Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[CH3:12][O-].[Na+].CI>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:12])[N:6]=[C:5]2[I:11]
Reactant: C[O-]
Reactant: Brc1ccc2[nH]nc(I)c2c1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1nc(I)c2cc(Br)ccc21
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of 184.30 g of 5-bromo-3-iodo-1H-indazole [459133-66-5] in 2500 ml of methanol is admixed at 40° C. with 212 ml of a sodium methoxide solution (5.4M in methanol). 90 ml of methyl iodide are then added and the reaction mixture is heated to 65° C. After 30 minutes, the reaction mixture is cooled to room temperature, concentrated by evaporation to approx. 1000 ml, diluted with water and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a dark brown solid from the residue by means of flash chromatography (SiO2 60 F). Rf=0.68 (dichloromethane). Rt=4.94 (gradient I). As a by-product, the 5-bromo-3-iodo-2-methyl-2H-indazole regioisomer is also isolated as a red-orange solid. Rf=0.52 (dichloromethane). Rt=4.58 (gradient I).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:9]
Reactant: O=C(Cl)c1cc(Cl)cnc1Cl
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1cc(Cl)cnc1Cl)c1ccccc1
Yield: 93.9 %

Procedure:
In a similar manner to Step 1 of Example 16, 2,5-dichloropyridine-3-carbonylchloride (669 mg, 3.19 mmol) was dissolved in dichloromethane (13 mL), and the solution was treated with cumylamine (0.505 mL, 3.51 mmol), triethylamine (0.667 mL, 4.79 mmol) and DMAP (39.0 mg, 0.319 mmol), followed by purification by slurry using diisopropylether/hexane to obtain 2,5-dichloro-N-(1-methyl-1-phenylethyl)nicotinamide (926 mg, yield 94%).
Reaction SMILES: [F:1][C:2]1[C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:21][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][N:11]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][O:16]4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.[CH2:33]([N:35]([CH2:39][CH3:40])[C:36](Cl)=[O:37])[CH3:34].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:33]([N:35]([CH2:39][CH3:40])[C:36]([NH:14][C:13]1[C:9]([C:7]2[NH:6][C:5]3[CH:21]=[C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:2]([F:1])=[CH:3][C:4]=3[N:8]=2)=[N:10][N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:12]=1)=[O:37])[CH3:34]
Reactant: CCN(CC)C(=O)Cl
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(OCCCN3CCCCC3)cc2[nH]1
Temperature: 50 °C

Procedure:
130 mg of 3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine are solubilized in 10 mL of tetrahydrofuran and then 372 μl of diethylcarbamoyl chloride and 487 μL of N,N-diisopropylethylamine are added. The reaction medium is heated at 50° C. over night. The solvent is evaporated off under vacuum in a rotary evaporator and the reaction crude is purified by flash chromatography on a 4 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 70 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(3-piperidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea are isolated in the form of a chestnut-brown oil. Analytical LC/MS: Tr=2.91 min, [M+H]+=542.00 DAD=95%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>O1CCCC1.O.C(OC(=O)C)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
2 g (12.81 mmol) of 4-fluoro-3-nitroaniline and 3.2 g (38.43 mmol) of sodium bicarbonate were diluted in 20 mL of tetrahydrofuran and 5 mL of distilled water, and 1.14 mL (14.09 mmol) of acryloyl chloride was slowly added thereto at 0° C., and stirred for 1 hour. Upon the completion of the reaction, the resulting mixture was diluted with ethylacetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried over anhydrous Na2SO4, and filtered and distilled under a reduced pressure to obtain 2 g of the title compound (yield: 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[NH:23][C:22]2=[O:33])[CH2:17][CH2:16]1.[CH3:34]OC1C=C2C(=CC=1OC)N=CN=C2N1CCC(N2C(=O)C3C(=CC=C([N+]([O-])=O)C=3)NC2=O)CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][C:28]=3[CH3:32])[N:23]([CH3:34])[C:22]2=[O:33])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5cccc(C)c5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5c(C)cccc5n(C)c4=O)CC3)c2cc1OC
Yield: 73 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.67 mmol) of 3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline (Compound 100) obtained in Reference Example 11 was used in place of Compound 24. As a result, 226.8 mg (yield: 73%) of Compound 57 was obtained as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=S)SC)=[CH:6][CH:5]=1)[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][C:28]=1[NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20].CO>CN(C=O)C.C(Cl)Cl.[Hg]=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:28]3[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=3[N:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(NC(=S)SC)cc1
Reactant: CCN(CC)C(=O)c1ccc(NCCC(C)C)c(N)c1
Agent: O=[Hg]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(Nc2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Reaction time: 5.5 h
Yield: 56.6 %

