Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH2:11].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[C:3]([CH2:12][S:13][C:14]2[NH:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][NH:11][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1c(SCCN)ccnc1CSc1nc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(SCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 5 h

Procedure:
2-((3-Methyl-4-(2-aminoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (8.5 g) was dissolved in ethanol and thereto was added benzaldehyde (2.8 g). The mixture was stirred at 50°-55° C. for 5 hours and sodium borohydride (0.98 g) was added thereto under ice-cooling. The mixture was stirred at room temperature for 2 hours. After the completion of the reaction, ethanol was distilled away and the residue was eluted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away. The residue was purified by column chromatography to give 2-((3-methyl-4-(2-benzylaminoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:3]=1.C=O.[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na].C(=O)(O)[O-]>ClCCCl>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:20])[CH2:14][CH2:13]2)[N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.45 mmol), formaldehyde (30% solution in water, 0.16 mL, 1.60 mmol) and sodium triacetoxyborohydride (430 mg, 2.03 mmol) were mixed in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 4 hours. Saturated sodium ,bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MGSO4, filtered and evaporated to give 3-iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (275 mg, 530%). 1H NMR (DMSO-d6) δ 1.85 (m, 2H), 2.09 (m, 4H), 2.22 (s, 3H), 2.88 (m, 2H), 4.75 (m, 1H), 8.19 (s, 1H), 8.32 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ 359.0, Rt=0.46 min.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1.P(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:3]2[NH:2][C:6]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:5]([CH3:13])[N:4]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(-c2nc(C)c(-c3cccnc3)n2O)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)cc1OC
Yield: 60.5 %

Procedure:
To a suspension of 1-hydroxy-2-(3,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.68 g) in methylene chloride (9 ml) was added phosphorus trichloride (0.76 ml) at ambient temperature. The mixture was refluxed for 1 hour, and cooled. The mixture was adjusted to pH 7.8 with aqueous sodium carbonate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was triturated with diisopropyl ether to give 2-(3,4-dimethoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.39 g).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.C[Si]([C:21]#[CH:22])(C)C>CN(C=O)C.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.[Cu]I>[C:21]([C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1)#[CH:22]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C#Cc1ccc(OC2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under N2, the mixture of the product from Example 1A (800 mg, 2.4 mmol), trimethylsilylacetylene (Aldrich, 392 mg, 4 mmol), Pd(PPh3)4 (Aldrich, 29 mg, 0.025 mmol) and CuI (Strem Chemicals, 10 mg, 0.05 mmol) in DMF (10 mL) was stirred at ambient temperature overnight. DMF then was removed under reduced pressure. The residue was treated with tetrabutyl ammonium fluoride (Aldrich, in THF, 1M, 5 mL) at room temperature for 3 h. The reaction was monitored with TLC. After the reaction was complete, it was diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic solution was concentrated and the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.30) as a solid (560 mg, yield, 99%). 1H NMR (300 MHz, CD3OD) δ 1.42–1.54 (m, 1H), 1.61–1.87 (m, 2H), 1.93–2.07 (m, 1H), 2.10–2.18 (m, 1H), 2.71–3.00 (m, 5H), 3.19–3.37 (m, 2H), 4.49–4.56 (m, 1H), 6.86 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.8 Hz, 2H) ppm. MS (DCl/NH3): m/z 228 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:15][C:8]2[C:9](=[O:14])[NH:10][CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][C:5]1[S:15][C:8]2[C:9](=[O:14])[NH:10][CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: O=C(CCl)c1cc2c(s1)C(=O)NCCC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NCCCc2cc(CCCl)sc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
A mixture of 1.9 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at 50° C. for 12 hours. The mixture was poured into water, alkali fled and extracted with ethyl acetate. The exract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 0.85 g of 2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 156°-158° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]([CH3:16])=[CH:15][C:11]=3[C:10]([C:17]([OH:19])=[O:18])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:20][O:18][C:17]([C:10]1[C:11]2[CH:15]=[C:14]([CH3:16])[O:13][C:12]=2[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[CH:8][CH:9]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(C(=O)O)ccc(OC3CCCC3)c2o1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(C)cc12
Temperature: 5 °C
Yield: 102.5 %

