Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19])[CH2:10][CH2:9]1)(C)(C)C.CO.Br.C(Br)(=O)C>C1(C)C=CC=CC=1>[Br:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCCCCBr)CC1
Agent: Br
Agent: CC(=O)Br
Solvent: Cc1ccccc1
Solvent: CO
Product: N[C@H]1CC[C@H](CCCCCBr)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., a solution of 4.4 g (12.63 mmol) of trans-[4-(5-Bromo-pentyl)-cyclohexyl]-carbamic acid tert-butyl ester were received in 9 m MeOH was added to 40 ml of a HBr solution in MeOH (made by dropping at 0° C., 4.7 ml (63.07 mmol) of acetylbromide to 35 ml MeOH). The suspension was stirred for 16 h at RT, diluted with toluene and evaporated (2×). The residue was suspended in EtOAc (40 ml) cooled (−10 to −15° C.) and filtered to give 4.05 g (97%) of trans-4-(5-Bromo-pentyl)-cyclohexylamine as hydrobromide salt, MS: 248 (MH+, 1Br).
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([C:17]([O-:19])=O)[CH:14]=[CH:13][N:12]3[CH:20]=2)[CH:6]=[CH:7][CH:8]=1.C(Cl)CCl.C1[CH:26]=[CH:27][C:28]2N(O)N=[N:31][C:29]=2C=1.[O:35]1CCC[CH2:37][CH:36]1CN.C(N(CC)CC)C>CN(C=O)C>[O:35]1[CH2:26][CH2:27][CH:28]([CH2:29][NH:31][C:17]([C:15]2[CH:14]=[CH:13][N:12]3[CH:20]=[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=4)[N:10]=[C:11]3[CH:16]=2)=[O:19])[CH2:37][CH2:36]1
Reactant: NCC1CCCCO1
Reactant: O=C([O-])c1ccn2cc(-c3cccc(Cl)c3)nc2c1
Reactant: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCOCC1)c1ccn2cc(-c3cccc(Cl)c3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid sodium salt (141 mg, 0.481 mmol) in DMF (2 mL) were added EDC (3 eq, 1.44 mmol, 277 mg) and HOBt (3 eq, 1.44 mmol, 195 mg). The mixture was stirred at room temperature for 15 minutes then tetrahydropyran-methylamine (1.5 eq, 0.72 mmol, 83 mg) and triethyl amine (3 eq, 1.44 mmol, 0.21 mL) were added. The reaction mixture was stirred at room temperature for 3 hours then quenched by the addition of water. The product was extracted three times with ethyl acetate and the crude product was purified by column chromatography to afford 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide in 65% yield. 1H NMR (DMSO-d6) δ 8.69 (1H), 8.61 (2H), 8.16 (1H), 8.11 (1H), 7.98 (1H), 7.51 (1H), 7.41 (1H), 7.38 (1H), 3.92 (2H), 3.18 (2H), 3.11 (2H), 1.95 (1H), 1.31 (2H), 1.12 (2H); m/z (M+H)=370.3
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C@@H:20]3[C:32]4[NH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]=4[CH2:23][CH2:22][NH:21]3)=[CH:19][C:14]=2[O:13][CH2:12]1.[K+].[Br-]>>[CH2:1]([NH:8][C:9]([N:21]1[CH2:22][CH2:23][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:31][C:32]=2[C@H:20]1[C:18]1[CH:17]=[CH:16][C:15]2[O:11][CH2:12][O:13][C:14]=2[CH:19]=1)=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=NCc1ccccc1
Reactant: c1ccc2c3c([nH]c2c1)[C@@H](c1ccc2c(c1)OCO2)NCC3
Agent: [Br-]
Agent: [K+]
Product: S=C(NCc1ccccc1)N1CCc2c([nH]c3ccccc23)[C@H]1c1ccc2c(c1)OCO2
Yield: 80 %

Procedure:
Addition of benzyl isothiocyanate to (1R)-benzo[1,3]dioxol-5-yl-2,3,4,9-tetrahydro-1H-β-carboline (1R isomer of compound (III)) provided Example 2b in 80% yield: mp 205–207° C. H1 NMR (DMSO-d6) δ: 11.0 (s, 1H), 8.5 (t, J=5 Hz, 1H), 7.8 (s, 1H), 7.6 (s, 1H), 7.43 (d, J=7 Hz, 1H), 7.4–7.28 (m, 8H), 6.85 (dd, J=1.4, 8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 5.88 (s, 2H), 4.88 (overlapping dd, J=4.7, 14 Hz, 2H), 4.11 (dd, J=4.4, 14 Hz, 1H), 3.51–3.44 (m, 1H), 2.94–2.84 (m, 1H), 2.78 (dd, J=4, 15 Hz, 1H); MS ES+m/e 442 (p+1), ES−m/e 440 (p−1); IR (KBr, cm−1): 1518, 1503, 1487; Elemental analysis: Anal. Calcd for C26H23N3O2S: C, 70.72; H, 5.25; N, 9.51. Found: C, 70.30; H, 5.27; N, 9.42; 74% ee.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1Cl.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[C:18]1[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C)nc1Cl
