Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])#[N:2].FC(F)(F)C(O)=O.[N-:15]=[N+:16]=[N-:17].[Na+].Cl>N1C=CC=CC=1>[NH:15]1[C:1]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:2][N:17]=[N:16]1
Reactant: CCOC(=O)C#N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nnn[nH]1
Temperature: 60 °C

Procedure:
To a stirred, room temperature solution of ethyl cyanoformate (19.57 g, 0.1975 mol) in pyridine (78 mL) was added a chilled (+5° C.) mixture of trifluoroacetic acid (33 mL) and pyridine (118 mL) followed by sodium azide (14.06 g, 0.2163 mol), and the mixture was heated at 60° C. for 46 hours. The mixture was allowed to cool, poured into a mixture of concentrated hydrochloric acid (180 mL) and ice (400 g), and extracted with ethyl acetate several times. The extracts were washed with saturated sodium chloride, dried (MgSO4), and rotoevaporated to an oil. The oil was chromatographed on silica gel (500 g, 70-230 mesh) using ethyl acetatemethanol (15:1, 10×1 L) as eluent. Fractions containing product were rotoevaporated to an oil. The oil was dissolved in chloroform, filtered to remove a precipitate, and the filtrate extracted with aqueous sodium hydroxide. The extracts were acidified to pH 1 and extracted with ethyl acetate. The extracts were dried (MgSO4) and rotoevaporated to a white solid, yield 1.91 g (7%) of the title compound, mp=87.5°-91.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([NH:22][CH3:23])=[O:21]>>[CH3:23][NH:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[NH:17][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12
Reactant: CNC(=O)c1ccccc1N
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Product: CNC(=O)c1ccccc1Nc1ccnc2cc(-c3ccccc3)oc12

Procedure:
The title compound was prepared by procedure D using 7-chloro-2-phenylfuro[3,2-b]pyridine (50.00 mg; 0.22 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and using 2-amino-N-methylbenzamide(39.23 mg; 0.26 mmol; 1.20 eq.) instead of N-(3-aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide and was obtained as a white solid (50 mg, 67%). (HPLC (method F): 92%, RT: 3.37 min); MS (m/z) 344 [M+H]+, RT: 2.5 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]([N:18]1[CH2:22][CH:21]=[N:20][C:19]1=O)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1CC=NC1=O
Reactant: Cc1cc(N)n(Cc2ccccc2)n1
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1Cc1ccccc1

Procedure:
5-Amino-1-benzyl-3-methylpyrazole (J. Gen. Chem. USSR, 31, 2307, 1961) (17.0 g.) and 1-acetyl-3-imidazolinone (14.0 g.) were reacted as described in Example I to give 11.7 g. of product, mp 148°-149°.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:15])[CH2:11][CH:12](N)[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C1(C)C=CC=CC=1.O>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:15])[CH:11]=[CH:12][CH3:13]
Reactant: C=C1CCCC(C)(C)C1C(=O)CC(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1CCCC(C)(C)C1C(=O)C=CC
Yield: 65.3 %

Procedure:
1 g of 2-methylene-6,6-dimethyl-1-[3-amino-butanoyl]-cyclohexane in 25 ml of toluene was refluxed for 3 hours in the presence of a catalytic amount of p-toluene-sulphonic acid. The obtained solution was wahsed with a 10% solution of sodium hydrogenocarbonate in water until neutrality, then dried and concentrated. 0.6 g of 2-methylene-6,6-dimethyl-1-[but-2-enoyl]-cyclohexane was thus obtained. The analytical data were in agreement with those of a pure sample prepared by one of the known methods.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]3[CH:11]=[CH:12][C:13]([C:15]([C:17]4[N:18]=[CH:19][N:20]([C:22]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:21]=4)=[O:16])=[CH:14][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3]1=[O:41].[CH3:42][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:16][C:15]([C:13]1[CH:12]=[CH:11][C:8]2[C:9]3[CH2:10][N:2]([CH3:1])[C:3](=[O:41])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:14]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:21]=1)[CH3:42]
Reactant: C[Mg]Br
Reactant: CN1Cc2c(ccc3cc(C(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc23)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1Cc2c(ccc3cc(C(C)(O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)ccc23)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methyl-7-[(1-trityl-1H-imidazol-4-yl)carbonyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one (1.07 g) was dissolved in THF (22 mL) and cooled to 0° C., and then a solution (1.0 M: 3.0 mL) of methylmagnesium bromide in THF was added dropwise. The reaction mixture was stirred at room temperature for 1 hr. and a solution (1.0 M: 3.0 mL) of methylmagnesium bromide in THF was added. The mixture was further stirred at room temperature for 30 min., and 20% aqueous ammonium chloride solution was added to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: dichloromethane-methanol=100:1→40:1) to give 7-(1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)ethyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (1.00 g) as an amorphous solid. This amorphous solid was dissolved in 90% formic acid (9 mL) and THF (9 mL) and the solution was stirred with heating at 60° C. for 2 hrs. The reaction mixture was concentrated and the residue was neutralized with saturated aqueous sodium hydrogen carbonate. Sodium chloride was added and the mixture was extracted three times with a mixed solution of ethyl acetate-THF (1:1) under salting out. The combined extracted layer was dried over anhydrous magnesium sulfate and concentrated. The residue was suspended in ethyl acetate, filtrated and recrystallized from ethanol-water to give the title compound (0.20 g) as pale-brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[N:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cncc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cncc(C(=O)OC)c1
Yield: 61.2 %