Procedure:
A solution of methyl 4-ethoxyphenyldithiocarbamate (0.0274 g, 0.121 mmol) in DMF (0.2 mL) was added to a mixture of 3-amino-N,N-diethyl-4-(isopentylamino)benzamide (0.0334 g, 0.120 mmol) and red mercury(II) oxide (0.0261 g, 0.121 mmol) in DMF (0.2 mL). The resulting suspension was stirred vigorously for 5.5 h, and an additional portion of red mercury(II) oxide (0.0130 g, 0.0600 mmol) was added. After stirring an additional 16 h, the reaction was diluted with 9:1 CH2Cl2:MeOH, loaded onto a small plug of silica gel, and eluted with the same solvent system. The eluant was concentrated, and the residue was purified by reverse phase HPLC (gradient 20–70% CH3CN in H2O) to provide the title compound (0.0287 g, 45%) as its TFA salt. This material was lyophilized from H2O/dioxane to produce a white solid. 1H-NMR (CD3OD): δ 7.60 (d, J=8.4 Hz, 1H), 7.44–7.38 (2 overlapping d; 3H), 7.35 (s, 1H), 7.11 (d, J=9.2 Hz, 2H), 4.32 (br t, J=7.2 Hz, 2H), 4.12 (q, J=7.6 Hz, 2H), 3.56 (br s, 2H), 3.32 (br s, 2H), 1.85–1.76 (br m, 3H), 1.43 (t, 7.6 Hz, 3H), 1.25 (br s, 3H), 1.14 (br s, 3H), 1.08 (d, J=6.4 Hz, 6H). 13C-NMR(CD3OD): δ 172.51, 160.57, 151.15, 134.20, 132.87, 130.29, 128.70, 128.44, 123.46, 117.18, 111.54, 111.23, 65.02, 45.07, 43.16, 41.13, 37.49, 27.26, 22.76, 15.07, 14.35, 13.07. Anal. Calcd for MS (ESI) (M+H)+=423.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][C:12]1[C:13](=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:14]=O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:28][S:29][CH2:30][S:31](=[O:33])[CH3:32]>CN(C)C=O>[CH2:20]([N:11]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[C:30]([S:31]([CH3:32])=[O:33])[S:29][CH3:28])[C:5]1[C:4]([Cl:3])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CSCS(C)=O
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(=Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl)S(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
In 133 g of dimethylformamide (DMF), 22 g of sodium hydride (55%; oil dispersion) was dispersed and the dispersion was cooled to lower than 25° C., and a solution of 133 g of N-(2,6-dichlorophenyl)anthranilaldehyde in 266 g of DMF was added dropwise during 30 minutes to the dispersion and then 85.5 g of benzyl bromide was added dropwise during 30 minutes and the mixture was stirred at 20° C. for 1 hour and 22 g of sodium hydride (55%; oil dispersion) was added and then, 62 g of formaldehyde dimethyl mercaptal S-oxide was added dropwise during 1 hour at the reaction temperature of lower than 25° C. The precipitate was filtered and washed with methanol and water and dried under a reduced pressure to obtain 210.2 g of 1-[N-benzyl-o-(2,6-dichloroanilino)phenyl]2-methylsulfinyl-2-methylthioethylene as pale yellow crystals. Melting point 194° to 196° C. (benzene)
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.C(O)C>CO.ClCCl.[Cl-].[NH4+]>[F:33][C:18]([F:17])([F:32])[C:19]1[CH:20]=[C:21]([C:25]2[O:29][C:28]([CH:30]=[C:6]3[S:5][C:4](=[S:7])[N:3]([CH:8]4[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]4)[C:2]3=[O:1])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: O=C(O)C1CCCC(N2C(=O)C(=Cc3ccc(-c4cccc(C(F)(F)F)c4)o3)SC2=S)C1
Temperature: 25 °C
Reaction time: 65 h
Yield: 73.7 %

