Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](O)(=[C:12]1[C:20](=[O:21])[CH2:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:13]1=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>CCO.C(O)(C(F)(F)F)=O>[NH:1]([C:7](=[C:12]1[C:13](=[O:14])[CH2:15][C:16]([CH3:17])([CH3:18])[CH2:19][C:20]1=[O:21])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: NCCC(=O)O
Reactant: CC(C)CC(O)=C1C(=O)CC(C)(C)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)CC(NCCC(=O)O)=C1C(=O)CC(C)(C)CC1=O
Yield: 98 %

Procedure:
To a stirred suspension of H-β-Ala-OH (1.02 g, 11.4 mmol) and ivDde-OH (5 ml, 22.9 mmol) in EtOH was added TFA (88 μL, 1 mmol) at room temperature.1 The mixture was then refluxed for 24 hours. After the solvent was evaporated in vacuo, a crude product was purified by column chromatography with CH3OH/CH2Cl2 (0.1% TFA) gradient to afford ivDde-β-Ala-OH (3.3 g, 97.6%). 1H NMR (CDCl3) δ 1.02 (m, 12H), 1.90-2.03 (m, 1H), 2.39 (s, 4H), 2.75 (t, J=6.0 Hz, 2H), 3.06 (br d, J=6.0 Hz, 2H), 3.78 (q, J=6.0 Hz, 2H); 13C NMR (CDCl3) δ 22.8, 28.4, 29.4, 30.2, 34.1, 37.4, 39.6, 52.9, 107.4, 173.0, 177.2; MS (MALDI): m/z: calcd for C16H26NO4 296.2; found 296.5 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)[CH3:18]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCN1CCN(c2ccc(C(C)(C)C)cc2)CC1
Yield: 84.8 %

Procedure:
A mixture of 1-(4-tert-butyl-phenyl)-piperazine (1.09 mg; 5.0 mmol), 4-bromo-butyric acid ethyl ester (975 mg; 5.0 mmol), potassium carbonate (691 mg; 5.0 mmol) and potassium iodide (914 mg; 5.5 mmol) in acetonitrile (15 mL) is heated to reflux for 2 hours. The reaction mixture is allowed to attain room temperature and all solids removed by filtration. The filtration residue is washed with acetonitrile and the filtrate concentrated under high vacuum to afford the desired compound (1.41 g; 4.24 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([S:17]CC3C=CC(OC)=CC=3)=[CH:8][CH:9]=2)[N:4]=1.C(O)=O.O.S>C(Cl)Cl>[SH:17][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:12]([C:13]([O:15][CH3:16])=[O:14])[C:3]([O:2][CH3:1])=[N:4]2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc2ccc(SCc3ccc(OC)cc3)cc2nc1OC
Agent: S
Solvent: O
Solvent: O=CO
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(S)cc2nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the ester from Step 4 (2.77 g), 90% formic acid (70 ml) and mercuric acetate (7.17 g) was stirred under an argon atmosphere at ambient temperature for 3 hours. The reaction mixture was poured into a mixture of water (350 ml) and CH2Cl2 (700 ml) and H2S gas was passed through the vigorously stirred mixture for 5 minutes. The organic phase was separated, filtered through celite, washed with water, dried (MgSO4) and reduced to dryness to provide the title compound, m.p. 103°-105°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCCNS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 17.3 %