Procedure:
Under the conditions of example 21 C, 464 mg of 5-(2-trimethylsilylethinyl)-nicotinic acid methyl ester is reacted with 2 ml of a 1-molar solution of tetrabutylammonium fluoride in tetrahydrofuran, worked up, and the residue is chromatographed on silica gel with hexane/0-7% ethyl acetate. 196 mg of 5-ethinylnicotinic acid methyl ester is obtained as oily crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CN=C1.C(O)(=O)C.C(OC1C=C(C(NC2C=CC(C(N)=N)=CC=2)C2NC(=O)N(C3N=CC=CN=3)N=2)C=CC=1OC)C.[C:55]([Si:59](Cl)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([CH3:58])([CH3:57])[CH3:56].Cl>C(OCC)(=O)C>[C:55]([Si:59]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:10][CH3:11])[CH:4]=1)([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)ccc1F
Agent: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 9.17 g of (4-fluoro-3-methoxyphenyl)methanol [CAS No. 128495-45-4] in 100 ml of DMT, 5g of imidazole and 17g of t-butyl -chlorodiphenylsilane were added and the mixture was stirred overnight at room temperature. Next, 1N hydrochloric acid was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give t-butyl-(4-fluoro-3-methoxybenzyloxy)diphenylsilane as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1Cl)([CH3:4])([CH3:3])[CH3:2].[C:25]([O-])([O-])=O.[Cs+].[Cs+].CB1OB(C)OB(C)O1.O>COCCOCCOC>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)C)cc2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C1=Cc2cc(C)c(C(C)(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 38.2 %

