Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:27]>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>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:32]=[C:33]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])=[O:25])=[CH:18][CH:19]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Reactant: CCOC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1cccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3)cc2)c1

Procedure:
Following the procedure described in Example 17, Step 2, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester, [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide {4′-[3-methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-3-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 17, Step 3.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:12][C:11]=2[C:23]([NH2:25])=[O:24])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[F:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[C:13]1[O:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][S:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)(=[O:42])=[O:41])=[CH:9][CH:8]=2)=[C:11]([C:23]([NH2:25])=[O:24])[N:12]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCc1ccc(-c2oc(-c3c(F)cccc3F)nc2C(N)=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide hydrochloride (0.030 g, 0.082 mmol) in DCM (2 mL) was added triethylamine (25 uL, 0.18 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016 g, 0.082 mmol) and the resulting mixture stirred at room temperature overnight. Triethylamine (13 uL, 0.093 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016 g, 0.082 mmol) was then added and the reaction stirred for a further 3 hours. After 2 hours triethylamine (6 uL, 0.043 mmol) and 4-fluorobenzenesulfonyl chloride (0.008 g, 0.041 mmol) was added. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-((4-fluorophenylsulfonamido)methyl)phenyl)oxazole-4-carboxamide (0.0230 g, 0.047 mmol, 57%) as a white solid. 1H NMR (DMSO) 4.07 (2H, d), 7.39 (6H, m), 7.74 (3H, m), 7.85 (2H, m), 8.13 (2H, d), 8.32 (1H, t). LCMS (2) Rt: 3.07 min; m/z (ES+) 488.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13](Cl)=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:12]2[O:11][C:10]([C:13]([NH:16][C:17]3[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=3[C:22]([NH2:24])=[O:23])=[O:14])=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cccc2cc(C(=O)Cl)oc12
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc2cccc(OCC)c2o1

Procedure:
From 7-ethoxybenzofuran-2-carbonyl chloride (4.124 g, 20 mmol), 1 (1.82 g, 10 mmol), DMAP (32.5 mg, 0.27 mmol) and Et3N (2.02 g, 20 mmol) in anhydrous CH2Cl2 (65 mL) using the same procedure as for 3 the title compound was obtained as?a white solid; mp: 219-221° C.; 1H NMR (DMSO-d6) δ 0.86 (t, J=7 Hz, 3 H), 1.43 (t, J=7 Hz, 3 H), 1.56 (sxt, J=7 Hz, 2 H), 2.42 (t, J=7 Hz, 2 H), 3.91 (s, 3 H), 4.28 (q, J=7 Hz,2 H), 7.10 (d, J=6 Hz, 1 H), 7.26 (t, J=6 Hz, 1 H), 7.35 (d, J=6 Hz, 1 H), 7.50 (s, br. 1 H), 7.71 (s, 1 H), 7.76 (s, br. 1 H); MS (m/z): 371 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].Cl>C1C=CC=CC=1>[CH2:7]([O:9][CH:10]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH3:11])[CH3:8]
Reactant: C=COCC
Reactant: Ic1cn[nH]c1
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(C)n1cc(I)cn1
Yield: 73 %

Procedure:
4-Iodo-1H-pyrazole (3.0 g) was suspended in benzene (150 mL) and the suspension was heated while stirring. Ethyl vinyl ether (4.4 mL) was added thereto, concentrated HCl was added dropwise thereto, and the resulting mixture was stirred at 60° C. for 3 hours. After completion of the reaction, the resulting mixture was concentrated by evaporation under a reduced pressure, and the residue was neutralized using aqueous saturated sodium hydrogen carbonate (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL) and the extract was washed successively with distilled water (100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound as a transparent yellow liquid (3.0 g, yield 73%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)Cl>[O:7]=[C:2]1[NH:1][CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:3]1
Reactant: O=C1CNCCN1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCNC(=O)C1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of 2-piperazinone (5.0 g, 50.0 mmol) and triethylamine (11.09 g, 110.0 mmol) in DCM (15 mL) is added ethyl chloroformate (5.9 g, 55.0 mmol) at room temperature and the reaction mixture is stirred for 2 h. The reaction is quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers are dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue is triturated with Et2O to give the title compound (5.0 g, 29.05 mmol) as a pale yellow solid. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (t, 3H), 3.16-3.19 (m, 2H), 3.48-3.51 (m, 2H), 3.85 (s, 2H), 4.05 (q, 2H), 8.06 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([C:47]2[CH:56]=[CH:55][CH:54]=[C:49]([C:50]([NH:52][NH2:53])=[O:51])[C:48]=2[OH:57])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:53][NH:52][C:50]([C:49]1[C:48]([OH:57])=[C:47]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:56]=[CH:55][CH:54]=1)=[O:51])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NNC(=O)c1cccc(-c2ccccc2)c1O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NNC(=O)c1cccc(-c2ccccc2)c1O
Yield: 23.8 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (93 mg, 0.17 mmol) and 3-phenylsalicylic acid hydrazide (45 mg, 0.20 mmol) according to Method C with HPLC purification to give the title compound (30 mg). 1H-NMR (400 MHz, CD3OD) d 4.80 (s, 2H), 4.27 (dd, J=4.9 Hz, J=9.8 Hz, 1H), 3.04 (m, 1H), 2.94 (m, 1H), 2.72 (dd, J=9.3 Hz, J=13.7 Hz, 1H), 1.34 (s, 9H); IR (KBr) 3280, 1694, 1653 cm−1; HRMS m/z 740.2666 (calc. of monoisotopic mass for C39H40N4O11 gives 740.2694).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C([Cl:16])=O>CN(C=O)C.C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:16])=[O:7])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCSc1ccccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCSc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
To a mixture of 2-ethylsulfanylbenzoic acid (9.11 g), chloroform (100 ml), and oxalyl chloride (9.72 g), DMF (2 drops) was added, and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give 10.03 g of 2-ethylsulfanylbenzoic acid chloride (Compound (1H)-241).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])C=CC=CC=1.[CH3:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[C:38]=1[CH:39]=O>>[CH3:29][C:30]1[N:31]=[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]2[C:38]=1[CH:39]=[CH:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:15])[CH3:16]
Reactant: Cc1nc2ccccn2c1C=O
Reactant: C[Si](C)(C)CCOC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: Cc1nc2ccccn2c1C=COCC[Si](C)(C)C
Yield: 96 %

