Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C:16]2[N:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:21]=[CH:22][C:15]1=2)=[O:13].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([N:20]2[C:16]3[CH2:17][CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]4)[C:15]=3[CH:22]=[N:21]2)=[CH:24][CH:25]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cn1cc(C(F)(F)F)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 65 °C
Yield: 113.7 %

Procedure:
A mixture of 4-(trifluoromethyl)-1H-pyrazole (0.030 g, 0.22 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.025 g, 0.085 mmol) and K2CO3 (0.060 g, 0.43 mmol) in THF (0.8 mL) and DMF (0.4 mL) was heated at 65° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.038 g, 100%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.89 (s, 1H), 7.77 (s, 1H), 7.44 (dd, J=8.8, 4.6 Hz, 2H), 7.16 (dd, J=8.8, 8.4 Hz, 2H), 5.20 (s, 2H), 3.83 (m, 2H), 2.85 (t, J=6.2 Hz, 2H), 2.10 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[CH3:44][S:45]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)(=[O:47])=[O:46]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NS(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:20])([CH3:19])[C:5](=[O:18])[C:6]([C:13](OCC)=[O:14])=[C:7]2[OH:12].C(N(C(C)C)C(C)C)C.Cl.[NH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH3:19])([CH3:20])[C:5](=[O:18])[C:6]([C:13]([NH:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:14])=[C:7]2[OH:12]
Reactant: CCOC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C(C)(C)C1=O
Temperature: 80 °C
Yield: 61.2 %

Procedure:
To a solution of ethyl 5-fluoro-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalene-2-carboxylate (2.0 g, 7.2 mmol) in 1,4-dioxane (15 mL), was added N-ethyl-N-isopropylpropan-2-amine (2.3 mL, 13 mmol) and tert-butyl 2-aminoacetate hydrochloride (1.6 g, 9.3 mmol). After heating at 80° C. for 12 hours, the solvent was removed in vacuo, and the residue was purified using flash chromatography (15% EtOAc/hexane) to afford the product as a white solid (1.6 g). MS (m/z)=362 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cc1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Yield: 90.7 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (172 mg, 0.596 mmol) in dry DMF (3 mL) under an atmosphere of dry nitrogen was added 2-(bromomethyl)-6-methylpyridine (122 mg, 0.656 mmol) and potassium carbonate (165 mg, 1.19 mmol) with stirring. The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with water (20 mL) and extracted into ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified using preparative chromatography on silica, eluting with hexane/ethyl acetate (3:1) to give 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (213 mg).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1N1C=NC(C(F)(F)F)=N1)=[O:11].CC1C=CC([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1)=[O:11]
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)O)c1
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 5-methyl-2-(1-methyl-1H-pyrazol-5-yl)benzoic acid. ESI-MS (m/z): 327 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(NC(=O)Cc2ncccc2F)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(F)cccn2c1=O
Temperature: 120 °C
Yield: 65 %

Procedure:
A mixture of 2-(3-fluoropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (9.01 g, 24.3 mmol) and CDI (15.78 g, 97 mmol) in toluene (97 mL) was heated at 120° C. for 7 h. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (220 g), eluting with EtOAc-hexanes (gradient from 20-100%), to provide 5-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid (6.26 g, 65% yield). Mass spectrum m/z 397 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.11 (dd, J=7.6, 0.8 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.8, 1.4 Hz, 1H), 6.85-6.76 (m, 1H), 6.35 (td, J=7.4, 5.0 Hz, 1H), 6.09 (s, 1H), 2.36 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[OH:15].[CH3:16]/[C:17](/[CH3:26])=[C:18](/[O:24][CH3:25])\[O:19][Si](C)(C)C.CN(C)C=O>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[F-].[Zn+2].[F-]>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([OH:15])=[C:2]([C:17]([CH3:26])([CH3:16])[C:18]([O:24][CH3:25])=[O:19])[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])cc1O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4-tert-butyl-5-nitrophenol (15.00 g, 54.72 mmol), bis(tri-tert-butylphospine)palladium(0) (1.422 g, 2.783 mmol), zinc fluoride (2.82 g, 27.27 mmol), methyl trimethylsilyl dimethylketene acetal (MTDA) (19.35 g, 111.0 mmol), and dimethylformamide (150 mL) was heated at 70° C. for 18 h. The mixture was cooled to room temperature and diluted with water. After stirring for one hour, the aqueous phase was extracted with MTBE. The organic phase was dried in vacuo to afford the crude product as a brown solid. Purification of the product was accomplished by trituration in n-heptane. 1H-NMR (400 MHZ, DMSO-d6) δ 10.38 (s, 1H); 7.37 (s, 1H); 6.79 (s, 1H); 3.54 (s, 3H); 1.45 (s, 6H); 1.32 (s, 9H)
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32]C(C(O)=O)=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[C:36]2[C:28](=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:30]3)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 4 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol) was added dropwise to a solution of 3-(tert-butyloxycarbonyl)-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.0 g, 3.7 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J. Org. Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.5 ml, 10 mmol) in 10 ml of anhydrous CH2Cl2. After 4 hrs, CH2Cl2 was removed by evaporation at reduced pressure. Flash chromatography (4×20 cm, hexane-ethyl acetate, 1:2) afforded 1b as a yellow crystalline solid (1.25 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.39 (d, 1H, J=1.4 Hz, NH), 8.02 (m, 1H, C6F4H), 7.9 (br s, 1H, C4—H), 7.45 (d, 1H, J=1.4 Hz, C8—H), 7.33 (d, 1H, J=9 Hz, C5—H), 4.02 (t, 2H, J=9 Hz, NCH2CH2), 3.26 (t, 2H, J=9 Hz, NCH2CH2), 1.51 (s, 9H, C(CH3)3). Anal. Calcd. for C22H18N2O4F4: C, 58.67; H, 4.03; N, 6.22. Found: C, 58.45; H, 4.09; N, 6.13.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Br:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)=[O:21]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCCC(C)(Br)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(C)(Br)C(=O)Nc1ccc(C(C)C)cc1
Yield: 65.3 %