Procedure:
The ethyl 7-tert-butyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 8, Step 2 (1 g, 2.75 mmole) was dissolved in diglyme (20 mL). Cs2CO3 (1.5 g, 3.07 mmole), trimethylboroxaine (0.75 mL, 5.36 mmole), and [(t-Bu3P)PdBr]2 (20 mg) were added to above solution. The mixture was heated to 115° C. for 15 hrs under nitrogen. LCMS indicated that there was 50% conversion. The reaction was cooled down and the water was added to quench the reaction. The product was extracted with EtOAc and washed with water. The crude mixture was purified by RPHPLC to give the desired product 360 mg as an oil (38% yield), which had suitable purity to use without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:19])[CH2:14][Si](C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH3:11][O:12][C:13](=[O:19])[CH2:14][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: COC(=O)C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)Cc1cc(Br)cnc1[N+](=O)[O-]
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-Bromo-2-nitro-pyridine (2.33 g, 11.5 mmol) and trimethylsilanyl-acetic acid methyl ester (1.8 g, 12.0 mmol) in THF (12 mL) is added at −78° C. a solution of dried TBAF (3.0 g, 11.5 mmol), obtained by drying TBAF×3 H2O (7.5 g) for 18 h at 70° C. under high vacuum, in a mixture of acetonitrile (6 mL) and THF (6 mL). The resulting deep red solution is stirred for 1 h at −40° C. TLC analysis indicated complete consumption of starting material. The reaction mixture is cooled to −78° C. and DDQ (2.6 g, 11.5 mmol) is carefully added. The black solution is slowly warmed to RT. Since TLC analysis indicated that no further changes occurred, the reaction mixture is partitioned between EtOAc and a saturated aq. NH4Cl solution. The layers are separated and the organic layer is washed with a saturated aqueous NH4Cl solution, brine, dried over Na2SO4 and concentrated at reduced pressure. The crude product is purified by FCC (cyclohexane/EtOAc 9:1 to 8:1) to afford the title compound as yellow needles. 1H NMR (CDCl3, 400 MHz): δ 3.94 (s, 3H), 4.17 (s, 2H), 8.20 (s, 1H), 8.78 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH:3]1[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>[Fe].C(O)C>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH:3]2[N:2]([CH3:1])[CH2:7][CH2:6][NH:5][C:4]2=[O:8])=[CH:14][CH:13]=1
Reactant: CN1CCNC(=O)C1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CN1CCNC(=O)C1c1ccc(N)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 104b (210 mg, 0.89 mmol), ethanol (6 mL), iron powder (−325 mesh, 491 mg, 8.93 mmol) and 2N hydrochloric acid (0.70 mL, 1.40 mmol), and the mixture was heated at reflux for 30 min. After this time, the reaction was cooled to room temperature, and powdered potassium carbonate (3.03 g, 22.0 mmol) was added. The resulting suspension was filtered and the filter cake washed with ethanol (4×10 mL). The filtrate was concentrated under reduced pressure to afford 104c in 100% yield (185 mg) as a white solid: mp 153-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (d, 1H, J=2.7 Hz), 6.90 (d, 2H, J=8.4 Hz), 6.47 (d, 2H, J=8.4 Hz), 4.95 (bs, 2H), 3.45 (m, 1H), 3.42 (s, 1H), 3.14 (m, 1H), 2.89 (m, 1H), 2.44 (m, 1H), 2.02 (s, 3H); MS (ESI+) m/z 206 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]2[CH3:20].[CH3:26][NH:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:27]([CH3:28])[CH3:26])=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]2[CH3:20]
Reactant: CNC
Reactant: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(CCl)cc3)cc2n1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc(CN(C)C)cc3)cc2n1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
A mixture of 1.34 g (3.53 mmol) of ethyl 4-chloro-6-[4-(chloromethyl)phenoxy]-1-methyl-2-indolecarboxylate, 8.0 g of dimethylamine and 80 ml of dimethylformamide was stirred at 0° C. for 3 hours. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was isolated and purified by silica gel column chromatography to give 0.29 g (21.2%) of ethyl 4-chloro-6-[4-(dimethylaminomethyl)phenoxy]-1-methyl-2-indolecarboxylate.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].N.C(COC)OC>>[F:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[C:9]([NH2:1])=[O:10]
Reactant: N
Reactant: O=C1OC(=O)c2c(F)cccc21
Solvent: COCCOC
Product: NC(=O)c1c(F)cccc1C(=O)O
Reaction time: 0.67 h

Procedure:
A first solution of 3.32 parts of 3-fluorophthalic anhydride in 43 parts of dimethoxyethane was prepared. Separately, 86 parts of dimethoxyethane was added to a reaction vessel and ammonia was bubbled in to form a saturated solution of ammonia in dimethoxyethane. The ammonia addition was continued to maintain an excess while the 3-fluorophthalic anhydride solution was added to the ammonia/dimethoxyethane solution, slower with stirring over a 40 minute period. When all of the 3-fluorophthalic anhydride had been added, the ammonia addition was stopped and the reaction mixture was stirred for an additional five minute period to assure completion of the reaction. The dimethoxyethane was removed under reduced pressure. The remaining crude product was analyzed by C13 nuclear magnetic resonance 3-fluorophthalamic acid. A portion of the salt was dissolved in water, acidified, with concentrated hydrochloric acid to a pH of about 2.0, then cooled to form a white crystalline 3-fluorophthalamic acid having a melting point of 129°-132° C.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:14]1[CH2:20][C:18](=[O:19])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1=[S:16].[Cl-].[NH4+].N>C(O)C>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[C:20]3[S:14][C:15](=[S:16])[N:17]([CH2:21][C:22]([OH:24])=[O:23])[C:18]3=[O:19])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1csc(N2CCCCC2)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(N3CCCCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated. but using 1.8 g of 2-piperidinothiazole-4-carbaldehyde, 1.4 g of rhodanine-3-acetic acid, 1.0 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 40 ml of ethanol, giving the title compound as yellow needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16](Br)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][C:19]([Cl:25])=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2Br)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Cl)cc3c2-c2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 44 %

