Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:18]=[CH:17][C:11]2[CH:12]=[C:13]([CH2:15]O)[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[O:1]([C:8]1[CH:18]=[CH:17][C:11]2[CH:12]=[C:13]([CH2:15][N:23]3[C:19](=[O:29])[C:20]4[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22]3=[O:24])[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2ccc(Oc3ccccc3)cc2o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(Oc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a tetrahydrofuran (4 mL) solution of (6-phenoxy-benzofuran-2-yl)-methanol (177 mg, 737 μmol) described in Production Example 49-1-2 were added phthalimide (119 mg, 811 μmol), triphenylphosphine (232 mg, 884 μmol) and diethylazodicarboxylate (403 μL, 884 mmol) at 0° C., which was stirred at room temperature for 4 hours and 30 minutes. Water was added to the reaction solution followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (209 mg, 77%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7](F)[C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][O-:16].[Na+]>CO>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([O:16][CH3:15])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1C(=O)O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(N)c1C(=O)O
Yield: 83.3 %

Procedure:
1.8 g (9.0 mmol) of 2-amino-6-fluoro-3-nitro-benzoic acid in methanol and 2.9 g (54 mmol) of NaOMe was heated at 90° C. overnight to produce 1.6 g (7.5 mmol 83%) of 2-amino-6-methoxy-3-nitro-benzoic acid. LCMS: 213 (M+1)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([N:12]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.O.NN.CCOCC>CCO>[CH:1]1([CH2:4][O:5][C@H:6]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC2CC2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: N[C@H]1CC[C@H](OCC2CC2)CC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A stirred solution of 12C (620 mg, 2.071 mmol) in EtOH (10 mL) was treated with hydrazine monohydrate (0.152 mL, 3.11 mmol) and stirred at 70° C. for 1 h. The reaction was judged complete by LCMS. Upon cooling, Et2O was added, and reaction was stirred at room temperature for 1 h. The resulting white solid was removed by filtration, and the filtrate was concentrated. The residue was triturated with Et2O, the small amount of white solid was filtered, and the filtrate was concentrated to provide 12D (120 mg, 34% yield) as pale brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.11 (d, 2H, J=6.8 Hz); 2.99-3.08 (m, 1H); 2.48-2.57 (m, 1H); 1.64-1.89 (m, 6H); 1.06-1.18 (m, 2H); 0.81-1.02 (m, 3H); 0.31-0.39 (m, 2H); −0.02-0.04 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[O:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:26]=[CH:27][C:3]([OH:2])=[CH:4][CH:5]=4)=[CH:9][CH:10]=3)[N:18]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(Oc2ccc(-c3noc(-c4ccc(F)cc4)n3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Oc2ccc(-c3noc(-c4ccc(F)cc4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
3-(4-(4-Methoxyphenoxy)phenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (150 mg, 0.414 mmol) was suspended in dry methylene chloride (10.0 mL) and the mixture was placed under nitrogen and cooled to −80 C. Boron tribromide (1.0 M in CH2Cl2, 2.07 mmol) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature and stirred for 19 hours 30 minutes. The reaction mixture was then cooled to −80 C and H2O (2.0 mL) was added dropwise. The organic layer was removed under reduced pressure and the compound was purified by column chromatography (Hex/EtOAc 2:1) to give a white powder (144 mg, 100%). 1H NMR (500 MHz, DMSO-d6) δ(ppm): 6.83 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.04 (2H, t, J=8.8 Hz), 7.49 (2H, t, J=8.8 Hz), 8.03 (2H, d, J=9.0 Hz), 8.23 (2H, dd, J=8.8, 5.4 Hz), 9.49 (1H, s). 13C NMR (125 MHz, DMSO-d6) δ(ppm): 116.5 (CH), 116.9 (CH, d, J=22.5 Hz), 116.9 (CH), 119.7, 121.6 (CH, d, J=3.8 Hz), 121.7 (CH), 129.1, 130.8 (CH, d, J=10.0 Hz), 146.6, 154.5, 161.3, 164.9 (C, d, J=251.2 Hz), 167.8, 174.4. 19F (282 MHz, DMSO-d6) δ(ppm): −105.1-−105.2 (1F, m). MS (FAB+): 348 (MH+). HRMS for C20H13FN2O3 (MH+): calculated: 348.0910; found 348.0897.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[C:17]([O:29]CC3C=CC=CC=3)[CH:16]=1)=[C:9]([OH:37])[C:8]2=[O:38])(=[O:3])[CH3:2].C1(=O)[O:44][C:42](=[O:43])[CH2:41]C1>Cl.C(O)(=O)C.O.N1C=CC=CC=1>[OH:29][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[OH:21])[C:10]1[O:11][C:12]2[C:7]([C:8](=[O:38])[C:9]=1[OH:37])=[CH:6][C:5]([NH:4][C:1]([CH2:2][CH2:41][C:42]([OH:44])=[O:43])=[O:3])=[CH:14][CH:13]=2