Reactant: OB(O)c1ccc(C(F)(F)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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
2-Chloro-6-methylnicotinic acid methyl ester (18.6 g) and 4-trifluoromethylphenylboronic acid (22.0 g) were dissolved in a mixed solvent of ethanol (100 mL) and toluene (100 mL), and to this solution were added 2M sodium carbonate (100 mL) and tetrakis(triphenylphosphine)palladium(0) (2.90 g). The mixture was stirred at 120° C. for 3 hours under heating. Ethyl acetate (200 mL) was added to the reaction solution. The aqueous layer was separated off. The organic layer was washed successively with 0.1N sodium hydroxide, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with (hexane:ethyl acetate=1:4, v/v) to give the title compound (25.8 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:17][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:18])[CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-[(1,1-dimethylethyl)dimethylsilyl]oxy-4-methylbenzoate (11.36 g, 40.5 mmol) from Preparation 13, N-bromosuccinimide (6.5 g, 36.5 mmol), and AIBN 100 mg, 0.61 mmol) in CCl4. The reaction mixture is stirred at room temperature for 1 hour while exposed to a high intensity light bulb. The precipitate is removed by suction filtration and the filtrate is concentrated. The residue is purified by silica gel chromatography (1% tetrahydrofuran/petroleum ether). An oil of methyl 4-(bromomethyl)-3-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]benzoate is obtained 99.87 g, 75%).
Reaction SMILES: [Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16](I)[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1.[F:28][C:29]1[CH:30]=[N:31][NH:32][C:33]=1[Sn](CCCC)(CCCC)CCCC.CCOC(C)=O>CS(C)=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>[Cl:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[C:12]2[CH:17]=[C:16]([C:33]3[NH:32][N:31]=[CH:30][C:29]=3[F:28])[C:15]([N:19]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20]3)=[N:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(CO)C2)c(-c2[nH]ncc2F)c1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)azetidin-1-yl)-5-iodonicotinamide (Stage 92.1, 200 mg, 0.392 mmol), 4-fluoro-5-(tributylstannyl)-1H-pyrazole (147 mg, 0.392 mmol), Pd(PPh3)4 (22.67 mg, 0.02 mmol) in DMSO (2 mL) was stirred at 100° C. under argon atmosphere for 21 h. The RM was treated with EtOAc, washed with sat. aq. NaHCO3 and brine dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography on silica gel, dissolved in MeOH (3 mL), filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg 1.5 mmol), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was further purified by preparative SFC (Column Diol, from 21% to 26% in 6 min) to give the title product as a white solid. HPLC (Condition 7) tR=5.701 min, UPLC-MS (Condition 8) tR=0.95 min, m/z=468.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.58-2.73 (m, 1H) 3.43-3.51 (m, 2H) 3.51-3.60 (m, 2H) 3.75-3.85 (m, 2H) 4.68-4.77 (m, 1H) 7.30-7.38 (m, 3H) 7.83-7.91 (m, 2H) 7.99-8.07 (m, 1H) 8.73-8.83 (m, 1H) 10.21 (s, 1H) 12.92-13.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:42])[CH:40]=[CH2:41]>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:13]3[N:14]=[C:15]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:22][CH:21]=4)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:42])[CH:40]=[CH2:41]
Reactant: C=CC(=O)Cl
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(=O)Nc1cccc(C2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