Procedure:
According to general procedure B, 4-bromo-N-propylbenzenesulfonamide (111 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-propylbenzenesulfonamide (21 mg, 17%) was provided after purification. MS (ESI) m/z 303. HPLC purity 100.0% at 210-370 mn, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C:1]([C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2)[C:7](=[O:8])[CH2:6][S:5][CH2:4]1)#[N:2].Br>O1CCOCC1>[C:1]([C:3]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:21])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)[C:7](=[O:8])[CH2:6][S:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C(C)c1ccc(CC2(C#N)CSCC2=O)cc1
Agent: Br
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(CC2(C#N)CSCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Methyl 2-[4-(3-cyano-4-oxothiolan-3-ylmethyl)phenyl]propionate (2.0 g) obtained in Example 6 was dissolved in 1,4-dioxane (14 ml), then, 47% aqueous hydrobromic acid (10.0 ml) was added and stirred overnight at room temperature. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (1.36 g, 78%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(C(F)(F)F)c1
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-(trifluoromethyl)benzoic acid (347 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide (250 mg, 71% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)[CH:27]=3)[C:13]=2[CH3:38])[CH:6]=1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH2:29][OH:30])[CH:27]=3)[C:13]=2[CH3:38])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CCO[Si](C)(C)C(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CCO)c3)c3c(F)c(Cl)ccc23)c1
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-(1-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-4-yl}-6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester (0.125 g, 0.21 mmol) in THF (2 mL) at room temperature was added TBAF (0.30 mL of a 1.0 M solution in THF, 0.30 mmol). The mixture was stirred for and additional 5 minutes, then subjected to standard aqueous workup to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]2[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=2[N:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:6]2[C:5]3[C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=[CH:25][C:4]=3[N:3]=[C:2]2[N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:9][CH:10]=1)#[N:21]
Reactant: COC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: C1COCCN1
Product: COC(=O)c1cccc2nc(N3CCOCC3)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of methyl 2-chloro-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.8 g) in morpholine (15 ml) was stirred at 100° C. for 2 hours and the reaction mixture was concentrated to dryness. The residue was extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The resulting crystals were recrystallized from ethyl acetate-hexane to afford colorless prisms (0.69 g, 77%).
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8](O)=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C>C1COCC1>[C:1]([C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[O:14][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C(=O)O)c(O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OC(=O)C2(C)C
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a solution of compound 18 (7.10 g, 25.2 mmol) in 710 mL of anhydrous THF was added EDCI (14.5 g, 75.6 mmol). The resulting suspension was left stirring at 30° C. overnight. The precipitate was filtered and thoroughly washed with DCM. The filtrate was concentrated to dryness and the residue was dissolved in DCM (100 mL). The solution was washed with water (50 mL×2) and brine (50 mL×1). The DCM layer was then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified via column chromatography on silica gel (Petroleum ether/EtOAc 200:1→100:1→50:1) to give compound 19 as a white solid. 1H NMR (CDCl3; 400 MHz) δ 7.36 (s), δ 7.10 (s), δ 1.53 (s), δ 1.41 (s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: ClCc1cnc2ccccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3cnc4ccccc4c3)c2cc1OC
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (120 mg, 547 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.58 mL, 1.16 mmol) at RT followed by MDE 32004 (130 mg, 607 μmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with CH2Cl2 (50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) gave 67 mg of 6,7-dimethoxy-1-methyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol. The free base was dissolved in MeOH (2 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (6 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 26 as a brown solid (80 mg, 31% yield).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Br:18]Br>ClCCl>[Br:18][C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([OH:13])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Temperature: -8 °C
Reaction time: 0.25 h

Procedure:
(trans)-4-Phenylcyclohexanol (2 g) is dissolved in dichloromethane (40 mL) and cooled to −8° C. AlCl3 (3 g) is added portionwise and the mixture is stirred for further 15 minutes after addition is complete. Then a solution of bromine (1.87 mL) in dichloromethane (10 mL) is added dropwise. The mixture is stirred for 10 minutes and is then partitioned between dichloromethane and ice-water. Concentrated hydrochloric acid (20 mL) is added, the phases are separated and the aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 2:1) to give the title compound. TLC: rf=0.3 (silicagel, cyclohexane/ethylacetate 2:1).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:34][CH3:35])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13](COCC[Si](C)(C)C)[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([Cl:33])[CH:27]=1)[N:5]=2.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:3]([CH2:34][CH3:35])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([Cl:33])[CH:27]=1)[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(-c3ccc(O)c(Cl)c3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(-c3ccc(O)c(Cl)c3)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.5 %

Procedure:
400 mg (0.59 mmol) of impure 2-amino-7-(3-chloro-4-hydroxy-phenyl)-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one was dissolved in 20 ml DCM. At 0° C., 3.39 g of TFA were added and the mixture was stirred at room temperature for 24 hours. The solution is neutralized by adding an excess of aqueous NaHCO3 solution. The mixture was then extracted three times with DCM. The combined organic phases were dried over MgSO4 and the solvents were evaporated off under reduced pressure. The so-gained raw material was purified on silica gel (DCM:MeOH:NH4OH=4:10.1) yielding 0.035 g of the unprotected title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][OH:19]>>[CH2:20]([C:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH2:18][OH:19])[CH2:22][CH3:23])[CH3:21]
Reactant: CCC(N)(CC)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CCC(CC)(CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and 2-amino-2-ethyl-1-butanol (CAN 19792-52-0) as starting materials and isolated (22 mg, 67% as colorless oil; LC-MS (UV peak area, m/z) 98%, 327.1470 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([OH:15])[CH:3]=1.S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[NH2:1][C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:15][CH3:20])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1cc(C#N)c(N)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C#N)c(N)cc1OC
Yield: 79.5 %

