Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21][C:7]=3[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]=2[CH:10]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[N:40]=[N:39][C:38]([C:41]2[CH:46]=[CH:45][NH:44][C:43](=[O:47])[CH:42]=2)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[O:47]=[C:43]1[CH:42]=[C:41]([C:38]2[N:39]=[N:40][C:35]([C:34]([F:49])([F:48])[F:33])=[CH:36][CH:37]=2)[CH:46]=[CH:45][N:44]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21][C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nn2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)ccc3c2C1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.20 g, 0.39 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.10 g, 0.43 mmol), and Cs2CO3 (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (95 mg, 0.50 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL), the resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 12 column volumes) gave tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (40 mg, 19%) and the title compound (59 mg, 22%) as a yellow film.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH:16]=[O:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[CH2:16][OH:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[S:11]3)=[CH:4][CH:3]=1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: OCc1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a suspension of 2 g of 2-(p-chlorophenyl)-3-formylimidazo[2,1-b]benzothiazole in 100 ml of chloroform and 200 ml of ethanol was added 1 g of sodium borohydride and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and 900 ml of chloroform was added to the residue. After removing the insoluble materials which formed, the residue was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was recrystallized from isopropyl alcohol to provide 1.2 g of 2-(p-chlorophenyl)-3-hydroxymethylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:28]=[CH:29][C:24]([N:13]2[C:12]3[CH:11]=[C:10]4[C:2]([CH3:22])([CH3:1])[C:3]5[C:8]([C:9]4=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:7][CH:6]=[CH:5][CH:4]=5)=[CH:25][CH:26]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccccc5)cc4)c3cc21
Yield: 50.7 %

Procedure:
20 g (70.58 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene and 24.6 g (105.87 mmol) of 4-bromobiphenyl are dissolved in toluene and degassed by introduction of a protective gas. 4.94 ml (4.94 mmol, 1 M solution in toluene) of tri-tert-butylphosphine, 633.8 mg (2.82 mmol) of Pd(OAc)2 and 10.2 g (105.87 mmol) of NaOtBu are subsequently added. The solids are degassed in advance, the reaction mixture is subsequently degassed, and then stirred under reflux for 3 h. The warm reaction solution is filtered through Alox B (activity grade 1), washed with water, dried and evaporated. Crystallisation from toluene gives 15.6 g (50.8%) of the product as a white solid having a purity of 99.7%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1.[CH2:30]([NH2:38])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH2:30]([NH:38][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=c1n(-c2ccc(OCCNCCc3ccccc3)cc2)ccn1-c1ccc(Oc2ccccc2)cc1

Procedure:
A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was mixed with phenethylamine (47 mg), potassium carbonate (70 mg) and sodium iodide (5 mg) and boiled under reflux for 2 hours. The cooled solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 491.60 (C31 H29N3O3); MS (ESI): 492 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17](COCC[Si](C)(C)C)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].C1(OC)C=CC=CC=1.O1CCOCC1>Cl>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][NH:17][C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1COCCO1
Product: CCc1cncc(-c2cc3[nH]ncc3cn2)c1
Yield: 174.1 %

Procedure:
A solution of 2-[[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (0.2456 mmol; 106.8 mg) and anisole (1.228 mmol; 133 mg; 0.134 ml) in hydrogen chloride, 4.0 M in 1,4-dioxane (20 mmol; 5 ml) was stirred at room temperature overnight. The mixture was concentrated to afford 6-(5-ethyl-3-pyridyl)-1H-pyrazolo[4,3-c]pyridine (˜95.9 mg), which was used without purification.
Reaction SMILES: [Sn](Cl)Cl.[N+:4]([C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:24]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:27]4[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=4[N:25]=3)=[N:12][N:13]2[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=1)([O-])=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[NH2:4][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:24]3[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[C:27]4[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=4[N:25]=3)=[N:12][N:13]2[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c2ccc(N)cc21
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
Tin(II) chloride (12.0 g, 63.3 mmol) was added to a solution of 6-nitro-1-[2-(trimethyl-silanyl)ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)-ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole (7.18 g, 13.3 mmol) in DMF/H2O (160 mL/10 mL), and the reaction stirred at 50° C. for 2.5 h. The reaction was cooled to 0° C., and saturated sodium bicarbonate was added slowly, with mixing, until all frothing from quenching had subsided. The material was concentrated in vacuo and taken up in ether (100 mL). Insoluble material was removed by filtration and rinsed with ether (50 mL). The filtrate was washed with brine (50 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (25% ethyl acetate/hexane) gave 6.05 g (89%) of 6-amino-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl)ethoxymethyl]-1-H-benzoimidazol-2-yl}-1-H-indazole as a faintly yellow waxy solid. 1H NMR (300 MHz, CDCl3) δ 8.40 (d, 1H, J=9.0 Hz), 7.89-7.86 (m, 1H), 7.63-7.60 (m, 1H), 7.35-7.31 (m, 2H), 6.78 (dd, 1H, J=8.7, 1.8 Hz), 6.75 (s, 1H), 6.25 (s, 2H), 5.69 (s, 2H), 3.93 (br s, 2H), 3.65-355 (m, 4H), 0.93 (t, 2H, J=8.1 Hz), 0.85 (t, 2H, J=8.1 Hz), −0.04 (s, 9H), −0.15 (s, 9H). Anal. (C26H39N5O2Si2) C, H, N. Calculated: C, 61.26; H, 7.71; N. 13.74. Found: C, 61.18; H, 7.65; N, 13.82.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@@H:6]([CH:8]2[CH2:10][N@@:9]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[O:5][C:4]1=[O:23])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1=[O:39]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[C:32](=[O:39])[CH2:33][N:34]([CH2:10][C@H:8]([NH:9][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])(=[O:13])=[O:12])[C@@H:6]2[CH2:7][C@@H:3]([CH2:1][CH3:2])[C:4](=[O:23])[O:5]2)[C:35]([CH3:38])([CH3:37])[CH2:36]1
Reactant: CC1(C)CN(c2ccccc2Cl)C(=O)CN1
Reactant: CC[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 95.7 %