To a solution of 7-(3-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 0.071 mmol) in DCM (2 mL) was added pyridine (0.2 mL). Then acryloyl chloride (6 mg, 0.084 mmol) was added dropwise. The mixture was stirred at RT for 0.5 hr and partitioned between DCM (20 mL) and brine (20 mL). Organic layer was separated from aqueous layer, washed with brine (2×20 mL), dried over Na2SO4 and purified by Pre-TLC (DCM/CH3OH=10/1) to afford 1.82 mg (5.38%) of 7-(3-acrylamidophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.58 (d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.34-7.26 (m, 4H), 7.10 (t, J=7.6 Hz, 1H), 7.04-6.95 (m, 4H), 6.84 (d, J=7.6 Hz, 1H), 6.39-6.25 (m, 2H), 5.69 (dd, J=2.4, 9.6 Hz, 1H), 5.47-5.44 (m, 1H), 3.38-3.31 (m, 1H), 3.22-3.12 (m, 1H), 2.52-2.42 (m, 1H), 2.23-2.17 (m, 1H). MS (ESI) m/e [M+1]+ 480.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:17]=[C:16]3[O:18]C[O:20][C:15]3=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccccc2)oc2cc3c(cc12)OCO3
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Cc2ccccc2)oc2cc(O)c(O)cc12
Temperature: -25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A solution of 2-benzyl-3-methyl-5,6-methylenedioxybenzofuran (226 mg, 0.85 mmole) in methylene chloride (10 mL) was cooled at -65° C. and a 1M solution of boron tribromide in methylene chloride (0.85 mL) was added dropwise. The mixture was allowed to warm up to -25° C. and was kept in that range for 1 hour. Methanol (5 mL) was then added and the mixture was evaporated in vacuo. The residue was chromatographed on silica gel and eluted with 25% ethylacetate in hexane to yield 128 mg of 2-benzyl-3-methyl-5,6-dihydroxybenzofuran, mp. 95.5°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.CN(C)C=O.S(Cl)([Cl:33])=O.C>ClCCCl>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:17]([Cl:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([Cl:33])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 78.5 %

Procedure:
79.2 g of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid and 0.5 ml of dimethylformamide were introduced into 150 ml of 1,2-dichloro-ethane. 28.6 g of thionyl chloride were added dropwise at 60° to 65° C. and the mixture was heated under reflux for 1 hour. The solution was clarified with active charcoal and filtered through kieselguhr. The mother liquor was concentrated and the residue was recrystallized from cyclohexane. 65.1 g (79% of theory) of 5-(2,6-dichloro-4-trifluoromethyl-phenoxy)-2-nitro-benzoic acid chloride, of melting point 95° C., were obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC.CS(C)=O>[C:12]1([S:18]([N:3]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2ncccc21
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
Sodium hydride (60% in mineral oil, 203 mg, 5.08 mmol) was washed twice with hexane, and the residue suspended in DMSO (5 ml). 1H-Pyrrolo[3,2-b]pyridine (500 mg, 4.24 mmol) was added and the reaction stirred for 15 minutes. Benzenesulphonyl chloride (749 mg, 4.42 mmol) was added rapidly and the reaction stirred for 0.5 h. After quenching with water the product was extracted into EtOAc, dried (Na2SO4) and concentrated in vacuo. Chromatography (EtOAc, silica) yielded the title compound as a white crystalline solid (903 mg, 83%). δH (d6-DMSO) 8.48 (1H, dd, J 0.8, 3.8 Hz), 8.31 (1H, m), 8.15 (1H, d, J 3.8 Hz), 8.04 (2H, m), 7.72 (1H, m,), 7.61 (2H, m,), 7.36 (1H, dd, J 4.7, 8.4 Hz), 6.98 (1H, dd, J 0.8, 3.8 Hz). LCMS (ES+) RT 3.056 minutes, 259 (M+H)+.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[C:17]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[OH-].[OH-].[Pd+2]>[N:25]1([C:17]2[N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH2:8])=[CH:10][CH:11]=3)[CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: c1ccc(CN(Cc2ccccc2)c2ccc(-c3cc4ncccc4c(N4CCOCC4)n3)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Nc1ccc(-c2cc3ncccc3c(N3CCOCC3)n2)cc1