Procedure:
3-(4-Oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(3-trifluoromethyl-phenyl)-furan-2-carbaldehyde (79 mg, 0.33 mmol) (purchased from Aldrich Chemical Company), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6 N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5, 30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(3-trifluoromethyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (110 mg, 74%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.41 (2H, m), 1.67 (1H, m), 1.87-1.92 (3H, m), 2.29-2.45 (3H, m), 4.97 (1H, m), 7.37 (1H, d, J=3.6 Hz), 7.55 (1H, d, J=3.6 Hz), 7.62 (1H, s), 7.77-7.85 (2H, m), 8.11-8.18 (2H, m), 12.18 (1H, s); APCI-MS: 481.47; HPLC: 95%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH2:44]([S-:46])[CH3:45].[Na+].C(OCC)(=[O:50])C.CO.I([O-])(=O)(=O)=O.[Na+]>CN(C=O)C.O>[CH2:44]([S:46]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:42])[CH2:30][C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[O:32])=[CH:24][C:23]=3[F:43])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:50])[CH3:45]
Reactant: CCOC(C)=O
Reactant: CC[S-]
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCCCl)c4)sc23)c(F)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCS(=O)CCCOc1cccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 29 %

Procedure:
To chloride 366 (0.048 g, 0.077 mmol) in dry DMF (10 mL) was added sodium ethanethiolate (100 mg, 1.19 mmol) and the mixture was heated to 50° C., for 18 h. It was cooled, partitioned between ethyl acetate and water, washed with brine, dried (MgSO4), filtered, run through a short plug of silica gel, and concentrated. The residue was suspended in 1:1 ethyl acetate/methanol (50 mL) and sodium periodate (0.060 g, 0.28 mmol) in water (5 mL) was added. The reaction mixture was stirred for 6 h, concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was collected, washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. Reverse phase HPLC (Aquasil C-18 column, 60-95% MeOH/H2O+HCO2H, 30 min. linear gradient elution) of the residue followed by lyophilization afforded 368 (0.015 g, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.71 (s, 1H); 9.66 (s, 1H); 8.51 (d, J=5.5, 1H); 8.12 (s, 1H); 8.07 (d, J=8.8, 1H); 7.89 (dd, J=12.9, 2.2, 1H); 7.53-7.41 (m, 5H); 7.09-7.03 (m, 3H); 6.94-6.90 (m, 1H); 6.64 (dd, J=5.5, 0.5, 1H); 4.22 (t, J=6.3, 2H); 3.86 (s, 3H); 3.65 (s, 2H); 2.93-2.65 (m, 4H); 2.13 (quint, J=8.0, 2H); 1.29 (t, J=7.4, 3H). LCMS: (M+H) 662.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[O:25][CH:26]=[CH:27][CH:28]=2)[O:21][C:22]=1[CH3:23]>>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:20]1[O:21][C:22]([CH3:23])=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 79 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-furyl)-5-methyloxazole to give 2-(2-furyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyloxazole. The yield was 79%. Recrystallization from acetone-isopropyl ether gave colorless prisms, mp 89-90° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.24 min; [M+H]+=493.1.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:22]2[CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[N:26][CH:27]=2)O1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C.COCCOC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:22]1[CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH:25]=[N:26][CH:27]=1
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cncc(-c2ncccn2)c1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
2-Bromopyrimidine (73 mg), sodium carbonate (81 mg), water (0.3 mL), and bis(triphenylphosphine)palladium(II) dichloride (5.3 mg) were added to an ethylene glycol dimethyl ether (1 mL) solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. After cooling the reaction mixture to room temperature, ethyl acetate and water were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-50% hexane/ethyl acetate] to obtain 30 mg of methyl 5-(pyrimidin-2-yl)pyridine-3-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:14]1[CH:13]=[C:12]([C:3]2[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)c(CBr)c2)c(Cl)c1OC(F)F

