Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11](O)=[O:12])[NH:8][C:7](=[O:14])[C:6]=12.C(N1C=CN=C1)(N1C=CN=C1)=O.O/[N:41]=[C:42](\[NH2:49])/[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[Ca+2].[Ca+2].[Ca+2]>CN(C)C=O>[CH3:1][C:2]1[NH:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:5]2[CH:10]=[C:9]([C:11]3[O:12][N:49]=[C:42]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:41]=3)[NH:8][C:7](=[O:14])[C:6]=12
Reactant: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(C(=O)O)[nH]c(=O)c12
Reactant: N/C(=N\O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2cc(-c3nc(-c4ccccc4)no3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A solution of Example 12b (500 μL, 0.005 g, 0.0139 mmol) in N,N-dimethylformamide and a solution of 1,1′-carbonyldiimidazole (500 μL, 0.0113 g, 0.069 mmol) in N,N-dimethylformamide were combined and shaken for 1 hour at ambient temperature. A solution of (Z)—N′-hydroxybenzimidamide (69.4 μL, 0.042 mmol) in N,N-dimethylformamide was added and the resulting mixture was reacted in an Anton Paar Synthos 3000 microwave optimizer at 180° C. for 45 minutes. Upon completion, the crude material was concentrated to dryness and purified by reverse phase HPLC (C8, acetonitrile/water (0.1% ammonium acetate), 25-55%) to yield 0.0027 g (37%) of the title compound as the acetic acid salt. 1H NMR (400 MHz, DMSO-d6/D2O) δ 12.39 (s, 1 H), 10.30 (s, 1 H), 8.09 (m, 2 H), 7.61 (m, 4 H), 7.54 (m, 1 H), 7.41 (m, 1 H), 7.33 (m, 3 H), 7.07 (m, 2 H), 6.95 (d, J=7.93 Hz, 2 H), 2.65 (s, 3 H). MS (ESI+) m/z 461.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24]([CH:25]=O)=[CH:23][N:22]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1.[CH2:38](P(=O)(OCC)OCC)[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].[H-].[Na+].Cl>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24](/[CH:25]=[CH:38]\[P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:23][N:22]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: COc1cc(COc2nc(-c3ccccc3)ncc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C\c1cnc(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a mixture of 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carbaldehyde (1.00 g), tetraethyl methylenediphosphonate (0.58 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.090 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, 2N hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (2:3, v/v) to give diethyl (Z)-2-(4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidin-5-yl)ethenylphosphonate as crystals (0.095 g, yield 7%). Recrystallization from acetone-hexane gave colorless needle crystals. melting point: 154-155° C.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14].O.[OH-].[Li+]>C1COCC1.CO.O>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(Br)ccc1SC(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C(=O)Sc1ccc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (10.0 g, 31.42 mmol) and lithium hydroxide hydrate (1.98 g, 47.14 mmol) in (1/1/1) THF/MeOH/H2O (70 mL total volume) was stirred at room temperature for 4 h. The reaction mixture was concentrated to remove most organic solvents. The residue was diluted with water (500 mL) and extracted with EtOAc (100 mL), which is discarded. The aqueous layer was acidified to pH 3-4 using 1 N HCl and extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide crude 5-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid which was used directly and without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.[CH2:28]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[C:32]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[N:31]1)[CH3:29].C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH2:28]([N:30]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)(=[O:21])=[O:20])[C:9]([C:11]4[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=4)=[CH:10][C:3]=23)[C:32]([C:44]2[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][CH:45]=2)=[N:31]1)[CH3:29]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2cccc(CO)c2)cc2c(Br)ccnc21
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(CO)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
In a large pressure bottle (˜1 L) was added {3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanol (22.75 g, 51.3 mMol), 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21.0 g of a ˜85% pure lot, 52.0 mMol, Intermediate 5), dioxane (400 mL), aq. sat. NaHCO3 (120 mL), and Pd(PPh3)4 (1.5 g, 1.3 mMol). The reaction was purged with N2, capped, and stirred at 110° C. for 16 h. After cooling to RT the reaction was concentrated under vacuum, taken up in EtOAc, washed with H2O, brine, dried (Mg2SO4), filtered, and evaporated to dryness under vacuum. Purification by flash chromatography by silica gel (20 to 30% EtOAc/CH2Cl2) gave the title compound (26.90 g, 90%) as a yellow solid: MS (ES) m/e 580.4 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.32 (d, J=5.1 Hz, 1H), 8.15 (app. d, 2H), 7.89 (d, J=7.3 Hz, 2H), 7.74 (t, J=7.5 Hz, 1H), 7.61 (app. t, J=7.8 Hz, 2H), 7.54 (app. d, 2H), 7.39-7.43 (m, 2H), 7.32-7.36 (m, 2H), 7.06 (d, J=5.1 Hz, 1H), 6.52 (s, 1H), 5.31 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.3 Hz, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C-:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=O)[CH:6]=[CH:5][CH:4]=CC=1.[C-:16]1([NH:21][C:22](=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=CC=2)[CH:20]=[CH:19][CH:18]=[CH:17]1.[Fe+2:31].[OH-].[K+]>>[C:8]1([NH:10][C-:11]2[CH:12]=[CH:13][CH:14]=[CH:15]2)[CH:4]=[CH:5][CH:6]=[CH:1][CH:7]=1.[C-:16]1([NH:21][C:22]2[CH:23]=[CH:24][CH:29]=[CH:28][CH:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20]1.[Fe+2:31]
Reactant: O=C(Cc1ccccc1)N[c-]1cccc1
Agent: [Fe+2]
Agent: [K+]
Agent: [OH-]
Product: c1ccc(N[c-]2cccc2)cc1