Procedure:
A solution of 916 mg of (3R,5S)-3-ethyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (106g) (2.69 mmol) and 771 mg of 1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (1k) (3.23 mmol) in toluene (27 ml) was stirred at 110° C. for two hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=3/1-2/1) to obtain 1.49 g of the title compound (yield: 96%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH2:21][CH2:22][CH3:23])(=O)=O.[CH:26]([O:28]CCCC)=[CH2:27].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([C:26](=[O:28])[CH3:27])=[C:8]([CH2:21][CH2:22][CH3:23])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: C=COCCCC
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1C(C)=O
Temperature: 80 °C

Procedure:
A mixture of the product from Step 6 (2.0 g, 5.0 mmol), n-butyl vinyl ether (25 mmol), triethylamine (0.83 mL, 6.0 mmol), palladium acetate (0.125 mmol) and 1,3-bis(diphenylphosphino)propane (51.5 mg, 0.125 mmol) in DMF (25 mL) was heated at 80° C. under nitrogen for 4 h. The reaction mixture was poured into 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was purified by chromatography on silica gel to afford the title product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:64])([CH3:63])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[N:56]([CH3:57])[C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[N:53]=2)[C:47]1=[O:62])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution containing the product from Example 1H (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 59F(0.070 mmol), DEPBT (0.021 g, 0.070 mmol), and N,N-diisopropylethylamine (0.041 mL, 0.240 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The reaction was partitioned between ethyl acetate and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated, to give the title compound (0.021 g, 50% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.88 (s, 9 H), 1.38 (m, 1 H), 1.53 (m, 1 H), 2.40 (m, 1 H), 2.64 (m, 3 H), 2.83 (m, 1 H), 3.12 (m, 4 H), 3.54 (m, 4 H), 3.82 (m, 3 H), 3.95 (m, 1 H), 4.03 (s, 1 H), 4.18 (m, 1 H), 4.43 (d, J=6.99 Hz, 1 H), 4.60 (m, 2 H), 6.92 (m, 4 H), 7.04 (m, 2 H), 7.21 (m, 4 H), 7.32 (m, 1 H), 7.58 (m, 3 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: C(N1C(C2C=CC=CC=2)=CN=C1)C1C=CC=CC=1.Br[C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH3:31].[CH2:32]([N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(C1C=NC=CC=1)#N.B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[CH2:32]([N:39]1[C:43]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH3:31])=[CH:42][N:41]=[C:40]1[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1.[CH2:32]([N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1nc(-c2ccccc2)sc1Br
Agent: N#Cc1cccnc1
Agent: OB(O)c1cccc(F)c1
Agent: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2)sc1-c1cnc(-c2cccnc2)n1Cc1ccccc1

Procedure:
The title compound was prepared by the method described in Example 1, except that (i) commercially available 5-bromo-4-methyl-2-phenylthiazole (Apollo Scientific) was used instead of 5-bromo-2-phenylpyrimidine in Step C, and (ii) 3-(1-benzyl-1H-imidazol-2-yl)pyridine was used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C. 3-(1-Benzyl-1H-imidazol-2-yl)pyridine was prepared by the procedure described in Example 8, Steps A and B except the commercially available 3-cyanopyridine was used instead of 3-fluorobenzonitrile; Rf 0.34 with 95:5 v/v dichloromethane-methanol; 1H-NMR (400 MHz; DMSO-d6) δ 8.87 (dd, 1H), 8.64-8.63 (dd, 1H), 7.94-7.91 (m, 1H), 7.86-7.84 (m, 2H), 7.43-7.22 (m, 8H), 6.83-6.81 (m, 2H), 5.25 (s, 2H), 2.31 (s, 3H); MS (ESI+) m/z 409.1 (M+1); H-PGDS FPBA IC50: >20 μM.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=O)[CH2:23][CH:24]1[CH2:27][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:22]([CH2:23][CH:24]2[CH2:25][CH:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27]2)=[N:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CC(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CC(Cc2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl 3-(2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)cyclobutylcarbamate (1.0 g, 1.99 mmol) in DCM (20 mL) was added pyridine (1.5 mL). (CF3SO2)2O (1.4 g, 4.97 mmol) was added slowly at −10° C. The reaction mixture was stirred at 0° C. for 1 h. Sat. NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the water layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10˜50% EtOAc/petroleum ether) to afford tert-butyl 3-((5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)methyl)cyclobutylcarbamate (0.7 g, 48%) as a slight yellow solid. ESI-MS (EI+, m/z): 484.0 [M-+H]+.
Reaction SMILES: Cl.[OH:2]/[N:3]=[C:4](/[C:10]1[N:11]=[C:12]([NH:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:13][CH:14]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:35]1([CH2:38][O:2]/[N:3]=[C:4](/[C:10]2[N:11]=[C:12]([NH:15][C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:13][CH:14]=2)\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:37][CH2:36]1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OCC1CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 67.3 %

