Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1Cl)[CH3:2].[NH:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11](=[O:24])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:8]=[N:7][C:6]=1[N:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1)[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid ethyl ester (Stage 72.5, 3.00 g, 7.7 mmol), (R)-3-pyrrolidinol (0.807 g, 9.26 mmol) and DIPEA (2.19 g, 17.0 mmol) in iPrOH (50 mL) was stirred at 22° C. for 60 min. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOAc, washed with sat. aq. NaHCO3 and brine, dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure to give the title compound as a foam. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 8) tR=1.06 min, m/z=440.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.04 Hz, 3H), 1.79-2.01 (m, 2H), 3.09 (d, J=11.73 Hz, 1H), 3.41 (d, J=8.21 Hz, 1H), 3.54 (dd, J=11.73, 4.30 Hz, 1H), 3.65 (dd, J=10.17, 3.52 Hz, 1H), 4.25-4.39 (m, 3H), 4.96 (d, J=3.13 Hz, 1H), 7.34 (d, J=8.21 Hz, 2H), 7.78-7.90 (m, 2H), 8.36 (d, J=2.35 Hz, 1H), 8.81 (d, J=2.35 Hz, 1H), 10.28 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35]([OH:37])=[O:36])=[CH:30][CH:29]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
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: COCCOC
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 18 %

Procedure:
A mixture of 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine (285 mg, 1.0 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid. (315 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) in 2M sodium carbonate aqueous solution (3 mL, 8 mmol) and 20 mL of DME was stirred at 80° C. for 2 hr. Then the reaction mixture was diluted with 50 mL of ethyl acetate and extracted with 1N NaOH (50 mL, three times)). The combined aqueous layers were neutralized to pH=6. Then the aqueous solution was extracted with ethyl acetate (50 mL, three times). The combined organic layers were washed with saturated sodium carbonate and brine. Then the organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl) acetic acid (68 mg, 18% yield). HPLC: Rt=2.04 min; MS 386 [M+H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCOC(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:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([C:17]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=3[F:15])=[CH:3][C:4]([C:13]#[N:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: N#Cc1cc(Cl)c2ccc(Cl)cc2n1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C#N)nc3cc(Cl)ccc23)c(F)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of 4,7-dichloroquinoline-2-carbonitrile (6 g, 26.9 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (5.03 g, 29.6 mmol), 2M sodium carbonate (29.6 ml, 59.2 mmol) in 10:1 toluene (48.9 ml) ethanol (4.89 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.777 g, 0.672 mmol). The mixture was stirred at 75° C. under N2 for 18 hours. The reaction was allowed to cool to ambient temperature. The cooled reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was mostly dissolved in warm EtOAc (100 ml), added 100 ml of Et2O, allowed to stand at ambient temperature for 1 hour. The solid was collected and washed with cold Et2O (50 ml) to give 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g, 14.07 mmol, 52.3% yield) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([SiH2:15][O:16][C:17]([CH3:43])([CH3:42])[C@@:18]([NH:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:23][CH:22]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([SiH2:15][O:16][C:17]([CH3:43])([CH3:42])[C@@:18]([NH:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[CH:23][CH:22]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C(O)CCCCC(F)(F)F)cc1)C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@](C)(CCc1ccc(C(=O)CCCCC(F)(F)F)cc1)C(C)(C)O[SiH2]C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxalylchloride (0.15 mmol) in CH2Cl2 is added at −78° C. first DMSO (0.2 mmol) and then a solution of N-{(R)-1-(tert-Butyl-dimethyl-silanyloxymethyl)-1-methyl-3-[4-(6,6,6-trifluoro-1-hydroxy-hexyl)-phenyl]-propyl}-acetamide (0.1 mmol) in CH2Cl2. After stirring for 1 h at −78° C., triethylamine (0.7 mmol) is added and the mixture is warmed to RT. Quenching with water is followed by extraction with AcOEt. After drying (MgSO4), the solvent is evaporated.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[C:8]2[C:33]([O:35]C)=[O:34])(=[O:4])=[O:3].[OH-].[Na+].CO>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[C:8]2[C:33]([OH:35])=[O:34])(=[O:3])=[O:4]
Reactant: COC(=O)c1c(CN2CCC(=O)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(=O)CC3)c(C(=O)O)c2c1
Yield: 126.2 %