Procedure:
(0.55 mmol) of 1,1′-bis(phenylacetamido)ferrocene in 30 ml of argon-saturated ethanol (96%) were heated under argon with 2 g (35.6 mmol) of potassium hydroxide for 16 hours under reflux. After cooling, the reaction mixture was (without inert gas) diluted with 30 ml of argon-saturated water, transferred to a separating funnel and extracted a number of times with ether. The combined ether phases were dried over sodium sulfate, filtered and evaporated under argon in a high vacuum.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+:18].[K+].C>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O-:13])=[O:12])=[CH:3][N:2]=1.[K+:18]
Reactant: O=C(O)c1cnnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C([O-])c1cnnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.10 g of (1) was added over 30 minutes to a vigorously stirred solution of 2.02 g of potassium carbonate in 25 ml of water, at room temperature. The resulting mixture was stirred for one hour at room temperature, then treated with charcoal, and after filtration the water was evaporated. The residue was azeotropically distilled with toluene and dried at 70° C. under reduced pressure, to give 2, as a light tan powder, m.p.: above 280° C.
Reaction SMILES: [CH3:1][C:2]([O:4][F:5])=[O:3].FC(C[C@H]([C@@H]([C@@H](CO)O)O)O)=O.[O:18]([F:20])[F:19].[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([Sn](C)(C)C)=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22]>C(Cl)(Cl)(Cl)F.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([F:5])=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22].[CH3:1][C:2]([O:4][F:5])=[O:3].[O:18]([F:20])[F:19]
Reactant: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1[Sn](C)(C)C)NC=O
Agent: CC(=O)OF
Agent: FOF
Agent: O=C(F)C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Solvent: FC(Cl)(Cl)Cl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1F)NC=O

Procedure:
The electrophilic fluorinating agent, CH3COOF (prepared from 200 μmol) of F2 in 1% He, (Bida, G. T., Satyamurthy, N. and Barrio, J. R. (1984) The synthesis of 2- 18F!fluoro-2-deoxy-D-glucose using glycals: A reexamination. J. Nucl. Med. 25, 1327) F2 (1% in He, 200 μmol) or OF2 (1% in He, 200 μmol), was bubbled into a solution of trimethyltin derivative 6 (0.123 g, 200 μmol) in Freon-11 (CFCl3) (20 mL) at room temperature over a period of 30 min. The reaction mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 1M Na2S2O5 (2×20 mL), water (2×20 mL) and dried (MgSO4). Evaporation of solvents gave a yellow syrup which was chromatographed (silica gel, diethyl ether) to yield a colorless viscous oil 9 (41 mg, 43% in the case of CH3COOF), (65 mg, 69% for F2), 7(62 mg, 66% for OF2).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8](=[O:36])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[C:40]1[CH:41]=[CH:42][C:43]([F:46])=[N:44][CH:45]=1.[F-].[Cs+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][NH:7][C:8](=[O:36])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:40]4[CH:45]=[N:44][C:43]([F:46])=[CH:42][CH:41]=4)=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccc(C(=O)NCc4ccc(F)cc4)cc3)c3ccccc23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccc(F)nc3)c3ccccc32)cc1
Yield: 69.5 %