Procedure:
A mixture of 20.0 g (65 mmol) of 4-chloro-5-difluoromethoxy-3-(4-chloro-3-methylphenyl)-1-methyl-1H-pyrazole (prepared as described in Example 2), 17.4 g (98 mmol) of N-bromosuccinimide and 200 ml of carbon tetrachloride was refluxed for 3 h under irradiation with a UV lamp. The solid constituents were then filtered off and were washed with a little methylene chloride. The solvent was removed under reduced pressure, and then the residue was purified by chromatography on silica gel (eluent: methylene chloride/hexane=8:2). Yield: 11.0 g; 1H-NMR (270 MHz, in CDCl3); δ [ppm]=7.98 (s, 1H), 7.80 (d, 1H), 7.46 (d, 1H), 6.70 (t, 1H), 4.64 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C[O:13][C:14](=[O:29])[CH:15]([O:27][CH3:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25]Br)[CH:18]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:28][O:27][CH:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][O:11][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[CH:18]=1)[C:14]([OH:29])=[O:13]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCOc2ccc3c(c2)CCCC3)c1)C(=O)O

Procedure:
The title compound was prepared from 5,6,7,8-tetrahydro-naphthalen-2-ol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C22H26O5 [M−H]−: 369.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14](=[O:17])[N:15]=[N:16][C:12]3=[CH:11][C:10](=[O:18])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14](=[O:17])[N:15]=[N:16][C:12]3=[CH:11][C:10](=[O:18])[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1
Reactant: O=c1cc2nnc(=O)n-2c2ccc([N+](=O)[O-])cc2n1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)n(-c1ccccc1)c(=O)cc1nnc(=O)n2-1

Procedure:
33.5 g of 8-nitro-6-phenyl-1H-s-triazolo[4,3-a][1,5]benzodiazepine-1,5-dione in 100 ml of ethanol containing 2.0 g of 10% palladium-on-charcoal is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped when 0.3 moles of hydrogen has been absorbed; the suspension is filtered and the filtrate evaporated to give the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.[Li]C(C)(C)C.N1([CH:26]=[O:27])CCCCC1.[NH4+].[Cl-]>C1COCC1>[CH:26]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:27]
Reactant: O=CN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C=O
Temperature: -20 °C
Reaction time: 8 h

Procedure:
At −78° C., to a solution of tert-butyl pyridin-3-ylcarbamate (2.98 g, 15.34 mmol) in THF (60 mL) is added t-BuLi (1.7 N, 21.65 mL, 36.8 mmol) dropwise while maintaining the internal temperature below −70° C. Then, the mixture is allowed to warm to −20° C. for 2 hr and piperidine-1-carbaldehyde (5.11 mL, 46.02 mmol) is added dropwise and the mixture is stirred at −20° C. to rt overnight. Saturated NH4Cl solution (30 mL) is added and the layers are separated. The aqueous layer is extracted with EtOAc (45 ml) and the combined extracts are dried and evaporated. The residue is purified by flash column with hexane/EtOAc (4:1) to give the title compound as a white solid. MS (M+1): 223.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([CH3:28])[N:18]=1>>[CH2:24]([NH:23][C:21]1[CH:20]=[C:19]([CH3:28])[N:18]=[C:17]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Cc1cc(NCC(C)C)nc(Cl)n1
Product: COc1cc(Nc2nc(C)cc(NCC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 89 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and (2-chloro-6-methyl-pyrimidin-4-yl)-isobutyl-amine (66 mg, 0.33 mmol) in analogous manner as described in example 90. It was obtained in 89% yield as a yellow solid. MS ISP (m/e): 367.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.12 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.34 (d, 1H), 7.13 (d, 1H), 7.10 (br s, 1H), 7.01 (s, 1H), 5.87 (s, 1H), 3.78 (s, 3H), 3.16 (br s, 2H), 2.13 (s, 3H), 1.74 (sept, 1H), 0.91 (d, 6H).