Procedure:
To a suspension of 7-cyclopentyloxy-2-methylbenzo[b]furan-4-carboxylic acid (40.0 g, 0.153 moles) and potassium carbonate (42.0 g, 0.184) in acetone (400 mL) added dimethyl sulfate (24.0 g, 0.307 moles) and refluxed for 4-5 hrs. acetone (305 mL) was distilled off and reaction mixture was cooled to 5° C., ice cold water (500 mL) was and the solid separated was filtered, washed with water (2×100 mL) and dried to get off white solid (43.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=[C:9]2[NH:8][CH:7]=1)[CH3:2].[H-].[Na+].[CH3:22]I>O1CCCC1.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[CH:15]=[C:9]2[N:8]([CH3:22])[CH:7]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)Cc1c[nH]c2cc(C3CC3)nn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cn(C)c2cc(C3CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
To a suspension of (2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic acid ethyl ester (80 mg, 0.3 mmol, 1 eq) described in example 90 in tetrahydrofuran (2 mL) was added sodium hydride (16 mg, 3.9 mmol, 1.3 eq). The mixture was stirred during 30 min at room temperature and methyl iodide (30 μL, 0.5 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 5 h. The mixture was then diluted with ethyl acetate (5 mL) and water (5 mL) was added. The aqueous layer was extracted with ethyl acetate (2×10 mL) and the aqueous phases were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 0/100) to afford the expected compound as white powder (16 mg, 59% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[O:8][CH:9]=1)=[O:4].O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.[Cl-].[Na+].C(OCC)C>[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[O:8][CH:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 4-[4-(methoxycarbonyl)-2-oxazolyl]-1-piperidinecarboxylate (i.e. the product of Example 7, Step C) (1.41 g, 4.55 mmol) was dissolved in 12 mL tetrahydrofuran, and 8 mL of water was added. The reaction mixture was cooled to 0° C. with vigorous stirring. A 1 N aqueous sodium hydroxide solution (9.1 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated sodium chloride solution (10 mL), 30 mL of diethyl ether was added and the aqueous phase was acidified to pH 3-4 by dropwise addition of 20% citric acid solution. The precipitated solid was filtered and dried to give 1.21 g of the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[CH:22][C:23]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:15][CH:14]=1)(=[O:12])=[O:11].CC(O)=O>CO.C(Cl)(Cl)Cl>[Br:8][C:21]1[S:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([S:10]([CH3:9])(=[O:12])=[O:11])=[CH:18][CH:17]=2)=[C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccsc1-c1ccc(S(C)(=O)=O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)Cc1cc(Br)sc1-c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NBS (209 mg, 1.18 mmol) was added in small portions to a stirred solution of Intermediate Y (365 mg, 1.18 mmol) in a mixture of MeOH (10 ml) and chloroform (5 ml) at 0° C. AcOH (0.250 ml) was added and the reaction was stirred at 0° C. for 1 hour then at r.t. for 3 hours. More NBS (35 mg, 0.20 mmol) was added at 0° C. and the reaction was stirred at r.t. over night. A new reaction was also started. NBS (342 mg, 1.92 mmol) was added in small portions to a stirred solution of Intermediate Y (519 mg, 1.67 mmol) in a mixture of MeOH (15 ml) and chloroform (7 ml) at 0° C. AcOH (0.50 ml) was added and the reaction was stirred at r.t. over night.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[OH:15][C:16]1[CH:20]=[C:19]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[N:18]([C:32]2[C:37]([Cl:38])=[CH:36][C:35]([Cl:39])=[CH:34][C:33]=2[Cl:40])[N:17]=1.O>ClC(Cl)C(Cl)Cl.CO>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:20]1[C:16]([OH:15])=[N:17][N:18]([C:32]2[C:33]([Cl:40])=[CH:34][C:35]([Cl:39])=[CH:36][C:37]=2[Cl:38])[C:19]=1[N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26])=[O:9]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)nn1-c1c(Cl)cc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)C(Cl)Cl
Solvent: CO
Product: O=C(c1ccccc1Cl)c1c(O)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum trichloride (2.34 g, 17.6 mmol) was added to a solution of 2-chlorobenzoyl chloride in 60 mL of 1,1,2,2-tetrachloroethane and the resulting mixture was stirred for 30 minutes at room temperature. Then 2.87 g of the compound of Step B was added all at once and the reaction mixture was refluxed overnight. The cooled mixture was poured into water and the aqueous phase was extracted three times with ethyl acetate. The organic extracts were dried with brine and magnesium sulfate and evaporated to give a red oil which was taken up in methanol and crystallized to give the title compound, 2.97 g (77%), m.p. 245-246° C.
Reaction SMILES: C([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]3[CH:22]=[C:23]([C:31]([S:34]([CH3:37])(=[O:36])=[O:35])([CH3:33])[CH3:32])[CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][S:34]([C:31]([C:23]1[CH:24]=[C:25]2[C:30](=[C:21]([C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9](=[O:8])[NH:14][CH:13]=4)[CH:20]=[CH:19][CH:18]=3)[CH:22]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)([CH3:33])[CH3:32])(=[O:35])=[O:36]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(OCc4ccccc4)nc3)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1cc(-c2cccc(-c3ccc(=O)[nH]c3)c2)c2ncccc2c1)S(C)(=O)=O
Reaction time: 72 h