Reactant: O=C1CCC(=O)O1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(O)c(=O)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)Nc1ccc2oc(-c3ccc(O)c(O)c3)c(O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.4 %

Procedure:
A mixture of the protected flavonol (15) (500 mg, 0.985 mmol) in aqueous HCl (36%, 37 mL) and acetic acid (37 mL) was heated under reflux for 3 h. The mixture was then cooled on ice and diluted with water. The resulting suspension was centrifuged and the collected solid washed with water, then freeze-dried to afford the salt as a crude yellow solid (322 mg). A mixture of the crude yellow product and succinic anhydride (118 mg, 1.18 mmol) in pyridine was stirred at room temperature for 4 h. Water (1 mL) was added and the mixture was acidified with 6 M HCl. The mixture was left to stand at room temperature for 30 min, and the resulting suspension was centrifuged, and the collected solid was washed with water, freeze-dried and recrystallised from DMF/water to afford the succinamic acid (3) as a yellow powder (70.0 mg, 19%), m.p 257-258° C. 1H NMR (399.7 MHz, d6-DMSO) δ 2.54-2.60 (m, 4H, CH2CH2); 6.89 (d, 1H, J5′,6′ 8.5 Hz, H5′); 7.57 (dd, 1H, J2′,6′ 2.5, J5′,6′ 8.5 Hz, H6′); 7.66 (d, 1H, J7,8 9 Hz, H8); 7.73 (d, 1H, J2′,6′ 2.5 Hz, H2′); 7.85 (dd, 1H, J5,7 2.5, J7,8 9.0 Hz, H7); 8.43 (d, 1H, J5,7 2.5 Hz, H5); 9.29, 9.32, 9.59 (3 br s, 3×1H, 3×OH); 10.29 (s, 1H, NH); 12.20 (br s, 1H, CO2H). 13C NMR (100.5 MHz, d6-DMSO) δ 28.83, 31.11 (2C, CH2CH2); 112.7, 115.25, 115.65, 118.76, 120.00, 121.43, 122.39, 125.17, 135.80, 137.67, 145.12, 146.04, 147.63, 150.38 (14C, Ar); 170.46, 172.32, 173.93 (3C, 3×C═O). Low resolution mass spectrum (ESI) m/z 384.4 [C19H15NO8 (M-H)+ requires 384.08].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=O)=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[N:10]=1.Cl.Cl.[CH3:30][C:31]1[N:35]=[C:34]([C@H:36]([NH2:38])[CH3:37])[O:33][N:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([NH:38][C@@H:36]([C:34]3[O:33][N:32]=[C:31]([CH3:30])[N:35]=3)[CH3:37])=[O:20])=[CH:15][CH:16]=2)[N:11]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[N:10]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)O)cc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(-c3c(F)cccc3F)c3ccc(C(=O)N[C@H](C)c4nc(C)no4)cc32)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
3-(2,6-Difluorophenyl)-1-(4-methylphenyl)-1H-indazole-6-carboxylic acid (30.0 mg, 0.040 mmol, with 6 equivalents of sodium chloride), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (12.5 mg, 0.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.2 mg, 0.085 mmol), 1-hydroxy-7-azabenzotriazole (3.4 mg, 0.025 mmol), and N-methylmorpholine (20 μl, 0.182 mmol) were dissolved in N,N-dimethylformamide (500 μl) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 30 min. The reaction was stopped and quenched by addition of water (ca 0.1 mL) and trifluoroacetic acid (ca 0.1 mL). The crude reaction mixture was purified directly by preparative HPLC (Reverse phase (C-18)), eluting with acetonitrile/water+0.1% trifluoroacetic acid (5-95%), to afford the title compound (16.3 mg, 0.023 mmol, 58.2% yield) as a white solid. HRMS [M+1]=474.1739. 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H); 7.77 (d, J=8.6 Hz, 1H); 7.66 (d, J=8.2 Hz, 2H); 7.61 (dd, J=8.5, 1.4 Hz, 1H); 7.48-7.40 (m, 1H); 7.38 (d, J=8.1 Hz, 2H); 7.10 (m, 2H); 6.79 (d, J=7.7 Hz, 1H); 5.62 (m, 1H); 2.46 (s, 3H); 2.41 (s, 3H); 1.73 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5]C(C)=[CH:7][CH:8]=1.[O-][Mn](=O)(=O)=O.[K+].CC[O:21][C:22]([CH3:24])=[O:23]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:24]([C:22]([OH:21])=[O:23])=[N:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C(=O)O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-methoxy-6-methyl-2-nitropyridine (7 g, 0.041 mol) in water (140.0 mL) was added KMnO4 (32.88 g, 0.208 mol, S.d.fine chemicals, India) at 80° C. The reaction mixture was stirred for 16 h at 100° C. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was filtered and the solids were washed with water. The filtrate was acidified and extracted with EtOAc (500 mL×2). The organic layers were then dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 13.6 (br. s., 1H), 8.39 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.06 (s, 3H). MS (ESI, positive ion) m/z: 199 (M+H).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:17]=3[N:16]=2)[SH:14])=[CH:9][CH:8]=1.Cl>O.C1COCC1>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:15]([CH:13]([SH:14])[C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:26])=[O:5])=[CH:8][CH:9]=3)=[N:16][C:17]=2[CH:23]=1