Procedure:
To a stirred solution of 4.1 parts of ethyl 4-amino-5-cyano-2-hydroxybenzoate in 40 parts of 2-propanone were added successively 2.52 parts of dimethyl sulfate and 4.1 parts of potassium carbonate. The whole was stirred and refluxed for 3 hours. The reaction mixture was filtered while hot and the filter-cake was washed with 2-propanone. The filtrate was evaporated and the solid residue was crystallized from 24 parts of 2-propanol, yielding 3.5 parts (79.5%) of ethyl 4-amino-5-cyano-2-methoxybenzoate; mp. 164.5° C. (intermediate 110).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([O:50][CH3:51])[C:44]=1[O:45]S(C)(=O)=O)[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CO>[CH3:51][O:50][C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:44]=1[OH:45])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[C:31]4[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OS(C)(=O)=O)c(OC)c4)C3)CC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(O)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (0.5 mmol) and methanol (4 mL). Add potassium carbonate (0.5 g). After 18 hours, add a 1 M aqueous sodium hydroxide solution (1 mL) and extract with dichloromethane. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.Cl.Cl.Cl.Cl.[N:14]1([CH2:18][CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=3)[N:22]=[C:21]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[N:14]1([CH2:18][CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=3)[N:22]=[C:21]2[CH:33]2[CH2:34][CH2:35][N:36]([C:7]3[N:6]=[CH:5][N:4]=[C:3]([NH2:9])[C:2]=3[Br:1])[CH2:37][CH2:38]2)[CH2:15][CH2:16][CH2:17]1
Reactant: Nc1ncnc(Cl)c1Br
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccc1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The reaction mixture of 5-bromo-6-chloro-pyrimidin-4-ylamine (215.00 mg; 1.03 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine tetrahydrochloride (503.6 mg; 1.03 mmol; 1 eq.), and Cs2CO3 (1344.27 mg; 4.13 mmol; 4 eq.) in DMSO (1.5 ml) was stirred at 120° C. overnight. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([C@H:9]3[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@@H]1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(=O)CCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 86.2 %

Procedure:
The title compound (D63) (295 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (200 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (206 mg). Reaction time: 18 hrs
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:19])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][C:23]=1[CH3:30]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:19])[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:30])[CH:24]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc([Mg]Br)cc1C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 18.36 mmol) in 50 mL dry THF at ambient temperature was added (4-methoxy-3-methylphenyl)magnesium bromide (55.1 mL, 0.5 M) was added dropwise under N2, the reaction mixture was stirred at the same temperature for 16 hours. The reaction was quenched with saturated sodium sulfate solution (10 mL) and partitioned between brine (150 mL) and 10% isopropyl alcohol/chloroform (200 mL), and the organic layer was removed to yield the crude product. Purification by flash chromatography (silica: 5-35% ethyl acetate/pentane) gave the title compound as a white solid (6.4 g, 19.21 mmol, >99% yield). HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) retention time=4.131 min.
Reaction SMILES: [BH4-].[CH2:2]([C:9]1[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=2)=[C:19]([O:37][CH2:38][CH2:39][CH3:40])[CH:18]=1>O1CCCC1.C(O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][CH2:21][C:20]2[CH:35]=[CH:36][C:17]([S:14][C:11]3[N:10]([CH3:15])[C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:13][N:12]=3)=[CH:18][C:19]=2[O:37][CH2:38][CH2:39][CH3:40])=[CH:24][CH:25]=1)[CH3:34]
Reactant: CCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Reactant: CCCCCCCc1nnc(S)n1C
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCc1nnc(Sc2ccc(CNc3ccc(CC(=O)OCC)cc3)c(OCCC)c2)n1C
Reaction time: 8 h

Procedure:
2.647 g (6.62 mmol, 3 eq) of resin-supported borohydride and 30 mg (0.06 mmol, 0.03 eq) of bis(bipyridine)dibromonickel (II) are added to a solution of 0.706 g (3.31 mmol, 1.5 eq) of 5-heptyl-4-methyl-4H-[1,2,4]-triazole-3-thiol in 10 ml of tetrahydrofuran/ethanol 5/5. To the suspension obtained there is added a solution of 100 mg (0.22 mmol, 1 eq) of ethyl [4-(4-iodo-2-propoxybenzylamino)phenyl]acetate in 10 ml of tetrahydrofuran/ethanol 5/5. The reaction mixture is stirred overnight under reflux. After returning to room temperature, the reaction medium is filtered, concentrated and then chromatographed on silica gel (heptane/ethyl acetate 40/60). After evaporation of the solvents, 0.750 g (63%) of the expected compound is recovered.