Procedure:
Combine N-(4-Fluoro-benzyl)-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-sulfonyl]-benzamide (150 mg, 0.28 mmol), 5-Bromo-2-fluoro-pyridine (0.05 mL, 0.56 mmol), CsF (212 mg, 1.4 mmol) and Pd(Ph3P)4 (32 mg, 0.028 mmol) in 1.0 mL DMF and 0.100 mL of water. Evacuate the reaction vessel and place under an atmosphere of nitrogen. Heat the resulting reaction at 90 degrees 12 h. Load the reaction directly onto silica gel and purify by flash column chromatography (EtOAc/Hexanes) to yield 98 mg of white foam (70%) LRMS: MH+ 504.02.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.CC1(C)C(C)(C)OB([C:57]2[CH2:62][CH2:61][CH:60]([CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:59][CH:58]=2)O1>>[O:42]=[S:38]1(=[O:41])[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][NH:32][C@:16]23[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]2[C@@H:18]2[C@@:13]([CH3:43])([CH2:14][CH2:15]3)[C@@:12]3([CH3:44])[C@@H:21]([C@:22]4([CH3:25])[C@@H:9]([CH2:10][CH2:11]3)[C:8]([CH3:45])([CH3:46])[C:7]([C:57]3[CH2:62][CH2:61][CH:60]([CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:59][CH:58]=3)=[CH:24][CH2:23]4)[CH2:20][CH2:19]2)[CH2:36][CH2:37]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCOC(=O)CC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(CC(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 42.7 %

Procedure:
The title compound was prepared following the method described in step 1 for the preparation of Example 1, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate as the reactants. The product was obtained as a mixture of diasteromers in 42.7% yield. MS: m/e 737.65 (M+H)+, 2.939 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.32 (br. s., 1H), 5.19 (d, J=5.8 Hz, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.61 (d, J=1.5 Hz, 1H), 4.21-4.09 (m, 2H), 3.15-2.96 (m, 8H), 2.77-2.54 (m, 4H), 2.52-2.40 (m, 1H), 2.34-2.08 (m, 4H), 2.03-1.72 (m, 7H), 1.70 (s, 3H), 1.61-1.39 (m, 9H), 1.39-1.19 (m, 10H), 1.12-1.04 (m, 7H), 1.01-0.97 (m, 6H), 0.96-0.91 (m, 3H), 0.87 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:23])=[C:5]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:6]([C:8](=[CH:14]OCC)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([F:23])=[C:5]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:6]([C:8](=[CH:14][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(OC)c1F
Reactant: NC1CC1
Solvent: ClCCl
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of ethyl 2-(3-methoxy-2,4,5-triflurobenzoyl)-3-ethoxyacrylate (590 mg, 1.8 mmol) in methylene chloride (15 mL) at 0° C. was added a solution of cyclopropylamine (114 mg, 1.98 mmol, 1.2 equiv) in methylene chloride (5 mL). The reaction mixture was warmed to room temperature and allowed to stir for 2 hours. The solvent was removed in vacuo and the crude concentrate was purified by flash chromatography on silica gel (methylene chloride/ethyl acetate 50:1 v/v) to provide 438 mg, 62% yield over two steps, of a viscous yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7][CH2:6]1.Cl[CH2:61]Cl.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>ClCCl>[C:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH2:18][C:19]2[N:20]=[C:21]([C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:29][C:28]=3[C:39]3[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=4)[CH:42]=[CH:41][N:40]=3)=[O:59])[CH:22]=[CH:23][CH:24]=2)[CH3:1])[CH2:10][CH2:9]1)(=[O:13])[CH3:61]
Reactant: ClCCl
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 0 °C

Procedure:
The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)-methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 50-mL round-bottom flask, was placed a solution of this amine (110 mg, 0.15 mmol, 1.00 equiv) in dichloromethane (5 mL), and N,N-diisopropylethylamine (30 mg, 0.23 mmol, 1.50 equiv). This was followed by dropwise addition of a solution of acetyl chloride (14.4 mg, 0.18 mmol, 1.20 equiv) in dichloromethane (1 mL) with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 90.3 mg (44%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.77 (s, 1H), 9.56 (t, J=5.7 Hz, 1H), 9.06 (d, J=5.1 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.28 (s, 1H), 8.15-8.09 (m, 2H), 7.90-7.79 (m, 2H), 7.72-7.56 (m, 5H), 7.34 (s, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.20 (s, 2H), 3.56 (s, 4H), 3.34 (s, 4H), 3.18-2.95 (m, 7H), 2.56-2.49 (m, 4H), 1.96 (s, 3H), 1.74 (s, 4H), 1.60 (d, J=4.2 Hz, 2H). MS (ES, m/z): 757 [M+H]+.
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]([CH3:23])(=[O:22])=[O:21])[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]([CH3:23])(=[O:22])=[O:21])[NH:9][C:8]=2[CH:7]=1)([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: CS(=O)(=O)c1cccc2c1Sc1ccc(O)cc1N2
Product: CC(C)Oc1ccc2c(c1)Nc1cccc(S(C)(=O)=O)c1S2
Yield: 99.9 %

