Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2C=CC=CC=2C(C(N)=O)=C1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[CH:32]=[CH:31][C:30]([C:33]4[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=4)[C:36](O)=[O:37])=[CH:29][C:23]=3[C:24]=2[C:25](=[O:28])[NH:26][CH3:27])=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C[NH:55][S:56]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)(=[O:58])=[O:57]>CN(C1C=CN=CC=1)C.CN(C=O)C.ClCCCl>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[CH:32]=[CH:31][C:30]([C:33]4[CH:41]=[CH:40][CH:39]=[C:35]([C:36](=[O:37])[NH:55][S:56]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)(=[O:58])=[O:57])[CH:34]=4)=[CH:29][C:23]=3[C:24]=2[C:25]([NH:26][CH3:27])=[O:28])=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: CNS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(=O)(=O)c4ccccc4)c3)cc12
Yield: 56.8 %

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(methyhphenylsulfonyl)carbamoyl)phenyl)benzofuran-3-carboxamide. In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and N-methylbenzenesulfonamide (50 μL, 0.26 mmol). 1,2-Dichloroethane (0.5 mL) and DMF (0.5 mL) were added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was filtered, purified by prep HPLC, and concentrated on a speedvac to give 27 mg (55% yield) of the title compound as a white powder. 1H NMR (500 MHz, CDCl3) δ ppm 7.91-8.02 (m, 5H) 7.75-7.82 (m, 2H) 7.65 (t, J=7.48 Hz, 1H) 7.47-7.60 (m, 6H) 7.15-7.24 (m, 2H) 5.91 (d, J=4.27 Hz, 1H) 3.36 (s, 3H) 3.04 (d, J=4.88 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, Solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.89 min, (ES+) m/z (MH+)=543. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=17.42 min, purity=92%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=17.86 min, purity >90%.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:21]2[CH2:22][C@@H:23]3[C@H:28]([CH3:29])[C@:27]([CH3:30])([C:20]=2[C:19]=1[N+:36]([O-:38])=[O:37])[CH2:26][CH2:25][NH:24]3.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.C(N(CC)CC)C>[CH:1]1([C:6]([N:24]2[CH2:25][CH2:26][C@:27]3([CH3:30])[C@@H:28]([CH3:29])[C@H:23]2[CH2:22][C:21]2[CH:31]=[C:32]([N+:33]([O-:35])=[O:34])[C:18]([O:17][CH3:16])=[C:19]([N+:36]([O-:38])=[O:37])[C:20]=23)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1c([N+](=O)[O-])cc2c(c1[N+](=O)[O-])[C@]1(C)CCN[C@H](C2)[C@@H]1C
Reactant: O=C(Cl)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c([N+](=O)[O-])cc2c(c1[N+](=O)[O-])[C@]1(C)CCN(C(=O)C3CCCC3)[C@H](C2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopentanecarbonyl chloride (0.12 g) is added to the trifluoroacetic acid salt of (2R,6R,11R)-8-methoxy-6,11-dimethyl-7,9-dinitro-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine (0.43 g) and triethylamine (0.31 mL) dissolved in dichloromethane (10 mL). The resulting solution is stirred at room temperature overnight. Then, aqueous Na2CO3 solution is added and the resulting mixture is extracted with dichloromethane. The combined extracts are washed with water and dried (Na2SO4) and the solvent is evaporated. The residue is purified by HPLC on reversed phase (MeCN/H2O) to give the product as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:14]=2[N:15]=1)[CH:8]([CH3:10])[CH3:9].O.[OH-].[Na+]>C1COCC1>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:13]2[S:12][C:11]([CH2:7][CH:8]([CH3:9])[CH3:10])=[N:15][C:14]=2[CH:16]=1
Reactant: CC(C)Cc1nc2cc(C#N)ccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1nc2cc(CN)ccc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
Add lithium aluminum hydride (0.78 mL, 0.78 mmol, 1M solution in THF) to 2-isobutyl-benzothiazole-5-carbonitrile (113 mg, 0.52 mmol) in THF (5 mL) and stir for 4 h at room temperature. Add water (0.27 mL), 2N sodium hydroxide (0.27 mL) and water (0.37 mL). Filter the precipitate and wash the filtrate with brine. Dry over Na2SO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:1) and then 1M ammonia in methanol/dichloromethane (1:9). Purify the polar fraction by SCX chromatography to give the title compound (63 mg, 55%). MS (ES+) m/z: 221 (M+HE).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)N.Cl.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.Cl>C(O)(C)C>[CH3:14][N:15]1[CH2:20][CH2:19][C:18]2[NH:2][C:4]3[C:12]([C:17]=2[CH2:16]1)=[C:8]1[CH:9]=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc2sccc2c1
Agent: Cl
Solvent: CC(C)O
Product: CN1CCc2[nH]c3ccc4sccc4c3c2C1