Procedure:
410 mg (3.04 mmoles) of 4-isopropylaniline was dissolved in 10 ml of benzene, and 500 mg of triethylamine was added. With stirring under ice cooling, 800 mg (4.10 mmoles) of 2-bromo-2-methylvaleryl chloride was added dropwise. After the addition, the mixture was further stirred at room temperature for 1 hour. The crystals that precipitated were separated by filtration. The filtrate was concentrated, and the residue was recrystallized from benzene to give 620 mg of 2-bromo-2-methyl-4'-isopropylvaleranilide. m.p. 87.2°-88.2° C. IR νmaxcm-1 3300 and 1650. Yield 65.4%.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22](O)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[CH3:26][O:27][C:28]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:28]=4[O:27][CH3:26])[CH2:33]3)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(CNC(C)=O)cc3)nc3ccccc13)C2
Yield: 5 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 67 (5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.73 and 2.98 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.69-3.82 (4s, 6H), 4.34-4.36 (m, 2H), 4.41 and 4.93 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.42-7.47 (m, 2H), 7.75-8.17 (m, 4H), 8.44-8.51 (m, 3H); MS (ESI) m/z 497 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[CH3:1][C:2]1[C:10]2[C:5]([N:6]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[CH:7]=[CH:8][CH:9]=2)=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(-c2[nH]c3ncccc3c2C)cc1
Product: Cc1ccc(-c2nc3n(CC(=O)c4ccccc4)cccc-3c2C)cc1

Procedure:
The title compound was prepared from 3-methyl-2-(p-methylphenyl)-pyrrolo[2,3-b]pyridine and phenacyl bromide on a 3 mmol scale according to the procedure described in example 8 yielding 1.21 g (96%).
Reaction SMILES: [OH:1][C:2]1[C:6]([I:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[C:6]([I:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1noc(-c2ccccc2)c1I
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1noc(-c2ccccc2)c1I
Yield: 73.4 %

Procedure:
3-Hydroxy-4-iodo-5-phenylisoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.12 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.22 g, 73%) as a colorless powder.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C[N+]1C=CN([S:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])C=1.Cl.[CH3:25][C:26]1[C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[S:29][C:30]=1[NH2:31]>CC#N>[CH3:25][C:26]1[C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[S:29][C:30]=1[NH:31][S:15]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)(=[O:17])=[O:16]
Reactant: Cc1c(N)sc2ccccc12
Reactant: C[n+]1ccn(S(=O)(=O)N2CCCCC2)c1
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1c(NS(=O)(=O)N2CCCCC2)sc2ccccc12
Temperature: 140 °C
Yield: 40 %