Reactant: COC(=O)c1ccc(C(S)c2nc3cc(OC)ccc3[nH]2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(S)c3ccc(C(=O)O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of LiOH.H2O (1.02 g, 24.4 mmol) in water (15 ml) was added to a suspension of 376a (3.99 g, 9.75 mmol of in THF (10 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was acidified with a solution of HCl 1 M to pH 4. The desired product was triturated 20 min. at 0° C. and then filtered and dried. Compound 376b was obtained as a white powder (100% yield, 3.05 g). 1H NMR: (DMSO) δ (ppm): 12.85 (bs, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.76 (dd, J=8.8, 2.2 Hz, 1H), 4.60 (s, 2H), 3.82 (s, 3 H). MS: (calc.) 314.1. (obt.), 315.1 (MH)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([CH3:62])=[C:44]([CH:61]=1)[O:45][C:46]1[N:51]=[C:50]2[S:52][C:53]([NH:55][C:56]([CH:58]3[CH2:60][CH2:59]3)=[O:57])=[N:54][C:49]2=[CH:48][CH:47]=1.O>N1C=CC=CC=1>[CH:58]1([C:56]([NH:55][C:53]2[S:52][C:50]3[C:49]([N:54]=2)=[CH:48][CH:47]=[C:46]([O:45][C:44]2[CH:61]=[C:40]([NH:39][C:7](=[O:9])[C:6]4[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=4)[CH:41]=[CH:42][C:43]=2[CH3:62])[N:51]=3)=[O:57])[CH2:59][CH2:60]1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(OC(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzoic acid (37.5 mg, 0.185 mmol) in pyridine (2.0 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (70 mg, 0.185 mmol), and the mixture was stirred at room temperature for 10 min. N-[5-(5-Amino-2-methylphenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (60 mg, 0.176 mmol) produced in Example C47(i) was added to the obtained solution, and the mixture was stirred at 70° C. for 20 hr. After the reaction mixture was cooled to room temperature, water (2 mL) was added, and the obtained yellow precipitate was collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (48.5 mg, 52%) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]CC3C=CC=CC=3)[N:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[N:18]=2)([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(Cc2cccc(OCc3ccccc3)n2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CO)(Cc2cccc(O)n2)CC1

Procedure:
A mixture of N-tert-butoxycarbonyl-4-(6-benzyloxypyridin-2-ylmethyl)-4-hydroxymethylpiperidine (0.19 g, 0.5 mmol) and 5% palladium on charcoal (38 mg) in absolute ethanol (10 mL) was stirred under a balloon of hydrogen gas at room temp. for 3 h. The resultant mixture was filtered through a plug of Celite. The filtrate was concentrated under vacuum to provide the title compound as colorless gum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[N:46][CH:45]=[CH:44][N:43]=2)[C:27]1=[O:48].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:20][C:14]1([CH3:21])[CH2:13][C:12]2[S:11][C:10]3[C:9](=[O:22])[N:8]([C:4]4[C:3]([CH:23]=[O:24])=[C:2]([C:30]5[CH:29]=[C:28]([NH:41][C:42]6[CH:47]=[N:46][CH:45]=[CH:44][N:43]=6)[C:27](=[O:48])[N:26]([CH3:25])[CH:31]=5)[CH:7]=[CH:6][N:5]=4)[CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:15]1
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cnccn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2cnccn2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (100 mg, 0.30 mmol), 184a (170 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), K3PO4 (130 mg, 0.60 mmol), sodium acetate trihydrate (85 mg, 0.60 mmol), acetonitrile (10 mL), and water (6 drops). The system was evacuated and refilled with N2. The reaction mixture was stirred at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 25:1 of dichloromethane/methanol to afford 184b (80 mg, 54%) as a yellow brown solid. MS-ESI: [M+H]+ 527.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][CH2:24][CH3:25])[C:13]=2[C:14]([O-:16])=[O:15])[N:4]=1.[CH:26]([NH2+]C(C)C)(C)C.CI>O1CCCC1.CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][CH2:24][CH3:25])[C:13]=2[C:14]([O:16][CH3:26])=[O:15])[N:6]=1
Reactant: CC(C)[NH2+]C(C)C