Procedure:
Following procedures analogous to those described in Example 6 and use triphenyl-(2-trimethylsilanyl-ethoxymethyl)phosphonium chloride, 2-methyl-imidazo[1,2-a]pyridine-3-carbaldehyde was converted into 2-methyl-3-[2-(2-trimethylsilanyl-ethoxy)-vinyl]-imidazo[1,2-a]pyridine (96% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:21])[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>O1CCOCC1>[Br:21][C:4]1[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(Br)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)c1cc(Br)nc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
0.222 g (0.0005 mol) of 2,6-dibromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridine was dissolved in 10 ml of dioxan and treated with 0.047 g (0.00055 mol) of piperazine and 0.7 ml of triethylamine. The mixture was stirred at room temperature for 20 hrs. and subsequently at 40° C. for 3 hrs., the solvent was then removed and the residue was chromatographed on silica gel with 5% methanol in dichloromethane. There was obtained 0.14 g (62%) of 1-[6-bromo-4-(3-trifluoromethylbenzenesulphonyl)-pyridin-2-yl]-piperazine as yellow crystals; m.p.: 160-162° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][S:27](=[O:30])(=[O:29])[NH2:28])[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:35][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][S:27](=[O:30])(=[O:29])[NH2:28])=[O:34]
Reactant: CC(C)N(CCS(N)(=O)=O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCS(N)(=O)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 64 h

Procedure:
A solution of (2-{3-chloro-5-[isopropyl-(2-sulfamoyl-ethyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.012 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64 h and then concentrated under reduced pressure to give the title compound (0.011 g) as a colourless gum.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([C:11](=O)[CH:12]([CH3:14])[CH3:13])=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>C1COCC1>[Cl:4][C:5]1[C:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:2][NH:3][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: NN
Reactant: CC(C)C(=O)c1c(Cl)ccnc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1n[nH]c2ccnc(Cl)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
Normal-butyllithium (a 1.6 M solution in hexane, 8.13 mL) was dropwise added to a solution of N,N-diisopropylamine (1.99 mL) in THF (30 mL) at −78° C. under a nitrogen atmosphere, followed by increasing the temperature to 0° C. Then, the solution was cooled to −78° C., and a solution of 2,4-dichloropyridine (1.0 g) in THF (3 mL) wad dropwise added thereto at −78° C., followed by stirring for 1.5 hr. Then, a solution of isobutylaldehyde (1.85 mL) in THF (3 mL) was dropwise added to the reaction solution at −78° C., followed by stirring at the same temperature for 30 min. Then, the reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the organic layer after the washing was dried over anhydrous sodium sulfate. Then, the solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.48 g, 99%) as a colorless oily substance. A solution of DMSO (0.9 mL) in dichloromethane (5 mL) and a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.39 g) in dichloromethane (5 mL) were sequentially added to a solution of oxalyl chloride (0.8 mL) in dichloromethane (30 mL) at −78° C., followed by stirring for 30 min. Then, triethylamine (3.52 mL) was added to the reaction solution at 0° C., followed by stirring for 1 hr. The reaction solution was poured into ice water and was extracted with chloroform. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (1.18 g, 86%) as a colorless oily substance. Hydrazine monohydrate (1.3 mL) was added to a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (0.93 g) in THF (13 mL), followed by stirring at room temperature for 12 hr and then at 50° C. for 25 hr. The reaction solvent was distilled away under reduced pressure, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4a) (0.55 g, 66%) as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CCOC(C)=O>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (157 mg, 0.5 mmole) with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e (150 mg, 0.7 mmole) and Cs2CO3 (673 mg, 2.1 mmole) in a manner as previously described for example 1 to give 51 mg (39%) of a crisp foam. 1H NMR (DMSO-d6) δ 8.54 (1H, dd, J=5.5, 1.13 Hz), 8.05 (1H, s), 7.84 (1H, d, J=8.6 Hz, 7.61–7.55 (1H, m), 7.54 (1H, d, J=2.1 Hz), 7.03(1H, dd, J=2.1, 8.6 Hz), 6.64 (1H, d, J=5.5 Hz), 4.12–3.51 (5H, m), 3.67 (3H, s), 3.27, 3.24 (3H, 2s), 2.80 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.35–1.95 (2H, m). Anal. Calcd for C25H26N4O4S.0.9 H2O0.2 EtOAc: C, 60.47; H, 5.78; N, 10.93; S, 6.26. Found: C, 60.46; H, 5.56; N, 10.81; S, 6.34.
Reaction SMILES: C[O:2][CH:3]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)C.C([Li])CCC.[CH:19]([O:21][CH2:22][CH3:23])=O>CCCCCC>[CH3:19][O:21][CH:22]([C:13]1[C:7]2[NH:6][C:5]([CH:3]=[O:2])=[N:9][C:8]=2[CH:10]=[CH:11][CH:12]=1)[CH3:23]
Reactant: COC(C)c1nc2ccccc2[nH]1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COC(C)c1cccc2nc(C=O)[nH]c12