Procedure:
To a solution of 8-[3-(6-Benzyloxy-pyridin-3-yl)-phenyl]-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline from Step 2 (1.0 eq.) in CH2Cl2 (0.2M) was added an equi volume of TFA. The mixture was stirred for 72 h, concentrated, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (CH2Cl2:MeOH; 95:5) afforded the title compound as a light yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 8.95 (dd, 1H), 8.53 (d, 1H), 8.28 (d, 1H), 8.04 (d, 1H), 7.89 (dd, 1H), 7.79 (s, 1H), 7.75 (s, NH), 7.63–7.53 (m, 4H), 6.46 (d, 1H), 2.82 (s, 3H), 1.94 (s, 6H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].Cl[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]([C:15]1[S:14][C:13]([CH3:12])=[CH:17][CH:16]=1)=[O:11]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(C)s1
Temperature: 0 °C
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a suspension of aluminum trichloride (2.75 g, 20.6 mmol) and methyl 2-chloro-2-oxoacetate (1.90 mL, 20.7 mmol) in dry DCM (25 mL), cooled at 0° C. and under nitrogen atmosphere, is added 2-methylthiophene (1.00 mL, 10.33 mmol) dropwise. The reaction is stirred at RT for 15 hours. Then the mixture is cooled at 0° C. ice-water is slowly added and the organic phase is washed with aq. NaHCO3 and brine, dried over Na2SO4 and evaporated to obtain intermediate I266 as a brown oil (1.9 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 100.1 %

Procedure:
The mixture of 4-chloro-3-(trifluoromethyl)phenol (3.2 g, 16.28 mmol), 4-fluorobenz aldehyde (2.425 g, 19.54 mmol) and K2CO3 (3.38 g, 24.42 mmol) in DMF (25 mL) was heated with a microwave reactor at 120° C. for 20 min. Purification via an ISCO system then afforded the title compound as a yellow solid (4.9 g, 100% yield). LCMS: rt=3.78 min, [M+H+]=300.9
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Br[C:18]1[CH:19]=[C:20]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27]2)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:24][N:22]1[CH:23]=[C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[CH:19]=[C:20]([N:26]2[CH2:31][CH2:30][CH2:29][C@H:28]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:27]2)[C:21]1=[O:25]
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Reactant: Cn1cc(Br)cc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)c1=O
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)c(=O)n(C)c2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (0.49711 mmol; 105 mg), tert-butyl N-[(3S)-1-(5-bromo-1-methyl-2-oxo-3-pyridyl)-3-piperidyl]carbamate (0.59653 mmol; 230.4 mg), N,N′-Dimethylethylenediamine (0.049711 mmol; 4.382 mg; 0.00495 mL), copper iodide (0.49711 mmol; 95.629 mg), and potassium carbonate (0.99422 mmol; 138.79 mg) in 1,4-Dioxane (10 mL) was purged with Argon, then sealed and stirred at 100° C. overnight. The mixture was cooled to room temperature, and then filtered through Celite. The filtrate was concentrated; the residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford tert-butyl N-[(3S)-1-[1-methyl-5-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-oxo-3-pyridyl]-3-piperidyl]carbamate (116. mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)C(OCC)=O)=O)=[CH:4][CH:3]=1.[OH-:31].[Na+].C([O-])(O)=O.[Na+]>Cl>[F:1][C:2]1[C:3]2[C:4](=[CH:30][CH:2]=[CH:3][CH:4]=2)[C:5]([CH2:6][C:8](=[O:31])[CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[N:23]=[CH:24][C:25]([F:28])=[CH:26][N:27]=3)[CH2:20][CH2:21]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(CCN1CCN(c2ncc(F)cn2)CC1)C(=O)c1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCN1CCN(c2ncc(F)cn2)CC1)Cc1ccc(F)c2ccccc12
Temperature: 23 °C

