° C. BBr3 (1 mL) was added by dropwise stirred for 2 hours at that temperature. Then warmed to 25° C. and stirred for 10 hours. H2O (20 mL) was added by dropwise at −78° C. and extracted with EtOAc (3*50 mL), washed by aq NaHCO3 (3*50 mL) and brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=3:1) to provide 2-(5-bromo-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (40 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 10.29 (s, 1H), 9.76 (s, 1H), 7.78˜7.79 (m, 2H), 7.65˜7.69 (m, 1H), 7.46˜7.48 (m, 1H), 7.20˜7.22 (m, 1H), 7.00˜7.02 (m, 1H). MS (M+H)+: 317/319.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].Br[CH2:18][CH:19]=[CH2:20].[In]>CO.O>[CH2:20]([C:2]1([OH:1])[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH:19]=[CH2:18]
Reactant: O=C1CCCC1C(=O)OCc1ccccc1
Reactant: C=CCBr
Agent: [In]
Solvent: O
Solvent: CO
Product: C=CCC1(O)CCCC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl 2-oxocyclopentanecarboxylate (from step A, 5 g, 22.91 mmol) in a mixture of methanol (20 ml) and water (60.00 ml) was added 3-bromoprop-1-ene (8.31 g, 68.7 mmol) and indium (1.081 ml, 68.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and to the residue was added 1N hydrogen chloride (15 mL) and stirred at room temperature for 5 min. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (4 mL). The ethyl acetate layer is washed with brine (4 mL), dried over anhydrous Na2SO4 and concentrated under the reduced pressure. The residue was subjected to preparative HPLC (Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM). The desired fractions were collected, concentrated under reduced pressure to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC to yield four individual isomers. The fractions corresponding to the second isomer was concentrated and freeze dried to yield a solid (800 mg, 3.08 mmol, 13.4% yield). Chiral HPLC method: Column: ChiralPak AD-H, 250×3 cm, 5 μm; Flow rate: 130 mL/min; Mobile Phase: CO2/MeOH=70/30; Inj. Vol.=0.7 mL, Wavelength=220 nM, :Retention time=3.18 min. MS (ESI+)=283 (M+Na)+
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][CH2:22][C:21]2[CH:20]=[C:19]([C:18]3[C:17]4[C:12](=[C:13]([C:27]([F:29])([F:30])[F:28])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:26]=[CH:25][CH:24]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(CNCc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 4-methoxy-benzylamine according to the procedure of Example 66. MS (ES) m/z 527.2.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:29]2([CH3:30])[C@H:14]([C@H:15]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:18]([CH2:19][C@H:20]([CH2:22][CH2:23]2)[OH:21])=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH3:5].Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].O>O1CCCC1.C(OCC)C>[CH3:5][CH:4]([CH2:6][CH2:7][CH2:8][C@H:9]([C@@H:11]1[C@:29]2([CH3:30])[C@H:14]([C@H:15]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:18]([CH2:19][C@@H:20]([O:21][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:22][CH2:23]2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)[CH3:10])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a stirred 60% suspension of NaH in mineral oil (400 mg; 3 mmol) under nitrogen a solution of cholesterol (387 mg, 1 mmol) in dry tetrahydrofuran (30 ml) and tert-butyl bromoacetate (585 mg; 3 mmol) was slowly added and the mixture was refluxed under stirring for 16 h. After cooling to room temperature, water (50 ml) was carefully added and the product was taken in diethyl ether (2×50 ml). The combined extracts were dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography of the residue on silica gel column (200 ml) in hexane-tert-butyl methyl ether (gradient: 0-30%—tert-butyl methyl ether, 10 ml/min, 160 min) afforded compound tert-Butyl cholest-5-en-3β-yloxyacetate (general formula XII, where n2=1; 131 mg, 26%). 1H NMR (400 MHz, CDCl3) δ (ppm): 5.34-5.38 m, 1H (H-6); 4.01 s, 2H (H-1′); 3.24 tt, J=11.23, 4.56 Hz, 1H (H-3); 2.37-2.43 m, 1H (H-4a); 2.22-2.32 m, 1H (H-4b); 1.76-2.07 m, 5H (CH-1, H-12, H-2, H-7, H-16); 1.48 s, 9H (t-butyl); 1.01 s, 3H (CH3-19); 0.92 d, J=6.60 Hz, 3H (CH3-21); 0.88 d, J=1.80 Hz, 3H (CH3-26); 0.86 d, J=1.80 Hz, 3H (CH3-27); 0.83-1.63 m, 42H (cholesterol+tert-butyl) 0.68 s, 3H (CH3-18); 13C NMR (101 MHz, CDCl3) δ (ppm): 170.11 (C-2′) 140.69 (C-5) 121.78 (C-6) 81.33 (CCH3) 79.81 (C-3) 66.11 (C-1′) 56.80 (C-14) 56.20 (C-17) 50.20 (C-9) 42.35 (C-13) 39.81 (C-12) 39.53 (C-24) 38.79 (C-4) 37.17 (C−1) 36.85 (C-10) 36.21 (C-22) 35.78 (C-20) 31.95 (C-7) 31.92 (C-8) 28.22 (C-2) 28.16 (C-16) 28.12 3C (3×CCH3) 28.00 (C-25) 24.29 (C-15) 23.84 (C-23) 22.80 (C-26) 22.55 (C-27) 21.08 (C-11) 19.35 (C-19) 18.72 (C-21) 11.86 (C-18); for C33H56O3 monoisotopic mass: calculated: 500.4. found: MS ESI m/z: 524.0 [M+Na]+. for C33H56O3—Na+ HR-MS calculated: 523.41217. found: 523.41201; IR (CHCl3): 2954, 2869, 1467, 1457, 1370, 1394, 1161, 1032, 843 (tert-butyl); 1744, 1712, 1125 (C═O); 1670 (C═C); 1125 (C—O); 1181, 1370 (C-26, C-27); 1125 (ether); [α]D −33.7° (c 0.338; CHCl3).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[CH:29]1[CH2:30][CH2:31][N:32]([CH2:2][C:3]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: COc1ccc(C2CCNCC2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (2.2 g) and 4-(2,4-Dimethoxy-phenyl)-piperidine (2.0 g) are dissolved in Acetone (30 ml) and potassium carbonate (3.6 g) is added to the solution. The reaction mixture is stirred for 6 h at room temperature. The mixture is diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and filtrated. Ethyl acetate is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=1:1 (v/v).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]([CH3:20])[CH2:26]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(CCCCCl)c2cccnc2)cc1
Reactant: CCOC(=O)N1CCNCC1C
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(CCCCC(c2ccc(F)cc2)c2cccnc2)CC1C
Temperature: 70 °C
Reaction time: 40 h
Yield: 96.7 %

Procedure:
A mixture of 14 parts of 3-[5-chloro-1-(4-fluorophenyl)pentyl]pyridine, 7.75 parts of ethyl 2-methyl-1-piperazinecarboxylate, 8.7 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 198 parts of N,N-dimethylformamide was stirred for 40 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in a mixture of water and sodium carbonate. The aqueous layer was extracted with trichloromethane. The extract was washed with a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18 parts (96.7%) of ethyl 4-[5-(4-fluorophenyl)-5-(3-pyridinyl)pentyl]-2-methyl-1-piperazinecarboxylate as a residue (int. 38).