Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([F:14])[CH:3]=1.[CH2:15]([NH:22][C:23](=[O:41])[N:24]([CH3:40])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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>[F:14][C:4]1[CH:3]=[C:2]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N:24]([CH3:40])[C:23]([NH:22][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:41])[CH:30]=2)[CH:7]=[CH:6][C:5]=1[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COC(=O)C=Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OC)c(F)c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
44 mg (5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 200 mg (0.77 mmol, 1.0 eq) of methyl 3-(4-bromo-2-fluorophenyl)acrylate and 430 mg (1.15 mmol, 1.5 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea (prepared as in 1e) in a mixture of dimethylformamide and 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 2 hours at 90° C. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 138 mg of methyl 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate are obtained. Yield=42%
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]([N:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=O)[CH2:14][CH2:13]1)(=[O:11])[CH3:10].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[OH-].[NH4+]>C(Cl)Cl.O>[CH:2]1[N:1]=[C:18]([CH:15]2[CH2:16][CH2:17][N:12]([C:9](=[O:11])[CH3:10])[CH2:13][CH2:14]2)[N:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=12
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: NCc1ccccn1
Agent: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ncc3ccccn23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of 2-(aminomethyl)pyridine (3.17 g, 29.3 mmol), 1-acetylpiperidine-4-carboxylic acid (5.02 g, 29.3 mmol) and HOBT (4.78 g, 35.2 mmol) in 30 mL of CH2Cl2 was added EDC (8.43 g, 44.0 mmol) at rt. After stirring at rt overnight, the reaction mixture was diluted with methylene chloride and washed with aqueous sodium bicarbonate followed by brine. The organic phase was dried over anhydrous MgSO4. Concentration under reduced pressure afforded a viscous oil, which was dissolved in polyphosphoric acid (5 mL). The mixture was heated at ˜120° C. for 18 h. After cooling to rt, the syrup was poured onto ice and water was added to keep the solution temperature below 10° C. The resulting dark brown solution was basified with ammonium hydroxide. Aqueous layer was extracted with EtOAC (3×). The combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure afforded 761 mg of the title compound as a viscous oil. 1H NMR (400 MHz, CDCl3): δ 1.80˜2.20 (m, 6H), 2.88˜2.95 (m, 1H), 3.30˜3.34 (m, 2H), 4.00˜4.04 (br d, 1H), 4.62˜4.65 (br d, 1H), 6.58 (dt, J=6.8, 1.1 Hz, 1H), 6.68 (dt, J=6.4, 0.7 Hz, 1H), 7.38 (s, 1H), 7.44 (d, J=9.2 Hz, 1H), 7.79 (dd, J=7.3, 0.8 Hz, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:7]=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C=O.[C:20]([O-])(=[O:22])C.[Na+]>C(O)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([CH2:20][OH:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)[O-]
Reactant: CCCCc1nccn1Cc1ccccc1Cl
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Reaction time: 4 h
Yield: 41.1 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole (95.5 g, 0.384 mol), 37% formaldehyde (500 mL), sodium acetate (80 g) and acetic acid (60 mL) was heated to reflux for 40 hours under argon. The reaction was concentrated in vacuo, and the residue was stirred with 500 mL of 20% sodium hydroxide solution for 4 hours, diluted with water and extracted with methylene chloride. The extract was washed, dried, and concentrated. The crude product (117 g) was flash chromatographed over 600 g of silica gel with a gradient of ethyl acetate to 10% of methanol in ethyl acetate to give 8.3 g of starting material, 24.5 g of a mixture of starting material and product, and 44 g (41%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole; mp 86-88° C. (from ethyl acetate). Further elution provided the bis (4,5-hydroxymethyl) derivative; mp 138-140° C. (from ethyl acetate).