Procedure:
150 mg of 4-(5-Bromo-3-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (181) were dissolved in a mixture of 9 ml of dioxane and 3 ml of water, 47 mg of 4-fluoro-benzene-boronic acid, 47 mg of Na2CO3 and 40 mg of Pd(PPh3)4 were added and the resulting mixture was heated to 100° C. for 6 h. The solvent was removed in vacuo and the residue subjected to chromatography on a HPLC system. Yield: 44% LCMS: detected mass: 457.22, Rt=2.45 min (Method #1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH:22]=[CH:23][CH2:24][CH2:25][N:26]=[N+]=[N-])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[CH:14][CH:13]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C=CCCN=[N+]=[N-])c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1ccc(CCCCN)c2ccccc12
Yield: 89.4 %

Procedure:
{3-[4-(4-Azido-but-1-enyl)-naphthalen-1-yloxy]-propyl}-carbamic acid tert-butyl ester 3.5 g was hydrogenated in ethanol with 5% Pd/C (50% wet) for 2 h. Catalyst was removed, and the filtrate was concentrated to give 2.94 g of {3-[4-(4-Amino-butyl)-naphthalen-1-yloxy]-propyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3ccc(N)cc3)CC2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Yield: 72.4 %

Procedure:
1-(4-Aminophenyl)-4-(4-aminophenethyl)piperazine (1.9 g) was dissolved in dry pyridine (15 ml) and methanesulphonyl chloride (1.85 g) was added dropwise with stirring. The mixture was stirred overnight, evaporated to dryness, and the residue triturated with aqueous sodium bicarbonate. The insoluble product was washed with water and digested with ethyl acetate/methanol then cooled and filtered, giving the pure title compound (2.1 g) as a white solid, m.p. 254°-6° (dec.).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>COCCOC>[CH:1]1([CH2:4][CH2:5][O:6][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[C:16]([NH2:29])[N:15]=2)[CH2:3][CH2:2]1
Reactant: OCCC1CC1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a mixture of 2-cyclopropylethanol (3.45 g) in DME (20 mL) was added sodium tert-butoxide (3.86 g) gradually. The reaction was stirred under nitrogen for 30 mins, then 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.54 g) and DME (20 mL) were added. The reaction was heated to reflux (110° C.) overnight, then for another 8 h. The reaction was quenched into water (100 mL) and extracted with EtOAc (2×100 mL). The organics were combined and washed with brine (100 mL) and dried using a hydrophobic frit. The resultant oil was azeotroped with toluene (×2) to give a gum. This was triturated with Et2O (cooled CO2/acetone bath) until the title compound was obtained as a yellow powder (1.579 g) which was placed under high vacuum for 24 h.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH:29]=[CH2:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:43].[Na+].OO>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][CH2:30][OH:43])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: [OH-]
Reactant: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1[C@@H](CCCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (61.5 mg, 0.13 mmol) in dry THF (1 mL) at 0° C. and argon is added dropwise a 9-BBN solution (0.57 mL, 0.5 M in hexane). After the addition is complete, the reaction mixture is stirred at 0° C. for 2 h and at room temperature for 3 h. The mixture is then cooled to 0° C. and treated with a 3M NaOH (0.3 mL). The oxidation is carried out by slow addition of 35% H2O2 (0.3 mL) at 0° C. The reaction mixture is stirred at 0° C. for 1 h and then at room temperature overnight. The resulting solution is poured into ethyl acetate (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one (64 mg, 100%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.60-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.43-7.35 (m, 3H), 7.28-7.22 (m, 2H), 6.93-6.83 (m, 4H), 5.24 (dd, J=10.5, 3.0 Hz, 1H), 3.70 (t, J=7.2 Hz, 2H), 2.87-2.75 (m, 1H), 2.45-2.33 (m, 1H), 2.26-2.16 (m, 1H), 2.11-1.98 (m, 1H), 1.87 (s, br, 1H), 1.75-1.58 (m, 3H). HPLC-MS calculated for C26H23ClF3NO3 (M+H+) 490.13, found 490.10.