Procedure:
4 g of 5-hydrazinobenzothiophene hydrochloride, suspended in 100 ml of isopropanol, are combined with 2.8 ml of 1-methyl-4-piperidone hydrochloride under N2. The solution is brought to the boil and 10 ml of isopropanol saturated with HCl re added whilst the solution is hot. After boiling the mixture of 1/2 hour, the solvent is distilled off, the residue is treated with ammonia and the precipitate is filtered off and recrystallised from methanol. 9-Methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole of melting point 189° C. is obtained.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[N:31]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:32]=[C:33]([I:34])[C:26]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[CH:1]1([CH2:7][C:8]2[N:13]([CH3:14])[C:12](=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:25]4[CH:30]=[CH:29][N:28]=[C:27]5[N:31]([CH2:35][C:36]6[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=6)[N:32]=[C:33]([I:34])[C:26]=45)=[C:18]([F:23])[CH:17]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(CC2CCCCC2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(CC6CCCCC6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Reaction time: 96 h
Yield: 86 %

Procedure:
A mixture of 2-(cyclohexylmethyl)-5-(3-fluoro-4-hydroxyphenyl)-3-methylpyrimidin-4(3H)-one (0.026 g, 0.082 mmol), 4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.033 g, 0.083 mmol; prepared according to the procedure of Example 84, Step D), and DMAP (0.020 g, 0.165 mmol) in bromobenzene (1 mL) under N2 was stirred at 150° C. for 4 days. The reaction was concentrated in vacuo to remove as much bromobenzene as possible and then purified directly by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The desired product (0.048 g, 86%) was obtained as a pale yellow solid. LRMS (APCI pos) m/e 680 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[CH:18]([OH:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Solvent: O
Product: CCC1=C(Cc2ccc(F)cc2)C(O)c2c(OCC(=O)OC)ccc(Cl)c2N1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (1.0 g), 2-(4-fluorobenzyl)-3-oxopentanoic acid ethyl ester (2.1 g) and polyphosphoric acid (10 g) was heated at 130° C. for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1:0 to 19:1 by volume) to afford title compound, 0.25 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])O[CH2:18][CH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:18][CH3:19])[S:9]([C:12]([F:15])([F:13])[F:14])(=[O:11])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(Nc1ccc(Br)cc1)C(F)(F)F
Reactant: CCOC([O-])[O-]
Product: CCN(c1ccc(Br)cc1)S(=O)(=O)C(F)(F)F
Yield: 93 %