Procedure:
To a solution of compound 1-I (85.2 mg, 0.37 mmol) in MeCN (1.0 mL) was added a solution of compound 1-C (120.8 mg, 0.74 mmol) in MeCN (1.0 mL) and the reaction mixture was heated under microwave irradiation at 140° C. for 10 minutes. The reaction mixture was purified by reverse-phase semi-prep HPLC (method 3) eluting with a 45% MeCN—H2O (0.1% TFA) to 65% MeCN—H2O (0.1% TFA) gradient to afford 46 mg of compound 1-J as a film. 1H-NMR (CDCl3, 400 MHz): δ 7.71-7.73 (t, 1H), 7.63-7.66 (t, 1H), 7.34-7.40 (m, 2H), 6.28 (s, 1H), 3.27-3.29 (m, 4H), 2.39 (s, 3H), 1.53-1.73 (m, 6H); MS (method 2): m/z 311.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[NH:24][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:49]([O:56][C:57]1[CH:62]=[CH:61][C:60]([CH2:63][CH2:64][C:65](O)=[O:66])=[CH:59][CH:58]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.CN1CCOCC1>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:10](/[N:12]=[C:13]2\[NH:14][CH2:15][C:16]3([CH2:23][CH:22]4[N:24]([C:65](=[O:66])[CH2:64][CH2:63][C:60]5[CH:61]=[CH:62][C:57]([O:56][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[CH:58][CH:59]=5)[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[NH:17]\2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4)N2)nc1Cl
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CC4CCC(C3)N4C(=O)CCc3ccc(OCc4ccccc4)cc3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(E)-3,5-diamino-6-chloro-N-(8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-2′-ylidene)pyrazine-2-carboxamide (prepared as described for Ex. 252) (280 mg, 0.798 mmol) is dissolved in DMF (8 ml) along with HATU (303 mg, 0.798 mmol) and 3-(4-benzyloxy-phenyl)-propionic acid (205 mg, 0.798 mmol). N-Methyl morpholine (0.263 ml, 2.394 mmol) is added and the solution stirred at room temperature for 6 hours. The mixture is then concentrated in vacuo. EtOAc (100 ml) is added and the solution washed with water (100 ml). The organic phase is dried (MgSO4) and concentrated. The residue is dissolved in MeOH (20 ml) and dry loaded onto silica (5 g). Purification by flash chromatography (SiO2, DCM/MeOH) gives the title compound as a tan solid; [M+H]+ 589.20, 591.19 for Cl isotopes.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[S:27][CH:28]=[CH:29][C:30]=1B(O)O>>[Cl:25][C:26]1[S:27][CH:28]=[CH:29][C:30]=1[C:5]1[CH:6]=[CH:7][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:24]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccsc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccsc1Cl
Yield: 45 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-chlorothiophene-3-boronic acid (available from Combi-Blocks Inc.; 65 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2-(2-chloro-thiophen-3-yl)-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid (42 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.44-8.56 (m, 2H), 8.33 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.45-7.61 (m, 2H), 7.08 (d, J=5.5 Hz, 1H)
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][CH:5]([CH2:20][CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](O)=[O:17])=[CH:9][CH:8]=1>C(O)C>[NH2:22][CH2:21][CH2:20][CH:5]([CH3:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:17])[NH:2][N:3]=2)=[CH:9][CH:8]=1
Reactant: NN
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CC(CCN)Cc1ccc(C2=NNC(=O)CC2)cc1
Yield: 82 %

Procedure:
9.61 g of hydrazine monohydrate was added to an ethanol solution (500 ml) containing 15.06 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene, and the mixture was refluxed under heating for 2.5 hours. After cooling, precipitated crystal was collected by filtration and recrystallized from ethyl acetate to obtain 8.14 g of 6-[4-(4-amino-2-methylbutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.II.[CH:12]([C@@H:14]1[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:13].[NH4+].[Cl-]>CCOCC.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:12]([C@@H:14]2[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][C@@H:15]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1C=O
Reactant: Clc1cccc(CBr)c1
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A portion of a mixture of 3-chlorobenzyl bromide (0.53 mL, 4.0 mmol) and Et2O (0.5 mL) was added to Mg turnings and I2 (catalytic amount) in Et2O (4 mL). Once the reaction was initiated, the rest of the 3-chlorobenzyl bromide was added. When the reaction subsided, the resulting green mixture was transferred into a −78° C. suspension of CeCl3 (1.05 g, 4.3 mmol) in THF (4 mL). A solution of the (±)-(4R*,5R*)-5-formyl-1-methyl-4-phenylpyrrolidin-2-one (Intermediate Z, 1M in THF, 3 mL, 3 mmol) was added and the reaction mixture was allowed to warm to room temperature, then was treated with a saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and a saturated NaCl solution, dried (Na2SO4) and concentrated under reduced pressure. The crude green oil was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-[(1R*)-2-(3-chlorophenyl)-1-hydroxyethyl]-1-methyl-4-phenylpyrrolidin-2-one (340 mg, 34%): mp 50-52° C.; TLC (EtOAc) Rf 0.25.
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].N>ClCCl>[NH2:3][C:34](=[O:35])[CH2:33][C@H:32]([NH:31][C:29](=[O:30])[O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-hydroxybenzotriazole hydrate (3.46 g, 25.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.91 g, 25.6 mmol), and (S)-N-tert-butoxycarbonyl-3-amino-3-phenylpropanoic acid (6.80 g, 25.6 mmol) in dichloromethane (250 ml) was stirred at room temperature for 1 hour. 0.88 Ammonia (20 ml) was added and the mixture stirred at room temperature for a further 18 hours. The resulting solid was filtered off and washed with sodium bicarbonate solution, then water and dried under vacuum at 50° C. to afford the title compound, 6.78 g.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH:53]1([C:58](Cl)=[O:59])[CH2:57][CH2:56][CH2:55][CH2:54]1>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:58]([CH:53]5[CH2:57][CH2:56][CH2:55][CH2:54]5)=[O:59])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(Cl)C1CCCC1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(C1CCCC1)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Cyclopentane carbonyl chloride (80 μl, 0.6 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E43); MS (ES+) m/e 397 [M+H]+.