Reactant: CCCC#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)[O-]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCC#Cc1cccc(Oc2nc(OC)cc(OC)n2)c1C(=O)OC
Yield: 74.4 %

Procedure:
Diisopropylammonium 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pentynyl)benzoate (1.00 g, 2.3 mmol) was dissolved in tetrahydrofuran (20 ml)-DMF (10 ml) in a 50 ml round bottom-flask, and methyl iodide (1.4 g, 10.0 mmol) was added thereto little by little. The resultant mixture was stirred at 50° C. for 2 hours and THF-DMF was distilled off under reduced pressure. Water was added to the resultant residue, and the residue was extracted with ethyl acetate. The organic layer thus obtained was washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. To the resultant mixture, was added an appropriate amount of Florisil, and the mixture was eluted with ispropyl ether. The solvent was then distilled off under reduced pressure to obtain 0.61 g (yield: 76.3 %) of the aimed product (yellow viscous liquid).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:23][C:24]1[S:25][C:26]([CH2:29]Cl)=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:29][C:26]3[S:25][C:24]([Cl:23])=[CH:28][CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Reactant: ClCc1ccc(Cl)s1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ccc(OC)cc23)CC1
Reaction time: 15 h
Yield: 42 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.1 g (0.33 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.052 mL (0.43 mmol) of 2-chloro-5-chloromethyl-thiophene. After standard work-up, 0.06 g (44% of yield) of 4-[1-(5-chloro-thiophen-2-ylmethyl)-5-methoxy-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[CH2:15]([O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[CH:11][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCc1ccc(O)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
In an argon atmosphere, dry DMF (115 ml) was added to 4-(4-hydroxybutyl)phenol (9.43 g) and 65% oily sodium hydride (2.4 g), followed by stirring for 15 minutes. Next, under ice cooling and stirring, a solution of benzyl bromide (9.87 g) in dry dimethylformamide (29.5 ml) was added drop by drop, followed by stirring at the same temperature for 2 hours. After ice water and a 1 N solution of potassium hydrogen sulfate were added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, after which it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography to yield the titled compound (10.67 g) as a colorless crystalline powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[CH2:7][C:8]1[N:13]2[CH:14]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:26])[NH:10][CH:9]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[CH2:7][C:8]1[N:13]2[CH:14]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH:16]=[C:12]2[C:11](=[O:26])[NH:10][CH:9]=1
Reactant: O=c1[nH]cc(Cc2cccc([N+](=O)[O-])c2)n2cc(-c3c[nH]c4ncccc34)cc12
Agent: [Ni]
Solvent: CO
Product: Nc1cccc(Cc2c[nH]c(=O)c3cc(-c4c[nH]c5ncccc45)cn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 14 (180 mg, 0.47 mmol) in methanol (20 ml) was added Raney nickel (20 mg). The mixture was stirred at room temperature under hydrogen overnight. Methanol (100 ml) was added and the mixture was heated until all solid material went into solution. The Raney nickel was filtered off, and the filtrate was concentrated to afford the title compound. MS (DCI/NH3) m/z 356 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 4.04 (s, 2H), 6.44 (d, J=5.42 Hz, 1H), 6.64 (d, J=7.46 Hz, 1H), 6.74 (s, 1H), 6.86 (d, J=7.46 Hz, 1H), 7.07-7.21 (m, 2H), 7.27 (s, 1H), 7.60 (s, 1H), 7.81 (d, J=2.03 Hz, 1H), 8.12 (d, J=7.80 Hz, 1H), 8.24 (d, J=3.73 Hz, 1H), 10.50 (d, J=5.42 Hz, 1H), 11.73 (s, 1H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(C#N)cc4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 4-cyanophenyl boronic acid. Mass spectrum (ESI) 417.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2ccccn2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
The title compound was prepared from the reaction of trifluoro-methanesulfonic acid 4-methyl-2-nitro-phenyl ester (3.50 g, 12.27 mmol) reacting with pyridine-2-thiol (2.046 g, 18.41 mmol), and K2CO3 (2.968 g, 21.48 mmol) in DMF at 100° C. for 16 h the reaction mixture was then cooled to room temperature and diluted with water, extracted with EtOAc Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (2.52 g, 78%).