Temperature: 80 °C

Procedure:
To a solution of dibenzyl-[4-(5-morpholin-4-yl-[1,6]naphthyridin-7-yl)-phenyl]-amine B (30 mg, 0.06 mmol, leg) in dry EtOH (3 mL) was added Pd(OH)2 (16 mg, 50% w/w) and 1,4-cyclohexanediene (120 μL, 1.24 mmol, 20 eq) under Ar(g). The mixture was heated at 80° C. overnight; once cooled down, the reaction mixture was then filtered through a short celite pad, eluting with MeOH (10 mL). The solvent was subsequently removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (1:4-0:1) to yield the product, C, as a pale yellow solid (9.6 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH2:12][CH3:13])[OH:11])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([CH:10]([OH:11])[CH2:12][CH3:13])=[CH:9][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCC(O)c1cc2cc(O)c(Cl)c(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(C(O)CC)sc2c(Cl)c1Cl
Reaction time: 3 h

Procedure:
To a mixture of 6,7-dichloro-5-hydroxy-α-ethylbenzo[b]thiophene-2-methanol and 200 ml of 2-butanone is added a mixture of 7.35 g of ethyl bromoacetate in 100 ml of 2-butanone, followed by 7.4 g of potassium carbonate and 3.3 ml of sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 3 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and the mixture is extracted with ethyl ether. The organic layers are washed, dried over anhydrous magnesium sulfate, filtered and the solvent removed to give an oil which solidifies on cooling. Recrystallization from ethyl ether and hexane gives 10 g of ethyl[(6,7-dichloro-2-(1-hydroxypropyl]benzo[b]thien-5-yl]oxy]acetate, mp 69°-70°.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Cl.[Cl:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH:17]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:10].[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[CH:15]=[N:14][CH:13]=[C:12]([CH2:11][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH3:3])[CH:17]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccn1Cc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (17 mg of a 55% dispersion in mineral oil, 0.39 mmol) in DMF (5 ml) was added 2-methylimidazole (32 mg, 0.39 mmol). This mixture was stirred for 1.5 h at 20° C. Following this, 3-chloromethyl-5-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) (100 mg, 0.32 mmol) and triethylamine (78 mg, 0.78 mmol) were added and the mixture heated to 100° C. for 4 h. After cooling, the DMF was evaporated and the residue was directly chromatographed [silica, elution with CH2Cl2/(2M NH3 in MeOH)=85:15] to afford the free base of the title compound as a yellow oil. This material was dissolved in MEOH, cooled to 4° C. with stirring and treated with HCl/EtOH (1.46 M 1.1 eq) for 15 min. Evaporation of the solvent and drying under high vacuum at 50° C., for 2 h afforded the title compound (71 mg, 62%) as a light yellow solid. MS: m/e=317.1 (M+)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.O1CCCC1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44](=[O:47])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][C:44]([OH:47])([C:11]2[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=3)[N:10]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nc(-c3cccc(C(F)(F)F)c3)cn2COCC[Si](C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a 100 mL round bottom flask (fitted with cooling bath, stir bar and nitrogen blanket) add 