Procedure:
Following the procedure of Example 1D, 2.36 g of 1-methoxyethylbenzimidazole, 5.15 ml of 2.6M n-butyl lithium in hexane, 1.08 ml of ethyl formate gave on work-up 1.73 g of the desired product as a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([CH2:17][OH:18])[CH2:6]1)(=[O:3])[CH3:2].[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:7]([CH2:17][O:18][C:25]2[CH:26]=[CH:27][C:22]([C:21]([O:20][CH3:19])=[O:29])=[CH:23][CH:24]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC(C)=O)CN2C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
To a stirred mixture of (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol (9.70 g, 37.4 mmol), p-hydroxybenzoic acid methyl ester (5.69 g, 37.4 mmol) and PPh3 (10.8 g, 41.1 mmol) in THF (200 ml) was added DIAD (8.10 ml, 41.1 mmol) at room temperature. After 1.5 h stirring, the mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [700 g, CHCl3/EtOAc (10/1)], to give methyl 4-[(2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-pyrrolidinyl]methoxybenzoate (11.8 g, 81%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.03 (s, 3H), 2.27 (m, 2H), 3.46 (m, 1H), 3.72 (m, 1H), 3.88 (s, 3H), 3.98 (t, J=9.0 Hz, 1H), 4.21–4.47 (m, 2H), 5.31 (br, 1H), 6.96 (br, 2H), 7.98 (d, J=8.8 Hz, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][C:43]3=[O:48])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][C:43]3=[O:48])=[CH:40][CH:41]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(N3CCOCC3=O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3=O)cc1)nn2-c1c(F)cccc1F
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a mixture of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (150 mg) obtained in Step C of Example 35, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholin-3-one (145 mg) and sodium carbonate (78 mg) in DME/water (1.5 mL/0.070 mL) was added dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) (21 mg) under nitrogen atmosphere. The reaction mixture was stirred under microwave irradiation at 120° C. for 1 hr. The insoluble substance was removed by the filtration, the filtrate was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (143 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C=O)CC1
Yield: 95.7 %

Procedure:
In a manner similar to the method described in example 4a, 5-bromosalicylaldehyde (5.65 g, 28 mmol) (Aldrich) reacted with 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 14 mmol, ASTATECH) and K2CO3 in N,N-dimethylformamide to give 4-(4-bromo-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellow gum (Yield 5.15 g, 51%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)(=O)=O.O>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:41][CH2:42][N:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)OCCN1CCCCC1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc(OCCN4CCCCC4)cc3)nn3ccnc23)n1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(piperidin-1-yl)ethyl methanesulfonate (25 mg, 0.12 mmol). The mixture was heated at 50° C. for 16 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine then dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)-6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.63 (s, 1H), 8.01-7.90 (m, 4 h), 7.57 (s, 1H), 7.42 (t, 1H, J=7.8 Hz), 7.05-7.01 (m, 2H), 6.21 (d, 1H, J=7.8 Hz), 6.04 (d, 1H, J=8.7 Hz), 4.30-4.20 (m, 3H), 3.70-3.64 (m, 1H), 3.53-3.45 (m, 1H), 2.84 (t, 2H, J=6.2 Hz), 2.56 (brs, 4 h), 2.20-2.03 (m, 3H), 1.78 (brs, 1H), 1.67-1.62 (m, 4 h), 1.50-1.48 (m, 2H), 1.27 (d, 3H, J=6.3 Hz). LC/MS: 498 [M+H]+, tR=1.13 min. HPLC: 99.24% at 214 nm, 99.34% at 254 nm, tR=5.70 min.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]([F:21])([F:31])[F:32])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccccc1C(F)(F)F
Yield: 34 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and o-trifluoromethyl-phenylhydrazine according to the method described for Example 1 in 34% yield. MS: M=383.0 (M+H)+