Procedure:
Methyl 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.796 g, 1.529 mmol) and 3N NaOH (5.097 mL, 15.29 mmol) were suspended in tetrahydrofuran (5.097 mL) and methanol (5.097 mL) and heated to 50° C. for 20 h. The tetrahydrofuran and methanol were removed under reduced pressure, and the residue was diluted with water. The mixture was purified via Oasis SPE cartridge to afford 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.977 g). This material was used without further purification. MS (m/z) 507.2 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cc(OC)ccc2OC)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol) and 2,5-dimethoxyaniline (62 mg, 0.402 mmol) similar to Example 13 and isolated as a pale white solid (65 mg, 45%). 1H NMR (CDCl3): 8.30 (d, J=3.0 Hz, 1H), 8.26–8.23 (m, 2H), 7.37–7.25 (m, 3H), 6.81 (d, J=9.0 Hz, 1H), 6.73 (s, 1H), 6.55 (dd, J=3.0, 8.7 Hz, 1H), 4.52 (d, J=0.9 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CN(C([O:33]N1N=N[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:48]1[CH2:52][O:51][CH2:50][CH2:49]1>CN(C=O)C>[CH:49]1([C:50]([OH:33])=[O:51])[CH2:3][CH2:2][CH2:52][CH2:48]1.[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:35]([CH:40]2[CH2:36][CH2:37][CH2:38][CH2:39]2)=[O:51])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: C1CCOC1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C1CCCC1
Product: O=C(O)C1CCCC1

Procedure:
The title compound was prepared according to the procedure described in Example-17 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.100 g, 0.271 mmol), TEA (1.0 mL), TBTU (0.261 g, 0.813 mmol), THF:DMF (10 mL), cyclopentanecarboxylic acid (0.061 g, 0.542 mmol) to afford 0.025 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.50-1.76 (m, 8H), 2.62 (s, 1H), 4.30 (d, 2H), 7.45 (m, 1H), 7.61 (m, 2H), 7.85 (d, J=9.6 Hz, 2H), 8.19 (d, J=8.1 Hz, 2H), 8.40 (m, 1H), 12.69 (s, 1H); MS (m/z): 465.08 (M+H)+.
Reaction SMILES: [NH:1]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:69][CH2:68][CH2:67][C@H:31]1[C:32]([NH:34][C@H:35]([C:37]([NH:39][C@H:40]([C:57]([O:59]CC1C=CC=CC=1)=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=1[Cl:52])=[O:47])=[O:38])[CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:70]([O:72][C:73]([CH3:74])([CH3:76])[CH3:75])=[O:71])[C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:69][CH2:68][CH2:67][C@H:31]1[C:32]([NH:34][C@H:35]([C:37]([NH:39][C@H:40]([C:57]([OH:59])=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45][C:46]([O:48][CH2:49][C:50]1[CH:56]=[CH:55][CH:54]=[CH:53][C:51]=1[Cl:52])=[O:47])=[O:38])[CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16][S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 108.7 %

Procedure:
At 0° C. to the solution of 300 mg (0.210 mmol) of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17) in 8 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 230 mg (83%) of the title compound as a colorless powder.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:19])[C:7]=2[C:20]=1[O:21][CH3:22])=[O:2].[C:23]([Mg]Br)(=O)[CH:24]([CH3:26])[CH3:25].Cl>O1CCCC1.C(Cl)Cl>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:11]=3[CH2:10][O:9][C:8](=[O:19])[C:7]=2[C:20]=1[O:21][CH3:22])[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)[Mg]Br
Reactant: COc1c(C=O)ccc2c1C(=O)OCc1cc(C)ccc1S2
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)ccc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
660 mg (2.1 mmol) of the compound from Example I in 10 ml of absolute tetrahydrofuran are treated under argon at 0° C. with 1.2 ml (2.3 mmol) of a 2M isobutyryl-magnesium bromide solution in tetrahydrofuran and the mixture is stirred at 25° C. for 1 h. After addition of 2 ml of 1N hydrochloric acid, the mixture is diluted with methylene chloride, washed with water, dried and evaporated. After chromatographic purification on silica gel Si60 (petroleum ether/ethyl acetate 5:1), 121 mg (15% of theory) of the main product are obtained as a colourless solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1.CCCCCC.[C:18](=[O:20])=[O:19].C([Li:25])CCC>C(OCC)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[S:1][C:2]([C:18]([O-:20])=[O:19])=[N:3][CH:4]=2)[CH:7]=1.[Li+:25]
Reactant: [Li]CCCC
Reactant: O=C=O
Reactant: c1cncc(-c2cncs2)c1
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C([O-])c1ncc(-c2cccnc2)s1
Product: [Li+]
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-thiazolyl)pyridine (400 mg) in diethyl ether (15 mg), n-butyl lithium (a 1.52 N hexane solution, 1.45 ml) was added dropwise at −78° C. After stirring for 30 minutes, a carbon dioxide gas was blown into the reaction mixture. After 10 minutes, a cooling bath was removed and the temperature of the reaction mixture was allowed to rise back slowly to room temperature. The reaction mixture was concentrated, whereby the residue of lithium 5-(3-pyridyl)thiazole-2-carboxylate was obtained as a white solid. To a solution of the resulting residue in N,N-dimethylformamide (10 ml) were added 1-[(5-chloroindol-2-yl)sulfonyl]piperazine hydrochloride (600 mg), 1-hydroxybenzotriazole monohydrate (255 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360 mg) at room temperature. After stirring for 3 days, ethyl acetate (50 ml) and water (100 ml) were added to the reaction mixture. The white precipitate thus obtained was collected by filtration and washed with water and ethyl acetate, whereby the title compound (727 mg) was obtained as a pale brown solid. A portion of the compound was added with an aqueous solution of hydrochloric acid, followed by concentration and drying. The product thus obtained showed the following data.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(Br)cnc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)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: C1COCCO1
Solvent: O
Product: Cc1cc(Br)cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 68.6 %