Procedure:
2-Isopropoxy-6-methylsulphonylphenothiazine (21.7 g.) is prepared by reacting 2-iodopropane (17.0 g.) with 2-hydroxy-6-methylsulphonylphenothiazine (m.p. 218°-219°C.; 19.0 g.).
Reaction SMILES: [CH3:1][CH:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[CH2:4][CH2:3]1.[BH4-].[Na+].[CH3:15]O>>[CH3:1][CH:2]1[C:12]2[C:7](=[CH:8][C:9]([CH3:15])=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH2:3]1
Reactant: CC1CCC(=O)c2ccccc21
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: Cc1ccc2c(c1)C=CCC2C
Reaction time: 8 h
Yield: 61 %

Procedure:
Following a similar procedure to that reported in Ferraz, which is hereby incorporated by reference, to a stirred solution of 4-methyl-α-tetralone (0.867 g, 4.98 mmol) in methanol (20 mL) was added NaBH4 (0.56 g, 14.9 mmol) portionwise. The reaction mixture was followed by TLC and, after complete consumption of the starting material (about 2 h), was quenched with saturated NaHCO3. The aqueous layer was extracted with diethyl ether, dried with magnesium sulfate (MgSO4), and filtered; and the solvent was removed under reduced pressure. The crude alcohol was dissolved in toluene (25 mL) and a few crystals of p-TsOH were added. The reaction mixture was stirred overnight, then neutralized by slow addition of saturated sodium bicarbonate (NaHCO3) and extracted with diethyl ether. The combined organic layers where washed with brine, dried with magnesium sulfate (MgSO4), and filtered; and the solvent was removed under reduced pressure. The product was purified by flash chromatography (SiO2, hexanes) to give 1,2-dihydro-1,6-dimethylnaphthalene ((±)-4) as a clear oil (0.479 g, 61% yield). This compound is volatile and cannot be dried for long periods (>30 min) under high vacuum. The spectroscopic data are consistent with previously reported data (Adachi et al., Bull. Chem. Soc. Jpn., 56:651ff (1983), which is hereby incorporated by reference).
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([OH:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:19]([C@@:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([OH:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(O)ncnc32)C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a 100 mL flask was added deoxyinosine (1.5 g, 5.95 mmol) and N,N-dimethyl-4-aminopyridine (0.036 g, 0.297 mmol). N,N-dimethylformamide (35 mL) was added via cannula with stirring, the flask was purged with argon gas and pyridine (15 mL) was added via cannula. The slurry was allowed to cool 10 min. in an ice/NaCl bath and palmitoyl chloride (2.0 mL, 6.54 mmol) was added dropwise. The mixture was allowed to stir while it slowly warmed to 25° C. After 18 h, the mixture was poured into 300 mL of ice-cold 0.1 M sodium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 100 mL water, and dried overnight in a vacuum desiccator giving 2.72 g (93%) of palmitoyldeoxyinosine.
Reaction SMILES: I.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30].C(O)C>CN1CCN(C)C1=O.C(OCC)(=O)C>[CH2:27]([S:31]([NH:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH2:14][CH2:15][C:16](=[O:19])[NH:17][N:18]=3)[CH:9]=2)[CH2:4]1)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]
Reactant: NC1CCc2cc(C3=NNC(=O)CC3)ccc2C1
Reactant: CCCCS(=O)(=O)Cl
Agent: I
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CN1CCN(C)C1=O
Product: CCCCS(=O)(=O)NC1CCc2cc(C3=NNC(=O)CC3)ccc2C1
Reaction time: 0.5 h

Procedure:
To 10.3 g of 2-amino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-1,2,3,4-tetrahydronaphthalene.hydroiodide suspended in 100 ml of 1,3-dimethyl-2-imidazolidinone was added 26.7 ml of triethylamine at room temperature, and the mixture was stirred for 30 minutes. Under ice cooling, to the mixture was added dropwise 12.6 ml of butanesulfonyl chloride, and the mixture was stirred at room temperature for 4 hours. To the mixture was added 40 ml of ethanol, and the mixture was further stirred for 30 minutes. Ethyl acetate was added to the reaction mixture, the organic layer was washed with water and dried, and then the solvent was removed. The resulting crude crystals were recrystallized from isopropanol to obtain 8.5 g of 2-n-butylsulfonylamino-6-[4,5-dihydropyridazin-3(2H)-on-6-yl]-1,2,3,4-tetrahydronaphthalene.