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([Cl:65])[CH:61]=[CH:62][CH:63]=2)[N:58]=[C:57]([C:66]2[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:59]=1[N:58]=[C:57]([C:66]1[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=1)[C:56]([CH3:73])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1ccnc(-c2nc3c(Cl)cccc3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3c(Cl)cccc3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.105 g, 0.40 mmol), 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.1 g, 0.33 mmol) and Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.079 g, 0.83 mmol) in toluene (3.3 mL) at 100° C. for 1.6 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)). The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)-quinolin-4-amine. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.57 (1H, d, J=4.9 Hz), 7.82 (3H, m), 7.57 (1H, d, J=2.5 Hz), 7.43 (1H, dd, J=8.4, 7.4 Hz), 7.27 (1H, d, J=4.3 Hz.), 6.89 (1H, br. s.), 6.22 (1H, br. s.), 3.88 (4H, br. s.), 3.68 (4H, m), 3.20 (4H, br. s.), 2.90 (4H, m), 2.51 (3H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=531.2 (M+1).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:42])[CH2:34][S:35][C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[C:13]1=[O:43])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.CCCCCC>C1(OC)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH2:15][N:14]([C:16](=[C:33]([CH3:42])[CH2:34][S:35][C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[C:17]([OH:19])=[O:18])[C:13]1=[O:43])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CSc1nnnn1C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Solvent: COc1ccccc1
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CC(CSc1nnnn1C)=C(C(=O)O)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.25 h

Procedure:
The product from Example 13 above was dissolved in 1 ml of anisole. At 0° 1 ml of trifluoracetic acid was added. After 15 minutes at 0°, hexane was added. The solvents were removed under reduced pressure. Ether was added to the residue. The resulting slurry was filtered to provide 210 mg (53% from bromo derivative) of the title product: nmr (CDCl3) δ 2.10 and 2.27 (s, 3, CH3), 3.92 (s, 3, N--CH3), 4.3 (m, 2, --CH2S), 3.50 (m, 2, C4 --H), 5.00 (m, 1, C3 --H), 4.50 (s, 2, side chain CH2) and 7.2 (b, ArH).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[NH:8][CH:7]=1.I.CS[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[NH:21].N.Cl>C(O)C.CO.ClCCl.CCOCC>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[NH:21])[CH:13]=2)[NH:8][CH:7]=1
Reactant: CN(C)CCCc1c[nH]c2ccc(N)cc12
Reactant: CSC(=N)c1cccs1
Agent: Cl
Agent: I
Agent: N
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCc1c[nH]c2ccc(NC(=N)c3cccs3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an argon purged round bottom flask containing 55 (340 mg, 1.56 mmol) was added thiophene-2-carboximidothioic acid methyl ester hydroiodide (669 mg, 2.35 mmol). The two were suspended in absolute ethanol (10 mL) and stirred at room temperature for 16 hours. TLC (10% 2M ammonia in methanol, 90% dichloromethane) revealed all amine had reacted. The reaction was diluted with ether (80 mL) and the fluffy yellow precipitate collected by vacuum filtration. The precipitate was washed with ether (50 mL) and became an oil on the fritted filter. Ethanol was used to wash the product through the filter into a round bottom flask (50 mL). The flask was fitted with a stir bar and DOWEX-66 (5.5 g) was added. The reaction was stirred for 2 hours. The reaction was filtered and the filtrate concentrated to afford a yellow foam. The product was purified by silica gel column chromatography (5-10% 2M ammonia in methanol, 95-90% dichloromethane) to afford a yellow oil. The oil was taken up in methanol (5 mL) and stirred during the addition of 1M hydrogen chloride in ether (3 mL). After stirring for 2 hours the reaction was concentrated on the rotary evaporator. The resulting yellow foam was dried further on the high vacuum line. Yield: 347 mg of yellow foam, compound 56, 1H NMR (DMSO) δ 11.44 (br s, 1H), 11.26 (s, 1H), 10.62 (bs, 1H), 9.66 (bs, 1H), 8.61 (bs, 1H), 8.18-8.17 (d, 2H, J=4.2 Hz), 7.65 (s, 1H), 7.54-7.51 (d, J=8.7 Hz, 1H), 7.41-7.36 (q, 2H, J=4.5 Hz), 7.13-7.09 (dd, J=1.2, 8.7 Hz, 1H), 3.10-3.04 (t, J=7.5, 2H), 2.79-2.74 (t, J=7.5 Hz, 2H), 2.72 (s, 6H), 2.05 (m, 2H). ESI-MS m/z (%): 327 (M+, 100).