Procedure:
To 2,5-dibromo-3-methylpyridine (5.0 g), tetrakis(triphenylphosphine)palladium(0) (1.15 g), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (6.16 g) were added 1,4-dioxane (40 ml) and 2M aqueous solution of sodium carbonate (25 ml), stirred at 90° C. for 6 hours, then tetrakis(triphenylphosphine)palladium(0) (115 mg) was added thereto, and stirred at 90° C. for 1 hour. To the reaction solution was added water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (4.83 g) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccnc(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccn1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
To a solution of 2-fluoro-4-methylpyridine (0.510 g, 4.59 mmol) in 20 mL of carbon tetrachloride was added N-bromosuccinimide (0.899 g, 5.05 mmol) and benzoyl peroxide (0.148 g, 0.459 mmol). The mixture was heated to 90° C. for 1 h, and then additional benzoyl peroxide (0.074 g, 0.23 mmol) was added. After 20 h, the reaction was diluted with dichloromethane, washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% ethyl acetate in hexanes to provide the 4-(bromomethyl)-2-fluoropyridine that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 191.9 (81Br) for [M+H]+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][S:35]([CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:37])=[O:36])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCNS(=O)(=O)Cc3ccccc3)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and phenylmethanesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][N:22]4[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Reactant: O=S1(=O)CCNCC1
Product: Cn1c(-c2cncc(CN3CCS(=O)(=O)CC3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and thiomorpholine-1,1-dioxide are processed according to the method described in Example 170 to give 6-chloro-2-[5-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-pyridin-3-yl]-1-methyl-1H-indole-3-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.93-2.98 (m, 4H), 3.12-3.18 (m, 4H), 3.81 (s, 3H), 3.87 (s, 2H), 7.37 (dd, J=8.5, 1.9 Hz, 1H), 7.73 (d, J=8.3 Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H). HRMS (ESI) m/z 415.1015 [(M+H)+ Calcd for C20H20ClN4O2S: 415.0996].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14]O)[CH:8]=[N:9]2)[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl>[ClH:18].[Cl:18][CH2:14][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=[CH:12][CH:11]=2
Reactant: O=S(Cl)Cl
Reactant: CCOc1cccc2ncc(CO)cc12
Solvent: ClCCl
Product: CCOc1cccc2ncc(CCl)cc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (5-ethoxyquinolin-3-yl)methanol MDE 32076 (40 mg, 197 μmol) in dry CH2Cl2 (10 mL) at 0° C. under N2 in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added dropwise SOCl2 (0.30 mL, 4.13 mmol) and the mixture was stirred for 30 min at 0° C. then for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (20 mL) before concentration back to dryness at 40° C. under vacuum (done 3 times) to give 3-(chloromethyl)-5-ethoxyquinoline hydrochloride CCH 29192 as a yellow solid (51 mg, 100% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[CH3:10][NH2:11]>>[OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:11][CH3:10])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Reactant: CN
Product: CNC(=O)C(C)(C)CO
Yield: 51 %

Procedure:
Prepared as in Example 215d from methyl 3-hydroxy-2,2-dimethylpropanoate and methylamine in 51% yield. MS 132 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][C:19]([F:20])([F:22])[F:21])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:15])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: CC(C)c1cc(CN)on1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Product: CC(C)c1cc(CNC(=O)c2ccc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)n2)on1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-2-pyridine carboxylic acid (example AF) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN 543713-30-0) as starting materials; LC-MS (UV peak area/ESI) 100.0%, 454.4 (M+H)+.