Procedure:
A mixture of Ethyl 2-(4-fluorobenzoyl)-4-(4-(5-fluoro-2-pyrimidinyl)piperazin-1-yl)butanoate (2.95 g, 6.3 mmol) in aqueous HCl (65 mL, 1N) was refluxed for 2 h, cooled at 23° C. and basified, first with aqueous NaOH solution (30 mL, 2N) and then with saturated NaHCO3 solution until pH=9. The aqueous solution was extracted with CH2Cl2 (3×150 mL). Organic extracts were combined, washed with water (30 mL) and brine, dried (MgSO4) and concentrated to dryness. The crude material was chromatographed on silica gel using a mixture of 50% CH2Cl2 in EtOAc. Appropriate fractions were combined and solvent evaporated under reduced pressure leaving 2.3 g (92%), mp 119°-120° C. Recrystallization from EtOH afforded analytical sample; mp 120°-1° C.; 1H NMR (CDCl3, 200 MHz) δ: 2.03 (t, J=7.0 Hz, CH2CH2CH2, 2H), 2.4-2.6 (m, 6H), 3H (t, J=7.0, CH2CO, 2H), 3.8-3.9 (m, 4H), 7.1-7.2 (m, 1H), 7.5-7.8 (m, 2H), 7.9-8.0 m, 1H), 8.18 (s), 8.1-8.3 (m, 3H), 8.7-8.8 (m, 1H); IR (KBr) ν: 1681, 1630, 1611, 1600, 1575, 1555, 1494 cm-1 ; UV (CH3CN) λ: 226 (ε 40377), 298 (ε 7498);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:22])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[Si:38]([O:22][C@@H:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]
Reactant: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(C#N)cc2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a mixture of (S)-ethyl 1-((S)-2-(4-cyanophenyl)-2-hydroxyethyl)piperidine-3-carboxylate (17.0 g, 56.2 mmol) and DIPEA (17.68 ml, 101 mmol) in CH2Cl2 (187 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (16 ml, 69.6 mmol) slowly. The reaction was monitored with HPLC. The reaction completed in 2 hours. The reaction mixture (a light brown solution) was quenched with water, the aqueous layer was extracted with DCM. The organic phase was combined and dried with Na2SO4. After concentration, the crude material was further purified on a silica gel cartridge (330 g silica, 10-30% EtOAc/hexanes gradient) to afford a purified product (S)-ethyl 1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-cyanophenyl)ethyl)piperidine-3-carboxylate (22.25 g, 53.4 mmol, 95% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (2H, d), 7.45 (2H, d), 4.79 (1H, m), 4.15 (2H, m), 2.88 (1H, m), 2.75 (1H, m), 2.60 (1H, dd), 2.48 (1H, m), 2.40 (1H, dd), 2.33 (1H, tt), 2.12 (1H, tt), 1.90 (1H, m), 1.68 (1H, dt), 1.52 (1H, m), 1.48 (1H, m), 1.27 (3H, t), 0.89 (9H, s), 0.08 (3H, s), −0.07 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:16][CH:15]3[N:17](C)[CH:11]([CH2:12][CH2:13][CH2:14]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(Cl)(Cl)COC(Cl)=O.[OH-].[Na+].Cl>C(OCC)C.[Zn].O.C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:16][CH:15]3[NH:17][CH:11]([CH2:12][CH2:13][CH2:14]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2CCCC1CN(c1ccc(Cl)c(Cl)c1)C2
Agent: Cl
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(N2CC3CCCC(C2)N3)cc1Cl

Procedure:
A mixture of 3-(3,4-dichloro-phenyl)-9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (0.50 g, 1.75 mmol), 2,2,2-trichloroethylchloroformate (1.11 g, 5.26 mmol) and toluene (30 ml) was stirred at reflux for 15 h. Water (30 ml) was added and the phases were separated. The organic phase was evaporated. Acetic acid (10 ml) and water (10 ml) and zinc powder (0.57 g, 8.8 mmol) was added. The mixture was stirred for 15 h. Aqueous sodium hydroxide (20 ml, 1 M) was added followed by extraction with dichloromethane (3×10 ml). The crude product was purified by silica gel column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9:1:1%). Yield 150 mg (32%). The corresponding salt was obtained by addition a mixture of hydrogen chloride solved in diethylether (1 ml, 2 M). Mp 295.4° C. LC-ESI-HRMS of [M+H]+ shows 271.0769 Da. Calc. 271.076879 Da, dev. 0.1 ppm.