4-(3-Trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (0.995 g; 1.00 equiv; 2.91 mmoles; 995.00 mg), n-Butyl Lithium (2.8 mL; 1.54 equiv; 4.48 mmoles; 2.80 mL; 1.90 g), and Tetrahydrofuran (30 mL; 368.66 mmoles; 30.00 mL; 26.58 g) and cool the mixture to −78° C. with stirring on and hold for 30 min. Add N-T-Butoxycarbonyl-4-piperidone (0.706 g; 1.22 equiv; 3.54 mmoles; 706.00 mg) and allow the reaction to warm to room temperature. Dilute the reaction with CH2Cl2, wash with water, dry over Na2SO4, filter, and concentrate to dryness. Purify the crude mixture by flash chromatography on silica eluting with ethyl acetate/hexane from 10-50% EtOAc. Combine the appropriate fractions and concentrate to give 4-Hydroxy-4-[4-(3-trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (1.248 g; 0.79 equiv; 2.30 mmoles; 1.25 g; 79.29% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:14])[CH3:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To ethyl 4-bromophenylacetate (2.137 g, 8.8 mmol) in THF (20 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1M in hexane; 11.4 mL, 11.4 mmol), and the solution was stirred for 1 hour at −78° C. Iodomethane (0.71 mL, 11.4 mmol) in THF (5 mL) was added, and the reaction was warmed to room temperature. The mixture was quenched with water and concentrated. The residue was dissolved in EtOAc and washed three times with water and once with brine. The organic layer was dried and concentrated, and the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give 2-(4-bromo-phenyl)-propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[C:13]([F:20])([F:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CS(C)=O.[Cu]>[CH2:17]([O:16][C:14](=[O:15])[C:13]([F:20])([F:19])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:18]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccc2ccccc2n1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc2ccccc2n1
Temperature: 55 °C
Reaction time: 5 h
Yield: 69.7 %

Procedure:
A mixture of 2-bromoquinoline (5.0 g, 24.0 mmol), ethyl 2-bromo-2,2-difluoroacetate (5.8 g, 28.8 mmol) and copper power (3.5 g, 55.2 mmol) in DMSO (20 ml) was stirred at 55° C. for 5 hours. The solid was filtered off and water (100 ml) and EA (150 ml) were added. The organic layer was separated and evaporated and concentrated to give the title product (4.2 g, 70%) which was used for the next step without further purification. LC-MS (ESI+): m/e 252 (M+H)+, Rt: 0.934 min/2.5 min.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].O.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CCCCCC>[OH:19][CH:23]([C:22]1[CH:2]=[CH:1][N:4]=[CH:20][CH:21]=1)[C:14]([CH3:16])([CH3:15])[C:13]#[N:17]
Reactant: CC(C)NC(C)C
Reactant: CC(C)C#N
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C#N)C(O)c1ccncc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
A solution of diisopropylamine (10.0 ml, 71.5 mmol) in tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere, and a 1.6 N solution of butyllithium in hexane was added dropwise thereto over 10 minutes. The mixture was cooled with ice-cold water for 20 minutes and then cooled to −78° C. again, and isobutyronitrile (3.03 ml, 33.3 mmol) was added dropwise to the mixture over five minutes. Further, 4-pyridinecarboxyaldehyde (3.18 ml, 33.3 mmol) was added dropwise thereto over five minutes, and the whole was stirred for one hour 20 minutes. Water (100 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (200 ml) by using a continuous extracting apparatus for three days. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered off with diethyl ether to give 4.20 g (71.6%) of 3-hydroxy-2,2-dimethyl-3-(4-pyridyl)propionitrile as a colorless solid.