Procedure:
Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate, hydrochloride salt (30 g) was stirred with cyclopropylmethyl bromide (13.5 g) in dimethylsulphoxide (150 ml) containing potassium carbonate (30 g) under nitrogen at 21° for 7 hours. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with more methylene chloride and the combined organic solutions were washed with water. After drying with magnesium sulphate, the solution was concentrated and loaded onto a column of Sorbsil U30 silica gel (200 g). The column was eluted with ethyl acetate (10 to 30%) in petroleum ether (b.p. 40°-60°). Evaporation of appropriate fractions gave the title compound (20.9 g); λmax (ethanol) 234.5 nm (E1 cm1% 403); λinf. 254.5 nm (E1 cm1% 302), 259.5 nm (E1 cm1% 267), 265 nm (E1 cm1% 229), 271.5 nm (E1 cm1% 190) and 294 nm (E1 cm1% 111); νmax (CHBr3) 3398 (NH), 1730 (ester), and 1593 and 1491 cm-1 (aromatic double bond).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:20](=[O:25])(=[O:24])[N:21]([CH3:23])[CH3:22])[NH:9][C:8]=2[CH:7]=1>>[CH:2]([O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[S:20](=[O:25])(=[O:24])[N:21]([CH3:22])[CH3:23])[NH:9][C:8]=2[CH:7]=1)([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: CN(C)S(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Product: CC(C)Oc1ccc2c(c1)Nc1cccc(S(=O)(=O)N(C)C)c1S2
Yield: 94.6 %

Procedure:
2-Isopropoxy-6-dimethylsulphamoylphenothiazine (42.8 g.) is prepared by reacting 2-iodopropane (33.8 g.) with 2-hydroxy-6-dimethylsulphamoylphenothiazine (40.0 g.) prepared as indicated in Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH2:4][N:5]([CH2:13][C:14]([NH:16][CH3:17])=[O:15])CC1C=CC=CC=1>CO.[Pd]>[CH3:17][NH:16][C:14](=[O:15])[CH2:13][NH:5][CH2:4][C:3]([NH:2][CH3:1])=[O:18]
Reactant: CNC(=O)CN(CC(=O)NC)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)CNCC(=O)NC
Temperature: 40 °C

Procedure:
The mixture of N-(2-methylamino-2-oxoethyl)-N-(phenylmethyl)-glycine methylamide (3.09 g, 11.2 mmol) in MeOH (30 mL) was added 10% Pd/C (0.15 g). The mixture was stirred and heated to 40° C. under 40 psi H2 for 10 h, filtered and concentrated in vacuo to yield N-(2-methylamino-2-oxoethyl)-glycine methylamide in quantitative yield (1.76 g). 1H NMR (CDCl3): δ 6.95 )br s, 2H), 3.23 (s, 4H), 2.79 (d, J=6.0, 4.8 Hz), 2.25 )br s 1H); MS (ESI) m/e 160 )M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH:28]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:26][CH2:27][CH2:28][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: O=CCCc1c[nH]c2ccc(F)cc12
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 8-amino-2,3,8,9-tetrahydropyrano[3,2-e]isoindol-1(7H)-one (1) (200 mg, 0.98 mmol) in anhydrous MeOH (20 ml) was added 3-(5-fluoro-1H-indol-3-yl) propanal (2) (191 mg, 1 mmol), AcOH (0.14 ml), and NaBH3CN (123 mg, 1.96 mmol). Resulting reaction mixture was stirred at room temperature for 2 hr. The solvent was removed in vacuo and the residue was re-dissolved in CH2Cl2 (150 ml). The solution was washed with 1 N NaOH (20 ml) and H2O, Sat. NaCl. The organic solution was separated, dried over Na2SO4, then concentrated in vacuo. The crude compound was purified on silica gel eluting with EtOAc/Hexane (4:1) to yield (3) (304 mg, 82%) as a white solid. MS (APPI) m/z 380.