Procedure:
A solution of 1.52 g (5 mmol) of N-(4-bromophenyl)-C,C,C-trifluoro-methanesulphonamide (Example 13bv)) in 25 ml of ethyl orthoformate was heated to reflux for 6 hours. Subsequently, the readily volatile constituents were distilled off on a water-jet vacuum and the residue was chromatographed over a flash column with hexane/ethyl acetate 95:5. There were obtained 1.55 g (93%) of N-(4-bromophenyl)-N-ethyl-C,C,C- trifluoro-methanesulphonamide as a pale yellow oil. MS (EI): 331 and 333 (M+, 44%), 198 and 200 ([M-SO2 CF3 ]+, 80%), 118 ([M-(SO2CF3 +HBr)]+, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]#[CH:14])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(N(CC)CC)C.CCOCC>[CH3:15][S:16]([O:1][CH2:2][CH2:3][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:12][C:13]#[CH:14])(=[O:18])=[O:17]
Reactant: C#CCN(CCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C#CCN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 700 mg of 10d in 1 ml of triethyl amine and 15 ml of ether was treated at 0° C. with 320 μl of methanesulfonyl chloride in 3 ml of ether. The reaction mixture was stirred for ½ h and then quenched by addition of 20 ml of water and the product was extracted into ether. The organic extract was washed with 1M aq. K2CO3 and once with water, dried and concentrated, to give 900 mg of 10e as a colorless oil, essentially pure according to TLC and NMR, which was used without further purification in the next step. Rf 0.40 (heptane/ethyl acetate 1/1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:24])[CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][N:9]=1.[F:25][C:26]([F:32])([F:31])[S:27](O)(=[O:29])=[O:28]>N1C=CC=CC=1>[O:24]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:13]=2)=[C:2]([F:1])[CH:3]=1)[S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2F)nc1
Solvent: c1ccncc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2F)nc1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
1.80 g (2.42 mM) of 3-fluoro-4-(5-decylpyrimidine-2-yl)phenol, 2.42 ml of pyridine were mixed and stirred on a common salt-ice bath. To the mixture, 0.80 ml (4.76 mM) of anhydrous trifluoromethanesulfonic acid was added dropwise and stirred for 20 minutes, followed by further stirring for 140 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water, followed by extraction with isopropyl ether. The isopropyl ether layer was successively washed with a common salt aqueous solution, 12%-HCl and a common salt aqueous solution, followed by drying with anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated into a solid product, whereby 1.11 g of 3-fluoro-4-(5-decylpyrimidine-2-yl)phenyl triflate (Yield: 99.1%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[CH3:42][S:43]([Cl:46])(=[O:45])=[O:44]>CN1C(=O)CCC1>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[CH:7]=1.[ClH:46]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and MsCl (0.047 mL, 0.6 mmol). The mixture was stirred at RT for 30 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C25H28FN5O3S: 498.5. NMR (CD3OD): 8.13 (1H, s), 7.39-7.34 (3H, m), 7.29 (1H, td, J=8.0; 2.0 Hz), 7.19-7.10 (4H, m), 5.88 (1H, s), 4.51 (2H, s), 3.86 (2H, m), 2.88 (2H, m), 2.85 (3H, s), 2.75 (1H, m), 1.97 (2H, m), 1.79 (2H, m) ppm.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1
Reactant: OB(O)c1ccccc1Cl
Reactant: CCOC(=O)c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
400 mg (2.85 mmol) of ethyl 1H-pyrazole-4-carboxylate, 893 mg (5.71 mmol) of 2-chlorophenyl-boronic acid, 100 mg of 3 Å molecular sieve and 778 mg (4.28 mmol) of copper(II) acetate were initially charged in 2 ml of dichloromethane, and 461 μl (5.71 mmol) of pyridine were added. The mixture was stirred at RT for 20 h. For work-up, the mixture was filtered through a little kieselguhr, the filter residue was rinsed with about 10 ml of dichloromethane and the combined filtrates were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 71 mg (10% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>C1COCC1.O>[CH3:31][CH:30]([CH3:32])[C:29]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH2:21][CH2:20]2)[CH:23]=1)=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Yield: 43.5 %

Procedure:
A solution of 4-methylbenzenesulfonyl chloride (16.6 mg, 0.0870 mmol), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mmol), TEA (10.0 mg, 0.174 mmol) in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (20 mL), the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product 2-methyl-N-{3-[1-(3-{[(4-methylphenyl)sulfonyl]amino}propyl)-4-piperidinyl]phenyl}propanamide (17.3 mg, 43.6%): 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.32–7.21 (m, 4H), 7.16 (s, 1H), 6.97 (d, 1H, J=7.9 Hz), 3.44 (t, 2H, J=6.3 Hz), 3.15 (d, 2H, J=9.8 Hz), 2.62–2.45 (m, 4H), 2.15 (m, 3H), 2.05 (s, 3H) 1.95–1.71 (m, 5H), 1.26 (d, 6H, J=6.6 Hz); ESMS m/e: 458.2 (M+H)+. Procedure Q2 The Capture and Release Method for the Synthesis and Purification of the Piperidine Library
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7](O)=[O:8].C[CH2:12][N:13](C(C)C)C(C)C.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][CH2:6][C:7]([NH:13][CH3:12])=[O:8]
Reactant: CN(C)CCCC(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
A stirred solution of 4-dimethylamino-butyric acid hydrochloride salt (0.50 g, 2.98 mmol; for reference procedure from 4-aminobutyric acid see JACS, 1963, 85, 1-8) and DIPEA (3.22 mL, 18.50 mmol) in DMF (5 mL) was treated with a methylamine solution (2 M in THF; 5.96 mL, 11.93 mmol) and then HATU (1.42 g, 3.73 mmol). The mixture was stirred at RT for 4 hours before being diluted with MeOH (15 mL). This resultant solution was purified via a SCX-2 cartridge and the relevant fractions were concentrated in vacuo to afford the title compound as a colourless oil (0.31 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.O>[OH-].[Na+]>[CH2:1]([CH:3]1[N:4]2[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12]1)[C:16](=[O:15])[C:17]([C:18]([OH:20])=[O:19])=[CH:23]2)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCC1CCc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1CCc2cccc3c(=O)c(C(=O)O)cn1c23
Temperature: 115 °C