Reaction SMILES: [C:1]([CH:3](OS(C)(=O)=O)[CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[N:8]12[CH2:9][CH2:10][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(C#N)OS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CC2CCN1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of tert-butyl 4-{2-cyano-2-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (80.0 g) in dichloromethane (200 mL) was added a solution of trifluoroacetic acid (137.0 g) in dichloromethane (200 mL), and the reaction system was stirred at room temperature overnight. The reaction system was concentrated, acetonitrile (200 mL) was added to the residue, and triethylamine (98.0 g) was slowly added at 0° C. The mixture was concentrated, the residue was diluted with dichloromethane, and the mixture was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (13.0 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(S(C)(=O)=O)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol) and triethylamine (50 uL, 0.36 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (18 uL, 0.24 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was filtered and the filtrate was purified by preparative RP-HPLC to give 5-Chloro-N2-(2-fluoro-5-methyl-4-(1-(methylsulfonyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid: ESMS m/z 494.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([O:53][CH3:54])=[C:47]([S:49](Cl)(=[O:51])=[O:50])[CH:48]=1>C(#N)C>[CH3:54][O:53][C:46]1[CH:45]=[CH:44][C:43]([Cl:42])=[CH:48][C:47]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 42.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0279 g, 0.0604 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-2-methoxybenzenesulfonyl chloride (0.0470 g, 0.195 mmol) to obtain 4-(2-methoxy-5-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0172 g, yield 434).
Reaction SMILES: [Cl:1][CH:2]([Cl:17])[S:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:17][CH:2]([Cl:1])[S:3]([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([F:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[CH:5]=1)=[O:26]
Reactant: Cn1cc(SC(Cl)Cl)c(=O)c2ccc(F)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1cc(S(=O)C(Cl)Cl)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
665 mg (2.276 mmol) of the 3-dichloromethylthio-7-fluoro-1-methyl-4-quinolone (Compound 2, FIG. 1), as prepared in Step A, was dissolved in 20 ml of DCM at 0° C. to form a solution. To this solution was added 505.7 mg (2.345 mmol) of 80% MCPBA to form a mixture. This stirred mixture was then allowed to warm to room temperature and was stirred for 1 hour. An additional 25 mg of MCPBA was added and the mixture and stirred for 1 hour. The mixture was washed with 5% aqueous Na2CO3. The aqueous layer was extracted with DCM, and the combined DCM extracts were dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel with hexane-ethyl acetate (gradient 4:1,2:1,1:1) to give 352 mg (50%) of the product (Compound 3, FIG. 1) as a white solid, that was approximately 98% pure according to 1H NMR, CDCl3; d=3.96 s, 3H, N—CH3; 7.09 s, 1H, CHCl2; 7.22 dd, 1H, J=10.2 & 2.4 Hz, H at C8, 7.27 ddd, 1H, J=9.0, 7.6 & 2.2 Hz, H at C6; 8.03 s, 1H, H at C2; 8.43 dd, 1H, J=8.8 & 6.1 Hz, H at C5. This white solid product was further purified by recrystallization from methanol to give 252 mg of white crystals.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1([CH2:8][N:9]2[C:14]([C:15](=[O:25])[C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=3)=[C:13]([CH:26]([CH3:28])[CH3:27])[C:12](=[O:29])[NH:11][C:10]2=[O:30])[CH2:7][CH2:6]1.[OH-].[Li+]>C1COCC1.O>[C:23]([C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([CH3:22])[CH:19]=1)[C:15]([C:14]1[N:9]([CH2:8][C:5]2([CH2:4][C:3]([OH:31])=[O:2])[CH2:6][CH2:7]2)[C:10](=[O:30])[NH:11][C:12](=[O:29])[C:13]=1[CH:26]([CH3:28])[CH3:27])=[O:25])#[N:24]
Reactant: COC(=O)CC1(Cn2c(C(=O)c3cc(C)cc(C#N)c3)c(C(C)C)c(=O)[nH]c2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2(CC(=O)O)CC2)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To a stirred solution of {1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetic acid methyl ester (170 mg, 0.4 mmol) in THF (4 mL), were added lithium hydroxide (20 mg, 0.8 mmol) and two drops of water. The mixture was then refluxed for 2 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, from ethyl acetate to 20% methanol in ethyl acetate) to give 100 mg (62%) of {1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetic acid (83) as a white solid. m.p. 244-245° C.; 1H-NMR (500 MHz, DMSO-d6) δ 0.21-0.26 (2H, m), 0.34-0.36 (1H, m), 0.46-0.48 (1H, m), 0.98 (3H, d, J=6.8 Hz), 1.08 (3H, d, J=6.8 Hz), 2.06-2.12 (2H, m), 2.23 (1H, d, J=17.0 Hz), 2.44 (3H, s), 3.32 (1H, d, J=15.0 Hz), 3.74 (1H, d, J=15.0 Hz), 8.08 (1H, s), 8.19 (1H, s), 8.43 (1H, s), 11.45 (1H, s), 12.02 (1H, br. s); m/z (EI) 409 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].B(F)(F)F.O(CC)CC.[N+](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N-]>CCOCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)OCC)CCC1=O