Procedure:
Following the procedure set forth in Example 1, 2-ethyltetrahydroquinoline is mixed with diethyl ethoxymethylenemalonate and heated to 125° to 130° C. for two hours. Polyphosphoric acid is added, and the mixture is heated at 115° C. for one hour. The mixture is poured into water, neutralized with 40 percent sodium hydroxide, and the product is isolated and saponified in 10 percent sodium hydroxide solution. The solution is neutralized, and the solid product, 6,7-dihydro-5-ethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, is isolated by filtration.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49]C(=O)OC(C)(C)C)[CH2:44]2)=[C:27]2[CH:33]=[CH:32][N:31](S(C3C=CC=CC=3)(=O)=O)[C:28]2=[N:29][CH:30]=1)=[O:23])=O)(C)(C)C.C1COCC1>CO.[OH-].[Na+].CCOC(C)=O>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:24][C:25]1[C:26]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH2:49])[CH2:44]2)=[C:27]2[CH:33]=[CH:32][NH:31][C:28]2=[N:29][CH:30]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2[nH]ccc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.4 %

Procedure:
To solution of tert-butyl {(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (194.4 mg, 0.2400 mmol) in MeOH (2.0 mL), aq. NaOH (1.0 M, 2.0 mL) was added followed by THF (2.0 mL). After stirring at room temperature for 5 h, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (46.6 mg, 41%). LCMS calc. for C22H22F2N7OS (M+H)+: m/z=470.1. found 470.2. 1H NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.49 (s, 1H), 9.04 (s, 1H), 7.64-7.47 (m, 3H), 7.35 (d, J=3.3 Hz, 1H), 7.27 (t, J=8.8 Hz, 2H), 6.57 (d, J=3.4 Hz, 1H), 3.29-3.23 (m, 1H), 3.10-3.03 (m, 1H), 3.00-2.86 (m, 2H), 2.85-2.77 (m, 1H), 1.87-1.79 (m, 1H), 1.79-1.65 (m, 2H), 1.24-1.10 (m, 1H) ppm.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4])=[CH:16][CH:17]=1
Reactant: NCc1ccncc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CNCc1ccncc1

Procedure:
The product was made from D-glucose and 4-aminomethyl-pyridine comparable as in Example A. A resin-like, yellow product was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:25]3[CH:26]=[C:27]([CH2:31]O)[CH:28]=[CH:29][CH:30]=3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33]1(=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[NH:34]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:25]3[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=3)[CH2:31][N:34]3[C:35](=[O:42])[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]3=[O:43])=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1nccn2c(-c3cccc(CO)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c(-c3cccc(CN4C(=O)c5ccccc5C4=O)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution/suspension of {3-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-phenyl}-methanol (312 mg, 0.737 mmol), isoindole-1,3-dione (130 mg, 0.885 mmol), and PS-PPh3 (loading 2.12 mmol/g; 696 mg, 1.47 mmol) in anhydrous THF (15 mL), cooled to 0° C., DIAD (218 μL, 224 mg, 1.11 mmol) was added dropwise, under N2 atmosphere. After 10 min, the cooling bath was removed and the reaction mixture stirred at ambient temperature for 3d. The resin was filtered off on a glass frit (porosity M) and washed with large volumes of THF and then CH2Cl2. The filtrate was concentrated, adsorbed onto Hydromatrix, and the crude material (0.6843 g) was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with MeOH:CH2Cl2 0.5%→3%], yielding the title compound as a yellow solid. Sample contains ≈0.3 eq. of reduced DIAD by 1H NMR; 1H NMR (CDCl3, 400 MHz) δ 4.94 (s, 2H), 5.07 (s, 2H), 5.16 (s, 2H), 7.07 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 7.28-7.33 (m, 3H), 7.33-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.43-7.47 (m, 2H), 7.50 (t, J=7.6 Hz, 1H), 7.53-7.56 (m, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.72 (dd, J=5.6, 2.8 Hz, 2H), 7.74-7.77 (m, 1H), 7.86 (dd, J=5.2, 3.2 Hz, 2H), 7.92 (s, 1H); MS (ES+): m/z 552.3 (100) [MH+].