Temperature: -30 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
4-Oxo-piperidine-1-carboxylic acid ethyl ester (20 g, 117 mmol) was dissolved in 120 mL Et2O and cooled to −30° C. BF3-OEt2 (14.8 mL) and ethyl diazoacetate (16 mL, 152 mmol) were added simultaneously (each in 15 mL Et2O) over the course of 30 minutes, maintaining an internal temperature of approximately −20° C. The reaction was warmed to room temperature and stirred for 3 hours after which time the reaction was quenched carefully with 30% K2CO3 (60 mL). The organic layer was dried over K2CO3 and concentrated to give 30.4 g of the subtitle compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[Br:26]Br>C(O)(=O)C.[Fe]>[ClH:22].[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:24])[C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])=[C:12]([Br:26])[CH:13]=1)[NH2:6]
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reactant: BrBr
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Reference Example 56 was prepared as follows: To a solution of 4-[(2,6-Dichlorobenzoyl)amino]-L-phenylalanine methyl ester hydrochloride salt, 37-B-1, (205.7 mg) in acetic acid(5 mL) was added an excess of bromine (5.55 g) in acetic acid (5 mL) and iron powder (416.2 mg). The reaction was stirred at ambient temperature for 3 hours. The reaction concentrated in vacuo and the remaining acetic acid removed as an azeotrope with toluene. The crude material was diluted with water, made basic with saturated sodium bicarbonate and extracted with AcOEt. The extract was purified by flash chromatography on silica gel eluting with methanol-methylene chloride. The purified material was dissolved in methanol saturated with hydrogen chloride and concentrated in vacuo and then crystallized from methanol with AcOEt to obtain 3-Bromo-4-[(2,6-dichlorobenzoyl)amino]-L-phenylalanine methyl ester hydrochloride salt (540.4 mg). Physical properties as follows: m.p. 200-205; 1H NMR (CD3OD) δ 7.76 (1H), 7.64 (1H), 7.46 (3H), 7.34 (1H), 4.38 (1H), 3.85 (3H), 3.30 (1H), 3.15 (1H); HRMS (FAB) Calcd for C17H15BRCL2N2O3+H1 444.9722, found 444.9724.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH2:11])=[CH:8][C:6]=2[N:7]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([NH:11][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C(Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1)c1ccccc1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-amine (35 mg) was reacted with 30 μL of benzoyl chloride via General Procedure G to give N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzamide.
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:16]=[N:17][C:18]([NH:47][C:48]2[CH:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)=[C:19]([C:21]2[N:26]=[C:25]([N:27](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:24]=[C:23]([CH3:46])[N:22]=2)[CH:20]=1)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>>[F:59][C:58]([F:61])([F:60])[C:56]([OH:62])=[O:57].[NH2:1][CH:2]([C:15]1[CH:16]=[N:17][C:18]([NH:47][C:48]2[CH:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=2)=[C:19]([C:21]2[N:26]=[C:25]([NH2:27])[N:24]=[C:23]([CH3:46])[N:22]=2)[CH:20]=1)[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(N)c3ccc(S(=O)(=O)N(C)C)cc3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
A solution of 4-(amino(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylbenzenesulfonamide (12.88 mg, 0.017 mmol) in TFA (1 mL) was heated at 100° C. in a sealed tube for 4 h, after which time reaction was complete. The mixture was concentrated and purified by prep HPLC to give 4-(amino(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N,N-dimethylbenzenesulfonamide trifluoroacetate (3.2 mg). m/z (ESI, +ve ion) 522 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]4)=[N:6][CH:7]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CN(C)C1CCN(c2ccc(I)cn2)C1
Product: CN(C)C1CCN(c2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cn2)C1

Procedure:
Prepared according to general working method I from [1-(5-iodo-pyridin-2-yl)-pyrrolidin-3-yl]-dimethyl-amine (160 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (108 mg, 0.50 mmol).